Fluorescence imaging sheds light on the immune evasion mechanisms of hepatic stellate cells mediated by superoxide anion.

Whether and how the reactive oxygen species generated by hepatic stellate cells (HSCs) promote immune evasion of hepatocellular carcinoma (HCC) remains mysterious. Therefore, investigating the function of superoxide anion (O2•-), the firstly generated reactive oxygen species, during the immune evasion become necessary. In this work, we establish a novel in situ imaging method for visualization of O2•- changes in HSCs based on a new two-photon fluorescence probe TPH. TPH comprises recognition group for O2•- and HSCs targeting peptides. We observe that O2•- in HSCs gradually rose, impairing the infiltration of CD8+ T cells in HCC mice. Further studies reveal that the cyclin-dependent kinase 4 is deactivated by O2•-, and then cause the up-regulation of PD-L1. Our work provides molecular insights into HSC-mediated immune evasion of HCC, which may represent potential targets for HCC immunotherapy.

Unveiling Collagen's Role in Breast Cancer: Insights into Expression Patterns, Functions and Clinical Implications.

Collagen, the predominant protein constituent of the mammalian extracellular matrix (ECM), comprises a diverse family of 28 members (I-XXVIII). Beyond its structural significance, collagen is implicated in various diseases or cancers, notably breast cancer, where it influences crucial cellular processes including proliferation, metastasis, apoptosis, and drug resistance, intricately shaping cancer progression and prognosis. In breast cancer, distinct collagens exhibit differential expression profiles, with some showing heightened or diminished levels in cancerous tissues or cells compared to normal counterparts, suggesting specific and pivotal biological functions. In this review, we meticulously analyze the expression of individual collagen members in breast cancer, utilizing Transcripts Per Million (TPM) data sourced from the GEPIA2 database. Through this analysis, we identify collagens that deviate from normal expression patterns in breast cancer, providing a comprehensive overview of their expression dynamics, functional roles, and underlying mechanisms. Our findings shed light on recent advancements in understanding the intricate interplay between these aberrantly expressed collagens and breast cancer. This exploration aims to offer valuable insights for the identification of potential biomarkers and therapeutic targets, thereby advancing the prospects of more effective interventions in breast cancer treatment.

The role of zyxin in signal transduction and its relationship with diseases.

This review highlighted the pivotal role of zyxin, an essential cell focal adhesions protein, in cellular biology and various diseases. Zyxin can orchestrate the restructuring and dynamic alterations of the cellular cytoskeleton, which is involved in cell proliferation, adhesion, motility, and gene transcription. Aberrant zyxin expression is closely correlated with tumor cell activity and cardiac function in both tumorigenesis and cardiovascular diseases. Moreover, in fibrotic and inflammatory conditions, zyxin can modulate cellular functions and inflammatory responses. Therefore, a comprehensive understanding of zyxin is crucial for deciphering signal transduction networks and disease pathogenesis. Investigating its role in diseases holds promise for novel avenues in early diagnosis and therapeutic strategies. Nevertheless, targeting zyxin as a therapeutic focal point presents challenges in terms of specificity, safety, drug delivery, and resistance. Nonetheless, in-depth studies on zyxin and the application of precision medicine could offer new possibilities for personalized treatment modalities.

Mean Blood Glucose Level During ICU Hospitalization is a Strong Predictor of the Mortality of COVID-19.

Objective: To investigate the potential prognostic value of mean blood glucose (MBG) in hospital for prognosis of COVID-19 adult patients in the intensive unit care unit (ICU). Methods: A single-site and retrospective study enrolled 107 patients diagnosed as COVID-19 from department of critical care medicine in the Second Xiangya Hospital between October 2022 and June 2023. Demographic information including glucose during ICU hospitalization, comorbidity, clinical data, types of medications and treatment, and clinical outcome were collected. The multivariate logistic and cox regression was used to explore the relationship between blood glucose changes and clinical outcomes of COVID-19 during ICU stay. Results: In total, 107 adult patients confirmed with COVID-19 were included. Multivariate logistic regression results showed an increase in MBG was associated with ICU mortality rate. Compared with normal glucose group (MBG <= 7.8 mmol/L), the risk of ICU mortality, 7-day mortality and 28-day mortality from COVID-19 were significantly increased in high glucose group (MBG >7.8mmol/L). Conclusion: MBG level during ICU hospitalization was strongly correlated to all-cause mortality and co-infection in COVID-19 patients. These findings further emphasize the importance of overall glucose management in severe cases of COVID-19.

Dissecting microenvironment in cystadenomas and hepatic cysts based on single nucleus RNA-sequencing data.

Hepatic cystadenoma is a rare disease, accounting for about 5% of all cystic lesions, with a high tendency of malignant transformation. The preoperative diagnosis of cystadenoma is difficult, and some cystadenomas are easily misdiagnosed as hepatic cysts at first. Hepatic cyst is a relatively common liver disease, most of which are benign, but large hepatic cysts can lead to pressure on the bile duct, resulting in abnormal liver function. To better understand the difference between the microenvironment of cystadenomas and hepatic cysts, we performed single-nuclei RNA-sequencing on cystadenoma and hepatic cysts samples. In addition, we performed spatial transcriptome sequencing of hepatic cysts. Based on nucleus RNA-sequencing data, a total of seven major cell types were identified. Here we described the tumor microenvironment of cystadenomas and hepatic cysts, particularly the transcriptome signatures and regulators of immune cells and stromal cells. By inferring copy number variation, it was found that the malignant degree of hepatic stellate cells in cystadenoma was higher. Pseudotime trajectory analysis demonstrated dynamic transformation of hepatocytes in hepatic cysts and cystadenomas. Cystadenomas had higher immune infiltration than hepatic cysts, and T cells had a more complex regulatory mechanism in cystadenomas than hepatic cysts. Immunohistochemistry confirms a cystadenoma-specific T-cell immunoregulatory mechanism. These results provided a single-cell atlas of cystadenomas and hepatic cyst, revealed a more complex microenvironment in cystadenomas than in hepatic cysts, and provided new perspective for the molecular mechanisms of cystadenomas and hepatic cyst.

The effect of oral motor intervention with different initiation times to improve feeding outcomes in preterm infants: protocol for a single-blind, randomized controlled trial.

BACKGROUND: Premature infants commonly encounter difficulties with oral feeding, a complication that extends hospital stays, affects infants' quality of life, and imposes substantial burdens on families and society. Enhancing preterm infants' oral feeding skills and facilitating their transition from parenteral or nasal feeding to full oral feeding pose challenges for neonatal intensive care unit (NICU) healthcare professionals. Research indicates that oral motor interventions (OMIs) can enhance preterm infants' oral feeding capabilities and expedite the transition from feeding initiation to full oral feeding. Nonetheless, the most suitable timing for commencing these interventions remains uncertain. METHODS: This is a single-blind, randomized controlled trial. Preterm with a gestational age between 29+0 to 34+6 weeks will be eligible for the study. These infants will be randomized and allocated to one of two groups, both of which will receive the OMIs. The intervention commences once the infant begins milk intake during the early OMIs. Additionally, in the late OMIs group, the intervention will initiate 48 h after discontinuing nasal continuous positive airway pressure. DISCUSSION: OMIs encompass non-nutritive sucking and artificial oral stimulation techniques. These techniques target the lips, jaw, muscles, or tongue of premature infants, aiming to facilitate the shift from tube feeding to oral feeding. The primary objective is to determine the ideal intervention timing that fosters the development of oral feeding skills and ensures a seamless transition from parenteral or nasal feeding to full oral feeding among preterm infants. Furthermore, this study might yield insights into the long-term effects of OMIs on the growth and neurodevelopmental outcomes of preterm infants. Such insights could bear substantial significance for the quality of survival among preterm infants and the societal burden imposed by preterm birth. TRIAL REGISTRATION: chictr.org.cn ChiCTR2300076721. Registered on October 17, 2023.

Mechanism of efferocytosis in atherosclerosis.

Atherosclerosis (AS) is a chronic inflammatory vascular disease that occurs in the intima of large and medium-sized arteries with the immune system's involvement. It is a common pathological basis for high morbidity and mortality of cardiovascular diseases. Abnormal proliferation of apoptotic cells and necrotic cells leads to AS plaque expansion, necrotic core formation, and rupture. In the early stage of AS, macrophages exert an efferocytosis effect to engulf and degrade apoptotic, dead, damaged, or senescent cells by efferocytosis, thus enabling the regulation of the organism. In the early stage of AS, macrophages rely on this effect to slow down the process of AS. However, in the advanced stage of AS, the efferocytosis of macrophages within the plaque is impaired, which leads to the inability of macrophages to promptly remove the apoptotic cells (ACs) from the organism promptly, causing exacerbation of AS. Moreover, upregulation of CD47 expression in AS plaques also protects ACs from phagocytosis by macrophages, resulting in a large amount of residual ACs in the plaque, further expanding the necrotic core. In this review, we discussed the molecular mechanisms involved in the process of efferocytosis and how efferocytosis is impaired and regulated during AS, hoping to provide new insights for treating AS.

Integrated physiological, transcriptomic and metabolomic analyses provide insights into phosphorus-mediated cadmium detoxification in Salix caprea roots.

Phosphorus (P) plays a crucial role in facilitating plant adaptation to cadmium (Cd) stress. However, the molecular mechanisms underlying P-mediated responses to Cd stress in roots remain elusive. This study investigates the effects of P on the growth, physiology, transcriptome, and metabolome of Salix caprea under Cd stress. The results indicate that Cd significantly inhibits plant growth, while sufficient P alleviates this inhibition. Under Cd exposure, P sufficiency resulted in increased Cd accumulation in roots, along with reduced oxidative stress levels (superoxide anion and hydrogen peroxide contents were reduced by 16.8% and 30.1%, respectively). This phenomenon can be attributed to the enhanced activities of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT), as well as increased levels of antioxidants including ascorbic acid (AsA) and flavonoids under sufficient P conditions. A total of 4208 differentially expressed genes (DEGs) and 552 differentially accumulated metabolites (DAMs) were identified in the transcriptomic and metabolomic analyses, with 2596 DEGs and 113 DAMs identified among treatments with different P levels under Cd stress, respectively. Further combined analyses reveal the potential roles of several pathways in P-mediated Cd detoxification, including flavonoid biosynthesis, ascorbate biosynthesis, and plant hormone signal transduction pathways. Notably, sufficient P upregulates the expression of genes including HMA, ZIP, NRAMP and CAX, all predicted to localize to the cell membrane. This may elucidate the heightened Cd accumulation under sufficient P conditions. These findings provide insights into the roles of P in enhancing plant resistance to Cd stress and improving of phytoremediation.

The screened compounds from Ligustri Lucidi Fructus using the immobilized calcium sensing receptor column exhibit osteogenic activity in vitro.

Calcium sensing receptor (CaSR) has become the novel target of treating osteoporosis with herbal medicine Ligustri Lucidi Fructus (LLF), however, the bioactive compounds responsible for anti-osteoporosis are hard to clarify due to the complexity and diversity of chemical constituents in it. Herein, the immobilized CaSR column was packed with stationary phase materials, which were derived from integrating CLIP-tagged CaSR directly out of crude cell lysates onto the surface of silica gels (5.83 mg/g) in a site-specific covalent manner. The column had a great specificity of recognizing agonists and kept a good stability for at least 3 weeks. The two compounds from LLF extract were screened and identified as olenuezhenoside and ligustroflavone using the immobilized CaSR column in conjunction with mass spectrometry. Molecular docking predicted that both compounds were bound in venus flytrap (VFT) domain of CaSR by the formation of hydrogen bonds. Cellular results showed that both compounds exhibited the distinct osteogenic activity by enhancing the proliferation, differentiation and mineralization of osteoblastic cells. Our study demonstrated that, the immobilized protein column enables to screen the bioactive compounds rapidly from herbal extract, and the newly discovered natural product ligands towards CaSR, including olenuezhenoside and ligustroflavone, will be the candidates for the treatment of osteoporosis.

A Novel Approach to Clinical Thinking Training for Medical Students: The Combined World Café Discussion and Case-Based Learning Experience Introduction.

OBJECTIVE: It is essential for modern medical students to continuously enhance their clinical thinking abilities. This study aims to evaluate the efficacy of the combined World Café discussion and case-based learning (CBL) approach within the clinical thinking training course. METHODS: The clinical thinking training course incorporated the combined World Café discussion and CBL approach. The assessment of the accuracy and rationality of clinical symptoms, medical examination, pathological processes, diagnostic results, diagnostic basis, and drug use was conducted through case-related queries. Feedback from students and instructors regarding the teaching content, teaching process, and teaching effect was gathered through questionnaires. RESULTS: The findings indicate that the students achieved high marks in all assessed areas, including clinical symptoms, medical examination, pathological processes, diagnostic results, diagnostic basis, and drug use. The feedback from students and instructors on the teaching content, teaching process, and teaching effect was positive. CONCLUSION: Medical educators can use our findings to implement the combined World Café discussion and CBL mode to enhance student engagement.

The cardiovascular system at high altitude: A bibliometric and visualization analysis.

BACKGROUND: When exposed to high-altitude environments, the cardiovascular system undergoes various changes, the performance and mechanisms of which remain controversial. AIM: To summarize the latest research advancements and hot research points in the cardiovascular system at high altitude by conducting a bibliometric and visualization analysis. METHODS: The literature was systematically retrieved and filtered using the Web of Science Core Collection of Science Citation Index Expanded. A visualization analysis of the identified publications was conducted employing CiteSpace and VOSviewer. RESULTS: A total of 1674 publications were included in the study, with an observed annual increase in the number of publications spanning from 1990 to 2022. The United States of America emerged as the predominant contributor, while Universidad Peruana Cayetano Heredia stood out as the institution with the highest publication output. Notably, Jean-Paul Richalet demonstrated the highest productivity among researchers focusing on the cardiovascular system at high altitude. Furthermore, Peter Bärtsch emerged as the author with the highest number of cited articles. Keyword analysis identified hypoxia, exercise, acclimatization, acute and chronic mountain sickness, pulmonary hypertension, metabolism, and echocardiography as the primary research hot research points and emerging directions in the study of the cardiovascular system at high altitude. CONCLUSION: Over the past 32 years, research on the cardiovascular system in high-altitude regions has been steadily increasing. Future research in this field may focus on areas such as hypoxia adaptation, metabolism, and cardiopulmonary exercise. Strengthening interdisciplinary and multi-team collaborations will facilitate further exploration of the pathophysiological mechanisms underlying cardiovascular changes in high-altitude environments and provide a theoretical basis for standardized disease diagnosis and treatment.

Manual Therapy in Primary Dysmenorrhea: A Systematic Review and Meta-Analysis.

Objective: This research aimed to assess the effectiveness of manual therapy in alleviating pain among women undergoing primary dysmenorrhea (PD). Methods: All randomized controlled trials (RCTs) regarding manual therapy for PD were searched from online databases, spanning from their inception to July 2023. The identified literature underwent a thorough screening process, and the data were meticulously extracted and analyzed using RevMan 5.3. Subsequently, the included studies underwent Cochrane's quality assessment and meta-analysis. The evidence obtained was then assessed using the grading of recommendations, assessment, development, and evaluation (GRADE) approach. Results: 32 RCTs, involving 2566 women were finally included for analysis. The overall quality of the concluding evidence was generally rated as low or very low. Performance bias and blind bias were found to be the main risk of bias of the included studies. In comparison to no treatment, manual therapy demonstrated a significant increase in pain relief in short-term (n=191, MD=1.30, 95% CI: 0.24~2.37). The differences in the effects of manual therapy and the placebo on pain intensity may not be statistically significant (n=255, MD=0.10, 95% CI: -0.37~0.58). In contrast to NSAIDs, manual therapy exhibited superior pain alleviation (n=507, MD=3.01, 95% CI: 1.08~4.94) and a higher effective rate (n=1029, OR=4.87, 95% CI: 3.29~7.20). Importantly, no severe adverse events were reported across all studies, indicating a relatively safe profile for manual therapy. Conclusion: Manual therapy presented promise in effectively relieving menstrual pain with minimal adverse events in short term, outperforming both no treatment and NSAIDs. However, this conclusion is tempered by the low quality of the included RCTs, highlighting the necessity for more robust trials to validate it.

Tumor-Targeted Oxaliplatin(IV) Prodrug Delivery Based on ROS-Regulated Cancer-Selective Glycan Labeling.

Platinum-drug-based chemotherapy in clinics has achieved great success in clinical malignancy therapy. However, unpredictable off-target toxicity and the resulting severe side effects in the treatment are still unsolved problems. Although metabolic glycan labeling-mediated tumor-targeted therapy has been widely reported, less selective metabolic labeling in vivo limited its wide application. Herein, a novel probe of B-Ac3ManNAz that is regulated by reactive oxygen species in tumor cells is introduced to enhance the recognition and cytotoxicity of DBCO-modified oxaliplatin(IV) via bioorthogonal chemistry. B-Ac3ManNAz was synthesized from Ac4ManNAz by incorporation with 4-(hydroxymethyl) benzeneboronic acid pinacol ester (HBAPE) at the anomeric position, which is confirmed to be regulated by ROS and could robustly label glycans on the cell surface. Moreover, N3-treated tumor cells could enhance the tumor accumulation of DBCO-modified oxaliplatin(IV) via click chemistry meanwhile reduce the off-target distribution in normal tissue. Our strategy provides an effective metabolic precursor for tumor-specific labeling and targeted cancer therapies.

Energy metabolism analysis of exogenous glutamate on promoting co-accumulation of astaxanthin yield and biomass in Phaffia rhodozyma D3.

Effective metabolic regulators play an essential role in regulating astaxanthin biosynthesis in Phaffia rhodozyma. In this study, it was found that 5 mM glutamate increased the astaxanthin yield and biomass of P. rhodozyma D3 to 22.34 mg/L and 6.12 g/L, which were 1.22 and 1.33 times higher than the control group, respectively. Meanwhile, glucose uptake was increased and the level of reactive oxygen species (ROS) was reduced with 5 mM glutamate. To further explore the interrelationship between glutamate and astaxanthin synthesis, the energy metabolism of P. rhodozyma D3 with and without glutamate was analysed. Glutamate promoted the Embden-Meyerhof-Parnas pathway (EMP) metabolic flux, modulated the tricarboxylic acid (TCA) cycle and the pentose phosphate pathway (PPP), activated the ornithine cycle and purine metabolism, and provided more ATP and NADPH for astaxanthin accumulation. This study clarified the possible mechanism by which glutamate promoted astaxanthin accumulation in P. rhodozyma.

Rhizobial-induced phosphatase GmPP2C61A positively regulates soybean nodulation.

Symbiotic nitrogen fixation (SNF) is crucial for legumes, providing them with the nitrogen necessary for plant growth and development. Nodulation is the first step in the establishment of SNF. However, the determinant genes in soybean nodulation and the understanding of the underlying molecular mechanisms governing nodulation are still limited. Herein, we identified a phosphatase, GmPP2C61A, which was specifically induced by rhizobia inoculation. Using transgenic hairy roots harboring GmPP2C61A::GUS, we showed that GmPP2C61A was mainly induced in epidermal cells following rhizobia inoculation. Functional analysis revealed that knockdown or knock-out of GmPP2C61A significantly reduced the number of nodules, while overexpression of GmPP2C61A promoted nodule formation. Additionally, GmPP2C61A protein was mainly localized in the cytoplasm and exhibited conserved phosphatase activity in vitro. Our findings suggest that phosphatase GmPP2C61A serves as a critical regulator in soybean nodulation, highlighting its potential significance in enhancing symbiotic nitrogen fixation.

Persistent production of multiple active species with copper doped zinc gallate nanoparticles for light-independent photocatalytic degradation of organic pollutants.

Photocatalysis is considered as an environmentally friendly and sustainable method as it can produce active species to degrade pollutants. However, its applications are hindered by the turbidity of pollutants and the requirements for continuous or repeated in situ irradiation. To avoid the need for continuous in situ irradiation in the photocatalytic process, herein we report the doping of Cu(II) ions into zinc gallate (ZnGa2O4) as traps to capture photo-generated electrons. In this way, long lifetime charge release and separation were effectively achieved for the persistent degradation of organic dyes in wastewater. The Cu(II) doped ZnGa2O4 (ZGC) nanoparticles with a small size about 7.7 nm synthesized via a hydrothermal method exhibited a persistent photocatalytic activity with continuous production of reactive oxygen species for at least 96 h without in situ irradiation due to its unique electronic structure and carrier transport path, and enabled to degrade 82.2 % of rhodamine B in 1 h. Further investigation revealed that the doped Cu(II) ions occupied the octahedral sites of ZGC and highly increased the persistent production and availability of active species for the persistent degradation of organic dyes under pre-illuminated conditions.

Effects of Dexmedetomidine Added to Ropivacaine in Ultrasound-Guided Continuous Pericapsular Nerve Group Block Among Elderly Patients Undergoing Total Hip Arthroplasty.

Total hip arthroplasty (THA) is a highly effective intervention for addressing hip joint issues, yet managing perioperative pain remains a significant challenge. In this study, we aimed to investigate the impact of supplementing ropivacaine with dexmedetomidine in ultrasound-guided continuous pericapsular nerve group block (PENGB) among elderly patients undergoing THA. We conducted a retrospective analysis involving 112 elderly patients who underwent THA. These patients were divided into two groups: the Control group, receiving ropivacaine alone, and the DEX group, receiving ropivacaine combined with dexmedetomidine. We evaluated various parameters including hemodynamic data, postoperative pain levels assessed using the Visual Analog Scale, cognitive status measured with the Montreal Cognitive Assessment, and serum markers (S100ß and GFAP). Our findings revealed that the DEX group exhibited improved stability in blood pressure and oxygen saturation following surgery. Moreover, patients in the DEX group reported significantly lower levels of pain at 6 and 12 hours postsurgery, with a prolonged duration of pain relief. Furthermore, dexmedetomidine administration was associated with preserved cognitive function during the early postoperative period. Analysis of serum markers suggested potential cognitive protection conferred by the addition of dexmedetomidine. Overall, our study underscores the multifaceted benefits of incorporating dexmedetomidine into ropivacaine-based PENGB for elderly THA patients.

Synthesis of Metal-Nitrogen-Carbon Electrocatalysts with Atomically Regulated Nitrogen-Doped Polycyclic Aromatic Hydrocarbons.

Tuning the active site structure of metal-nitrogen-carbon electrocatalysts has recently attracted increasing interest. Herein, we report a bottom-up synthesis strategy in which atomically regulated N-doped polycyclic aromatic hydrocarbons (N-PAHs) of NxC42-x (x = 1, 2, 3, 4) were used as ligands to allow tuning of the active site's structures of M-Nx and establish correlations between the structures and electrocatalytic properties. Based on the synthesis process, detailed characterization, and DFT calculation results, active structures of Nx-Fe1-Nx in Fe1-Nx/RGO catalysts were constructed. The results demonstrated that the extra uncoordinated N atoms around the Fe1-N4 moieties disrupted the π-conjugated NxC42-x ligands, which led to more localized electronic state in the Fe1-N4 moieties and superior catalytic performance. Especially, the Fe1-N4/RGO exhibited optimized performance for ORR with E1/2 increasing by 80 mV and Jk at 0.85 V improved 18 times (compared with Fe1-N1/RGO). This synthesis strategy utilizing N-PAHs holds significant promise for enhancing the controllability of metal-nitrogen-carbon electrocatalyst preparation.