We aimed to develop models for predicting programmed death-ligand 1 (PD-L1) expression following neoadjuvant chemoradiotherapy (nCRT) in esophageal squamous cell carcinoma (ESCC) using a multifaceted approach that integrates traditional radiomics, deep learning, and machine learning. Pre- and post-nCRT computed tomography (CT) images obtained before surgery and clinical data were retrieved for 101 patients with locally advanced ESCC who underwent nCRT followed by radical surgery. Post-nCRT PD-L1 expression levels, which were obtained from the surgical specimens, were categorized into three groups: < 1%, 1%-10%, and > 10%. Tumor regions on both pre- and post-nCRT CT scans were segmented for radiomic analysis. Radiomics features were extracted and selected prior to modeling using multinomial logistic regression. Predictive models were subsequently developed using machine learning algorithms that integrated radiomics features, clinical variables, and outputs from deep learning architectures, such as Residual Network (ResNet) and TabNet. Using logistic regression, six radiomics features were selected from an initial pool of 1873. Key clinical factors, including radiation technique and total radiation dose, were also identified as predictors. The combined clinical-radiomics model achieved the highest weighted AUROC of 0.8214. However, its improvement over the clinical-only model was small (AUROC, 0.8214 vs. 0.8171), indicating that radiomics provided limited incremental discrimination beyond clinical variables in this cohort. The combined clinical-radiomics model showed feasible performance for assessing post-nCRT PD-L1 expression in patients with locally advanced ESCC, although the incremental discriminative value of radiomics over clinical variables alone was small. Because this study predicted PD-L1 expression rather than actual response to immune checkpoint inhibitors, these findings should be interpreted as hypothesis-generating and require further external validation before clinical application.
To analyze the efficacy and safety of ifosfamide + vincristine + dexamethasone/etoposide + mitoxantrone (IVD/EM) regimen as maintenance therapy in adult patients with T-cell lymphoblastic lymphoma/leukemia (T-LBL/ALL). A total of 53 patients with T-LBL/ALL were enrolled, with a median age of 27 (range, 18-73) years and a male-to-female ratio of 2.5:1. Compared with the transplantation group, the 1‑, 3‑, and 5‑year progression‑free survival (PFS) rates in the alternating maintenance group were 77.8% vs 71.4%, 66.7% vs 64.8% and 58.3% vs 60.7%, respectively; the 1‑, 3‑, and 5‑year overall survival (OS) rates were 94.4% vs 74.3%, 66.2% vs 71.4% and 66.2% vs 71.4%, respectively. No statistically significant differences were observed in PFS and OS rates between the two groups (P = 0.908; P = 0.972). Although the recurrence rate in the maintenance group tended to be higher than that in the transplantation group (P = 0.129), non‑relapse mortality was significantly reduced in the alternating maintenance group (P = 0.046). Multivariate analysis demonstrated that male and elevated β2‑microglobulin levels were independent adverse factors for PFS in patients with T‑LBL/ALL (P < 0.05), while the presence of elevated β2-microglobulin levels at diagnosis was an independent prognostic factor for OS (P < 0.05). In terms of safety, adverse events in the alternating maintenance group were predominantly grade 1-2, and no treatment-related deaths were observed. The IVD/EM maintenance regimen is safe and effective in post-remission therapy for adult patients with T-LBL/ALL.
Students' emotional and social experiences at school are interrelated dimensions shaping their everyday functioning and development. Although recent research has examined reciprocal associations between emotional and social experiences as well as academic achievement, longitudinal evidence across lower secondary education remains scarce. This study aims to examine the development and reciprocal relations of key emotional (worries, anxiety, positive attitudes) and social (teacher-student relationship, peer relationships) dimensions of students' socio-emotional school experiences across the full range of lower secondary education (grade levels 5-11) over one school year, while taking into account students' achievement. The sample includes 407 students from grade levels 5-11 attending a secondary school in central Germany. Participants completed self-report questionnaires at three time points spanning one school year. Standardized scales were used to measure socio-emotional experiences and self-reported grades in German language and mathematics for achievement. To target directional within-person effects while accounting for stable individual differences, we used a random-intercept cross-lagged panel model (RI-CLPM) comprising random-intercept (between-person) components, contemporaneous within-wave links and cross-lagged paths, with gender and grades in German language and mathematics and grade level entered as control variables. Overall, the results suggest stronger between-person than within-person differences. Students' socio-emotional experiences differed according to grade level, gender and achievement in German language. At the within-person level, higher anxiety at t1 predicted more serious social problems with peers at t2. The findings underscore the significance of between-level differences in students, while they also indicate only small within-person fluctuations regarding socio-emotional school experiences.
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Mitochondrial gene expression is a remnant of the endosymbiotic origin of the organelle, which contains a complete gene expression system that contributes only a handful of subunits to the complexes driving oxidative phosphorylation (OXPHOS). During evolution, many processes of gene expression in mitochondria have diverged from the bacterial ancestor. A central problem to assemble oxidative phosphorylation complexes is that they contain subunits from two genetic sources. Hence, mechanisms have evolved to synchronize expression of nuclear and mitochondrial genes to avoid problems with stoichiometry, which could hamper their assembly. Here, we will summarize recent insights into how gene expression operates with a focus on the mechanisms related to the control of mitochondrial translation in yeast and human cells.
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With the advancement of High-NA EUV lithography and the continued evolution of transistor architectures toward GAA and CFET, semiconductor manufacturing has entered the sub-3 nm technology node era. At advanced nodes, photon shot noise becomes increasingly significant, while the process tolerance window narrows substantially. Photoresist film-formation-related defects may originate from multiple stages of the fabrication process, including coating, exposure, post-exposure bake, development, and etching/stripping, and are strongly influenced by microscopic stochastic effects. However, the isolated optimization of materials, processes, or intelligent control strategies still suffers from significant limitations. Therefore, this review systematically examines the formation mechanisms and cross-process evolution of photoresist film-formation-related defects within the development trajectory of advanced lithography. An integrated materials-process-intelligence co-optimization framework is proposed to elucidate the coupling mechanisms among these three dimensions and the construction of a full-chain closed-loop control strategy. The current challenges and future development directions are summarized, providing optimization insights for both academic research and industrial implementation. This review aims to establish a defect-control framework integrating fundamental understanding with engineering considerations, thereby supporting low defectivity, high robustness, and improved manufacturability for sub-3 nm node patterning.
Levosimendan is a calcium-sensitizing inotropic agent recommended for Heart Failure (HF) treatment but contraindicated in patients with Creatinine Clearance (Ccr) below 30 mL/min. This study aims to systematically evaluate its efficacy and safety in patients with severe renal insufficiency. A systematic literature search was conducted in PubMed, Embase, and the Cochrane Library. Randomized Controlled Trials (RCTs) and cohort studies comparing the efficacy and safety of levosimendan in patients with severe renal insufficiency were included. Studies reporting outcomes only in patients with normal renal function or those with Ccr greater than 30 mL/min were excluded. The primary outcome was all-cause mortality. A total of 1541 records were identified, and seven studies enrolling 814 patients were included in the meta-analysis. There was no significant difference in all-cause mortality between levosimendan and control groups [odds ratio (OR) 1.13, 95% confidence interval (CI) 0.66 to 1.94, p = 0.67, I2 = 23%]. Subgroup analyses showed no significant differences in 30-day mortality [OR 1.17, 95% CI (0.69, 1.99), p = 0.55, I2 = 15%] or 180-day mortality [OR 1.09, 95% CI (0.39, 13.06), p = 0.87, I2 = 57%]. The absence of mortality benefit may reflect levosimendan's altered pharmacokinetics and competing uremic risks in severe renal insufficiency. However, renoprotective mechanisms have been primarily characterized in populations without renal impairment, and the prolonged half-life of OR-1896 in this setting may potentiate both hemodynamic effects and adverse events. This study found that available evidence from small, heterogeneous observational studies is insufficient to determine whether levosimendan affects mortality in severe renal insufficiency. These findings do not support any clinical recommendation, provide no basis to modify the existing contraindication for Ccr below 30 mL/min, and highlight the need for further RCTs with comprehensive endpoints.
Metal-organic frameworks (MOFs), a class of porous crystalline materials with tunable coordination structures, offer unique opportunities for CO2 photoreduction; however, their application in piezo-photocatalysis remains limited by poor visible-light absorption, high structural symmetry, and low polarity. Herein, we report a CN-grafting strategy that anchors carbon-nitrogen (CN) species onto coordination-unsaturated Ni sites of Ni-BDC, constructing NiM-CN with a grafting-induced internal electric field (IEF). This modification enhances the structural asymmetry and polarity, thereby strengthening piezoelectric polarization and generating a polarization-induced electric field (PEF) under mechanical stimulation conditions, as demonstrated by the increased piezoelectric coefficient (d33, from 42.41 to 82.16 pm V-1 compared to the reference sample). Meanwhile, CN grafting narrows the band gap and strengthens the IEF in NiM-CN through Ni 3d-N 2p orbital hybridization and asymmetric charge redistribution. The synergistic effect of IEF and PEF accelerates charge separation and transfer, leading to enhanced surface charge accumulation, as confirmed by in situ Kelvin probe force microscopy (KPFM). Consequently, NiM-CN achieves a remarkable CO production rate of 3406.36 µmol g-1 h-1 under piezo-photocatalytic conditions. This work establishes grafting-induced IEF engineering as an effective strategy for constructing coupled electric-field systems in MOFs for efficient piezo-photocatalysts.
IntroductionXerostomia is a common condition that can impair quality of life. Google and ChatGPT are increasingly used for patient education, though the readability and understandability of this information remain unclear. This study evaluated commonly asked questions about xerostomia and assessed the quality of online and AI-generated patient educational material (PEM).Methods"SEO minion" was used to identify Google People Also Ask (PAA) questions from four primary search terms. Questions were categorized using Rothwell's classification and entered into ChatGPT. Online sources and ChatGPT responses were evaluated using the Flesch Kincaid Grade Level (FKGL), where higher scores indicate higher reading grade level; Flesch Reading Ease (FRE), where lower scores indicate more difficult readability (0 (complex) to 100 (easy)); JAMA benchmark criteria, where higher scores indicate greater source quality (0-4); and Patient Education Materials Assessment Tool (PEMAT), where higher scores indicate greater understandability (0-100).ResultsA total of 117 unique PAA questions were identified, most of which were value-based (55.6%) or fact-based (42.7%). Online sources had a mean JAMA score of 1.09, mean FKGL of 9.87, mean FRE of 51.37, and mean PEMAT score of 79.92. ChatGPT responses performed worse, with a mean FKGL of 15.24, mean FRE of 30.14, and mean PEMAT score of 72.33.ConclusionsBoth online PEM and ChatGPT responses on xerostomia exceeded recommended reading levels, with ChatGPT generating substantially less readable content. Although many materials met understandability thresholds, their elevated reading level may still limit accessibility. More readable, reliable, and patient-centered educational materials are needed.
Epithelial-mesenchymal transition (EMT) mediated metastasis remains the primary contributor to cancer-related mortalities worldwide, highlighting the critical need for therapeutic strategies that simultaneously eradicate primary tumors and suppress metastatic progression. However, conventional photodynamic therapy (PDT), particularly oxygen-dependent type-II photosensitizers, suffers from hypoxia-limited efficacy and may even induce EMT under suboptimal treatment conditions. Herein, we report enhanced type-I reactive oxygen species (ROS)-generating nanoparticles (NPs) based on the coassembly of two structurally similar small molecules (TQTT-NO and TQTT-NH), integrating light-controlled nitric oxide (NO) release to synergistically inhibit tumor growth and EMT. By leveraging precise molecular structure matching, the coassembled NPs (TQTT-NO/NH NPs) enable efficient intermolecular electron transfer, as revealed by the photocurrent results and Gibbs free energy calculations, thereby favoring type-I ROS generation under white-light irradiation while simultaneously triggering on-demand NO release. The developed TQTT-NO/NH NPs effectively suppress transforming growth factor-β (TGF-β)-induced EMT, inhibit cancer cell migration and invasion in vitro, and markedly reduce primary tumor growth and lung metastasis in a murine tumor model under light activation. Overall, this work establishes a generalizable molecular coassembly strategy for enhancing type-I PDT and EMT regulation, offering a promising paradigm for next-generation antimetastatic phototherapeutic platforms with translational potential.
Genetic diversity is critical to long-term survival of species but can be eroded by population declines driven by human pressures. Temporal genetic monitoring of threatened species can reveal changes in genetic diversity over time, providing key data for conservation. Specimens from natural history collections were used to assess changes in genetic diversity in the Critically Endangered largetooth sawfish (Pristis pristis). Historically, P. pristis had a circumtropical range, but following massive declines it is now primarily found in Australia, with limited depleted populations elsewhere. Genetic data (815-bp of the mitochondrial control region) from 87 specimens from across its historical range revealed significant population structure, with the Indo-West Pacific and the Atlantic/Eastern Pacific comprising distinct lineages. Comparisons between historical (approx. 1878-2000) and contemporary populations (2001-2014) revealed genetic diversity loss, with only six of 35 historical haplotypes represented in contemporary populations. Most of the lost haplotypes were from the Atlantic/Eastern Pacific, which is at risk of further genetic erosion. Genetic diversity in Australia appears stable since the 1960s, while Brazil showed a marked loss, despite contemporary estimates similar to those in Australia. These findings highlight the need to conserve remaining genetic diversity in P. pristis, emphasizing the importance of securing a stronghold in the Atlantic/Eastern Pacific.
Food Protein-Induced Enterocolitis Syndrome (FPIES) is a non-IgE-mediated food allergy marked by delayed vomiting and potential hypovolemic shock. This review by the French FPIES working group (SFA, GFRUP, Sp2A, SFP) analyzes recent literature on oral food challenges (OFC) adverse reactions and proposes a standardized protocol for OFC and emergency management. Early consensus OFC protocols from 2017 showed limitations-mainly short intervals between doses during OFC and high hospitalization burdens-leading to inconsistent practices. This narrative review of 2017-2025 studies shows that a single 25% age-appropriate portion generally suffices to trigger symptoms, typically within 1-4 h. This approach balances safety and feasibility while reducing hospital time. As part of the French FPIES monitoring register, and to easily apply this portion, the serving size for each food has been established with specialized dieticians. According to severity, acute reactions require prompt rehydration and ondansetron. Oral or sublingual ondansetron, effective for mild to moderate reactions, can limit dehydration and hospital transfers. In a hospital setting, oral rehydration is indicated in mild reactions, whereas vascular hydration (10 mL/kg over 5-20 min) is required for moderate to severe reactions. Corticosteroids may be added in severe cases. Adrenaline is unnecessary unless associated IgE-mediated symptoms are observed. The working group also proposes including oral rehydration solution and ondansetron in every home emergency kit. These proposals provide a national consensus on the management of FPIES by standardizing French practice from the OFC to the acute management of allergic reaction both in hospitals and at home.
Microtubule-based organelle transport is essential for organelle positioning within cells and defines the architecture and function of highly polarized cells, like animal neurons and fungal hyphae. Early endosome transport depends on kinesin-3 motors and on cytoplasmic dynein, which binds to this organelle via Hook adaptor proteins. In filamentous fungi, these proteins can propel the indirect transport of additional organelles that hitchhike on early endosomes, like peroxisomes. However, early endosomes carry different cargoes in different fungi, and the contribution of these systems to the subcellular organization of different polarized cells is unclear. Here, we analyzed the function of the kinesin-3 motor KIN2 and of the HOOK1 adaptor in the model fungus Podospora anserina. We found that hyphal growth and morphogenesis require KIN2 and HOOK1, and that early endosome, peroxisome, vacuole, endoplasmic reticulum and mitochondrial motility depends on microtubules. We show that KIN2 and HOOK1 are required for mitochondrial localization at the sites of polarized cell growth, and for the polarized arrangement of the endoplasmic reticulum and vacuoles. Both proteins are required for the bidirectional transport of early endosomes and peroxisomes, but they differently affect their distribution. We found that KIN2 associates with some peroxisomes, and observed a low frequency of peroxisome-early endosome co-transport. Finally, we show that the GTPase RAB5B is required for the distribution and motility of early endosomes but not of peroxisomes, suggesting independent transport systems for these organelles in P. anserina. Our findings reveal a major role for KIN2 and HOOK1 in organelle dynamics during polarized cell growth.
IL-6 family of cytokines is increasingly recognized as a potential contributor to the immune alterations observed in COVID-19 and its long-term sequelae. Beyond the well-established pro-inflammatory actions of IL-6 itself, members of this family collectively orchestrate a complex network integrating antiviral defence, tissue repair, and maladaptive inflammation. Evidence accumulated over the past five years suggests altered regulation and signalling of those cytokines may help explain the heterogeneity of clinical outcomes, ranging from acute respiratory failure to persistent post-COVID symptoms. Recent advances -including the development of multispecific fusion proteins capable of simultaneously blocking viral entry and selectively modulating IL-6-related inflammatory pathways- highlight the expanding therapeutic potential of targeting this cytokine axis. Effective intervention requires precise knowledge of the cytokines temporal expression patterns to avoid interfering with beneficial immune responses. This review examines the molecular mechanisms involving IL-6 family cytokines, their promise as biomarkers of disease progression, and the current or emerging therapeutic strategies aimed at modulating their signalling pathways.
Introduction: Community-based day center programs may support healthy ageing by promoting functional ability, mental well-being, and social participation among older adults, but real-world evidence from Latin America remains limited. Objective: We aimed to examine changes in functional status, mental health, and quality of life among older adults participating in the CEDIAM program in the Maule Region of Chile in 2022 and 2023. Methods: Pre-post observational study using routinely collected data from 15 CEDIAM centers. The 2022 and 2023 datasets were analyzed as independent cohorts. Functional status was assessed with the Barthel Index, the Lawton and Brody scale, and the Timed Up and Go test; mental health with the Mini-Mental State Examination and the 15-item Geriatric Depression Scale; and quality of life with the EuroQol-5D visual analogue scale. Paired comparisons, category-transition analyses, and multivariable logistic regression models of improvement were performed. Results: Baseline samples included 894 participants in 2022 and 897 in 2023. In 2022, all continuous outcomes improved significantly (all p ≤ 0.001). In 2023, the Barthel Index, the Timed Up and Go test, and the Geriatric Depression Scale improved (all p < 0.0001), and the EuroQol-5D visual analogue scale also improved (p < 0.01), whereas the Lawton and Brody scale (p = 0.204) and the Mini-Mental State Examination (p = 0.725) did not. Category-transition analyses showed significant improvements in basic activities of daily living and mobility in both cohorts (both p < 0.001), while significant categorical changes in instrumental activities of daily living, global cognition, depressive symptoms, and self-rated quality of life were observed only in 2022 (all p ≤ 0.01). Rural residence was associated with higher odds of improvement in basic activities of daily living (OR 1.62, 95% CI 1.17-2.25; p = 0.004), whereas age ≥75 years was associated with lower odds of improvement in depressive symptoms (OR 0.56, 95% CI 0.41-0.76; p < 0.001) and self-rated quality of life (OR 0.65, 95% CI 0.45-0.94; p = 0.023). Conclusions: Participation in CEDIAM was associated with favorable changes, particularly in basic functional status and mobility, although responses varied across outcomes and participant subgroups.
Microbial community coalescence, the merging of entire microbial communities, is common in estuaries, yet the ecological processes governing community assembly after coalescence remain unclear. To uncover these mechanisms, we conducted controlled microcosm experiments simulating coalescence between freshwater and brackish water bacterial communities across five mixing ratios and incubated them in either freshwater or brackish water. We tracked 40 mixed communities over six passages using Nanopore full-length 16S rRNA gene sequencing. Laboratory incubation reduced diversity and increased taxonomic overlap, but preserved habitat-associated compositional signatures. Coalescence outcomes were asymmetric and strongly shaped by the incubation water. In both environments, coalesced communities remained compositionally closer to the native than to the introduced community. However, the relative influence of environmental filtering differed between habitats. In freshwater, strong filtering drove communities to closely resemble the freshwater source, even when the freshwater inoculum was small. In brackish water, weaker filtering made coalescence outcomes more dependent on initial mixing ratios and propagule pressure. Neutral model analyses confirmed a greater contribution of stochastic processes in brackish water. Co-occurrence network analysis revealed predominantly positive associations within the same source community and fewer but negative associations across sources. These within-source associations may reinforce propagule pressure by facilitating the establishment of co-adapted species. Overall, our results demonstrate that environmental filtering primarily governs coalescence outcomes, modulated by source composition, stochasticity, and species co-adaptation, offering new insights into microbial assembly in dynamic estuarine systems.
The endoplasmic reticulum (ER), a major calcium ion (Ca2+) reservoir, plays a pivotal role in lipid synthesis, protein synthesis, and secretion. Disruption of ER function leads to the accumulation of misfolded proteins, resulting in ER stress. To restore cellular homeostasis, the unfolded protein response (UPR) is activated. However, prolonged or irreversible ER stress can trigger apoptosis and cell death. Cellular dysfunction and apoptosis arising from disrupted ER Ca2+ homeostasis are often implicated in neurodegenerative and metabolic disorders. We investigated the role of LRRC8B, an ER-resident protein previously linked to ER Ca2+ homeostasis, in the ER stress response. LRRC8B expression was upregulated in response to chemically induced ER stress. Overexpression of LRRC8B enhanced the viability of HEK293T cells exposed to the ER stressor tunicamycin, whereas LRRC8B knockdown increased their susceptibility to apoptosis. Furthermore, LRRC8B overexpression reduced protein aggregation during ER stress by upregulating cytoprotective genes associated with the adaptive UPR, including BiP, calnexin, and PDI. Conversely, LRRC8B knockdown decreased BiP expression and elevated the levels of ER stress-induced apoptotic proteins such as CHOP, Bax, and cleaved caspase-3. Co-treatment with the chemical chaperone, 4-PBA, partially rescued the LRRC8B knockdown cells undergoing apoptosis. In Neuro 2a (N2a) cells, LRRC8B overexpression diminished the aggregation of mutant huntingtin protein (HTT-83Q), associated with Huntington's disease, whereas its knockdown exacerbated HTT-83Q aggregation. Taken together, these findings suggest that LRRC8B is a key modulator of the ER stress response and plays a cytoprotective role.
The aim of our study was to develop consensus from experts and advocates on the health care transition for young people living with HIV from pediatrics to adult care in Thailand using a modified Delphi method. Participants included physicians (58%), nurses (20%), clinic coordinators (11%), and outreach workers (11%). Survey items were distributed to gather responses. Consensus was achieved after two rounds of surveys (response rates: 86% and 94.5%, respectively). Key priorities identified included (1) pediatric clinics: early transition planning, individualized readiness assessment, and focusing on youth with an increased risk of poor treatment outcomes; (2) transition process: strong pediatric-adult clinic collaboration; (3) health care coverage scheme and system: making sure that youth are familiar with their resources and options; (4) adult clinics: providing communication skills training for providers aimed at offering youth-friendly, nonstigmatizing services; and (5) post-transition follow-up: communication to ensure a warm handoff. Effective transition care for young people living with HIV requires early preparation, sustained interclinic communication, and continuity-supportive care models.