Search Results (15,810)

Background/Objectives: Chronic traumatic spinal cord injury (SCI) causes persistent neurological deficits for which no clinically effective regenerative therapy is currently available. Mesenchymal stromal/stem cells (MSCs), particularly Wharton’s jelly-derived MSCs (WJ-MSCs), demonstrate immunomodulatory and neurotrophic potential. This phase I/II study evaluated the safety and efficacy of intrathecal allogeneic WJ-MSC administration in individuals with chronic incomplete cervical SCI. Methods: In this multicentre, randomised, double-blind, placebo-controlled trial (NCT05054803, EudraCT 2021-000346-18), 18 participants with chronic (1–5 years post-injury) incomplete cervical SCI (AIS B–D) received two intrathecal injections of WJ-MSCs (0.7–1.3 × 10⁶ viable cells/kg) or a placebo at baseline and 3 months. Seventeen participants completed the 12-month follow-up. Primary outcomes assessed safety, and secondary endpoints included International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) motor and sensory scores, spasticity, neuropathic pain, functional independence, neurophysiological measures, and quality of life. Results: Intrathecal WJ-MSC administration was safe and well tolerated. Eighty adverse events occurred (placebo: 26; WJ-MSC: 54), predominantly mild or moderate; four severe events were unrelated to treatment. Both groups demonstrated significant within-group improvements in total motor scores at 12 months, with no between-group difference. No treatment effects were observed for sensory scores, electrophysiological measures, functional independence, spasticity, pain, or patient-reported outcomes. Conclusions: In this first randomised, placebo-controlled trial evaluating intrathecal WJ-MSCs in chronic incomplete cervical SCI, WJ-MSC administration demonstrated a favourable safety profile; however, no significant between-group differences were detected relative to the placebo. Given the limited sample size and early-phase design, the efficacy findings should be interpreted cautiously. Future research should explore enhanced cell products, intensified dosing schedules, optimised delivery strategies, early intervention, and multimodal therapeutic combinations. Full article

Background/Objectives: Identifying the causes of sentinel lymph node biopsy (SLNB) failure in early-stage oral cavity squamous cell carcinoma (OCSCC) is essential for refining surgical protocols and optimizing patient selection. This study aimed to evaluate the diagnostic performance, predictors of false-negative (FN) results, and long-term oncological outcomes of SLNB in patients with early-stage OCSCC. Methods: A retrospective, single-centre cohort study was conducted on 220 patients with cT1–cT2 N0 M0 OCSCC who were surgically treated between 2017 and 2024. Preoperative lymphatic mapping was performed using ^99mTc-nanocolloid and SPECT/CT. All sentinel lymph nodes (SLNs) underwent an ultrastaging protocol involving serial sectioning and immunohistochemistry. Diagnostic accuracy, survival outcomes, and clinicopathological predictors of FNs were analysed. Results: The SLN identification rate was 99.1%. Metastatic involvement was detected in 49 patients (22.3%), preventing 77.7% of the cohort from undergoing unnecessary neck dissection. Bilateral lymphatic drainage was observed in 55.9% of floor of the mouth tumours. During a median follow-up of 36 months, the diagnostic performance showed a sensitivity of 81.7%, a negative predictive value of 93.6%, and an overall accuracy of 95.0%. Analysis of the 11 FN cases showed that both depth of invasion (DOI) (6.0 mm vs. 3.0 mm; p = 0.010) and maximal tumour dimension (25 mm vs. 15 mm; p = 0.0008) were significant predictors of diagnostic failure. The five-year overall survival rate was significantly superior in patients with negative SLNs compared to the SLN-positive group (82% vs. 61%; p < 0.001). Conclusions: SLNB is an accurate and reliable staging tool for early-stage OCSCC, providing personalised lymphatic mapping that harmonizes oncological efficacy with the avoidance of overtreatment. However, an increased DOI and a larger tumour size significantly raise the risk of FN events, indicating the need for close postoperative surveillance in these high-risk subgroups. Full article

The push for higher energy density in electric vehicles has resulted in large-sized lithium-ion batteries, but their geometric upscaling exacts a heavy thermal price. Under high-rate discharge, these massive cells become heat traps, risking thermal runaway. To tame this instability, this paper engineered a hybrid management strategy fusing liquid cooling, Phase Change Materials (PCMs), and flow deflectors. With a primary focus on the structural optimization of the cooling channel, a three-dimensional numerical model, calibrated using experimentally determined thermophysical properties, was developed to overcome the thermal bottlenecks of conventional cooling architectures. Results indicated that the initial channel optimization effectively reduced the maximum temperature to 327.7 K, but it still remained near the safety threshold. Integrating PCM radically altered the thermal landscape, slashing the outlet temperature differential by 41.67% (from 2.76 K to 1.61 K) compared to pure liquid cooling and blunting peak thermal spikes. Furthermore, to overcome laminar stagnation, strategic deflector baffles were introduced to agitate the coolant, enhancing heat dissipation. Specifically, the optimal half-coverage (L = 1/2) baffle configuration successfully lowered the maximum temperature to 322.42 K while substantially reducing the system pressure drop from 948.16 Pa to 627.57 Pa, achieving a 33.33% reduction compared to the full-coverage scheme. Finally, a multi-variable sensitivity analysis confirmed the extraordinary engineering robustness of the optimized configuration, demonstrating a negligible maximum temperature fluctuation of less than 0.5% despite ±10% operational and material uncertainties. This synergistic system actively stabilizes the thermal envelope, offering a robust engineering blueprint for next-generation high-power battery packs. Full article

This study investigates the non-uniformity (NU%) of copper deposition in a three-dimensional panel electroplating cell using COMSOL Multiphysics^® 6.1 (COMSOL Inc., Burlington, MA, USA). To ensure the accuracy of the simulated current efficiency, the modeling was initially conducted on the electrodeposition of nanoscale metal wires (Nanowires, NWs) using the Finite Element Method (FEM) in COMSOL. After verifying that the simulation accurately reflected the current efficiency at the nanoscale, the model was scaled up to simulate full-sized panel-level electroplating. Various simulation conditions were explored, including two dimensional and three dimensional, electrode kinetics equations, electrolyte compositions, and current densities. The effects of these parameters on current efficiency and deposition uniformity were analyzed to develop a highly accurate COMSOL model. In terms of electrode kinetics, the study compares the advantages and limitations of secondary current distribution and tertiary current distribution models found in the previous literature, and evaluates their simulation results. Furthermore, to reflect the experimental condition where a pre-deposited copper seed layer was applied to reduce internal cathode resistance, the electrode shell physics module in COMSOL was implemented to simulate the potential distribution across the cathode surface. The results confirm that the numerical model using the tertiary current distribution provides more accurate predictions compared to the conventional secondary current distribution approach. Full article

Cells rely heavily on DNA repair networks to survive genomic damage. For repairing double-strand breaks, Non-Homologous End Joining (NHEJ) remains the primary pathway, which is largely controlled by the DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Researchers have long studied how phosphorylation drives this kinase. However, recent data point to an important additional layer of control. Drawing on evidence accumulated over the past two decades, we propose a “Spatiotemporal Logic Circuit” model for DNA-PKcs regulation. In this model, SUMO-associated interactions may help stabilize synaptic assembly, HUWE1-mediated neddylation may facilitate kinase activation at Lys4007, and K48-linked ubiquitination—potentially involving RNF144A—may contribute to the turnover of persistent repair complexes. Importantly, we frame these UBL-mediated events within the broader autophosphorylation-driven conformational cycle of DNA-PKcs, which remains central to NHEJ progression. Additionally, we highlight the structural interface where activation and degradation signals may converge and the extraction barrier posed by the massive DNA-PKcs scaffold. From a translational perspective, we argue that the exceptional size of DNA-PKcs (~470 kDa) and its topological entrapment on DNA render it an unusually challenging PROTAC target—one that may require p97/VCP-assisted extraction before proteolysis can proceed. We also highlight the underappreciated risk that E3 ligase loss-of-function, already documented in BET-PROTAC resistance, may similarly undermine DNA-PKcs degrader strategies. Full article

Background: Recombinant human growth hormone (rhGH) replacement therapy, administered to children with growth hormone deficiency (GHD), exerts pleiotropic effects on growth, metabolism, and tissue functions. Extracellular vesicles (EVs) are emerging mediators of inter-organ communication, but the effects of rhGH therapy on EV release in humans have not yet been investigated. Methods: In a preliminary prospective clinical study, children with GHD (n = 10; F/M = 5/5; age: 11.0 ± 2.7 years) were treated with rhGH for 6 months. Plasma samples were collected at baseline (T0) and after treatment (T6) to characterize the size distribution and tissue-derived composition of circulating EVs. Total EVs and EV subpopulations derived from monocytes/macrophages (CD14+), adipose tissue (FABP+), skeletal muscle (SCG+), endothelium (CD62E+), and platelets (CD42A+) were analyzed. Clinical, auxological/auxometric, and biochemical/metabolic parameters were assessed in parallel. Statistical methods included longitudinal analyses, interaction models, and adjustments for relevant covariates, including insulin-like growth factor 1 (IGF-1) and osteocalcin. Results: After 6 months of rhGH therapy, significant improvements in height velocity (cm/year and SDS) were observed, accompanied by increased circulating IGF-1 and osteocalcin levels. Hormone therapy induced no size-dependent changes in (total) EVs. Significant increases in CD14+ and FABP+ EVs were observed after treatment, without affecting the other tissue-derived EVs. Interaction analyses revealed that children with more severe GHD exhibited a stronger vesiculogenic response to rhGH. Furthermore, specific tissue-derived EVs were associated with metabolic/biochemical and auxological/auxometric parameters, including lipids, insulin resistance, and growth-related measures. Conclusions: When administered for six months, rhGH therapy seems to selectively change tissue-derived composition of circulating EVs in GHD children, particularly those derived from immune cells and adipose tissue. These preliminary findings suggest that EVs might represent an adjunctive component of GH-dependent inter-organ communication and might serve as biomarkers of treatment response and disease severity in pediatric endocrinology. Full article

Background/Objectives: BRAF and/or MEK inhibitors are widely used for patients with BRAF-mutated melanoma, but no biomarkers of response or resistance are currently available. Besides adverse events in different organs, target therapy with BRAF and/or MEK inhibitors may induce the onset of immune-related adverse events (irAEs) that have been considered as possible biomarkers of good prognosis in patients with melanoma. Methods: To investigate this aspect, we analyzed the occurrence of irAEs in a cohort of 158 patients treated with BRAF and MEK inhibitors. We also analyzed by flow cytometry the subsets of circulating immune cells in the patients who developed irAEs and matched controls. Results: We found that irAEs occurred in 3 out of 101 patients (3%) who experienced adverse events. These three patients did not exhibit any specific clinical features or circulating immune cell subtypes that could be associated with a positive response to treatment. However, the onset of toxicity in the entire patient cohort was associated with longer progression-free survival. Notably, the frequency of circulating follicular helper T cells increased in all examined patients during the first two months of treatment. Conclusions: The small sample size prevents us from determining whether irAEs are effectively caused by BRAF/MEK inhibitors or if they are a random event. Additionally, we cannot conclude whether irAEs are related to a better outcome. Nevertheless, we note that BRAF/MEK inhibition may alter the composition of circulating immune cells in melanoma patients. This aspect should be investigated further before proposing combinations of target therapies and immunotherapies. Full article

Chronic kidney disease (CKD) involves uremic toxin-driven tubular injury and systemic vascular dysfunction, in which mitochondrial impairment and apoptotic cell loss contribute to progressive tissue deterioration. Accordingly, a targeted EV platform is required to enable efficient miRNA delivery to the toxin-stressed tubular–endothelial compartment. Based on our previous study showing that melatonin restores miR-4516 levels under CKD-related stress, we directly loaded miR-4516 into engineered extracellular vesicles (EVs) to evaluate its effects on mitochondrial function and cell survival. Here, we engineered EVs with a G3-C12/RGD surface modification and established a miR-4516 loading strategy to enhance delivery to kidney proximal tubule cells and vascular endothelial cells. miR-4516 loading increased EV-associated miR-4516 levels without major changes in particle size distribution, and EV identity was supported by CD9 and CD81 expression. Confocal microscopy and flow cytometry demonstrated increased cellular uptake of miR-4516-loaded G3-C12/RGD-EVs compared with control EVs in TH1 proximal tubule cells and HUVECs. Under indoxyl sulfate stress, engineered EV treatment restored intracellular miR-4516 and improved mitochondrial function, as indicated by recovery of respiratory Complex I and Complex IV activities and improved Seahorse bioenergetic parameters (OCR/ECAR, basal and maximal respiration, ATP-linked respiration, and spare respiratory capacity). Annexin V staining further indicated reduced toxin-induced apoptosis. In an adenine diet-induced CKD mouse model, intravenous administration of miR-4516-loaded G3-C12/RGD-EVs improved urinary albumin-to-creatinine ratio (UACR), blood urea nitrogen (BUN), and serum creatinine. These findings indicate that miR-4516-loaded, targeting-engineered EVs may mitigate uremic toxin-associated mitochondrial dysfunction and renal impairment in CKD. Full article

Synchronously enhancing the light response range and electron–hole separation efficiency is essential to improve photocatalytic activity. Herein, we synthesized a Cu-doped ZnIn₂S₄ (ZIS) catalyst with S-vacancy (Cu_n-VZIS) via hydrothermal synthesis, incorporating sulfur vacancies and directionally substituting copper ions for zinc ions. The experimental results elucidate the synergistically photocatalytic mechanism associated with the two types of defects. Both the sulfur vacancies within the structure and the copper doping sites lead to a reduction in the size of the ZnIn₂S₄ unit cell. The sulfur vacancy traps electrons, thereby mitigating the recombination of photogenerated carriers. Meanwhile, the copper ions optimize the carrier migration pathways, enhancing the overall carrier separation efficiency. Consequently, Cu_1.5-VZIS demonstrates a stable and markedly enhanced photocatalytic hydrogen production activity, achieving a performance that is 7.5 times greater than that of pristine ZIS. Our study elucidates the effect of vacancy defects and ion doping on the photogenerated charge dynamics in ZIS, and paves a novel pathway for optimizing carrier dynamics through the concurrent utilization of both types of defects. Full article

Direct measurement of thermogenic heat production remains a major challenge in adipose biology. Isothermal microcalorimetry offers a label-free approach to quantify metabolic heat output, yet key parameters governing its application to adipose tissue remain poorly defined. Here, we systematically evaluate the use of the CalScreener isothermal microcalorimetry platform to quantify thermogenic heat production across multiple adipose models, including adipocyte spheroids, freshly isolated adipocytes, and intact adipose tissue explants. Heat production scaled with spheroid size within a defined range and increased linearly with spheroid number per well, demonstrating the quantitative sensitivity of the calorimetric measurements. Pharmacological modulation of mitochondrial respiration in cultured primary beige adipocytes demonstrated that oxidative phosphorylation is a major driver of the calorimetric heat signal, including heat generation associated with mitochondrial proton leak. Freshly isolated adipocytes and intact adipose tissue exhibited depot-specific thermogenic activity and retained responsiveness to β-adrenergic stimulation ex vivo. Across adipose depots, intact tissue explants revealed unexpected differences in thermogenic heat production that were not fully reflected by thermogenic gene expression, highlighting divergence between molecular and functional readouts. Intact adipose tissue maintained measurable thermogenic heat production following extended ex vivo handling in nutrient-containing medium, such that tissues collected across a prolonged harvest window exhibited comparable calorimetric activity, enabling batch analysis of large experimental cohorts. Microcalorimetry further resolved regional differences in thermogenic heat production within the inguinal adipose depot following cold exposure. Together, these findings define key experimental considerations for applying isothermal microcalorimetry to adipose biology and demonstrate its utility for directly quantifying thermogenic metabolism in cells and intact tissues. Full article

Hypoxia-dependent microRNAs play an important role in orchestrating a plant’s response to low-oxygen stress. To assess the regulatory mechanisms of the adaptive response of maize (Zea mays L.) to hypoxia, an antisense sequence was developed, and the short tandem target mimic (STTM) system was used to induce the loss of function of the mature microRNA775A (miR775a) in maize. A recombinant binary vector pBI121 cloned in E. coli cells containing the antisense sequence anti-miR775A to maize miR775A was acquired to create a line of modified A. tumefaciens EHA105. Using the puncturing method on soaked seeds, maize plants with an active anti-miR775A construct were obtained, as evidenced by a decrease of more than 10-fold in mature miR775A content and by developmental changes in the seedlings. The size of seedlings of the maize knockdown line was almost twice smaller than that of the wild-type (WT) plants. An assessment of the effects of hypoxic conditions induced by flooding of 14-day-old maize plants revealed differences in the expression and activity of several enzymes between WT and knockdown plants. The reduced miR775A levels led to a 2.1-fold drop in pyruvate levels, which resulted in decreased pyruvate kinase, pyruvate dehydrogenase, and lactate dehydrogenase activities as compared to WT plants. A decrease in miR775A content in the maize knockdown cell line also affected the function of mitochondrial and extramitochondrial isoenzymes of citrate synthase, aconitase, and fumarase under hypoxic conditions. Full article

For shipboard CCUS facilities, the integration of chemical absorption columns is constrained by a limited vertical envelope, which motivates packings with axially stretched or compressed Kelvin cells to support compact layout and flow control. This study employs computational fluid dynamics to investigate microscale flow and mass transfer characteristics in Kelvin cells. A comparison among the regular Kelvin cell (RKC), the vertically elongated Kelvin cell (VEKC), and the vertically compressed Kelvin cell (VCKC) indicates that axial stretching and compression modify internal flow distributions and gas–liquid mass transfer during CO₂ absorption. The liquid distribution transitions from a film along the struts with localized accumulation at the nodes in RKC to a continuous columnar stream in VEKC, and then to a stable hollow cylindrical liquid film promoted by lateral redistribution in VCKC. VCKC promotes a stable and expanded liquid film, whereas VEKC tends to induce columnar flow. Reducing the cell size and porosity improves mass transfer efficiency, and the liquid load governs mass transfer flux. These findings provide theoretical guidance for the design and optimization of compact packings for process intensification in shipboard carbon-capture applications. Full article

In situ cancer vaccines activate antitumor immune responses by locally capturing and presenting tumor-derived antigens, in which polymers play a key role as antigen-capturing materials. However, the influence of polymer composition and degree of polymerization (DP) on antigen capture efficiency and protection mechanisms remains insufficiently understood. In this study, the tumor-specific antigen MAGE-A3, highly expressed in esophageal squamous cell carcinoma (ESCC), was employed to investigate antigen capture and stabilization by five representative polymers—chitosan, polyethyleneimine (PEI), alginate, polycaprolactone (PCL), and poly (lactic-co-glycolic acid) (PLGA)—with different DPs, using molecular dynamics simulations and in vitro experiments. All-atom simulations revealed that hydrophobic interactions dominate polymer–antigen binding, while electrostatic interactions from cationic polymers synergistically enhance binding affinity and capture efficiency. Binding free energy analysis showed that van der Waals and electrostatic contributions stabilize the complexes, whereas polar solvation partially counteracts these effects. Experimentally, low-DP chitosan exhibited the highest antigen-capture efficiency (38.9%), attributed to its small molecular size, enabling multipoint binding across the antigen surface. In contrast, high-DP polymers generated pronounced steric hindrance that suppressed antigen–enzyme interactions and inhibited hydrolysis. These findings clarify how polymer composition and chain length jointly regulate antigen capture and protection, providing mechanistic guidance for the rational design of polymer-based in situ cancer vaccines. Full article

Growth-Regulating Factors (GRFs) are plant-specific transcription factors that, together with GRF-Interacting Factors (GIFs) and under post-transcriptional control by miR396, coordinate cell proliferation and expansion to define organ size. This GRF–GIF–miR396 regulatory module holds major agronomic importance, shaping leaf architecture, source–sink relationships, nitrogen-use efficiency (NUE), and stress resilience in crops. Upregulation of specific GRF genes has been shown to enhance leaf width, yield potential, and other important agronomic traits. Synthetic GRF–GIF chimeras have revolutionized regeneration and genome editing in multiple crop species, revealing both successes and species-specific limitations. Expanding GRF/GIF gene families and functional analyses across various crops highlight conserved developmental functions with variable outcomes, including improved drought and salinity tolerance through sustained canopy growth. This review, focused on crop systems, integrates current advances in GRF-regulated leaf development, their contributions to abiotic and biotic stress adaptation, and the emerging utility of GRF–GIF chimeras. Finally, it outlines key challenges and future opportunities for leveraging GRFs in designing climate-resilient, high-efficiency crop ideotypes. Full article

Curvularins, a class of macrocyclic lactones, have cytotoxic, antimicrobial, and anti-inflammatory properties. Curvularin, a 12-membered macrolactone, was used as a scaffold to design and synthesize structurally modified analogues to investigate structure–activity relationships and improve biological efficacy. Three series of curvularin-based analogues, Cur-5H-OMe, Cur-4P-OMe, and Cur-OMe, were synthesized with the same core structure but different substituent sizes and positions. Nine representative derivatives were evaluated for anti-inflammatory, anticancer, antibacterial, and antifungal activities. In LPS-stimulated RAW 264.7 macrophages, most compounds inhibited nitric oxide (NO) production in a concentration-dependent manner but exhibited cytotoxicity at high concentrations. Cytotoxicity assays against HaCaT cells and human cancer cell lines (HCT116, HeLa, and A375) revealed limited selectivity toward cancer cells. Antimicrobial evaluation indicated selective activity against the Gram-positive bacteria, Staphylococcus aureus. Compound 23 exhibited superior antibacterial potency compared with kanamycin and notable antifungal activity against Candida albicans. This study provides a versatile synthetic platform and identifies key structural features of curvularin derivatives, demonstrating their potential as anti-inflammatory and antimicrobial lead compounds. Full article