CRISPR Screen Identifies the RNA-Binding Protein Eef1a1 as a Key Regulator of Myogenesis.

Skeletal muscle myogenesis hinges on gene regulation, meticulously orchestrated by molecular mechanisms. While the roles of transcription factors and non-coding RNAs in myogenesis are widely known, the contribution of RNA-binding proteins (RBPs) has remained unclear until now. Therefore, to investigate the functions of post-transcriptional regulators in myogenesis and uncover new functional RBPs regulating myogenesis, we employed CRISPR high-throughput RBP-KO (RBP-wide knockout) library screening. Through this approach, we successfully identified Eef1a1 as a novel regulatory factor in myogenesis. Using CRISPR knockout (CRISPRko) and CRISPR interference (CRISPRi) technologies, we successfully established cellular models for both CRISPRko and CRISPRi. Our findings demonstrated that Eef1a1 plays a crucial role in promoting proliferation in C2C12 myoblasts. Through siRNA inhibition and overexpression methods, we further elucidated the involvement of Eef1a1 in promoting proliferation and suppressing differentiation processes. RIP (RNA immunoprecipitation), miRNA pull-down, and Dual-luciferase reporter assays confirmed that miR-133a-3p targets Eef1a1. Co-transfection experiments indicated that miR-133a-3p can rescue the effect of Eef1a1 on C2C12 myoblasts. In summary, our study utilized CRISPR library high-throughput screening to unveil a novel RBP, Eef1a1, involved in regulating myogenesis. Eef1a1 promotes the proliferation of myoblasts while inhibiting the differentiation process. Additionally, it acts as an antagonist to miR-133a-3p, thus modulating the process of myogenesis.

AKIMLpred: An interpretable machine learning model for predicting acute kidney injury within seven days in critically ill patients based on a prospective cohort study.

BACKGROUND: Early recognition and timely intervention for AKI in critically ill patients were crucial to reduce morbidity and mortality. This study aimed to use biomarkers to construct a optimal machine learning model for early prediction of AKI in critically ill patients within seven days. METHODS: The prospective cohort study enrolled 929 patients altogether who were admitted in ICU including 680 patients in training set (Jiefang Campus) and 249 patients in external testing set (Binjiang Campus). After performing strict inclusion and exclusion criteria, 421 patients were selected in training set for constructing predictive model and 167 patients were selected in external testing for evaluating the predictive performance of resulting model. Urine and blood samples were collected for kidney injury associated biomarkers detection. Baseline clinical information and laboratory data of the study participants were collected. We determined the average prediction efficiency of six machine learning models through 10-fold cross validation. RESULTS: In total, 78 variables were collected when admission in ICU and 43 variables were statistically significant between AKI and non-AKI cohort. Then, 35 variables were selected as independent features for AKI by univariate logistic regression. Spearman correlation analysis was used to remove two highly correlated variables. Three ranking methods were used to explore the influence of 33 variables for further determining the best combination of variables. The gini importance ranking method was found to be applicable for variables filtering. The predictive performance of AKIMLpred which constructed by the XGBoost algorithm was the best among six machine learning models. When the AKIMLpred included the nine features (NGAL, IGFBP7, sCysC, CAF22, KIM-1, NT-proBNP, IL-6, IL-18 and L-FABP) with the highest influence ranking, its model had the best prediction performance, with an AUC of 0.881 and an accuracy of 0.815 in training set, similarly, with an AUC of 0.889 and an accuracy of 0.846 in validation set. Moreover, the performace was slightly outperformed in testing set with an AUC of 0.902 and an accuracy of 0.846. The SHAP algorithm was used to interpret the prediction results of AKIMLpred. The web-calculator of AKIMLpred was shown for predicting AKI with more convenient(https://www.xsmartanalysis.com/model/list/predict/model/html?mid=8065&symbol=11gk693982SU6AE1ms21). AKIMLpred was better than the optimal model built with only routine tests for predicting AKI in critically ill patients within 7 days. CONCLUSION: The model AKIMLpred constructed by the XGBoost algorithm with selecting the nine most influential biomarkers in the gini importance ranking method had the best performance in predicting AKI in critically ill patients within 7 days. This data-driven predictive model will help clinicians to make quick and accurate diagnosis.

HTRA1 interacts with SLC7A11 to modulate colorectal cancer chemosensitivity by inhibiting ferroptosis.

Chemotherapy is an important therapuetic strategy for colorectal cancer (CRC), but chemoresistance severely affects its efficacy, and the underlying mechanism has not been fully elucidated. Increasing evidence suggests that lipid peroxidation imbalance-mediated ferroptosis is closely associated with chemoresistance. Hence, targeting ferroptosis pathways or modulating the tolerance to oxidative stress might be an effective strategy to reverse tumor chemoresistance. HtrA serine protease 1 (HTRA1) was screened out as a CRC progression- and chemoresistance-related gene. It is highly expressed in CRC cells and negatively correlated with the prognosis of CRC patients. Gain- and loss-of-function analyses demonstrated a stimulatory role of HTRA1 on the proliferation of CRC cells. The enrichment analysis of HTRA1-interacting proteins indicated the involvement of ferroptosis in the HTRA1-mediated chemoresistance. Moreover, electron microscope analysis, as well as the ROS and MDA levels in CRC cells also confirmed the effect of HTRA1 on ferroptosis. We also verified that HTRA1 could interact with SLC7A11 through its Kazal structural domain and up-regulate the expression of SLC7A11, which in turn inhibited the ferroptosis and leaded to the chemoresistance of CRC cells to 5-FU/L-OHP. Hence, we propose that HTRA1 may be a potential therapeutic target and a prognostic indicator in CRC.

Bone mineral density as an individual prognostic biomarker in NSCLC patients treated with immune checkpoint inhibitors.

Background: Immune checkpoint inhibitors (ICIs) have left a deep impression in the treatment of non-small cell lung cancer (NSCLC), however, not all patients benefit from it. The purpose of this study was to investigate the prognostic value of baseline bone mineral density (BMD) derived from chest computed tomography (CT) scans in NSCLC patients treated with ICIs. Methods: This study included patients with advanced NSCLC who underwent ICI treatment at the Wuhan Union Hospital from March 2020 to October 2022. Baseline BMD was evaluated at non-contrast chest CT at the level of first lumbar vertebra. Patients were divided into BMD-lower group and BMD-higher group according to the optimal cutoff value calculated by X-tile software. Baseline characteristics of the two groups were compared and variables between the two groups were balanced by propensity score matching (PSM) analysis. We calculated the objective response rate (ORR) and disease control rate (DCR) of the two groups and analyzed overall survival (OS) and progression-free survival (PFS) using BMD and other clinical indexes through Cox regression models and Kaplan-Meier survival curves. Results: A total of 479 patients were included in this study, and all patients were divided into BMD-lower group (n=270) and BMD-higher group (n=209). After PSM analysis, each group consisted of 150 patients. ORR (43.3% vs. 43.5% before PSM, P = 0.964; 44.7% vs. 44.7% after PSM, P = 1.000) and DCR (91.1% vs. 94.3% before PSM, P = 0.195; 93.3% vs. 96.7% after PSM, P =0.190) were similar in two groups. There was no statistically significant relationship between BMD degree and PFS before (16.0 months vs. 18.0 months, P = 0.067) and after PSM analysis (17.0 months vs. 19.0 months, P = 0.095). However, lower BMD was associated with shorter OS both before (20.5 months vs. 23.0 months, P< 0.001) and after PSM analysis (20.0 months vs. 23.0 months, P = 0.008). Conclusion: Lower baseline BMD is associated with worse clinical outcomes in NSCLC patients treated with ICIs. As a reliable and easily obtained individual prognostic biomarker, BMD can become a routine detection indicator before immunotherapy.

Augmented ERO1α upon mTORC1 activation induces ferroptosis resistance and tumor progression via upregulation of SLC7A11.

BACKGROUND: The dysregulated mechanistic target of rapamycin complex 1 (mTORC1) signaling plays a critical role in ferroptosis resistance and tumorigenesis. However, the precise underlying mechanisms still need to be fully understood. METHODS: Endoplasmic reticulum oxidoreductase 1 alpha (ERO1α) expression in mTORC1-activated mouse embryonic fibroblasts, cancer cells, and laryngeal squamous cell carcinoma (LSCC) clinical samples was examined by quantitative real-time PCR (qRT-PCR), western blotting, immunofluorescence (IF), and immunohistochemistry. Extensive in vitro and in vivo experiments were carried out to determine the role of ERO1α and its downstream target, member 11 of the solute carrier family 7 (SLC7A11), in mTORC1-mediated cell proliferation, angiogenesis, ferroptosis resistance, and tumor growth. The regulatory mechanism of ERO1α on SLC7A11 was investigated via RNA-sequencing, a cytokine array, an enzyme-linked immunosorbent assay, qRT-PCR, western blotting, IF, a luciferase reporter assay, and a chromatin immunoprecipitation assay. The combined therapeutic effect of ERO1α inhibition and the ferroptosis inducer imidazole ketone erastin (IKE) on mTORC1-activated cells was evaluated using cell line-derived xenografts, LSCC organoids, and LSCC patient-derived xenograft models. RESULTS: ERO1α is a functional downstream target of mTORC1. Elevated ERO1α induced ferroptosis resistance and exerted pro-oncogenic roles in mTORC1-activated cells via upregulation of SLC7A11. Mechanically, ERO1α stimulated the transcription of SLC7A11 by activating the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) pathway. Moreover, ERO1α inhibition combined with treatment using the ferroptosis inducer IKE exhibited synergistic antitumor effects on mTORC1-activated tumors. CONCLUSIONS: The ERO1α/IL-6/STAT3/SLC7A11 pathway is crucial for mTORC1-mediated ferroptosis resistance and tumor growth, and combining ERO1α inhibition with ferroptosis inducers is a novel and effective treatment for mTORC1-related tumors.

Design and study of mine silo drainage method based on fuzzy control and Avoiding Peak Filling Valley strategy.

Coal is a non-renewable fossil energy source on which humanity relies heavily, and producing one ton of raw coal requires the discharge of 2-7 tons of mine water from the ground. The huge drainage task increases the cost of coal mining in coal mines significantly, so saving the drainage cost while guaranteeing the safe production of coal mines is a problem that needs to be solved urgently. Most of the fuzzy controllers used in the traditional dynamic planning methods applied to mine drainage are two-dimensional fuzzy controllers with limited control effect, so the traditional two-dimensional fuzzy controllers are improved by introducing the rate of change of gushing water to form a three-dimensional fuzzy controller with three-dimensional control of instantaneous section-water level-rate of change of gushing water, and at the same time, the optimized dynamic planning method is designed by combining the Avoiding Peak Filling Valley strategy and the optimal dy-namic planning method is used in conjunction with the un-optimized dynamic planning method. The optimized dynamic planning method is applied to the same coal mine water silo gushing water experiments; experimental comparison found that the pumping station system before the optimi-zation of the electricity consumed is 52,586 yuan/day, while after the optimization of the electricity consumed is reduced to 41,692 yuan/day, the cost per day consumed compared with the previous reduction of 20.69%, a year can be saved 3,969,730 yuan. Therefore, the mine water bin drainage method based on fuzzy control and Avoiding Peak Filling Valley strategy proposed in this paper can be used as an improvement method of the existing mine drainage method, which can further ex-pand the economic benefits of coal mines and realize safe production while realizing cost savings.

Melatonin inhibits tongue squamous cell carcinoma: Interplay of ER stress-induced apoptosis and autophagy with cell migration.

Tongue squamous cell carcinoma (TSCC) occupies a high proportion of oral squamous cell carcinoma. TSCC features high lymph node metastasis rates and chemotherapy resistance with a poor prognosis. Therefore, an effective therapy strategy is needed to improve patient prognosis. Melatonin (MT) is a natural indole compound shown to have anti-tumor effects in several cancers. This study focused on the role and mechanism of MT in TSCC cells. The results of the study suggest that MT could inhibit cell proliferation in CRL-1623 cells. Western blot analysis showed the down-regulate of cyclin B1 and the up-regulate P21 protein by MT. MT was also shown to down-regulate the expression of Zeb1, Wnt5A/B, and ß-catenin protein and up-regulate E-cadherin to inhibit the migration of CRL-1623 cells. MT also promoted the expression of ATF4, ATF6, Bip, BAP31 and CHOP in CRL-1623 cells leading to endoplasmic reticulum stress, and induced autophagy and apoptosis in CRL-1623 cells. Western blots showed that MT could promote the expression of Bax, LC3, and Beclin1 proteins and inhibit the expression of p62. We screened differentially expressed long non-coding RNAs (lncRNAs) in MT-treated cells and found that the expression of MALAT1 and H19 decreased. Moreover, MT inhibited tumor growth in nude mice inoculated with CRL-1623 cells. These results suggest that MT could induce autophagy, promote apoptosis, and provide a potential natural compound for the treatment of TSCC.

Non-small cell lung cancer and immune checkpoint inhibitor therapy: does non-alcoholic fatty liver disease have an effect?

BACKGROUND: Immunotherapy based on the application of immune checkpoint inhibitors (ICIs) is one of the standard treatments for advanced non-small cell lung cancer (NSCLC). Non-alcoholic fatty liver Disease (NAFLD) has demonstrated predictive value for response to immunotherapy in non-lung cancer types. Our study investigated the effect of NAFLD on the efficacy of real-life use of ICIs for patients with stage III / IV NSCLC. METHODS: The clinical and imaging data of patients with stage III / IV NSCLC who were first admitted to Union Hospital, Tongji Medical College, Huazhong University of Science and Technology from March 2020 to July 2022 were retrospectively collected to ensure that they underwent at least one CT scan before treatment. A total of 479 patients were divided into the NAFLD group (Liver/Spleen density ratio ≤ 1) and the non-NAFLD group (Liver/Spleen density ratio > 1) by measuring the baseline liver and spleen CT value. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) of the patients were obtained. RESULTS: A total of 118 patients with NAFLD and 361 patients without NAFLD were included in the study. Patients with NAFLD tended to have higher BMI and higher total bilirubin compared to patients without NAFLD. The median duration of follow-up in the study was 22 m (IQR, 17-29 m). Both of 2 groups had a higher DCR (94% vs. 92%, p = 0.199) and ORR (38.1% vs. 44.9%, p = 0.452) respectively. There was no difference in efficacy between the two groups. In univariate analysis, NAFLD had no significant effect on PFS (p = 0.785) and OS (p = 0.851). Surprisingly, the presence of hypertension was observed to be associated with a higher OS (HR 1.471 95%CI 1.018-2.127, p = 0.040). Besides, based on multivariate analysis, lactic dehydrogenase was associated with PFS (HR 1.001 95%CI 1.000,1.002, p = 0.037) and OS (HR 1.002, 95%CI 1.001-1.003, p < 0.001). CONCLUSIONS: Among patients with NSCLC, NAFLD did not result in changes in survival or disease progression after immune checkpoint inhibitor therapy.

Hippocampal Lactate-Infusion Enhances Spatial Memory Correlated with Monocarboxylate Transporter 2 and Lactylation.

Lactate has emerged as a key player in regulating neural functions and cognitive processes. Beyond its function as an energy substrate and signal molecule, recent research has revealed lactate to serve as an epigenetic regulator in the brain. However, the molecular mechanisms by which lactate regulates spatial memory and its role in the prevention of cognitive disorders remain unclear. Herein, we injected L-lactate (10 µmol/kg/d for 6 d) into the mouse's hippocampus, followed by the Morris water maze (MWM) test and molecular analyses. Improved spatial memory performances were observed in mice injected with lactate. Besides, lactate upregulated the expression of synaptic proteins post-synaptic density 95 (PSD95), synaptophysin (SYP), and growth associated protein 43 (GAP43) in hippocampal tissues and HT22 cells, suggesting a potential role in synaptic transmission and memory formation. The facilitative role of monocarboxylate transporter 2 (MCT2), a neuron-specific lactate transporter, in this process was confirmed, as MCT2 antagonists attenuated the lactate-induced upregulation of synaptic proteins. Moreover, lactate induced protein lactylation, a post-translational modification, which could be suppressed by MCT2 inhibition. RNA sequencing of lactated-injected hippocampal tissues revealed a comprehensive gene expression profile influenced by lactate, with significant changes in genes associated with transcriptional progress. These data demonstrate that hippocampal lactate injection enhances spatial memory in mice, potentially through the upregulation of synaptic proteins and induction of protein lactylation, with MCT2 playing a crucial role in these processes. Our findings shed light on the multi-faceted role of lactate in neural function and memory regulation, opening new avenues for therapeutic interventions targeting cognitive disorders.

CircPHGDH downregulation decreases papillary thyroid cancer progression through miR-122-5p/PKM2 axis.

BACKGROUND: Although papillary thyroid carcinoma (PTC) has a favorable prognosis, it could affect patient life quality and become a serious threat because of invasion and metastasis. Many investigations have suggested that circular RNAs (circRNAs) are involved in different cancer regulations. Nevertheless, circRNAs role in invasive PTC remains unclear. METHODS: In the present investigation, next-generation sequencing was applied to explore abnormal circRNA expression. The expression of circRNA phosphoglycerate dehydrogenase (circPHGDH) in PTC cell lines and tissues were examined. Then, we investigated regulatory mechanism and circPHGDH downstream targets using bioinformatics analysis and luciferase reporting analysis. Then transwell migration, Cell Counting Kit-8 (CCK8) and 5-ethynyl-2'-deoxyuridine (EdU) assays were used for cells migration and proliferation analysis. In vivo metastasis and tumorigenesis assays were also employed to evaluate the circPHGDH role in PTC. RESULTS: The data showcased that circPHGDH expression increased in both PTC cell lines and tissues, which suggested that circPHGDH functions in PTC progression. circPHGDH downregulation suppressed PTC invasion and proliferation in both in vivo and in vitro experiments. Bioinformatics and luciferase reporter results confirmed that both microRNA (miR)-122-5p and pyruvate kinase M2 subtype (PKM2) were downstream targets of circPHGDH. PKM2 overexpression or miR-122-5p suppression reversed PTC cell invasion and proliferation post silencing circPHGDH by restoring aerobic glycolysis. CONCLUSION: Taken together, our research found that circPHGDH downregulation reduced PTC progression via miR-122-5p/PKM2 axis regulation mediated by aerobic glycolysis.

Perceptions and needs for a community nursing virtual simulation system for Chinese nursing students during the COVID-19 pandemic: A qualitative study.

Background: Virtual simulation systems are being increasingly used in the field of nursing education. However, these systems are mostly designed based on the perspective of developers, and the needs of the end users are often neglected. The purpose of this study was to explore the perceptions and needs of Chinese undergraduate nursing students for the development of a community nursing virtual simulation system. Methods: This was a descriptive qualitative study enrolling 12 undergraduate nursing students at a University in China. Data were collected through semi-structured interviews. The content analysis method was used for data analysis. Result: Three themes and 15 sub-themes were extracted from this study: (1) Positive perceptions regarding virtual systems: a) Provides space for trials and errors, b) Not limited by time and space, c) Provides auxiliary tools; (2) Design and use requirements: a) Performance needs, b) Contents design needs, c) Appearance design needs, d) Support Needs; (3) Competency enhancement needs: a) Community nursing practice ability, b) Critical thinking ability, c) Independent thinking ability, d) Ability to deal with emergencies, e)Teamwork skills, f) Self-efficacy, g) Resilience, h)Interpersonal communication skills. Conclusion: Designers and engineers should consider students' needs, aim to improve students' abilities, improve the diversity, the scientific and rigor of content, and enhance user immersion and interest. The system should be programmed to provide real-time feedback, timely technical and professional support, in order to optimize use experience of nursing students.

On-Chip Photonic Localization in Aharonov-Bohm Cages Composed of Microring Lattices.

Flatband localization endowed with robustness holds great promise for disorder-immune light transport, particularly in the advancement of optical communication and signal processing. However, effectively harnessing these principles for practical applications in nanophotonic devices remains a significant challenge. Herein, we delve into the investigation of on-chip photonic localization in AB cages composed of indirectly coupled microring lattices. By strategically vertically shifting the auxiliary rings, we successfully introduce a magnetic flux of π into the microring lattice, thereby facilitating versatile control over the localization and delocalization of light. Remarkably, the compact edge modes of this structure exhibit intriguing topological properties, rendering them strongly robust against disorders, regardless of the size of the system. Our findings open up new avenues for exploring the interaction between flatbands and topological photonics on integrated platforms.

Inhibition of YAP/TAZ pathway contributes to the cytotoxicity of silibinin in MCF-7 and MDA-MB-231 human breast cancer cells.

Breast cancer is one of the most common cancers threatening women's health. Our previous study found that silibinin induced the death of MCF-7 and MDA-MB-231 human breast cancer cells. We noticed that silibinin-induced cell damage was accompanied by morphological changes, including the increased cell aspect ratio (cell length/width) and decreased cell area. Besides, the cytoskeleton is also destroyed in cells treated with silibinin. YAP/TAZ, a mechanical signal sensor interacted with extracellular pressure, cell adhesion area and cytoskeleton, is also closely associated with cell survival, proliferation and migration. Thus, the involvement of YAP/TAZ in the cytotoxicity of silibinin in breast cancer cells has attracted our interests. Excitingly, we find that silibinin inhibits the nuclear translocation of YAP/TAZ in MCF-7 and MDA-MB-231 cells, and reduces the mRNA expressions of YAP/TAZ target genes, ACVR1, MnSOD and ANKRD. More importantly, expression of YAP1 gene is negatively correlated with the survival of the patients with breast cancers. Molecular docking analysis reveals high probabilities for binding of silibinin to the proteins in the YAP pathways. DARTS and CETSA results confirm the binding abilities of silibinin to YAP and LATS. Inhibiting YAP pathway either by addition of verteporfin, an inhibitor of YAP/TAZ-TEAD, or by transfection of si-RNAs targeting YAP or TAZ further enhances silibinin-induced cell damage. While enhancing YAP activity by silencing LATS1/2 or overexpressing YAPS127/397A, an active form of YAP, attenuates silibinin-induced cell damage. These findings demonstrate that inhibition of the YAP/TAZ pathway contributes to cytotoxicity of silibinin in breast cancers, shedding lights on YAP/TAZ-targeted cancer therapies.

Single-cell transcriptomics dissecting the development and evolution of nervous system in insects.

Insects can display a vast repertoire of complex and adaptive behaviors crucial for survival and reproduction. Yet, how the neural circuits underlying insect behaviors are assembled throughout development and remodeled during evolution remains largely obscure. The advent of single-cell transcriptomics has opened new paths to illuminate these historically intractable questions. Insect behavior is governed by its brain, whose functional complexity is realized through operations across multiple levels, from the molecular and cellular to the circuit and organ. Single-cell transcriptomics enables dissecting brain functions across all these levels and allows tracking regulatory dynamics throughout development and under perturbation. In this review, we mainly focus on the achievements of single-cell transcriptomics in dissecting the molecular and cellular architectures of nervous systems in representative insects, then discuss its applications in tracking the developmental trajectory and functional evolution of insect brains.

Nitric oxide nano-reactor DNMF/PLGA enables tumor vascular microenvironment and chemo-hyperthermia synergetic therapy.

BACKGROUND: Breast cancer ranks first among malignant tumors, of which triple-negative breast cancer (TNBC) is characterized by its highly invasive behavior and the worst prognosis. Timely diagnosis and precise treatment of TNBC are substantially challenging. Abnormal tumor vessels play a crucial role in TNBC progression and treatment. Nitric oxide (NO) regulates angiogenesis and maintains vascular homeostasis, while effective NO delivery can normalize the tumor vasculature. Accordingly, we have proposed here a tumor vascular microenvironment remodeling strategy based on NO-induced vessel normalization and extracellular matrix collagen degradation with multimodality imaging-guided nanoparticles against TNBC called DNMF/PLGA. RESULTS: Nanoparticles were synthesized using a chemotherapeutic agent doxorubicin (DOX), a NO donor L-arginine (L-Arg), ultrasmall spinel ferrites (MnFe2O4), and a poly (lactic-co-glycolic acid) (PLGA) shell. Nanoparticle distribution in the tumor was accurately monitored in real-time through highly enhanced magnetic resonance imaging and photoacoustic imaging. Near-infrared irradiation of tumor cells revealed that MnFe2O4 catalyzes the production of a large amount of reactive oxygen species (ROS) from H2O2, resulting in a cascade catalysis of L-Arg to trigger NO production in the presence of ROS. In addition, DOX activates niacinamide adenine dinucleotide phosphate oxidase to generate and supply H2O2. The generated NO improves the vascular endothelial cell integrity and pericellular contractility to promote vessel normalization and induces the activation of endogenous matrix metalloproteinases (mainly MMP-1 and MMP-2) so as to promote extravascular collagen degradation, thereby providing an auxiliary mechanism for efficient nanoparticle delivery and DOX penetration. Moreover, the chemotherapeutic effect of DOX and the photothermal effect of MnFe2O4 served as a chemo-hyperthermia synergistic therapy against TNBC. CONCLUSION: The two therapeutic mechanisms, along with an auxiliary mechanism, were perfectly combined to enhance the therapeutic effects. Briefly, multimodality image-guided nanoparticles provide a reliable strategy for the potential application in the fight against TNBC.

Selecting mode by the complex Berry phase in non-Hermitian waveguide lattices.

Bloch oscillations (BOs) in a parity-time (PT)-symmetric Su-Schrieffer-Heeger (SSH) waveguide array are theoretically investigated. We show that the BOs are amplified or damped even for the systems to exhibit entirely real energy bands. The amplified and damped BOs stem from the complex Berry phase and closely relate to the topological properties of the lattice. For the topological nontrivial lattice, the amplification and attenuation of BOs are much more prominent than the trivial case and the output Bloch mode can be selected. Furthermore, we propose an experimental scheme and perform a numerical simulation based on a bent waveguide array. Our work uncovers the impact of the topological properties on the dynamics of the bulk Bloch modes and unveils a horizon in the study of non-Hermitian physics. The mode selection induced by the complex Berry phase may also find application in integrated photonic devices such as the mode filter.

RNA modifications in cellular metabolism: implications for metabolism-targeted therapy and immunotherapy.

Cellular metabolism is an intricate network satisfying bioenergetic and biosynthesis requirements of cells. Relevant studies have been constantly making inroads in our understanding of pathophysiology, and inspiring development of therapeutics. As a crucial component of epigenetics at post-transcription level, RNA modification significantly determines RNA fates, further affecting various biological processes and cellular phenotypes. To be noted, immunometabolism defines the metabolic alterations occur on immune cells in different stages and immunological contexts. In this review, we characterize the distribution features, modifying mechanisms and biological functions of 8 RNA modifications, including N6-methyladenosine (m6A), N6,2'-O-dimethyladenosine (m6Am), N1-methyladenosine (m1A), 5-methylcytosine (m5C), N4-acetylcytosine (ac4C), N7-methylguanosine (m7G), Pseudouridine (Ψ), adenosine-to-inosine (A-to-I) editing, which are relatively the most studied types. Then regulatory roles of these RNA modification on metabolism in diverse health and disease contexts are comprehensively described, categorized as glucose, lipid, amino acid, and mitochondrial metabolism. And we highlight the regulation of RNA modifications on immunometabolism, further influencing immune responses. Above all, we provide a thorough discussion about clinical implications of RNA modification in metabolism-targeted therapy and immunotherapy, progression of RNA modification-targeted agents, and its potential in RNA-targeted therapeutics. Eventually, we give legitimate perspectives for future researches in this field from methodological requirements, mechanistic insights, to therapeutic applications.

IL-13 facilitates ferroptotic death in asthmatic epithelial cells via SOCS1-mediated ubiquitinated degradation of SLC7A11.

Th2-high asthma is characterized by elevated levels of type 2 cytokines, such as interleukin 13 (IL-13), and its prevalence has been increasing worldwide. Ferroptosis, a recently discovered type of programmed cell death, is involved in the pathological process of Th2-high asthma; however, the underlying mechanisms remain incompletely understood. In this study, we demonstrated that the serum level of malondialdehyde (MDA), an index of lipid peroxidation, positively correlated with IL-13 level and negatively correlated with the predicted forced expiratory volume in 1 s (FEV1%) in asthmatics. Furthermore, we showed that IL-13 facilitates ferroptosis by upregulating of suppressor of cytokine signaling 1 (SOCS1) through analyzing immortalized airway epithelial cells, human airway organoids, and the ovalbumin (OVA)-challenged asthma model. We identified that signal transducer and activator of transcription 6 (STAT6) promotes the transcription of SOCS1 upon IL-13 stimulation. Moreover, SOCS1, an E3 ubiquitin ligase, was found to bind to solute carrier family 7 member 11 (SLC7A11) and catalyze its ubiquitinated degradation, thereby promoting ferroptosis in airway epithelial cells. Last, we found that inhibiting SOCS1 can decrease ferroptosis in airway epithelial cells and alleviate airway hyperresponsiveness (AHR) in OVA-challenged wide-type mice, while SOCS1 overexpression exacerbated the above in OVA-challenged IL-13-knockout mice. Our findings reveal that the IL-13/STAT6/SOCS1/SLC7A11 pathway is a novel molecular mechanism for ferroptosis in Th2-high asthma, confirming that targeting ferroptosis in airway epithelial cells is a potential therapeutic strategy for Th2-high asthma.

Gelatin but not type I collagen promotes bacteria phagocytosis in PMA-treated U937 human lymphoma cells.

PURPOSE: Besides comprising scaffolding, extracellular matrix components modulate many biological processes including inflammation and cell differentiation. We previously found precoating cell plates with extracellular matrix collagen I, or its denatured product gelatin, causes aggregation of macrophage-like human lymphoma U937 cells, which are induced to differentiation by phorbol myristate treatment. In the present study, we investigated the influence of gelatin or collagen I precoating on the bacteria phagocytosis in PMA-stimulated U937 cells. MATERIALS AND METHODS: Colony forming units of phagocytosed bacteria, Giemsa-staining of cells with phagocytosed bacteria, confocal microscopic and flow cytometric analysis of cells with phagocytosed FITC-labeled bacteria and non-bioactive latex beats were conducted. RESULTS: Gelatin precoating enhances the phagocytosis of both Gram-negative and positive bacteria, as shown by the increased colony forming units of bacteria phagocytosed by cells, and increased intracellular bacteria observed after Giemsa-staining. But collagen I has no marked influence. Confocal microscopy reveals that both live and dead FITC-bacteria were phagocytosed more in the cells with gelatin-coating but not collagen-coating. Of note, both gelatin and collagen I coating had no influence on the phagocytosis of non-bioactive latex beads. Since gelatin-coating increases autophagy but collagen I has no such impact, we are curious about the role of autophagy. Inhibiting autophagy reduced the phagocytosis of bacteria, in cells with gelatin-coating, while stimulating autophagy enhanced phagocytosis. CONCLUSION: This study finds the bacteria-phagocytosis stimulatory effect of gelatin in PMA-treated U937 cells and reveals the positive regulatory role of autophagy, predicting the potential use of gelatin products in anti-bacterial therapy.

The Saturation- and Dose-Dependent Effects of a Teen Sexual Harassment Prevention Program: Findings from a Randomized Controlled Trial.

Using a randomized controlled trial, we investigated changes in both sexual harassment (SH) perpetration and victimization of 2104 middle school students in New York City who received divergent saturation and dosage levels of Shifting Boundaries, an SH prevention program, which was represented by the length of the program. We assessed the saturation effect of the program by comparing the outcomes across respondents from 26 schools in which there were varying percentages of students enrolled in the program. The data suggested that, overall, the program was effective in reducing sexual harassment victimization but achieved a null effect against respondents' SH perpetration and that neither the length nor the school-saturation level of the program exerted a significant effect on SH perpetration. Although the data indicated a significant difference in SH victimization between the treatment and control group, when comparing subgroups who received treatment with divergent saturation and dosage levels, no statistically significant difference was identified. Our results suggested that the program effect was not contingent on the portion of students in a school who enrolled in the program, nor was it contingent on the dosage.