Study on the treatment of dysphagia after stroke with electromyographic biofeedback intensive training.

BACKGROUND: Dysphagia, or swallowing disorder, is a common complication following stroke, significantly impacting patients' quality of life. Electromyographic biofeedback (EMGBF) therapy has emerged as a potential rehabilitation technique to improve swallowing function, but its efficacy in comparison with conventional treatments remains to be further explored. AIM: To investigate the effects of different treatment intensities of EMGBF on swallowing function and motor speed after stroke. METHODS: The participants were divided into three groups, all of which received routine neurological drug therapy and motor function rehabilitation training. On the basis of routine swallowing disorder training, the EMGBF group received additional EMGBF training, while the enhanced EMGBF group received two additional training sessions. Four weeks before and after treatment, the degree of swallowing disorder was evaluated using the degree of swallowing disorder score (VGF) and the Rosenbek penetration-aspiration scale (PAS). RESULTS: Initially, there was no significant difference in VGF and PAS scores among the groups (P > 0.05). After four weeks, all groups showed significant improvement in both VGF scores and PAS scores. Furthermore, the standardized swallowing assessment and videofluoroscopic dysphagia scale scores also improved significantly post-treatment, indicating enhanced swallowing function and motor function of the hyoid-bone laryngeal complex, particularly in the intensive EMGBF group. CONCLUSION: EMGBF training is more effective than traditional swallowing training in improving swallowing function and the movement rate of the hyoid laryngeal complex in patients with post-stroke dysphagia.

[Structure and Function of Fungal Community in Channel Sediments of Different Sections of Jialing River].

This study aimed to explore the effects of different disturbances on the fungal communities in the sediments of the Jialing River in order to provide scientific basis for the protection of the river ecosystem. The fungal community in the sediments of the main stream of the Jialing River was taken as the research object, and high-throughput sequencing and bioinformatics techniques were used to analyze the differences in the composition and function of fungal communities in river sediment of different types of disturbance （project disturbance, tributary disturbance, sand mining disturbance, and reclamation disturbance） and non-disturbance sections. The results showed that： ① The reclamation and project disturbances significantly inhibited the diversity and richness of fungal communities （P<0.05）. The tributary disturbance increased the richness of fungal communities, whereas the impact of sand mining disturbance on sediment fungal communities was not significant. ② The diversity and composition of fungal communities tended to be similar at the different sampling sites in the section with low input of exogenous substances （non-disturbance and sand mining disturbance）, whereas there were obvious differences in the diversity of fungal communities at the different sampling sites of high input of external substances （tributary disturbance, project disturbance, and reclamation disturbance） sections. ③ Ascomycota, Rozellomycota, and Basidiomycota were the main dominant fungal phyla in the sediments of the Jialing River. The relative abundance of Rozellomycota was the highest in the sand mining interference section, and the relative abundance of Basidiomycota was the highest in the tributary interference section. Project disturbance significantly increased the relative abundance of saprotrophs, animal pathogens, plant pathogens, and dung saprotrophs, whereas other disturbances inhibited the relative abundance of fungal parasitic fungi, plant pathogens, and plant saprophytes. In conclusion, human disturbance has caused changes in fungal diversity, community structure, and function in the sediment of the Jialing River, and xenobiotic input was a key factor contributing to this phenomenon. The results can provide a reference for predicting and evaluating the ecological quality of river sediments.

Two new cucurbitane-type triterpenoid saponins from the fruit of Citrullus colocynthis.

Two new cucurbitane-type triterpenoid saponins, 2,20ß,22ß-trihydroxy-16α,23(R)-epoxycucurbita-1,5,24-triene-3,11-dione 2-O-ß-D-glucopyranoside (1), 2,20ß,22α-trihydroxy-16α,23(S)-epoxycucurbita-1,5,11,24-tetraene-3-one 2-O-ß-D-glucopyranoside (2) were isolated from the fruit of Citrullus colocynthis (L.) Schrad. Their structures were elucidated by mass spectrometry, IR, 1D, and 2D NMR spectroscopy, etc. Besides, both of the compounds showed significant hepatoprotective activities at 10 µM against paracetamol-induced HepG2 cell damage.

The effect and mechanism of patchouli alcohol on cognitive dysfunction in AD mice induced by Aß1-42 oligomers through AMPK/mTOR pathway.

Alzheimer's disease (AD) is a neurodegenerative brain disorder that progressively impairs long-term and working memory. The function and mechanism of PA(Patchouli alcohol) in improving AD in the external treatment of encephalopathy remain unclear. This study aimed to investigate the therapeutic effect of PA on AD using an Aß1-42 induced AD mouse model with LPS(Lipopolysaccharide) stimulation of BV2 microglial cells. Additionally, we aimed to explore the potential mechanism of PA in enhancing autophagy and reducing neuroinflammation through the AMPK (AMP-activated protein kinase)/mTOR (Mammaliam target of rapamycin) signaling pathway. The Morris water maze was used to assess cognitive function, and cortical and hippocampal tissues were collected for further analysis of the corresponding signaling pathways and inflammatory changes through biological experiments. Our research findings demonstrate that PA has a significant positive impact on cognitive and memory impairments in mice that have been induced with Aß1-42-induced AD. Additionally, PA was also found to revert the activation of microglia induced by LPS. These effects may be attributed to the reduction of neuroinflammation and enhancement of the AMPK/mTOR autophagy pathway. Therefore, PA may serve as an effective therapeutic option to prevent or delay the progression of AD-associated memory dysfunction.

Synthetic macrolides overcoming MLSBK-resistant pathogens.

Conventional macrolide-lincosamide-streptogramin B-ketolide (MLSBK) antibiotics are unable to counter the growing challenge of antibiotic resistance that is conferred by the constitutive methylation of rRNA base A2058 or its G2058 mutation, while the presence of unmodified A2058 is crucial for high selectivity of traditional MLSBK in targeting pathogens over human cells. The absence of effective modes of action reinforces the prevailing belief that constitutively antibiotic-resistant Staphylococcus aureus remains impervious to existing macrolides including telithromycin. Here, we report the design and synthesis of a novel series of macrolides, featuring the strategic fusion of ketolide and quinolone moieties. Our effort led to the discovery of two potent compounds, MCX-219 and MCX-190, demonstrating enhanced antibacterial efficacy against a broad spectrum of formidable pathogens, including A2058-methylated Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and notably, the clinical Mycoplasma pneumoniae isolates harboring A2058G mutations which are implicated in the recent pneumonia outbreak in China. Mechanistic studies reveal that the modified quinolone moiety of MCX-190 establishes a distinctive secondary binding site within the nascent peptide exit tunnel. Structure-activity relationship analysis underscores the importance of this secondary binding, maintained by a sandwich-like π-π stacking interaction and a water-magnesium bridge, for effective engagement with A2058-methylated ribosomes rather than topoisomerases targeted by quinolone antibiotics. Our findings not only highlight MCX-219 and MCX-190 as promising candidates for next-generation MLSBK antibiotics to combat antibiotic resistance, but also pave the way for the future rational design of the class of MLSBK antibiotics, offering a strategic framework to overcome the challenges posed by escalating antibiotic resistance.

Immunogenicity of 4-dose Essen intramuscular regimen for rabies post-exposure prophylaxis: A multi-center cross-sectional study in China.

BACKGROUND: The 4-dose Essen intramuscular (IM) regimen for rabies post-exposure prophylaxis (PEP) has been recommended by Advisory Committee on Immunization Practices (ACIP) and World Health Organization (WHO), but the large-sample clinical evidence is still limited. METHOD: Rabies virus neutralizing antibodies of 11,752 patients were detected from 409 rabies prevention clinics in 27 provinces in China. Patients with serum collected before or no later than 1 h after injection on the day of the fifth dose (day 28) of 5-dose Essen regimen were included in Group A to observe the immune efficacy of 4-dose Essen IM regimen, and patients with serum collected 14-28 days after injection of the fifth dose were included in Group B to observe the immune efficacy of 5-dose Essen IM regimen. RESULTS: Finally, 2351 cases met the inclusion and exclusion criteria, including 2244 cases in Group A and 107 cases in Group B. The antibody titer of Group A was higher than that of Group B [12.21 (4.15, 32.10) IU/ml vs. 9.41 (3.87, 27.38) IU/ml] (P = 0.002). In Group A, the median antibody titers were 4.01IU/ml, 11.63IU/ml and 29.46IU/ml in patients vaccinated with purified hamster kidney cell vaccine (PHKCV), purified Vero cell vaccine (PVRV), and human diploid cell rabies vaccine (HDCV), respectively, with statistical significance (P < 0.001). CONCLUSIONS: The 4-dose Essen IM regimen could provide satisfactory immune effect, and HDCV induced higher antibody titer than PHKCV or PVRV.

Application of data-driven blended online-offline teaching in medicinal chemistry for pharmacy students: a randomized comparison.

BACKGROUND: The purpose of this study was to evaluate the effectiveness and efficiency of implementing a data-driven blended online-offline (DDBOO) teaching approach in the medicinal chemistry course. METHODS: A total of 118 third-year students majoring in pharmacy were enrolled from September 2021 to January 2022. The participants were randomly assigned to either the DDBOO teaching group or the traditional lecture-based learning (LBL) group for medicinal chemistry. Pre- and post-class quizzes were administered, along with an anonymous questionnaire distributed to both groups to assess students' perceptions and experiences. RESULTS: There was no significant difference in the pre-class quiz scores between the DDBOO and LBL groups (T=-0.637, P = 0.822). However, after class, the mean quiz score of the DDBOO group was significantly higher than that of the LBL group (T = 3.742, P < 0.001). Furthermore, the scores for learning interest, learning motivation, self-learning skill, mastery of basic knowledge, teamwork skills, problem-solving ability, innovation ability, and satisfaction, as measured by the questionnaire, were significantly higher in the DDBOO group than in the traditional group (all P < 0.05). CONCLUSION: The DDBOO teaching method effectively enhances students' academic performance and satisfaction. Further research and promotion of this approach are warranted.

[Non-targeted renal metabolomics reveals multi-target effects of Dahuang Zhechong Pills on renal aging in rats].

This study aims to observe the effects of the traditional Chinese medicine prescription Dahuang Zhechong Pills(DHZCP on renal aging and explore its potential multi-target effects. Rats were assigned into the normal, model, DHZCP, and vitamin E(VE)groups. Firstly, the rat model of D-galactose(D-gal)-induced renal aging was established. During the modeling period, the rats in the 4 groups were administrated with double distilled water, double distilled water, DHZCP suspension, and VE suspension, respectively,by gavage every day. On day 60 of intervention, the indicators of renal aging and injury in rats were measured, including the function,histopathological characteristics, senescence-associated ß-galactosidase( SA-ß-gal) staining, and expression levels of Klotho and proteins associated with cell cycle arrest and senescence-associated secretory phenotype(SASP) in the renal tissue. Moreover, nontargeted metabolomic analysis of the renal tissue was performed for the 4 groups of rats to screen out the potential biomarkers and metabolic pathways. Finally, the signaling pathways of key targets were preliminarily validated. The results showed that DHZCP and VE significantly improved the renal function, histopathological features of renal tubular/interstitial tissue, and degree of SA-ß-gal staining, up-regulated the expression level of Klotho, and down-regulated the expression levels of proteins associated with cell cycle arrest and SASP in the renal tissue of the aging rats. In addition, DHZCP and VE regulated the metabolites in the renal tissue of the aging rats. There were 21 common differential metabolites. Among them, 5 differential metabolites were significantly increased in the aging rats and recovered after DHZCP or VE treatment, and they were involved in the lipid metabolism and energy metabolism pathways. The areas under the curves of the groups in comparison varied within the range of 0. 88-1. DHZCP regulated multiple signaling pathways, such as the adenosine monophosphate-activated protein kinase(AMPK), cyclic guanosine monophosphate-protein kinase G( c GMP-PKG), cyclic adenylic acid( c AMP), phosphatidylinositol-3-kinase-protein kinase B( PI3K-Akt), mammalian target of rapamycin(mTOR), and autophagy signaling pathways. In addition, it affected the multiple metabolic pathways, such as renin secretion, longevity regulation pathway, diabetic cardiomyopathy, and niacin and nicotinamide metabolism. DHZCP and VE significantly up-regulated the expression level of the key proteins in the AMPK signaling pathway in the renal tissue of the aging rats. In all, DHZCP and VE could mitigate renal aging and injury. DHZCP exerted multi-target effects via multiple signaling pathways and metabolic pathways in the kidney, in which the AMPK signaling pathway may be one of the key targets for action.

In vitro evaluation of the impact of a bioceramic root canal sealer on the mechanical properties of tooth roots.

Bacground/purpose: Endodontically treated teeth are more prone to vertical root fracture with the mechanical property changes to some extent during root canal treatment. This study aimed to investigate the effects of a bioceramic sealer on the mechanical properties of tooth roots. Materials and methods: Dentin discs were dried by two different methods (ethanol drying and paper points drying) and then filled with a BC sealer named iRoot SP. SEM and EDS were used to analyze the newly formed minerals in dentin tubules. Elastic modulus and hardness of the secondary dentin in areas proximal to the primary dentin (PD-SD) and areas proximal to canal or iRoot SP (SD-C/SD-iRoot SP) were measured using nanoindentation technique. The compressive strength of roots filled with iRoot SP were tested by compressive loading test. Results: (1) Penetration and mineralization: Paper points drying was more conducive to iRoot SP adhesion, spreading and penetration into the dentin tubules than 95% ethanol drying. (2) Micromechanical properties: After filling root canal with iRoot SP, the elastic modulus and hardness of SD-iRoot SP were higher than those of PD-SD (P = 0.001 and P = 0.000). (3) Fracture resistance: The compressive strength of the roots filled with iRoot SP was not significantly different from that of the roots unprepared and unfilled (P = 0.957), but was higher than that of the roots prepared and unfilled (P = 0.009). Conclusion: Excessive drying (95% ethanol drying method) is not conducive to the penetration and mineralization of the BC sealer iRoot SP into dentin tubules. The good bioactivity of iRoot SP was responsible for increasing the elastic modulus and hardness of dentin, which strengthened the prepared roots.

Triazine-structured covalent organic framework nanosheets with inherent hydrophilicity for the highly efficient and selective enrichment of glycosylated peptides.

Protein glycosylation plays a crucial role in various biological processes and is related to various diseases. Highly specific enrichment of glycopeptides before mass spectrometry detection is crucial for comprehensive glycoproteomic analysis. However, it still remains a great challenge due to the absence of affinity materials with excellent enrichment efficiency. In this work, a triazine structure linked by a -NH- bond of two-dimensional (2-D) covalent organic framework (COF) nanosheets was synthesized as an affinity adsorbent for the selective capture of glycopeptides. In particular, by introducing hydrophilic monomers via a bottom-up approach, the 2-D COF (denoted as NENP-1) nanosheets were provided with abundant amino groups and inherent hydrophilicity. Owing to the specific surface area and excessive accessible sites for hydrophilicity, the resulting NENP-1 nanosheets exhibited an outstanding glycopeptide enrichment efficiency from standard samples with a superior detection sensitivity (1 × 10-10 M), good enrichment selectivity (1 : 800, HRP tryptic digest to BSA protein), excellent binding capacity (100 mg g-1), great reusability, and recovery (60.2%). Furthermore, using the NENP-1 nanosheet adsorbent, twenty-four endogenous glycopeptides in the serum of patients with gastric cancer were successfully identified by LC-MS/MS technology, which illustrates a promising prospective of hydrophilic COF nanosheets in glycoproteomics research.

Role of combined surgical and radiotherapy treatment in nonmetastatic WHO I nasopharyngeal carcinoma patients.

BACKGROUND: Keratinizing squamous cell carcinoma (KSCC) is recognized as WHO I nasopharyngeal carcinoma (NPC). Current guidelines for treating nasopharyngeal cancer do not delineate specific strategies for individual pathologic subtypes. OBJECTIVES: To explore the optimal treatment for KSCC of the nasopharynx. MATERIAL AND METHODS: Data on patients were extracted from the SEER database. Survival differences between patients treated with radiotherapy alone and combined surgery were assessed using Kaplan-Meier and Cox regression models and compared using propensity score matching (PSM). In addition, we explored the survival differences between the two groups of patients in different risk stratifications. RESULTS: In our study, 165 patients underwent surgical intervention, while 1238 patients did not. In both univariate (CSS: p = .001, HR = 0.612; OS: p < .001, HR = 0.623) and multivariate (CSS: p = .004, HR = 0.655; OS: p < .001, HR = 0.655) analyses, combined surgery was identified as a significant prognostic factor. These findings were consistent after PSM. Using RPA, patients were categorized into two groups. CSS improved in the high-risk group, whereas the difference in low-risk patients was not significant. CONCLUSIONS AND SIGNIFICANCE: For patients diagnosed with WHO I nasopharyngeal carcinoma, the combination of radiotherapy and surgery has significant clinical advantages, especially for patients at high risk.

FOXK2 facilitates the airway remodeling during chronic asthma by promoting glycolysis in a SIRT2-dependent manner.

Asthma is a chronic pulmonary disease with the worldwide prevalence. The structural alterations of airway walls, termed as "airway remodeling", are documented as the core contributor to the airway dysfunction during chronic asthma. Forkhead box transcription factor FOXK2 is a critical regulator of glycolysis, a metabolic reprogramming pathway linked to pulmonary fibrosis. However, the role of FOXK2 in asthma waits further explored. In this study, the chronic asthmatic mice were induced via ovalbumin (OVA) sensitization and repetitive OVA challenge. FOXK2 was upregulated in the lungs of OVA mice and downregulated after adenovirus-mediated FOXK2 silencing. The lung inflammation, peribronchial collagen deposition, and glycolysis in OVA mice were obviously attenuated after FOXK2 knockdown. Besides, the expressions of FOXK2 and SIRT2 in human bronchial epithelial cells (BEAS-2B) were increasingly upregulated upon TGF-ß1 stimulation and downregulated after FOXK2 knockdown. Moreover, the functional loss of FOXK2 remarkably suppressed TGF-ß1-induced epithelial-mesenchymal transition (EMT) and glycolysis in BEAS-2B cells, as manifested by the altered expressions of EMT markers and glycolysis enzymes. The glycolysis inhibitor 2-deoxy-d-glucose (2-DG) inhibited the EMT in TGF-ß1-induced cells, making glycolysis a driver of EMT. The binding of FOXK2 to SIRT2 was validated, and SIRT2 overexpression blocked the FOXK2 knockdown-mediated inhibition of EMT and glycolysis in TGF-ß1-treated cells, which suggests that FOXK2 regulates EMT and glycolysis in TGF-ß1-treated cells in a SIRT2-dependnet manner. Collectively, this study highlights the protective effect of FOXK2 knockdown on airway remodeling during chronic asthma.

Design, synthesis and structure-activity relationships of novel non-ketolides: 9-Oxime clarithromycin featured with seven-to thirteen-atom-length diamine linkers at 3-OH.

We report here on the structure-activity relationships of hybrids combining 3-descladinosyl clarithromycin with quinolones linked by extended diamine connectors. Several hybrids, exemplified by 23Bc, 23Be, 23Bf, 26Be, and 30Bc, not only restored potency against inducibly resistant pathogens but also exhibited significantly enhanced activities against constitutively resistant strains of Staphylococcus pneumoniae and Staphylococcus pyogenes, which express high-level resistance independent of clarithromycin or erythromycin induction. Additionally, the novel hybrids showed susceptibility against Gram-negative Haemophilus influenzae. Notably, hybrid 23Be demonstrated dual modes of action by inhibiting both protein synthesis and DNA replication in vitro and in vivo. Given these promising characteristics, 23Be emerges as a potential candidate for the treatment of community-acquired bacterial pneumonia.

Beyond Shell-Filling: Strong Enhancement of Electron Affinity of Metal Clusters through a Noninvasive Oriented External Electric Field.

Traditional electron counting rules, like the Jellium model, have long been successfully utilized in designing superhalogens by modifying clusters to have one electron less than a filled electronic shell. However, this shell-filling approach, which involves altering the intrinsic properties of the clusters, can be complex and challenging to control, especially in experiments. In this letter, we theoretically establish that the oriented external electric field (OEEF) can substantially enhance the electron affinity (EA) of diverse aluminum-based metal clusters with varying valence electron configurations, leading to the creation of superhalogen species without altering their shell arrangements. This OEEF approach offers a noninvasive alternative to traditional superatom design strategies, as it does not disrupt the clusters' geometrical structures and superatomic states. These findings contribute a vital piece to the puzzle of constructing superalkalis and superhalogens, extending beyond conventional shell-filling strategies and potentially expanding the range of applications for functional clusters.

Preparation empty peptide-receptive MHC class I complex for large-scale detection through photolabile peptide ligands.

Peptide-major histocompatibility complex (pMHC) multimers are wide recognized as the premier technique for detecting, characterizing, and isolating antigen-specific CD8+ T-cell subsets. These multimers are specifically useful in studying infections, autoimmune conditions, and cancer through single-cell analysis techniques such as flow cytometry and fluorescence microscopy. However, the development of high-throughput assays with commercially available pMHC tetramers can be expensive, while in-house production may pose challenges for most biology research laboratories. In this context, we introduce a cost-friendly and uncomplicated protocol to prepare empty MHC class I tetramers using disulfide-stabilized molecules and photolabile peptide ligands. Our method relies on disulfide bond-stabilized MHC-I molecules, which demonstrated stability when folded into stable monomers in the presence of a photolabile epitope. These monomers, upon ultraviolet irradiation and streptavidin binding, efficiently assemble into tetramers devoid of any peptide. Following a short incubation with the peptide of interest under gentle conditions, the resulting pMHC tetramer effectively detects patient-sourced, neoantigen-specific T cells. Our unique approach streamlines large-scale pMHC generation, thus paving the way for advancements in T cell-based diagnostics and personalized therapies.

Helicobacter pylori-Induced Angiopoietin-Like 4 Promotes Gastric Bacterial Colonization and Gastritis.

Helicobacter pylori infection is characterized as progressive processes of bacterial persistence and chronic gastritis with features of infiltration of mononuclear cells more than granulocytes in gastric mucosa. Angiopoietin-like 4 (ANGPTL4) is considered a double-edged sword in inflammation-associated diseases, but its function and clinical relevance in H. pylori-associated pathology are unknown. Here, we demonstrate both pro-colonization and pro-inflammation roles of ANGPTL4 in H. pylori infection. Increased ANGPTL4 in the infected gastric mucosa was produced from gastric epithelial cells (GECs) synergistically induced by H. pylori and IL-17A in a cagA-dependent manner. Human gastric ANGPTL4 correlated with H. pylori colonization and the severity of gastritis, and mouse ANGPTL4 from non-bone marrow-derived cells promoted bacteria colonization and inflammation. Importantly, H. pylori colonization and inflammation were attenuated in Il17a -/-, Angptl4 -/-, and Il17a -/- Angptl4 -/- mice. Mechanistically, ANGPTL4 bound to integrin αV (ITGAV) on GECs to suppress CXCL1 production by inhibiting ERK, leading to decreased gastric influx of neutrophils, thereby promoting H. pylori colonization; ANGPTL4 also bound to ITGAV on monocytes to promote CCL5 production by activating PI3K-AKT-NF-κB, resulting in increased gastric influx of regulatory CD4+ T cells (Tregs) via CCL5-CCR4-dependent migration. In turn, ANGPTL4 induced Treg proliferation by binding to ITGAV to activate PI3K-AKT-NF-κB, promoting H. pylori-associated gastritis. Overall, we propose a model in which ANGPTL4 collectively ensures H. pylori persistence and promotes gastritis. Efforts to inhibit ANGPTL4-associated pathway may prove valuable strategies in treating H. pylori infection.

Lysophosphatidic acid promotes ESCC progression by increasing the level of CCL2 secreted by esophageal epithelial cells.

BACKGROUND: Lysophosphatidic acid (LPA) is a small bioactive lipid which acts as a potent regulator in various tumor progressions through six G-protein-coupled receptors (LPA1-LPA6). Our previous study demonstrated that the LPA-producing enzyme, autotaxin (ATX), was upregulated in esophageal squamous cell carcinoma (ESCC) and ATX high expression levels indicated a poor prognosis. Esophageal squamous cell carcinoma is a type of malignant tumor which originates from epithelial cells. Its progression can be affected by the interaction between cancer cells and normal cells. However, the impact of LPA on the interaction between esophageal epithelial cells and cancer cells in the development of ESCC remains uncertain. METHODS: MTS and Edu assays were performed to determine ESCC cell proliferation in culture medium (CM) derived from LPA-stimulated esophageal epithelial cells (Het-1a). A wound healing assay, transwell migration and an invasion assay were performed to assess the metastatic ability of ESCC cells. Cytokine array analysis was conducted to detect the differentially secreted cytokines in CM. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were utilized to uncover the pathways and cytokines that are influenced by LPA in ESCC. Immunohistochemical staining was employed to measure the expression of ATX and CCL2 in early-stage ESCC. Quantitative real-time PCR, western blot, enzyme-linked immunosorbent assay and an antibody neutralization assay were employed to measure the mechanism of LPA-mediated communication between epithelial cells and cancer cells. RESULTS: Functional experiments showed that exposing ESCC cancer cells to CM from LPA-treated Het-1a results in promoting proliferation, migration, invasion and epithelial-mesenchymal transition processes. Using cytokine array analysis, we discovered that LPA triggers the release of multiple cytokines from epithelial cells. After screening of the TCGA and GEO databases, CCL2 was identified and found to be correlated with ATX expression in ESCC. Furthermore, CCL2 levels in both mRNA expression and secretion were observed to be upregulated in epithelial cells upon stimulation with LPA. Blocking CCL2 effectively reduced the pro-migration influence of CM derived from LPA-treated Het-1a. Mechanism studies have demonstrated that LPA activated the NF-κB signaling pathway through LPA1/3, ultimately causing an increase in CCL2 expression and secretion in Het-1a. CONCLUSIONS: Our findings, taken together, demonstrate that CM from LPA-treated esophageal epithelial cells plays a significant role in promoting the progression of ESCC, with CCL2 acting as the primary regulator.

Superior AlGaN/GaN-Based Phototransistors and Arrays with Reconfigurable Triple-Mode Functionalities Enabled by Voltage-Programmed Two-Dimensional Electron Gas for High-Quality Imaging.

High-quality imaging units are indispensable in modern optoelectronic systems for accurate recognition and processing of optical information. To fulfill massive and complex imaging tasks in the digital age, devices with remarkable photoresponsive characteristics and versatile reconfigurable functions on a single-device platform are in demand but remain challenging to fabricate. Herein, an AlGaN/GaN-based double-heterostructure is reported, incorporated with a unique compositionally graded AlGaN structure to generate a channel of polarization-induced two-dimensional electron gas (2DEGs). Owing to the programmable feature of the 2DEGs by the combined gate and drain voltage inputs, with a particular capability of electron separation, collection and storage under different light illumination, the phototransistor shows reconfigurable multifunctional photoresponsive behaviors with superior characteristics. A self-powered mode with a responsivity over 100 A W-1 and a photoconductive mode with a responsivity of ≈108 A W-1 are achieved, with the ultimate demonstration of a 10 × 10 device array for imaging. More intriguingly, the device can be switched to photoelectric synapse mode, emulating synaptic functions to denoise the imaging process while prolonging the image storage ability. The demonstration of three-in-one operational characteristics in a single device offers a new path toward future integrated and multifunctional imaging units.

Disruption of DNA-PKcs-mediated cGAS retention on damaged chromatin potentiates DNA damage-inducing agent-induced anti-multiple myeloma activity.

BACKGROUND: Targeting DNA damage repair factors, such as DNA-dependent protein kinase catalytic subunit (DNA-PKcs), may offer an opportunity for effective treatment of multiple myeloma (MM). In combination with DNA damage-inducing agents, this strategy has been shown to improve chemotherapies partially via activation of cGAS-STING pathway by an elevated level of cytosolic DNA. However, as cGAS is primarily sequestered by chromatin in the nucleus, it remains unclear how cGAS is released from chromatin and translocated into the cytoplasm upon DNA damage, leading to cGAS-STING activation. METHODS: We examined the role of DNA-PKcs inhibition on cGAS-STING-mediated MM chemosensitivity by performing mass spectrometry and mechanism study. RESULTS: Here, we found DNA-PKcs inhibition potentiated DNA damage-inducing agent doxorubicin-induced anti-MM effect by activating cGAS-STING signaling. The cGAS-STING activation in MM cells caused cell death partly via IRF3-NOXA-BAK axis and induced M1 polarization of macrophages. Moreover, this activation was not caused by defective classical non-homologous end joining (c-NHEJ). Instead, upon DNA damage induced by doxorubicin, inhibition of DNA-PKcs promoted cGAS release from cytoplasmic chromatin fragments and increased the amount of cytosolic cGAS and DNA, activating cGAS-STING. CONCLUSIONS: Inhibition of DNA-PKcs could improve the efficacy of doxorubicin in treatment of MM by de-sequestrating cGAS in damaged chromatin.