Fast, Efficient, Catalyst-Free Epoxidation of Butyl Rubber Using Oxone/Acetone for Improved Filler Dispersion.

Incorporation of a polar filler such as silica into a nonpolar rubber matrix is challenging and energy consuming due to their large difference in polarity. Epoxidation of carbon-carbon double bonds in unsaturated rubber, especially for rubber with low unsaturation such as butyl rubber, is an effective method to introduce polar functional groups to the rubber macromolecules for better filler dispersion. Although different epoxidation reagents including hydrogen peroxide (H2O2), peracid, and meta-chloroperoxybenzoic acid (mCPBA) have been previously reported, these reagents have different drawbacks. In this article, a metal-free epoxidation reagent, dimethyl dioxirane (DMDO), generated from acetone and Oxone is explored for efficient epoxidation of rubber with low unsaturation. The effects of the addition manner of the reactant Oxone and buffer sodium bicarbonate (NaHCO3) and reaction temperature on the epoxide formation are studied. Compared to peracid, a faster and more efficient epoxidation without the generation of a ring-opened product is achieved when DMDO is used as the epoxidation reagent. Furthermore, it is found that the epoxidation using DMDO is not sensitive to the water concentration in the rubber solution up to 20 wt %. The addition of quaternary ammonium salt as a phase transfer catalyst not only improves the conversion but also further increases the water tolerance to 25 wt %. The reaction conditions for preparation of epoxidized butyl rubber with different percentages of epoxide group are optimized by Design of Experiments (DoE). At the end, improved dispersion of silica in the matrix of epoxidized butyl rubber is achieved, as revealed by the rubber process analyzer (RPA) and atomic force microscopy (AFM).

How does urbanization affect the cognitive function among older adults: A geospatial analysis in China.

There has been a plethora of studies on urbanization and older adults, and more recent ones on how older adults adapt to this process with their cognitive competence. Yet it has been unclear about the relationship between them, like how the level and rate of urbanization affect the cognitive function among older adults. This study sourced, formed, and analyzed a set of geospatial big datasets from different sources, such as the Chinese Longitudinal Healthy Longevity Survey (CLHLS) data, and the NPP/VIIRS nighttime light (NTL) data. Results showed a generally negative linear association between the rate of urbanization and cognitive performance among older adults in China. The "U" shaped non-linear relationship between urbanization level and cognitive function, as well as the tipping point, were identified. At the same time, it should be noted that mediators such as education, physical activity, social activity, and community elderly service might be able to mitigate these negative associations. Furthermore, older adults living in eastern regions or urban areas appeared to have better cognitive function than those living in mid-western regions or rural areas in China. The findings also pointed to the importance of focusing on older adults with poor cognitive health status in rapidly urbanizing areas.

Aß42 and ROS dual-targeted multifunctional nanocomposite for combination therapy of Alzheimer's disease.

Amyloid-ß (Aß) readily misfolds into neurotoxic aggregates, generating high levels of reactive oxygen species (ROS), leading to progressive oxidative damage and ultimately cell death. Therefore, simultaneous inhibition of Aß aggregation and scavenging of ROS may be a promising therapeutic strategy to alleviate Alzheimer's disease pathology. Based on the previously developed antibody 1F12 that targets all forms of Aß42, we developed an Aß42 and ROS dual-targeting nanocomposite using biodegradable mesoporous silica nanoparticles as carriers to load ultra-small cerium oxide nanocrystals (bMSNs@Ce-1F12). By modifying the brain-targeted rabies virus glycoprotein 29 (RVG29-bMSNs@Ce-1F12), this intelligent nanocomposite can efficiently target brain Aß-rich regions. Combined with peripheral and central nervous system treatments, RVG29-bMSNs@Ce-1F12 can significantly alleviate AD symptoms by inhibiting Aß42 misfolding, accelerating Aß42 clearance, and scavenging ROS. Furthermore, this synergistic effect of ROS scavenging and Aß clearance exhibited by this Aß42 and ROS dual-targeted strategy also reduced the burden of hyperphosphorylated tau, alleviated glial cell activation, and ultimately improved cognitive function in APP/PS1 mice. Our findings indicate that RVG29-bMSNs@Ce-1F12 is a promising nanodrug that can facilitate multi-target treatment of AD.

Kurarinone, a flavonoid from Radix Sophorae Flavescentis, inhibits RANKL-induced osteoclastogenesis in mouse bone marrow-derived monocyte/macrophages.

Inflammation-induced osteoclast proliferation is a crucial contributor to impaired bone metabolism. Kurarinone (KR), a flavonoid extracted from the Radix Sophorae Flavescentis, exhibits notable anti-inflammatory properties. Nevertheless, the precise influence of KR on osteoclast formation remains unclear. This study's objective was to assess the impact of KR on osteoclast activity in vitro and unravel its underlying mechanism. Initially, a target network for KR-osteoclastogenesis-osteoporosis was constructed using network pharmacology. Subsequently, the intersecting targets were identified through the Venny platform and a PPI network was created using Cytoscape 3.9.1. Key targets within the network were identified employing topological algorithms. GO enrichment and KEGG pathway analysis were then performed on these targets to explore their specific functions and pathways. Additionally, molecular docking of potential core targets of KR was conducted, and the results were validated through cell experiments. A total of 83 target genes overlapped between KR and osteoclastogenesis-osteoporosis targets. Enrichment analysis revealed their role in inflammatory response, protein tyrosine kinase activity, osteoclast differentiation, and MAPK and NF-κB signaling pathways. PPI analysis and molecular docking demonstrate that key targets MAPK14 and MAPK8 exhibit more stable binding with KR compared to other proteins. In vitro experiments demonstrate that KR effectively inhibits osteoclast differentiation and bone resorption without cellular toxicity. It suppresses key osteoclast genes (NFATc1, c-Fos, TRAP, MMP9, Ctsk, Atp6v2), hinders IκB-α degradation, and inhibits ERK and JNK phosphorylation, while not affecting p38 phosphorylation. The results indicate that KR may inhibit osteoclast maturation and bone resorption by blocking NF-κB and MAPK signaling pathways, suggesting its potential as a natural therapeutic agent for osteoporosis.

Continuous and low-carbon production of biomass flash graphene.

Flash Joule heating (FJH) is an emerging and profitable technology for converting inexhaustible biomass into flash graphene (FG). However, it is challenging to produce biomass FG continuously due to the lack of an integrated device. Furthermore, the high-carbon footprint induced by both excessive energy allocation for massive pyrolytic volatiles release and carbon black utilization in alternating current-FJH (AC-FJH) reaction exacerbates this challenge. Here, we create an integrated automatic system with energy requirement-oriented allocation to achieve continuous biomass FG production with a much lower carbon footprint. The programmable logic controller flexibly coordinated the FJH modular components to realize the turnover of biomass FG production. Furthermore, we propose pyrolysis-FJH nexus to achieve biomass FG production. Initially, we utilize pyrolysis to release biomass pyrolytic volatiles, and subsequently carry out the FJH reaction to focus on optimizing the FG structure. Importantly, biochar with appropriate resistance is self-sufficient to initiate the FJH reaction. Accordingly, the medium-temperature biochar-based FG production without carbon black utilization exhibited low carbon emission (1.9 g CO2-eq g-1 graphene), equivalent to a reduction of up to ~86.1% compared to biomass-based FG production. Undoubtedly, this integrated automatic system assisted by pyrolysis-FJH nexus can facilitate biomass FG into a broad spectrum of applications.

Decreasing mitochondrial fission ameliorates HIF-1α-dependent pathological retinal angiogenesis.

Angiogenesis plays a critical role in many pathological processes, including irreversible blindness in eye diseases such as retinopathy of prematurity. Endothelial mitochondria are dynamic organelles that undergo constant fusion and fission and are critical signalling hubs that modulate angiogenesis by coordinating reactive oxygen species (ROS) production and calcium signalling and metabolism. In this study, we investigated the role of mitochondrial dynamics in pathological retinal angiogenesis. We showed that treatment with vascular endothelial growth factor (VEGF; 20 ng/ml) induced mitochondrial fission in HUVECs by promoting the phosphorylation of dynamin-related protein 1 (DRP1). DRP1 knockdown or pretreatment with the DRP1 inhibitor Mdivi-1 (5 µM) blocked VEGF-induced cell migration, proliferation, and tube formation in HUVECs. We demonstrated that VEGF treatment increased mitochondrial ROS production in HUVECs, which was necessary for HIF-1α-dependent glycolysis, as well as proliferation, migration, and tube formation, and the inhibition of mitochondrial fission prevented VEGF-induced mitochondrial ROS production. In an oxygen-induced retinopathy (OIR) mouse model, we found that active DRP1 was highly expressed in endothelial cells in neovascular tufts. The administration of Mdivi-1 (10 mg·kg-1·d-1, i.p.) for three days from postnatal day (P) 13 until P15 significantly alleviated pathological angiogenesis in the retina. Our results suggest that targeting mitochondrial fission may be a therapeutic strategy for proliferative retinopathies and other diseases that are dependent on pathological angiogenesis.

Daily Low-Level Red Light for Spherical Equivalent Error and Axial Length in Children With Myopia: A Randomized Clinical Trial.

Importance: Treatments are needed to slow progression of or reduce incidence of myopia. Objective: To evaluate the efficacy and safety of daily 650-nm low-level red light (LLRL) for myopia treatment. Design, Setting, and Participants: Single-masked, randomized clinical trial at 1 site in China. Baseline measurements were completed from August to September 2021. Participants were children aged 6 to 12 years with spherical equivalent error (SER) of -6 diopters (D) to 3 D. Data were analyzed from March to July 2023. Interventions: Irradiation daily with 650-nm LLRL for 3 minutes twice daily 4 or more hours apart or no intervention. Main Outcomes and Measures: Primary outcomes were changes in cycloplegia SER and axial length (AL) at 6- and 12-month follow-up visits. Safety was assessed on masked fundus photograph evaluations. Results: A total of 336 children were randomly allocated into the LLRL group or control group in a 1:1 ratio. The control group contained 86 female patients (51.2%), and the treatment group contained 90 female patients (53.6%). The mean (SD) age, SER, and AL were 9.0 (1.9) years, -1.3 (1.5) D, and 23.8 (1.0) mm for all patients. A total of 161 (95.8%) in the LLRL group and 159 (94.6%) in the control group returned for the 6-month follow-up. A total of 157 (93.5%) in the LLRL group and 152 (90.5%) in the control group returned for the 12-month follow-up. Mean (SD) changes in SER were 0.15 (0.16) D and -0.26 (0.21) D for the LLRL group and the control group, respectively (difference, -0.41 D; 95% CI, -0.48 to -0.34 D; P < .001), at 6 months and 0.24 (0.27) D and -0.65 (0.33) D for the LLRL group and the control group, respectively (difference, -0.89 D; 95% CI, -0.95 to -0.83 D; P < .001), at 12 months. Mean (SD) changes in AL were -0.06 (0.08) mm and 0.13 (0.12) mm for the LLRL group and control group, respectively (difference, 0.19 mm; 95% CI, 0.16 to 0.22 mm; P < .001), at 6 months and -0.11 (0.10) mm and 0.26 (0.16) mm for the LLRL group and control group, respectively (difference, 0.37 mm; 95% CI, 0.34 to 0.40 mm; P < .001). Masked fundus photograph review did not identify retinal changes in either group. Conclusions and relevance: These findings suggest daily use of 650-nm LLRL for 1 year can slow progression of SER and AL without safety concerns identified. Confirmation of these findings at independent sites seems warranted, as well as determining whether these effects can be sustained with or without continued treatment and whether LLRL has any effect on pathological myopia. Trial Registration: ChiCTR2200058963.

Association between sleep quality and dry eye disease: a literature review and meta-analysis.

OBJECTIVE: The purpose of this article is to systematically review the association between dry eye and sleep quality. METHODS: PubMed, EMBASE, Cochrane, Web of Science, and grey literature databases were searched for observational studies published before April 2023. Meta-analysis was performed using STAT15 software. RESULTS: A total of 21 studies with 419,218 participants were included. The results showed that the dry eye subjects had a worse sleep quality than the healthy population, with poorer subjective sleep quality, longer sleep latency, and a higher risk of unhealthy sleep duration such as insufficient sleep or excessive sleep. The Pittsburgh Sleep Quality Index (PSQI) scores of the dry eye subjects were significantly higher than those of the control subjects (WMD = 1.78, 95%CI: 1.06, 2.50, P < 0.001). The dry eye subjects scored higher than the control subjects in sleep quality, sleep latency, and sleep disturbance in PSQI; there was no difference between the dry eye individuals and control subjects in sleep duration, sleep efficiency, daytime dysfunction, and sleep medication scores. The risk of sleep disorders in the dry eye subjects was significantly higher than that in the non-dry eye subjects (RR = 2.20, 95%CI: 1.78, 2.72, P < 0.001); the risk of insufficient sleep in the dry eye subjects was higher than that in the control subjects (RR = 3.76, 95%CI: 3.15, 4.48, P < 0.001), and the prevalence of excessive sleepiness in dry eye subjects was higher than that in the control subjects (RR = 5.53, 95%CI: 3.83, 7.18, P < 0.001). The ESS scores of the dry eye subjects were significantly higher than those of the control subjects (WMD = 3.02, 95%CI: 2.43, 3.60, P < 0.01). CONCLUSION: Our meta-analysis suggests that individuals with dry eye have a worse sleep quality than the healthy population, with poorer subjective sleep quality, longer sleep latency, and higher risk of unhealthy sleep duration such as insufficient sleep or excessive sleepiness.

Recent advances in nanotechnology for programmed death ligand 1-targeted cancer theranostics.

Programmed cell death ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) checkpoint inhibitor-based immunotherapy has provided a unique and potent weapon against cancer in clinical practice. The likelihood of achieving beneficial effects from PD-L1/PD-1 immune checkpoint blockade (ICB) therapy is clinically assessed by detecting PD-L1 expression through invasive tissue biopsies. However, PD-L1 expression is susceptible to tumor heterogeneity and dynamic response to ICB therapy. Moreover, currently, anti-PD-L1 immunotherapy still faces challenges of the low targeting efficiency of antibody drugs and the risk of immune-associated adverse events. To overcome these issues, advanced nanotechnology has been developed for the purpose of quantitative, non-invasive, and dynamic analyses of PD-L1, and to enhance the efficiency of ICB therapy. In this review, we first introduce the nanoprobe-assisted in vitro/in vivo modalities for the selective and sensitive analysis of PD-L1 during the diagnostic and therapeutic process. On the other hand, the feasibility of fabricating diverse functional nanocarriers as smart delivery systems for precisely targeted delivery of PD-L1 immune checkpoint inhibitors and combined therapies is highlighted. Finally, the current challenges are discussed and future perspectives for PD-L1-targeted cancer theranostics in preclinical research and clinical settings are proposed.

Results of a phase I trial with Haploidentical mbIL-21 ex vivo expanded NK cells for patients with multiply relapsed and refractory AML.

Natural killer (NK)-cells have potent anti-tumor effects, yet it remains unclear if they are effective for patients with relapsed acute myeloid leukemia (AML). In a phase I clinical trial, we treated 12 patients (median age 60 years) with refractory AML (median 5 lines of prior therapy, median bone marrow blast count of 47%) with fludarabine/cytarabine followed by 6 infusions of NK-cells expanded from haploidentical donors using K562 feeder cells expressing membrane-bound IL21 and 4-1BBL. Patients received 106-107/kg/dose. No toxicity or graft-versus-host disease (GVHD) was observed and MTD was not reached. Seven patients (58.3%) responded and achieved a complete remission (CR) with/without count recovery. Median time to best response was 48 days. Five responding patients proceeded to a haploidentical transplant from the same donor. After a median follow-up of 52 months, 1-year overall survival (OS) for the entire group was 41.7%, better for patients who responded with CR/CRi (57.14%), and for patients who responded and underwent transplantation (60%). Persistence and expansion of donor-derived NK-cells were identified in patients' blood, and serum IFNγ levels rose concurrently with NK cell infusions. A higher count-functional inhibitory KIR was associated with higher likelihood of achieving CR/CRi. In conclusion, we observed a significant response to ex vivo expanded NK-cell administration in refractory AML patients without adverse effects.

Slightly acidic electrolyzed water significantly restrains the accumulation of the microalgae Pseudokirchneriella subcapitata in hydroponic systems.

AIMS: This study explored the effects of slightly acidic electrolyzed water (SAEW) on algae to exploit technologies that effectively suppress algal growth in hydroponic systems and improve crop yield. METHODS AND RESULTS: The effects of SAEW on algal growth and the response mechanisms of algae to SAEW were investigated. Moreover, we studied whether the application of SAEW adversely affected tomato seedling growth. The results showed that SAEW significantly inhibited algal growth and destroyed the integrity of the algal cells. In addition, the intracellular oxidation-reduction system of algae was greatly influenced by SAEW. The H2O2, O2-, malondialdehyde (MDA), and reactive oxygen species (ROS) fluorescence signals were significantly induced by SAEW, and superoxide dismutase (SOD), peroxidase (POD), and glutathione reductase (GR) activities were greatly enhanced by a low SAEW concentration but significantly inhibited by SAEW with a high available chlorine concentration, which may contribute to heavy oxidative stress on algal growth and cell structure break down, eventually causing the death of algae and cell number decrease. We also found that regardless of the concentration of SAEW (from 10 to 40 mg L-1), there was no significant change in the germination index, length, or fresh weight of the hydroponic tomato seedlings. CONCLUSIONS: Our findings demonstrate that SAEW can be used in hydroponic systems to restrain algae with no negative impact on tomato plants.

Alteration of Neurotrophic Factors and Innervation in Extraocular Muscles of Individuals With Concomitant Esotropia.

Purpose: To determine whether neurotrophic factors and innervation in extraocular muscles (EOMs) were altered in different types of concomitant esotropia, and to explore the possible association between neurotrophic factors and innervation of EOMs in humans. Methods: Patients with concomitant esotropia who required strabismus surgery were recruited from January to December 2022. Lateral rectus EOMs were obtained from patients, and controls were obtained from deceased organ donors. Immunofluorescence (IF) was performed to detect innervation of EOMs (neurofilament and synaptophysin), and immunohistochemistry (IHC) was used to detect the neurotrophic factors insulin-like growth factor-1 (IGF-1), brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), and neurotrophin-3 (NT-3). The positive IHC results were further verified using western blotting (WB). One-way ANOVA followed by a Dunnett's multiple comparison post hoc test was used for continuous variables and the χ2 test for categorical variables. Spearman correlation analysis was used for the correlation analysis. Results: We collected lateral rectus EOM samples from acute and chronic types of concomitant esotropia and controls. Consistent with IHC, WB showed that IGF-1 was significantly increased in patients with acute acquired comitant esotropia or essential infantile esotropia compared with controls. In IF, synaptophysins were significantly increased only in acute acquired comitant esotropia compared with controls. Furthermore, Spearman correlation analysis showed that the correlation between IGF-1 and synaptophysin was borderline (P = 0.057) for patients with acute acquired comitant esotropia. Conclusions: Our study highlights the role of IGF-1 and altered innervation of EOMs in acute acquired comitant esotropia, suggesting that an effect of increased IGF-1 on nerve innervation may temporarily cause a compensatory increase in the strength of lateral rectus muscles.

Effects of atropine eyedrops at ten different concentrations for myopia control in children: A systematic review on meta-analysis.

PURPOSE: To estimate the effect of atropine eyedrops at different concentrations for myopia control in children. METHODS: We conducted a Bayesian random-effects network meta-analysis based on randomized controlled trials (RCT). Primary outcomes include changes in spherical equivalent error (SER) and changes in axial length (AL), mean difference (MD) together with 95% credible interval (CrI) were used to evaluate the efficacy. RESULTS: 28 RCTs (6608 children) were included in this review. Comparing ten atropine eyedrops (0.0025%, 0.005%, 0.01%, 0.02%, 0.025%, 0.05%, 0.1%, 0.25%, 0.5% and 1% concentrations) with the placebo, the MDs and 95%CrIs of changes in SER are -0.006 (-0.269, 0.256) D, 0.216 (-0.078, 0.508) D, 0.146 (0.094, 0.199) D, 0.167 (0.039, 0.297) D, 0.201 (0.064, 0.341) D, 0.344 (0.251, 0.440) D, 0.255 (0.114, 0.396) D, 0.296 (0.140, 0.452) D, 0.331 (0.215, 0.447) D, and 0.286 (0.195, 0.337) D, respectively. The MDs and 95%CrIs of changes in AL are -0.048 (-0.182, 0.085) mm, -0.078 (-0.222, 0.066) mm, -0.095 (-0.130, -0.060) mm, -0.096 (-0.183, -0.009) mm, -0.083 (-0.164, -0.004) mm, -0.114 (-0.176, -0.056) mm, -0.134 (-0.198, -0.032) mm, -0.174 (-0.315, -0.061) mm, -0.184 (-0.291, -0.073) mm, and -0.171 (-0.203, -0.097) mm, respectively.Whether evaluated by SER or AL, 1% concentration ranks first in efficacy, but the risk of photophobia is 17 times higher than 0.01% concentration. CONCLUSIONS: 0.01% or higher concentration atropine eyedrops are effective for myopia control, while 0.0025% and 0.005% concentrations may not. As the concentration increases, the effect tends to increase, 1% concentration may have the strongest effect.

Bowel preparation protocol for hospitalized patients ages 50 years or older: A randomized controlled trial.

BACKGROUND: The incidence and mortality rate of colorectal cancer progressively increase with age and become particularly prominent after the age of 50 years. Therefore, the population that is ≥ 50 years in age requires long-term and regular colonoscopies. Uncomfortable bowel preparation is the main reason preventing patients from undergoing regular colonoscopies. The standard bowel preparation regimen of 4-L polyethylene glycol (PEG) is effective but poorly tolerated. AIM: To investigate an effective and comfortable bowel preparation regimen for hospitalized patients ≥ 50 years in age. METHODS: Patients were randomly assigned to group 1 (2-L PEG + 30-mL lactulose + a low-residue diet) or group 2 (4-L PEG). Adequate bowel preparation was defined as a Boston bowel preparation scale (BBPS) score of ≥ 6, with a score of ≥ 2 for each segment. Non-inferiority was prespecified with a margin of 10%. Additionally, the degree of comfort was assessed based on the comfort questionnaire. RESULTS: The proportion of patients with a BBPS score of ≥ 6 in group 1 was not significantly different from that in group 2, as demonstrated by intention-to-treat (91.2% vs 91.0%, P = 0.953) and per-protocol (91.8% vs 91.0%, P = 0.802) analyses. Furthermore, in patients ≥ 75 years in age, the proportion of BBPS scores of ≥ 6 in group 1 was not significantly different from that in group 2 (90.9% vs 97.0%, P = 0.716). Group 1 had higher comfort scores (8.85 ± 1.162 vs 7.59 ± 1.735, P < 0.001), longer sleep duration (6.86 ± 1.204 h vs 5.80 ± 1.730 h, P < 0.001), and fewer awakenings (1.42 ± 1.183 vs 2.04 ± 1.835, P = 0.026) than group 2. CONCLUSION: For hospitalized patients ≥ 50 years in age, the bowel preparation regimen comprising 2-L PEG + 30-mL lactulose + a low-residue diet produced a cleanse that was as effective as the 4-L PEG regimen and even provided better comfort.

Ref-MEF: Reference-Guided Flexible Gated Image Reconstruction Network for Multi-Exposure Image Fusion.

Multi-exposure image fusion (MEF) is a computational approach that amalgamates multiple images, each captured at varying exposure levels, into a singular, high-quality image that faithfully encapsulates the visual information from all the contributing images. Deep learning-based MEF methodologies often confront obstacles due to the inherent inflexibilities of neural network structures, presenting difficulties in dynamically handling an unpredictable amount of exposure inputs. In response to this challenge, we introduce Ref-MEF, a method for color image multi-exposure fusion guided by a reference image designed to deal with an uncertain amount of inputs. We establish a reference-guided exposure correction (REC) module based on channel attention and spatial attention, which can correct input features and enhance pre-extraction features. The exposure-guided feature fusion (EGFF) module combines original image information and uses Gaussian filter weights for feature fusion while keeping the feature dimensions constant. The image reconstruction is completed through a gated context aggregation network (GCAN) and global residual learning GRL. Our refined loss function incorporates gradient fidelity, producing high dynamic range images that are rich in detail and demonstrate superior visual quality. In evaluation metrics focused on image features, our method exhibits significant superiority and leads in holistic assessments as well. It is worth emphasizing that as the number of input images increases, our algorithm exhibits notable computational efficiency.

Network Pharmacology and Experimental Validation to Elucidate the Pharmacological Mechanisms of Luteolin Against Chondrocyte Senescence.

BACKGROUND: Luteolin, a flavonoid found in various medicinal plants, has shown promising antioxidant, anti-inflammatory, and anti-aging properties. The cartilaginous endplate (CEP) represents a crucial constituent of the intervertebral disc (IVD), assuming a pivotal responsibility in upholding both the structural and functional stability of the IVD. OBJECTIVE: Exploring the precise mechanism underlying the protective effects of luteolin against senescence and degeneration of endplate chondrocytes (EPCs). METHODS: Relevant targets associated with luteolin and aging were obtained from publicly available databases. To ascertain cellular functions and signaling pathways, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were employed. Core genes were identified through the construction of a protein-protein interaction (PPI) network. Molecular docking (MD) was utilized to assess the binding affinity of luteolin to these core genes. Finally, the impact of luteolin on the senescence and degeneration of EPCs was evaluated in an in vitro cellular senescence model induced by tert-butyl hydroperoxide (TBHP). RESULTS: There are 145 overlapping targets between luteolin and senescence. Analysis using GO revealed that these targets primarily participate in cellular response to oxidative stress and reactive oxygen species. KEGG analysis demonstrated that these markers mainly associate with signaling pathways such as p53 and PI3K-Akt. MD simulations exhibited luteolin's binding affinity to P53, Cyclin-dependent kinase (CDK)2, and CDK4. Cell cycle, cell proliferation, and ß- galactosidase assays confirmed that luteolin mitigated senescence in SW1353 cells. Western blot assays exhibited that luteolin significantly suppressed the expression of Matrix Metallopeptidase (MMP) 13, P53, and P21, while concurrently promoting CDK2, CDK4, and Collagen Type II Alpha 1 (COL2A1) expression. CONCLUSION: In summary, luteolin demonstrated beneficial properties against aging and degeneration in EPCs, offering novel insights to mitigate the progression of intervertebral disc degeneration (IVDD).

Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19+ B cell tumors: a phase 1/2 trial.

There is a pressing need for allogeneic chimeric antigen receptor (CAR)-immune cell therapies that are safe, effective and affordable. We conducted a phase 1/2 trial of cord blood-derived natural killer (NK) cells expressing anti-CD19 chimeric antigen receptor and interleukin-15 (CAR19/IL-15) in 37 patients with CD19+ B cell malignancies. The primary objectives were safety and efficacy, defined as day 30 overall response (OR). Secondary objectives included day 100 response, progression-free survival, overall survival and CAR19/IL-15 NK cell persistence. No notable toxicities such as cytokine release syndrome, neurotoxicity or graft-versus-host disease were observed. The day 30 and day 100 OR rates were 48.6% for both. The 1-year overall survival and progression-free survival were 68% and 32%, respectively. Patients who achieved OR had higher levels and longer persistence of CAR-NK cells. Receiving CAR-NK cells from a cord blood unit (CBU) with nucleated red blood cells ≤ 8 × 107 and a collection-to-cryopreservation time ≤ 24 h was the most significant predictor for superior outcome. NK cells from these optimal CBUs were highly functional and enriched in effector-related genes. In contrast, NK cells from suboptimal CBUs had upregulation of inflammation, hypoxia and cellular stress programs. Finally, using multiple mouse models, we confirmed the superior antitumor activity of CAR/IL-15 NK cells from optimal CBUs in vivo. These findings uncover new features of CAR-NK cell biology and underscore the importance of donor selection for allogeneic cell therapies. ClinicalTrials.gov identifier: NCT03056339 .

An in Vivo, Three-Dimensional (3D), Functional Centers of Rotation of the Healthy Cervical Spine.

OBJECTIVE: This study examined cervical center of rotation (COR) positions in 7 postures using validated cone beam computed tomography (CBCT) combined with 3D-3D registration in healthy volunteers. METHODS: CBCT scans were performed on 20 healthy volunteers in 7 functional positions, constructing a three-dimensional (3D) model. Images were registered to the neutral position using 3D-3D registration, allowing analysis of kinematic differences and rotational axes. COR measurements were obtained for each segment (C2/3 to C6/7) in each posture. RESULTS: The CORs of C2/3 to C6/7 were predominantly posterior (-5.3 ± 3.8 ∼ -0.6 ± 1.2 mm) and superior (16.5 ± 6.0 ∼ 23.6 ± 3.2 mm) to the intervertebral disc's geometric center (GC) in flexion and extension. However, the C4/5 segment's COR was anterior to the GC (2.0 ± 9.8 mm) during flexion and close to it in the right-left direction. During left-right twisting, the CORs of C2/3-C6/7 were posterior (-21.8 ± 10.5 ∼-0.9 ± 0.8 mm) and superior (3.1 ± 7.5 ∼23.2 ± 3.6 mm) to the GCs in anterior-posterior and superior-inferior directions, without consistent right-left directionality. During left-right bending, each segment's COR was predominantly posterior (-25.2 ± 13.1 ∼-6.5 ± 9.9 mm) and superior (0.3 ± 12.5 ∼12.1 ± 5.1 mm) to the GC in anterior-posterior and superior-inferior directions, except for the C2/3 segment, located inferiorly (-5.9 ± 4.1 mm) in left bending. The right-left COR position varied across segments. CONCLUSIONS: Our findings reveal segment-specific and posture-dependent COR variations. Notably, the CORs of C3/4, C4/5, and C5/6 consistently align near the intervertebral disc's GC at different postures, supporting their suitability for total disc replacement surgery within the C3/4 to C5/6 segments.

Efficacy of Morning Versus Evening Latanoprost/Timolol Fixed Combination for Open-Angle Glaucoma and Ocular Hypertension: A Randomized Clinical Trial.

Purpose: To compare the efficacy of morning and evening latanoprost/timolol fixed-combination (LTFC) dosing in patients with primary open-angle glaucoma (POAG) and ocular hypertension. Methods: In this double-blind, randomized clinical trial, 63 untreated Chinese patients with POAG and ocular hypertension were enrolled. All patients received LTFC and were randomized (1:1) to group 1, morning (8 AM) dosing, or group 2, evening (8 PM) dosing. Vehicle drops were used in the morning or evening, accordingly, to preserve masking. Patients were treated for 4 weeks. Outcomes included mean reduction of the 24-hour intraocular pressure (IOP) and IOP fluctuation from baseline after a 4-week treatment. Results: Fifty-six patients were included in the final analysis. In both groups, the posttreatment IOP values were significantly lower than those at baseline at each 24-hour measuring time point. A significant difference between the groups in IOP reduction from baseline was observed at the 9:30 AM time point (4.01 ± 2.62 vs. 2.42 ± 3.23 mm Hg, evening dosing versus morning dosing group; P = 0.048). Both groups showed decreased IOP fluctuation after treatment. However, the morning dosing group had a significantly greater decrease in diurnal IOP fluctuation than that of the evening dosing group (2.04 ± 2.32 mm Hg vs. 0.50 ± 1.70 mm Hg, respectively; P = 0.012). Conclusions: Both morning and evening LTFC dosing can effectively reduce 24-hour IOP and IOP fluctuation. Morning dosing is more likely to effectively control diurnal IOP fluctuations. Translational Relevance: This multicenter, double-blind, randomized clinical trial generates robust evidence on the optimal LTFC dosing regimen to help clinical decision-making in the treatment of raised IOP.