Integrative effects of resistance training and endurance training on mitochondrial remodeling in skeletal muscle.

Resistance training activates mammalian target of rapamycin (mTOR) pathway of hypertrophy for strength gain, while endurance training increases peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) pathway of mitochondrial biogenesis benefiting oxidative phosphorylation. The conventional view suggests that resistance training-induced hypertrophy signaling interferes with endurance training-induced mitochondrial remodeling. However, this idea has been challenged because acute leg press and knee extension in humans enhance both muscle hypertrophy and mitochondrial remodeling signals. Thus, we first examined the muscle mitochondrial remodeling and hypertrophy signals with endurance training and resistance training, respectively. In addition, we discussed the influence of resistance training on muscle mitochondria, demonstrating that the PGC-1α-mediated muscle mitochondrial adaptation and hypertrophy occur simultaneously. The second aim was to discuss the integrative effects of concurrent training, which consists of endurance and resistance training sessions on mitochondrial remodeling. The study found that the resistance training component does not reduce muscle mitochondrial remodeling signals in concurrent training. On the contrary, concurrent training has the potential to amplify skeletal muscle mitochondrial biogenesis compared to a single exercise model. Concurrent training involving differential sequences of resistance and endurance training may result in varied mitochondrial biogenesis signals, which should be linked to the pre-activation of mTOR or PGC-1α signaling. Our review proposed a mechanism for mTOR signaling that promotes PGC-1α signaling through unidentified pathways. This mechanism may be account for the superior muscle mitochondrial remodeling change following the concurrent training. Our review suggested an interaction between resistance training and endurance training in skeletal muscle mitochondrial adaptation.

Development and validation of a diagnostic prediction model for severe periventricular-intraventricular hemorrhage in newborns: insights from a retrospective analysis utilizing the MIMIC-III database

Abstract Objective: Periventricular-intraventricular hemorrhage is the most common type of intracranial bleeding in newborns, especially in the first 3 days after birth. Severe periventricular-intraventricular hemorrhage is considered a progression from mild periventricular-intraventricular hemorrhage and is often closely associated with severe neurological sequelae. However, no specific indicators are available to predict the progression from mild to severe periventricular-intraventricular in early admission. This study aims to establish an early diagnostic prediction model for severe PIVH. Method: This study was a retrospective cohort study with data collected from the MIMIC-III (v1.4) database. Laboratory and clinical data collected within the first 24 h of NICU admission have been used as variables for both univariate and multivariate logistic regression analyses to construct a nomogram-based early prediction model for severe periventricular-intraventricular hemorrhage and subsequently validated. Results: A predictive model was established and represented by a nomogram, it comprised three variables: output, lowest platelet count and use of vasoactive drugs within 24 h of NICU admission. The model's predictive performance showed by the calculated area under the curve was 0.792, indicating good discriminatory power. The calibration plot demonstrated good calibration between observed and predicted outcomes, and the Hosmer-Lemeshow test showed high consistency (p = 0.990). Internal validation showed the calculated area under a curve of 0.788. Conclusions: This severe PIVH predictive model, established by three easily obtainable indicators within the NICU, demonstrated good predictive ability. It offered a more user-friendly and convenient option for neonatologists.

Multi-Instance Learning for Vocal Fold Leukoplakia Diagnosis Using White Light and Narrow-Band Imaging: A Multicenter Study.

OBJECTIVES: Vocal fold leukoplakia (VFL) is a precancerous lesion of laryngeal cancer, and its endoscopic diagnosis poses challenges. We aim to develop an artificial intelligence (AI) model using white light imaging (WLI) and narrow-band imaging (NBI) to distinguish benign from malignant VFL. METHODS: A total of 7057 images from 426 patients were used for model development and internal validation. Additionally, 1617 images from two other hospitals were used for model external validation. Modeling learning based on WLI and NBI modalities was conducted using deep learning combined with a multi-instance learning approach (MIL). Furthermore, 50 prospectively collected videos were used to evaluate real-time model performance. A human-machine comparison involving 100 patients and 12 laryngologists assessed the real-world effectiveness of the model. RESULTS: The model achieved the highest area under the receiver operating characteristic curve (AUC) values of 0.868 and 0.884 in the internal and external validation sets, respectively. AUC in the video validation set was 0.825 (95% CI: 0.704-0.946). In the human-machine comparison, AI significantly improved AUC and accuracy for all laryngologists (p < 0.05). With the assistance of AI, the diagnostic abilities and consistency of all laryngologists improved. CONCLUSIONS: Our multicenter study developed an effective AI model using MIL and fusion of WLI and NBI images for VFL diagnosis, particularly aiding junior laryngologists. However, further optimization and validation are necessary to fully assess its potential impact in clinical settings. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

Nickel-Catalyzed Four-Component Carbonylation of 1,3-Butadiene To Access ß,γ-Unsaturated Ketones.

A new strategy to obtain ß,γ-unsaturated ketones via the cross-coupling of 1,3-butadiene, alkyl bromides, and arylboronic acids under 1 bar of CO with nickel as the catalyst has been developed. This newly developed four-component carbonylation procedure features advantages including using a cheap catalytic system, high step economy, mild reaction conditions, and excellent 1,4-regioselectivity, thereby providing a sustainable and alternative tool for ß,γ-unsaturated ketones production compared to the present tactics. To elucidate the application potential of this method, olefin synthons are derived from the representative coupling product.

Multi-instance learning based artificial intelligence model to assist vocal fold leukoplakia diagnosis: A multicentre diagnostic study.

OBJECTIVE: To develop a multi-instance learning (MIL) based artificial intelligence (AI)-assisted diagnosis models by using laryngoscopic images to differentiate benign and malignant vocal fold leukoplakia (VFL). METHODS: The AI system was developed, trained and validated on 5362 images of 551 patients from three hospitals. Automated regions of interest (ROI) segmentation algorithm was utilized to construct image-level features. MIL was used to fusion image level results to patient level features, then the extracted features were modeled by seven machine learning algorithms. Finally, we evaluated the image level and patient level results. Additionally, 50 videos of VFL were prospectively gathered to assess the system's real-time diagnostic capabilities. A human-machine comparison database was also constructed to compare the diagnostic performance of otolaryngologists with and without AI assistance. RESULTS: In internal and external validation sets, the maximum area under the curve (AUC) for image level segmentation models was 0.775 (95 % CI 0.740-0.811) and 0.720 (95 % CI 0.684-0.756), respectively. Utilizing a MIL-based fusion strategy, the AUC at the patient level increased to 0.869 (95 % CI 0.798-0.940) and 0.851 (95 % CI 0.756-0.945). For real-time video diagnosis, the maximum AUC at the patient level reached 0.850 (95 % CI, 0.743-0.957). With AI assistance, the AUC improved from 0.720 (95 % CI 0.682-0.755) to 0.808 (95 % CI 0.775-0.839) for senior otolaryngologists and from 0.647 (95 % CI 0.608-0.686) to 0.807 (95 % CI 0.773-0.837) for junior otolaryngologists. CONCLUSIONS: The MIL based AI-assisted diagnosis system can significantly improve the diagnostic performance of otolaryngologists for VFL and help to make proper clinical decisions.

Innovative utilization of ultra-wide field fundus images and deep learning algorithms for screening high-risk posterior polar cataract.

PURPOSE: To test a cataract shadow projection theory and validate it by developing a deep learning algorithm that enables automatic and stable posterior polar cataract (PPC) screening using fundus images. SETTING: Department of Ophthalmology, Far Eastern Memorial Hospital, New Taipei, Taiwan. DESIGN: Retrospective chart review. METHODS: A deep learning algorithm to automatically detect PPC was developed based on the cataract shadow projection theory. Retrospective data (n = 546) with ultra-wide field fundus images were collected, and various model architectures and fields of view were tested for optimization. RESULTS: The final model achieved 80% overall accuracy, with 88.2% sensitivity and 93.4% specificity in PPC screening on a clinical validation dataset (n = 103). CONCLUSIONS: This study established a significant relationship between PPC and the projected shadow, which may help surgeons to identify potential PPC risks preoperatively and reduce the incidence of posterior capsular rupture during cataract surgery.

Development and validation of a diagnostic prediction model for severe periventricular-intraventricular hemorrhage in newborns: insights from a retrospective analysis utilizing the MIMIC-III database.

OBJECTIVE: Periventricular-intraventricular hemorrhage is the most common type of intracranial bleeding in newborns, especially in the first 3 days after birth. Severe periventricular-intraventricular hemorrhage is considered a progression from mild periventricular-intraventricular hemorrhage and is often closely associated with severe neurological sequelae. However, no specific indicators are available to predict the progression from mild to severe periventricular-intraventricular in early admission. This study aims to establish an early diagnostic prediction model for severe PIVH. METHOD: This study was a retrospective cohort study with data collected from the MIMIC-III (v1.4) database. Laboratory and clinical data collected within the first 24 h of NICU admission have been used as variables for both univariate and multivariate logistic regression analyses to construct a nomogram-based early prediction model for severe periventricular-intraventricular hemorrhage and subsequently validated. RESULTS: A predictive model was established and represented by a nomogram, it comprised three variables: output, lowest platelet count and use of vasoactive drugs within 24 h of NICU admission. The model's predictive performance showed by the calculated area under the curve was 0.792, indicating good discriminatory power. The calibration plot demonstrated good calibration between observed and predicted outcomes, and the Hosmer-Lemeshow test showed high consistency (p = 0.990). Internal validation showed the calculated area under a curve of 0.788. CONCLUSIONS: This severe PIVH predictive model, established by three easily obtainable indicators within the NICU, demonstrated good predictive ability. It offered a more user-friendly and convenient option for neonatologists.

Experimental quantum e-commerce.

E-commerce, a type of trading that occurs at a high frequency on the internet, requires guaranteeing the integrity, authentication, and nonrepudiation of messages through long distance. As current e-commerce schemes are vulnerable to computational attacks, quantum cryptography, ensuring information-theoretic security against adversary's repudiation and forgery, provides a solution to this problem. However, quantum solutions generally have much lower performance compared to classical ones. Besides, when considering imperfect devices, the performance of quantum schemes exhibits a notable decline. Here, we demonstrate the whole e-commerce process of involving the signing of a contract and payment among three parties by proposing a quantum e-commerce scheme, which shows resistance of attacks from imperfect devices. Results show that with a maximum attenuation of 25 dB among participants, our scheme can achieve a signature rate of 0.82 times per second for an agreement size of approximately 0.428 megabit. This proposed scheme presents a promising solution for providing information-theoretic security for e-commerce.

Copper-catalyzed trichloromethylative carbonylation of ethylene.

Difunctionalization of alkenes is an efficient strategy for the synthesis of complex compounds from readily available starting materials. Herein, we developed a copper-catalyzed visible-light-mediated trichloromethylative carbonylation of ethylene by employing commercially available CCl4 and CO as trichloromethyl and carbonyl sources, respectively. With this protocol, various nucleophiles including amines, phenols, and alcohols can be rapidly transformed into ß-trichloromethyl carboxylic acid derivatives with good functional-group tolerance. Bis-vinylated γ-trichloromethyl amides can also be obtained by adjusting the pressure of carbon monoxide and ethylene. In addition, this photocatalytic system can be successfully applied in the late-stage functionalization of bioactive molecules and pharmaceutical derivatives as well.

Patients' Readiness Towards Teledentistry in the Malaysian Urban Population Attending an Undergraduate Teaching University.

Introduction: COVID-19 disease has resulted in suspension of all nonurgent routine dental treatments. In view of COVID-19 situation, social distancing, movement restriction orders, and affected health care systems, there is an urgent need to resume and deliver oral health care remotely. Hence, alternative means of dental care should be available for both patients and dentists. Therefore, this study aims to assess patients' readiness for teledentistry in Malaysian urban population attending an undergraduate teaching university. Methods: A cross-sectional study was conducted among 631 adult patients visiting the Faculty of Dentistry, SEGi University, from January 2020 to May 2021 in Selangor, Malaysia. A validated, self-administered, 5-point Likert scale online questionnaire comprising five domains was administered. (1) Patients' demographics and dental history, (2) patients' access to teledentistry, (3) patients' understanding towards teledentistry, (4) patients' willingness, and (5) barriers in using teledentistry were used to collect the required information. Results: Six hundred and thirty-one (n = 631) participants responded to the questionnaire. Ninety percent of patients were able to connect to Wi-Fi services independently and 77% participants were comfortable using online communication platforms. Seventy-one percent of the participants agreed that video and telephone clinics can reduce chances of infection rather than face-to-face consultation during the pandemic. Fifty-five percent of patients felt that virtual clinics would save time and 60% thought it could reduce travelling costs. Fifty-one percent showed their willingness to use video or telephone clinics when implemented at onsite clinics. Conclusion: Our study shows the readiness of patients to accept teledentistry as an alternative method of oral care if appropriate training and education are provided. The results of this study have prompted an increase in patients' education and shown a need to train clinicians and patients to integrate this technology at SEGi University. This might facilitate unhindered dental consultation and care in all situations.

Palladium-Catalyzed Carbonylative Multicomponent Fluoroalkylation of 1,3-Enynes: Concise Construction of Diverse Cyclic Compounds.

Multicomponent reactions, particularly those entailing four or more reagents, have presented a longstanding challenge due to the inherent complexities associated with balancing reactivity, selectivity, and compatibility. In this study, we describe a palladium-catalyzed multi-component fluoroalkylative carbonylation of 1,3-enynes. A series of products featuring three active functional groups-allene, fluoroalkyl, and carboxyl, were efficiently and selectively integrated in a single chemical operation. Furthermore, more intricate fluoroalkyl-substituted pyrimidinones can be constructed by simply altering the 1,3-bisnucleophilic reagent. This approach also provides a valuable strategy for the late-stage modification of naturally occurring molecules and concise construction of diverse cyclic compounds.

A modified SELEX approach to identify DNA aptamers with binding specificity to the major histocompatibility complex presenting ovalbumin model antigen.

Aptamers have sparked significant interest in cell recognition because of their superior binding specificity and biocompatibility. Cell recognition can be mediated by targeting the major histocompatibility complex (MHC) that presents short peptides derived from intracellular antigens. Although numerous antibodies have demonstrated a specific affinity for the peptide-MHC complex, the number of aptamers that exhibit comparable characteristics is limited. Aptamers are usually selected from large libraries via the Systemic Evolution of Ligands by Exponential Enrichment (SELEX), an iterative process of selection and PCR amplification to enrich a pool of aptamers with high affinity. However, the success rate of aptamer identification is low, possibly due to the presence of complementary sequences or sequences rich in guanine and cytosine that are less accessible for primers. Here, we modified SELEX by employing systemic consecutive selections with minimal PCR amplification. We also modified the analysis by selecting aptamers that were identified in multiple selection rounds rather than those that are highly enriched. Using this approach, we were able to identify two aptamers with binding specificity to cells expressing the ovalbumin alloantigen as a proof of concept. These two aptamers were also discovered among the top 150 abundant candidates, despite not being highly enriched, by performing conventional SELEX. Additionally, we found that highly enriched aptamers tend to contain fractions of the primer sequence and have minimal target affinity. Candidate aptamers are easily missed in the conventional SELEX process. Therefore, our modification for SELEX may facilitate the identification of aptamers for more application in diverse biomedical fields. Significance: we modify the conventional method to improve the efficiency in the identification of the aptamer, a single strand of nucleic acid with binding specificity to the target molecule, showing as a proof of concept that this approach is particularly useful to select aptamers that can selectively bind to cells presenting a particular peptide by the major histocompatibility complex (MHC) on the cell surface. Given that cancer cells may express mutant peptide-MHC complexes that are distinct from those expressed by normal cells, this study sheds light on the potential application of aptamers to cancer cell targeting.

Mitoguardin 1 and 2 promote granulosa cell proliferation by activating AKT and regulating the Hippo-YAP1 signaling pathway.

Mitochondria have been identified to be involved in oxidative phosphorylation, lipid metabolism, cell death, and cell proliferation. Previous studies have demonstrated that mitoguardin (Miga), a mitochondrial protein that governs mitochondrial fusion, mitochondria-endoplasmic reticulum (ER) contacts, lipid formation, and autophagy, is crucial for ovarian endocrine and follicular development. Nevertheless, whether mammalian MIGA1 or MIGA2 (MIGA1,-2) regulates ovarian granulosa cell proliferation remains unclear. This study revealed that mammalian MIGA1,-2 promotes cell proliferation and regulates the phosphorylation and localization of Yes-associated protein 1 (YAP1) in ovarian granulosa cells. MIGA2 upregulation resulted in reduced YAP1 activity, while MIGA2 removal led to increased YAP1 activity. Further analysis indicated that MIGA1,-2 regulated YAP1 via the Hippo signaling pathway and regulated protein kinase B (AKT) activity in collaboration with YAP1. In addition, lysophosphatidic acid (LPA) regulated MIGA2 expression and AKT activity by activating YAP1. Briefly, we demonstrated that the mitochondrial MIGA1 and MIGA2, especially MIGA2, promoted cellular proliferation by activating AKT and regulating the Hippo/YAP1 signaling pathway in ovarian granulosa cells, which may contribute to the molecular pathogenesis of reproductive endocrine diseases, such as polycystic ovary syndrome (PCOS).

Low-Temperature Specific Heat Capacity of Water-Ammonia Mixtures Down to the Eutectic.

Robust thermodynamic data are essential for the development of geodynamic and geochemical models of ocean worlds. The water-ammonia system is of interest in the study of ocean worlds due to its purported abundance in the outer solar system, geological implications, and potential importance for origins of life. In support of developing new equations of state, we conducted 1 bar specific heat capacity measurements (Cp) using a differential scanning calorimeter (DSC) at low temperatures (184-314 K) and low mass fractions of ammonia (5.2-26.9 wt %) to provide novel data in the parameter space most relevant for planetary studies. This is the first known set of data with sufficient fidelity to investigate the trend of specific heat capacity with respect to temperature. The obtained Cp in the liquid phase domain above the liquidus generally increases with temperature. Deviations of our data from the currently adopted equation of state by Tillner-Roth and Friend[Tillner-Roth R.; Friend D. G.J. Phys. Chem. Ref. Data1998, 27, 63-96]. are generally negative (ranging from +1 to -10%) and larger at lower temperatures. This result suggests that suppression of the critical behavior of supercooled water (rapid increase in specific heat with decreasing temperature) by ammonia starts at a smaller concentration than that set by Tillner-Roth and Friend.[Tillner-Roth R.; Friend D. G.J. Phys. Chem. Ref. Data1998, 27, 63-96]. Cp measurements of the liquid were also obtained in the partial melting domain between the eutectic and liquidus. This novel data set will be useful in future investigations of conditions where such partial melt may exist, such as the ice shell-ocean boundary or the interiors of ocean worlds that may contain relatively large proportions of dissolved ammonia.

Photo-Induced Carbonylation of Aryl Bromides for the Synthesis of Aryl Esters and Amides Under Transition Metal-Free Conditions.

In this work, we developed a photo-induced carbonylation of aryl bromides under transition metal-free conditions. The reaction shows good activity with alcohol and amine nucleophiles. Various esters and amides were formed from aryl halides and alcohols and amines under mild conditions in moderate to good yields.

Idiopathic hypereosinophilic syndrome with hepatic sinusoidal obstruction syndrome: A case report and literature review.

BACKGROUND: Hypereosinophilic syndrome (HES) is classified as primary, secondary or idiopathic. Idiopathic HES (IHES) has a variable clinical presentation and may involve multiple organs causing severe damage. Hepatic sinusoidal obstruction syndrome (HSOS) is characterized by damage to the endothelial cells of the hepatic sinusoids of the hepatic venules, with occlusion of the hepatic venules, and hepatocyte necrosis. We report a case of IHES with HSOS of uncertain etiology. CASE SUMMARY: A 70-year-old male patient was admitted to our hospital with pruritus and a rash on the extremities for > 5 mo. He had previously undergone antiallergic treatment and herbal therapy in the local hospital, but the symptoms recurred. Relevant examinations were completed after admission. Bone marrow aspiration biopsy showed a significantly higher percentage of eosinophils (23%) with approximately normal morphology. Ultrasound-guided hepatic aspiration biopsy indicated HSOS. Contrast-enhanced computed tomography (CT) of the upper abdomen showed hepatic venule congestion with hydrothorax and ascites. The patient was initially diagnosed with IHES and hepatic venule occlusion. Prednisone, low molecular weight heparin and ursodeoxycholic acid were given for treatment, followed by discontinuation of low molecular weight heparin due to ecchymosis. Routine blood tests, biochemical tests, and imaging such as enhanced CT of the upper abdomen and pelvis were reviewed regularly. CONCLUSION: Hypereosinophilia may play a facilitating role in the occurrence and development of HSOS.

Design and Implementation of an Integrated Control Scheme for GaN-Based Multiple Power Converters.

In response to the rapid changes in the international energy environment, developing renewable energy (RE)-based distributed generation (DG) and various smart micro-grid systems is crucial for creating a robust electric power grid and new energy industries. In this aspect, there is an urgent need to develop hybrid power systems suitable for coexistent AC and DC power grids, integrated by high-performance wide ban gap (WBG) semiconductor-based power conversion interfaces and advanced operating and control strategies. Due to the intrinsic feature of variation in RE-based power generation, the design and integration of energy storage devices, real-time regulation of power flow, and intelligent energy control schemes are key technologies for further promoting DG systems and micro-grids. This paper investigates an integrated control scheme for multiple GaN-based power converters in a small- to medium-capacity, grid-connected, and RE-based power system. This is the first time that a complete design case demonstrating three GaN-based power converters with different control functions integrated with a single digital signal processor (DSP) chip to achieve a reliable, flexible, cost effective, and multifunctional power interface for renewable power generation systems is presented. The system studied includes a photovoltaic (PV) generation unit, a battery energy storage unit, a grid-connected single-phase inverter, and a power grid. Based on system operation condition and the state of charge (SOC) of the energy storage unit, two typical operating modes and advanced power control functions are developed with a fully digital and coordinated control scheme. Hardware of the GaN-based power converters and digital controllers are designed and implemented. The feasibility and effectiveness of the designed controllers and overall performance of the proposed control scheme are verified with results from simulation and experimental tests on a 1-kVA small-scale hardware system.

Efficacy and safety of subcutaneous semaglutide in adults with overweight or obese: a subgroup meta-analysis of randomized controlled trials.

Introduction: Semaglutide shows significant performance on weight reduction in several clinical trials. However, it is not clear what kind of administration frequency or dosage will achieve better effects. This study aims to explore the different therapeutic effect of semaglutide on weight control under the diverse administration circumstances. Methods: The PubMed, Embase, Web of Science, Cochrane Library, and the Clinical Trials.gov were searched from inception until 6 June, 2022 to include randomized controlled trials evaluating the Efficacy and safety of subcutaneous semaglutide in overweight or obese adults. Random effects or fixed effects model was conducted based on the heterogeneity among trials. Subgroup analysis was performed to identify the detailed effects under different intervention situations. Results and discussion: Our study included 13 RCTs involving 5,838 participants with 3,794 ones in semaglutide group and 2,044 in placebo group. Semaglutide was associated with a significant reduction on weight loss related outcomes, including the absolute value of weight loss (WMD -8·97, 95% CI -10·73 to -7·21), percentage of weight loss (WMD -10·00, 95% CI -11·99 to -8·00), body mass index (WMD-3·19, 95% CI -4·02 to -2·37) and waist circumference (WMD -7·21,95% CI -8·87 to -5·56). Subgroup analyses illustrated participants with high weekly dosage, long-term treatment duration and severe baseline BMI (Class II obesity) had a more remarkably decreasing on the main outcomes of weight loss (P for interaction<0·05). Total adverse reactions occurred more frequently in the daily administration group than that in the weekly group (P for interaction =0·01). During the treatment, the incidence rate of hypoglycemia was higher in the group without lifestyle intervention compared with that with lifestyle intervention (P for interaction =0·04). Interpretation Subcutaneous semaglutide had significant benefits on weight loss with reasonable safety in overweight or obese adults. Moreover, additional benefits on cardiometabolic profiles were also seen. We recommended semaglutide treatment to be coupled with lifestyle interventions, and target dose of 2·0 mg or more subcutaneously once weekly. Clinicians can choose suitable treatment schemes based on diverse individual situations. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=337099, identifier PROSPERO (CRD42022337099).

Preclinical study of LMP1-RNAi-based anti-tumor therapy in EBV-positive nasopharyngeal carcinoma.

RNA interference (RNAi) treatment has been proven to be an important therapeutic approach in cancer based on downregulation of target-oncogenes, but its clinical efficacy still needs further investigation. LMP1 is usually presented by Epstein-Barr virus (EBV)-positive tumor cells like EBV-associated nasopharyngeal carcinoma (NPC) and acts as an oncogene in tumorigenesis. However, the mechanism of LMP1 as a proto-oncogene in nasopharyngeal carcinoma is still unclear. Two sequence-specific shRNAs 1 and 2 were designed to target the different nucleotide loci of EBV latent antigen LMP1 gene and a series of in vivo and in vitro experiments were performed to investigate the therapeutic effect of sequence-specific shRNAs targeting LMP1 and its related molecular mechanisms in EBV-positive NPC. LMP1-shRNA2 generated a truncated LMP1 mRNA and protein, whereas LMP1-shRNA1 completely blocked LMP1 mRNA and protein expression. Both LMP1-shRNAs inhibited the proliferation and migration of NPC cells overexpressing LMP1 (NPC-LMP1) as well as the NPC-associated myeloid-derived suppressor cell (MDSC) expansion in vitro. However, LMP1-shRNA2 maintained the immunogenicity of NPC-LMP1 cells, which provoked MHC-class I-dependent T cell recognition. LMP1-shRNAs inhibited tumor growth in nude mice but did not reach statistical significance compared to control groups, while the LDH nanoparticle loaded LMP1-shRNAs and the antigen-specific T cells induced by NPC-LMP1 cells treated with LMP1-shRNA2 significantly reduced tumor growth in vivo. LMP1-RNAi-based anti-tumor therapy could be a new hope for the clinical efficacy of RNAi treatment of tumors like NPC.

Structure Property Relationship of Micellar Waterborne Poly(Urethane-Urea): Tunable Mechanical Properties and Controlled Release Profiles with Amphiphilic Triblock Copolymers.

Waterborne polyurethane (WPU) has attracted significant interest as a promising alternative to solvent-based polyurethane (SPU) due to its positive impact on safety and sustainability. However, significant limitations of WPU, such as its weaker mechanical strength, limit its ability to replace SPU. Triblock amphiphilic diols are promising materials to enhance the performance of WPU due to their well-defined hydrophobic-hydrophilic structures. Yet, our understanding of the relationship between the hydrophobic-hydrophilic arrangements of triblock amphiphilic diols and the physical properties of WPU remains limited. In this study, we show that by controlling the micellar structure of WPU in aqueous solution via the introduction of triblock amphiphilic diols, the postcuring efficiency and the resulting mechanical strength of WPU can be significantly enhanced. Small-angle neutron scattering confirmed the microstructure and spatial distribution of hydrophilic and hydrophobic segments in the engineered WPU micelles. In addition, we show that the control of the WPU micellar structure through triblock amphiphilic diols renders WPU attractive in the applications of controlled release, such as drug delivery. Here, curcumin was used as a model hydrophobic drug, and the drug release behavior from WPU-micellar-based drug delivery systems was characterized. It was found that curcumin-loaded WPU drug delivery systems were highly biocompatible and exhibited antibacterial properties in vitro. Furthermore, the sustained release profile of the drug was found to be dependent on the structure of the triblock amphiphilic diols, suggesting the possibility of controlling the drug release profile via the selection of triblock amphiphilic diols. This work shows that by shedding light on the structure-property relationship of triblock amphiphilic diol-containing WPU micelles, we may enhance the applicability of WPU systems and move closer to realizing their promising potential in real-life applications.