DNMT1-targeting remodeling global DNA hypomethylation for enhanced tumor suppression and circumvented toxicity in oral squamous cell carcinoma.

BACKGROUND: The faithful maintenance of DNA methylation homeostasis indispensably requires DNA methyltransferase 1 (DNMT1) in cancer progression. We previously identified DNMT1 as a potential candidate target for oral squamous cell carcinoma (OSCC). However, how the DNMT1- associated global DNA methylation is exploited to regulate OSCC remains unclear. METHODS: The shRNA-specific DNMT1 knockdown was employed to target DNMT1 on oral cancer cells in vitro, as was the use of DNMT1 inhibitors. A xenografted OSCC mouse model was established to determine the effect on tumor suppression. High-throughput microarrays of DNA methylation, bulk and single-cell RNA sequencing analysis, multiplex immunohistochemistry, functional sphere formation and protein immunoblotting were utilized to explore the molecular mechanism involved. Analysis of human samples revealed associations between DNMT1 expression, global DNA methylation and collaborative molecular signaling with oral malignant transformation. RESULTS: We investigated DNMT1 expression boosted steadily during oral malignant transformation in human samples, and its inhibition considerably minimized the tumorigenicity in vitro and in a xenografted OSCC model. DNMT1 overexpression was accompanied by the accumulation of cancer-specific DNA hypomethylation during oral carcinogenesis; conversely, DNMT1 knockdown caused atypically extensive genome-wide DNA hypomethylation in cancer cells and xenografted tumors. This novel DNMT1-remodeled DNA hypomethylation pattern hampered the dual activation of PI3K-AKT and CDK2-Rb and inactivated GSK3ß collaboratively. When treating OSCC mice, targeting DNMT1 achieved greater anticancer efficacy than the PI3K inhibitor, and reduced the toxicity of blood glucose changes caused by the PI3K inhibitor or combination of PI3K and CDK inhibitors as well as adverse insulin feedback. CONCLUSIONS: Targeting DNMT1 remodels a novel global DNA hypomethylation pattern to facilitate anticancer efficacy and minimize potential toxic effects via balanced signaling synergia. Our study suggests DNMT1 is a crucial gatekeeper regarding OSCC destiny and treatment outcome.

Grape seed-derived procyanidins decreases neuropathic pain and nerve regeneration by suppression of toll-like receptor 4-myeloid differentiation factor-88 signaling.

Background: Recent studies have shown that peripheral nerve regeneration process is closely related to neuropathic pain. Toll-like receptor 4 (TLR4) signaling was involved in different types of pain and nerve regeneration. TLR4 induced the recruitment of myeloid differentiation factor-88 adaptor protein (MyD88) and NF-κB-depended transcriptional process in sensory neurons and glial cells, which produced multiple cytokines and promoted the induction and persistence of pain. Our study aimed to investigate procyanidins's effect on pain and nerve regeneration via TLR4-Myd88 signaling. Methods: Spinal nerve ligation (SNL) model was established to measure the analgesic effect of procyanidins. Anatomical measurement of peripheral nerve regeneration was measured by microscopy and growth associated protein 43 (GAP43) staining. Western blotting and/or immunofluorescent staining were utilized to detect TLR4, myeloid differentiation factor-88 adaptor protein (MyD88), ionized calcium-binding adapter molecule 1 (IBA1) and nuclear factor kappa-B-p65 (NF-κB-p65) expression, as well as the activation of astrocyte and microglia. The antagonist of TLR4 (LPS-RS-Ultra, LRU) were intrathecally administrated to assess the behavioral effects of blocking TLR4 signaling on pain and nerve regeneration. Result: Procyanidins reduced mechanical allodynia, thermal hyperalgesia and significantly suppressed the number of nerve fibers regenerated and the degree of myelination in SNL model. Compared with sham group, TLR4, MyD88, IBA1 and phosphorylation of NF-κB-p65 were upregulated in SNL rats which were reversed by procyanidins administration. Additionally, procyanidins also suppressed activation of spinal astrocytes and glial cells. Conclusion: Suppression of TLR4-MyD88 signaling contributes to the alleviation of neuropathic pain and reduction of nerve regeneration by procyanidins.

Remimazolam Dosing for Gastroscopy: A Randomized Noninferiority Trial.

BACKGROUND: Remimazolam, an ultra-short-acting benzodiazepine, may provide adequate sedation for endoscopy while causing less cardiovascular or respiratory disturbance than propofol. Although fixed-dose administration is suggested, body weight affects the volume of the central chamber and thus affects the sedation depth that can be achieved by the first dose. This study aimed to compare the efficacy and safety of different doses of remimazolam and propofol by body weight for sedation during gastroscopy. METHODS: This multicenter, randomized, single-blind, parallel-controlled noninferiority trial recruited patients from five centers between March 2021 and July 2022. A total of 1,883 patients scheduled to undergo gastroscopy were randomized to groups receiving 0.15 mg/kg remimazolam, 0.2 mg/kg remimazolam, or 1.5 mg/kg propofol. The noninferiority margin was set to 5%. The primary outcome was the success rate of sedation. Adverse events were recorded to evaluate safety. RESULTS: The sedation success rate of the 0.2 mg/kg remimazolam group was not inferior to that of the 1.5 mg/kg propofol group (98.7% vs. 99.4%; risk difference, -0.64%; 97.5% CI, -2.2 to 0.7%, meeting criteria for noninferiority). However, the sedation success rate of the 0.15 mg/kg remimazolam group was 88.5%, and that of the 1.5 mg/kg propofol group was 99.4% (risk difference, -10.8%; 97.5% CI, -14.0% to -8.0%), demonstrating inferiority. Simultaneously, the overall adverse events rate of remimazolam was lower than that of propofol, and the incidence of bradycardia, hypotension, subclinical respiratory depression, and hypoxia in the remimazolam groups was significantly lower than that in the propofol group. CONCLUSIONS: This trial established the noninferior sedation success rate of remimazolam (0.2 mg/kg but not 0.15 mg/kg) compared with propofol (1.5 mg/kg), with a superior safety profile.

Anesthesia/surgery-induced learning and memory dysfunction by inhibiting mitophagy-mediated NLRP3 inflammasome inactivation in aged mice.

Postoperative cognitive dysfunction (POCD) is a common postoperative complication, not only affects the quality of life of the elderly and increases the mortality rate, but also brings a greater burden to the family and society. Previous studies demonstrated that Nod-like receptor protein 3 (NLRP3) inflammasome participates in various inflammatory and neurodegenerative diseases. However, possible mitophagy mechanism in anesthesia/surgery-elicited NLRP3 inflammasome activation remains to be elucidated. Hence, this study clarified whether mitophagy dysfunction is related to anesthesia/surgery-elicited NLRP3 inflammasome activation. POCD model was established in aged C57BL/6 J mice by tibial fracture fixation under isoflurane anesthesia. Morris Water Maze (MWM) was used to evaluate learning and memory abilities. We found that in vitro experiments, lipopolysaccharide (LPS) significantly facilitated NLRP3 inflammasome activation and mitophagy inhibition in BV2 cells. Rapamycin restored mitophagy and improved mitochondrial function, and inhibited NLRP3 inflammasome activation induced by LPS. In vivo experiments, anesthesia and surgery caused upregulation of hippocampal NLRP3, caspase recruitment domain (ASC) and interleukin-1ß (IL-1 ß), and downregulation of microtubule-associated protein light chain 3II (LC3II) and Beclin1 in aged mice. Olaparib inhibited anesthesia/surgery-induced NLRP3, ASC, and IL-1ß over-expression in the hippocampus, while upregulated the expression of LC3II and Beclin1. Furthermore, Olaparib improved cognitive impairment in older mice. These results revealed that mitophagy was involved in NLRP3 inflammasome-mediated anesthesia/surgery-induced cognitive deficits in aged mice. Overall, our results suggested that mitophagy was related in NLRP3 inflammasome-induced cognitive deficits after anesthesia and surgery in aged mice. Activating mitophagy may have clinical benefits in the prevention of cognitive impairment induced by anesthesia and surgery in elderly patients.

Identification of drug-side effect association via correntropy-loss based matrix factorization with neural tangent kernel.

Adverse drug reactions include side effects, allergic reactions, and secondary infections. Severe adverse reactions can cause cancer, deformity, or mutation. The monitoring of drug side effects is an important support for post marketing safety supervision of drugs, and an important basis for revising drug instructions. Its purpose is to timely detect and control drug safety risks. Traditional methods are time-consuming. To accelerate the discovery of side effects, we propose a machine learning based method, called correntropy-loss based matrix factorization with neural tangent kernel (CLMF-NTK), to solve the prediction of drug side effects. Our method and other computational methods are tested on three benchmark datasets, and the results show that our method achieves the best predictive performance.

Lichen planus pemphigoides induced by anti-PD-1 antibody: A case only involved in oral mucosa with excellent topical treatment efficiency.

Lichen planus pemphigoides (LPP) is a rare autoimmune subepidermal disease that can occur in patients receiving immune checkpoint inhibitors. Its clinical manifestations are combined with the characteristics of lichen planus with bullous pemphigoid that can occur on either skin or oral mucosa. It should be noted that oral LPP is very rare. Here, we report a novel case of oral LPP induced by an anti-PD-1 agent. The patient presented with typical clinical features in oral mucosa, and the diagnosis was based on histopathology and immunological studies. Given that the patient was receiving an anti-PD-1 agent, topical therapy was chosen, and a nice therapeutic effect was obtained. No significant recurrence was observed after a 2-year follow-up. A good and stable therapeutic effect achieved by rapid and local symptomatic medication suggests that accurate and sensitive diagnosis is necessary.

Asymmetric catalytic synthesis of chiral covalent organic framework composite (S)-DTP-COF@SiO2 for HPLC enantioseparations by normal-phase and reversed-phase chromatographic modes.

A novel CCOF core-shell composite material (S)-DTP-COF@SiO2 was prepared via asymmetric catalytic and in situ growth strategy. The prepared (S)-DTP-COF@SiO2 was utilized as separation medium for HPLC enantioseparation using normal-phase and reversed-phase chromatographic modes, which displays excellent chiral separation performance for alcohols, esters, ketones, and epoxides, etc. Compared with chiral commercial chromatographic columns (Chiralpak AD-H and Chiralcel OD-H columns) and some previously reported chiral CCOF@SiO2 (CC-MP CCTF@SiO2 and MDI-ß-CD-modified COF@SiO2)-packed columns, there are 4, 3, 13, and 15 tested racemic compounds that could not be resolved on the Chiralpak AD-H column, Chiralcel OD-H column, CC-MP CCTF@SiO2 column, and MDI-ß-CD-modified COF@SiO2 column, respectively, which indicates that the resolution effect of (S)-DTP-COF@SiO2-packed column can be complementary to the other ones. The effects of the analyte mass, column temperature, and mobile phase composition on the enantiomeric separation were investigated. The chiral column exhibits good reproducibility after multiple consecutive injections. The RSDs (n = 5) of the peak area and retention time were less than 1.5% for repetitive separation of 2-methoxy-2-phenylethanol and 1-phenyl-1-pentanol. The chiral core-shell composite (S)-DTP-COF@SiO2 exhibited good enantiomeric separation performance, which not only demonstrates its potential as a novel CSP material in HPLC but also expands the range of applications for chiral COFs.

Knowledge, attitudes, and practice toward postoperative cognitive dysfunction among anesthesiologists in China: a cross-sectional study.

BACKGROUND: To investigate the knowledge, attitudes, and practice (KAP) toward postoperative cognitive dysfunction (POCD) among anesthesiologists in China. METHODS: This cross-sectional study was conducted nationwide among Chinese anesthesiologists between December 2022 and January 2023. The demographic information and KAP scores of the respondents were collected using a web-based questionnaire. The mean KAP dimension scores ≥ 60% were considered good. RESULTS: This study enrolled 1032 anesthesiologists (51.2% male). The mean total scores of knowledge, positive attitude, and positive practice were 9.3 ± 1.2 (max 12), 34.8 ± 3.3 (max 40), and 30.6 ± 6.7 (max 40), respectively. The knowledge items with correctness scores < 60% were "the anesthetic drugs that tend to cause POCD" (23.3%) and "Treatment of POCD" (40.3%). Multivariable analysis showed that ≥ 40 years old, master's degree or above, intermediate professional title (i.e., attending physician), senior professional title (i.e., chief physician), and working in tertiary hospitals were independently associated with adequate knowledge. Multivariable analysis showed that the attitude scores, middle professional title, and ≥ 16 years of experience were independently associated with good practice. CONCLUSIONS: These results suggest that Chinese anesthesiologists have good knowledge, favorable attitudes, and good practice toward POCD. Still, some points remain to be improved (e.g., the drugs causing POCD and managing POCD) and should be emphasized in training and continuing education. TRIAL REGISTRATION: ChiCTR2200066749.

Supramolecular Salicylic Acid Alleviates Skin Photoaging by Increasing Collagen Density and Elasticity.

BACKGROUND: Skin rejuvenation has always been of great concern. Although salicylic acid (SA) has multiple properties, it is mainly used in dermatology as a superficial peeling agent that can improve photodamaged epidermis. However, the effect of SA on the photoaging dermis is unclear. PURPOSE: To evaluate the efficacy and safety of supramolecular SA alone for treating photoaged skin, and the effect of SSA on photoaged dermis. METHODS: This is a double-blind, randomized, placebo-controlled trial. 36 patients with photodamaged hands were enrolled. One hand was randomly selected as SSA treated side. 30% SSA biweekly and 2% SSA daily was applied for 4 months; an additional follow-up was performed 2 weeks after the last treatment. Skin photoaging score (SPS), global aesthetic improvement scale (GAIS), viscoelasticity, ultrasound parameters, color and transepidermal water loss (TEWL) were assessed. RESULTS: SSA treatment induced a significant increase in collagen density and skin elasticity, accompanied by an increase in dermal thickness and a decrease in melanin index and TEWL. As result, the GAIS and the SPS were improved significantly after SSA treatment. No adverse events were observed after SSA treatments, and 98% of the subjects were satisfied or very satisfied with the treatment. CONCLUSION: SSA can increase collagen density and skin elasticity to alleviate skin photoaging effectively and safely. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Ionizing radiation-induced "zombie" carcinoma-associated fibroblasts with suppressed pro-radioresistance on OSCC cells.

OBJECTIVES: This study was to investigate the effect of ionizing radiation (IR) on oral carcinoma-associated fibroblasts (CAFs) and to further explore subsequent effects of IR-induced "zombie" CAFs on oral squamous cell carcinoma (OSCC) cells. MATERIALS AND METHODS: Three primary CAFs and one primary normal-associated fibroblasts (NAFs) were separated from human OSCC and normal oral mucosa tissues, identified by immunocytochemistry. Cells were exposed to IR by X-ray irradiator under different doses. The DNA damage, proliferation, and migration of irradiated CAFs were, respectively, detected by immunofluorescence and wound healing assay, while senescence was detected by ß-galactosidase staining. Finally, the effect of irradiated CAFs on biological behavior and radioresistance of Cal-27 cells were determined via assays mentioned above. RESULTS: Oral CAFs were sensitive to IR with DNA damage increasing and proliferation decreasing. 18 Gy IR could not kill oral CAFs but induce them to "zombies," with arrested proliferation, increased senescence, and reduced migration. "Zombie" CAFs (zCAFs) could enhance proliferation, migration, and invasion of Cal-27 cells, and show suppressed pro-radioresistance by reducing DNA damage and facilitating survival. CONCLUSIONS: IR-induced zCAFs could continuously promote radioresistance of OSCC cells though being suppressed, suggesting the potential promoting effect on tumor relapse post-radiotherapy that needed further exploring.

Pulmonary hypertension- a novel phenotypic hypothesis of Kabuki syndrome: a case report and literature review.

BACKGROUND: Pediatric pulmonary hypertension (PH) is a serious and rare disease that is often derived from genetic mutations. Kabuki syndrome (KS) is a chromosomal abnormality disease that has its origin in the mutation of lysine methyltransferase 2D(KMT2D). Recent evidence has shown that KMT2D mutations are associated with pediatric pulmonary disorders. However, the relationship between the clinical courses of PH and the KMT2D mutation is reported in extremely few cases. Therefore, in this paper, a case was presented and previous literature was reviewed for better understanding of the correlation between pediatric PH and KMT2D mutations. CASE PRESENTATION: A 3-year-old girl was transferred to our center for severe cough, shortness of breath, fatigue and fever. Physical examination revealed facial deformities and growth retardation. Echocardiography showed a small atrial septal defect (ASD), and right heart catheterization indicated a significant increase in pulmonary vascular pressure and resistance. The genetic test suggested that she had a KMT2D gene mutation. The patient was finally diagnosed with KS. She was given targeted drugs to reduce pulmonary vascular pressure, but the effect was unsatisfactory. CONCLUSIONS: KS can be complicated with multiple organ malformations and dysfunction. With the progress of next generation sequencing, an increasing number of new phenotypes related to KMT2D mutations have been reported. A bold hypothesis is proposed in this article, that is, PH may be a new phenotype associated with KMT2D mutations. It is suggested that KS and PH should be differentiated from each other to avoid delayed diagnosis and treatment in clinical practice. There is no specific drug for KS treatment. The prognosis of children with inherited PH is usually poor, and lung transplantation may increase their survival rates.

Efficacy and safety of Q-switched lasers for the treatment of naevus of Ota in children: a retrospective analysis.

To identify factors influencing the efficacy of Q-switched laser in the treatment of naevus of Ota in children and to compare the efficacy, safety, and recurrence rate between 1064 nm Q-switched Nd:YAG laser (QSNL) and 755 nm Q-switched alexandrite laser (QSAL). We retrospectively analysed 160 children with naevus of Ota who completed QSAL or QSNL laser treatment at our centre. Age at initial treatment (P = 0.004), colour of lesions (P = 0.025), and number of treatments (P = 0.002) were related to efficacy. Compared with patients aged 0-11 months at initial treatment, patients who started treatment at 1-3 years (OR adj = 0.47), 4-8 years (OR adj = 0.20), and 9-12 years (OR adj = 0.27) had inferior efficacy. The efficacy of brown-violet (OR adj = 2.67) and blue-violet lesions (OR adj = 2.51) was better than that of brown lesions. Moreover, patients who received 3-4 (OR adj = 2.83) or 5-6 (OR adj = 7.35) treatment sessions showed a better response than those who received 1-2 sessions. Additionally, as the age at initial treatment increased, the rate of complications increased from 2.0 to 14.3%, while the recurrence rate decreased from 8.2 to 0%. In addition, the complication rate increased with an increase in the number of treatments. There were no significant differences in clinical efficacy (P = 0.94), risk of complications (P = 0.752), or recurrence (P = 0.834) between QSAL and QSNL for treating naevus of Ota in children. QSAL and QSNL are equally effective for children's naevus of Ota, with low complications and recurrence rates. Younger age at initial treatment and a greater number of treatments are beneficial for efficacy, whereas brown lesions are a negative factor.

IDO-Kynurenine pathway mediates NLRP3 inflammasome activation-induced postoperative cognitive impairment in aged mice.

AIM: Postoperative cognitive dysfunction (POCD) is a common postoperative complication, especially in elderly patients. It extends hospital stay, increases the mortality rate and are heavy burdens to the family and society. Accumulating research has indicated that overactivation of pyrin domain-containing protein 3 (NLRP3) inflammasomes is related to POCD andplays a critical role in activating pro-inflammatory cytokines. According to existing studies, indoleamine 2,3-dioxygenase (IDO) is potently up-regulated by inflammatory factors, tryptophan in brain is mainly catalyzed by IDO to kynurenine (KYN), KYN metabolism may contribute to the development of depressive disorder and memory deficits. Hence, this study elucidated whether IDO-Kynurenine pathway mediates NLRP3 inflammasome activation-induced postoperative cognitive impairment in aged mice. MATERIAL AND METHODS: POCD model was established in aged C57BL/6J mice by exploratory laparotomy under isoflurane anesthesia. Learning and memory were determined using Morris water maze. RESULTS: The data showed that IDO and kynurenine aminotransferase-II (KAT-II) mRNA in hippocampus was up-regulated, and NLRP3, caspase recruitment domain (ASC), interleukin-1b (IL-1b) and IDO overexpressed, KYN levels increased after anesthesia and surgery. NLRP3 inflammasome inhibitor (MCC950) reversed NLRP3, ASC, IL-1b and IDO overexpression, and the elevation of KYN levels. To clarify the role of IDO-Kynurenine pathway in postoperative cognitive impairment, IDO inhibitor (1-methyl-Ltryptophan 1-MT) reduced the elevation of KYN and kynurenic acid (KYNA) levels, reduction of tryptophan (TRP), as well as improved learning and memory abilities. Finally, KAT-II inhibitor (PF-04859989) reduced brain KYNA levels and restored the cognitive impairment. CONCLUSION: These results reveal that IDO-Kynurenine pathway mediates NLRP3 inflammasome activation-induced postoperative cognitive impairment.

Significant efficacy of short-course, low-concentration betamethasone mouthwash therapy for severe erosive oral lichen planus: a randomized controlled trial.

OBJECTIVES: To evaluate the short-term efficacy of low-concentration betamethasone mouthwash for severe erosive oral lichen planus (EOLP). MATERIALS AND METHOD: In this randomized, investigator-blind, positive-controlled trial, OLP patients with erosive lesions received betamethasone mouthwash (0.137 mg/mL) or dexamethasone mouthwash (0.181 mg/mL) three times daily for 2 or 4 weeks and were followed up for 3 months to observe recurrence. The primary outcome was the week-2 reduction in erosive area. RESULTS: Fifty-seven participants were randomized to betamethasone (n = 29) and dexamethasone (n = 28). At week 2, participants using betamethasone (n = 28) experienced a greater reduction in erosive area than gargling with dexamethasone (n = 26). Similarly, secondary outcomes, including the healing proportion of erosions, reduced pain level, reduction in atrophic area, Thongprasom score, and recurrence interval, showed the superiority of betamethasone. At week 4, betamethasone (n = 7) was not superior to dexamethasone (n = 15) in further reducing lesional area and pain level. No serious adverse events were documented. CONCLUSIONS: The 0.137 mg/mL compound betamethasone mouthwash exhibited significant efficacy in rapidly enhancing erosion healing within 2 weeks and extending the recurrence interval with a good safety profile. CLINICAL RELEVANCE: This study proved the significant efficacy of short-course 0.137 mg/mL betamethasone mouthwash therapy for treating erosion and pain, providing a novel topical agent for patients with severe EOLP. TRIAL REGISTRATION: This study was prospectively registered at the International Clinical Trials Registry Platform ( ChiCTR1800016507 ) on 5 June 2018.

Correlation between individual physical characteristics and spinal cerebrospinal fluid volume.

Spinal cerebrospinal fluid (CSF) volume is the primary determinant for the spread of spinal anesthesia. However, it cannot generally be obtained during spinal anesthesia, and patient physical characteristics are always adopted to obtain a suitable spinal spread. In this study, we sought to explore the relationship between individual physical characteristics and thoracosacral CSF volume to provide a theoretical basis for more accurate spinal anesthesia. In total 35 healthy volunteers were enrolled in this study. Three-dimensional magnetic resonance imaging was used to reconstruct and measure the spinal CSF volume. Physical characteristics and spinal CSF volume were recorded. Bivariate and multiple linear regression analyses were used to analyze the correlation between the individual physical characteristics and thoracosacral CSF volume. Total of 31 participants were included in the final analysis. Bivariate linear correlation analysis showed that the volume of thoracosacral CSF was correlated with both individual dorso-sacral distance and height (both p < 0.01), but not with abdominal girth (p > 0.05). Multiple linear regression analyses revealed that the adjusted R2 values were 0.404 for the regression equation between thoracosacral CSF volume, dorso-sacral distance, and abdominal girth. Our study showed that dorso-sacral distance and abdominal girth were essential factors contributing to thoracosacral CSF volume. A longer dorso-sacral distance and smaller abdominal girth mean larger spinal CSF volume.

Pattern-Selective Molecular Epitaxial Growth of Single-Crystalline Perovskite Arrays toward Ultrasensitive and Ultrafast Photodetector.

The emergence of organic-inorganic perovskite has provided great flexibility for creating optoelectronic devices with unprecedented performance or unique functionality. However, the perovskite films explored so far have been difficult to be patterned to arrays owing to their poor solvent and moisture stability, which usually lead to serious structural damage of perovskites. The successful preparation of perovskite microarrays with uniform shape and size is more challenging. Here we report a straightforward approach to realize single-crystalline perovskite arrays through a relatively simple pattern-selective molecular epitaxial growth. This approach is applied to create diverse shaped perovskite arrays, such as hexagon, triangle, circle, square, and rectangle. A vertically aligned perovskite photodetector displays both an ultrasensitive and ultrafast photoresponse arising from the reduction in carrier diffusion paths and the high optical absorption. This work demonstrates a general approach to creating perovskite arrays with uniform shape, size, and morphology and provides a rich platform for producing high-performance photodetectors and photovoltage devices.

Identification and Biological Validation of a Chemokine/Chemokine Receptor-Based Risk Model for Predicting Immunotherapeutic Response and Prognosis in Head and Neck Squamous Cell Carcinoma.

Over 80% of head and neck squamous cell carcinoma (HNSCC) patients failed to respond to immunotherapy, which can likely be attributed to the tumor microenvironment (TME) remolding mediated by chemokines/chemokine receptors (C/CR). This study aimed to establish a C/CR-based risk model for better immunotherapeutic responses and prognosis. After assessing the characteristic patterns of the C/CR cluster from the TCGA-HNSCC cohort, a six-gene C/CR-based risk model was developed to stratify patients by LASSO Cox analysis. The screened genes were multidimensionally validated by RT-qPCR, scRNA-seq, and protein data. A total of 30.4% of patients in the low-risk group had better responses to anti-PD-L1 immunotherapy. A Kaplan-Meier analysis showed that patients in the low-risk group had longer overall survival. A time-dependent receiver operating characteristic curve and Cox analyses indicated that risk score served as an independent predictive indicator. The robustness of the immunotherapy response and prognosis prediction was also validated in independent external datasets. Additionally, the TME landscape revealed that the low-risk group was immune activated. Furthermore, the cell communication analysis on the scRNA-seq dataset revealed that cancer-associated fibroblasts were the main communicators within the C/CR ligand-receptor network of TME. Collectively, The C/CR-based risk model simultaneously predicted immunotherapeutic response and prognosis, potentially optimizing personalized therapeutic strategies of HNSCC.

[Research Progress in the Application of Terahertz Spectroscopy and Imaging Technology in Stomatology].

Terahertz waves, the electromagnetic waves in the range of 0.1 to 10 THz, has the advantages of being damage-free, causing no ionizing radiation injury, and being capable of recognizing the fingerprint spectrum of molecular characteristics, thus holding encouraging prospects for wide applications in the field of biomedicine. Terahertz spectrum can be used to identify and characterize biological structures of different levels, from biomolecules such as proteins to cells and tissues, through the spectral signals and/or restored images of the samples. Herein, we summarized the current stomatogical application of and research progress in terahertz spectroscopy and imaging in dentistry, reported the latest research findings, strengths and limitations from three perspectives, tooth anatomical structure, the extent of caries progression, and oral soft tissue, and suggested possible directions for future exploration.

The nuclear receptor co-repressor 1 is a novel cardioprotective factor against acute myocardial ischemia-reperfusion injury.

Acute myocardial ischemia/reperfusion (MI/R) is a major determinant of prognosis in myocardial infarction patients, while effective therapies are currently lacking. Nuclear receptor co-repressor 1 (NCoR1) is emerging as a critical regulator of cell survival and death signaling in mammals. However, the role of NCoR1 in the pathogenesis of acute MI/R injury remains unknown. Here, we observed that NCoR1 was highly expressed in the mouse heart and significantly downregulated after acute MI/R injury. Cardiomyocyte-specific NCoR1 deletion led to significantly increased infarct size and exacerbated cardiac dysfunction compared to wild-type littermates. Moreover, cardiomyocyte-specific NCoR1 deficiency exacerbated MI/R-induced mitochondrial dysfunction and apoptotic pathway activation. Transcriptomic profiling results indicated that cardiomyocyte-specific NCoR1 deficiency pivotally promoted activation of inflammatory pathways. Through integrated omics analysis, signal transducer and activator of transcription 1 (STAT1) was identified as a downstream target trans-repressed by NCoR1. STAT1 activation played a key mediating role in the detrimental effects of NCoR1 deficiency in MI/R injury. Collectively, our findings provided the first evidence that cardiomyocyte-expressed NCoR1 functioned as a crucial cardioprotective factor against acute MI/R injury by targeting the STAT1 pathway in heart.

Diminished Rbfox1 increases vascular constriction by dynamically regulating alternative splicing of CaV1.2 calcium channel in hypertension.

Calcium influx from depolarized CaV1.2 calcium channels triggers the contraction of vascular smooth muscle cells (VSMCs), which is important for maintaining vascular myogenic tone and blood pressure. The function of CaV1.2 channel can be subtly modulated by alternative splicing (AS), and its aberrant splicing involves in the pathogenesis of multiple cardiovascular diseases. The RNA-binding protein Rbfox1 is reported to regulate the AS events of CaV1.2 channel in the neuronal development, but its potential roles in vascular CaV1.2 channels and vasoconstriction remain undefined. Here, we detect Rbfox1 is expressed in rat vascular smooth muscles. Moreover, the protein level of Rbfox1 is dramatically decreased in the hypertensive small arteries from spontaneously hypertensive rats in comparison with normotensive ones from Wistar-Kyoto rats. In VSMCs, Rbfox1 could dynamically regulate the AS of CaV1.2 exons 9* and 33. By whole-cell patch clamp, we identify knockdown of Rbfox1 induces the hyperpolarization of CaV1.2 current-voltage relationship curve in VSMCs. Furthermore, siRNA-mediated knockdown of Rbfox1 increases the K+-induced constriction of rat mesenteric arteries. In summary, our results indicate Rbfox1 modulates vascular constriction by dynamically regulating CaV1.2 alternative exons 9* and 33. Therefore, our work elucidates the underlying mechanisms for CaV1.2 channels regulation and provides a potential therapeutic target for hypertension.