Identifying the role of carrier overflow and injection current efficiency in a GaN-based micro-LED efficiency droop model.

In this paper, we investigate the efficiency droop phenomenon in green and blue GaN-based micro-LEDs of various sizes. We discuss the distinct carrier overflow performance in green and blue devices by examining the doping profile extracted from capacitance-voltage characterization. By combining the size-dependent external quantum efficiency with the ABC model, we demonstrate the injection current efficiency droop. Furthermore, we observe that the efficiency droop is induced by injection current efficiency droop, with green micro-LEDs exhibiting a more pronounced droop due to more severe carrier overflow compared to blue micro-LEDs.

Co-occurrence of gut microbiota dysbiosis and bile acid metabolism alteration is associated with psychological disorders in Crohn's disease.

This study aims to elucidate the relationships between gut microbiota, bile acid metabolism, and psychological comorbidity in Crohn's disease (CD). We profiled the fecal microbiota composition and quantified the bile acid pool of 39 CD patients and 14 healthy controls using 16S rRNA gene sequencing and liquid chromatography-tandem mass spectrometry, respectively. Significant reductions in the secondary bile acids, LCA and DCA, were found in both the feces and serum samples of CD patients, while the concentration of 7-DHCA was particularly higher in the serum of CD patients with psychological disorders. The fecal levels of HDCA and 12-DHCA of the CD patients were inversely correlated with their Self-Rated Depression Scale (SDS) scores, whereas the serum level of 7-DHCA was positively correlated with the SDS scores. In addition, the fecal levels of TDCA, TLCA, and TßMCA showed a positive correlation with the Self-Rated Anxiety Scale (SAS) scores. The fecal microbiota biodiversity was particularly declined in CD patients with psychological disorders. An enrichment of Ruminococcus gnavus in CD patients may cause psychological disorders by affecting the microbiota-gut-brain axis via its ability to degrade the gut barrier, regulate the tryptophan-kynurenine metabolism, and modulate bile acid metabolism. In addition, the overabundant Enterobacteriaceae and Lachnospiraceae in CD patients may contribute to psychological comorbidity via dysregulating their bile acids metabolism. Taken together, changes in the gut microbiota composition may cooperate with alterations in the bile acid metabolism that are involved in the development of psychological disorders in CD.

Spatiotemporal Patterns of Five Small Heat Shock Protein Genes in Hyphantria cunea in Response to Thermal Stress.

Hyphantria cunea (Drury), a destructive polyphagous pest, has been spreading southward after invading northern China, which indicates that this insect species is facing a huge thermal challenge. Small heat shock proteins (sHSPs) function as ATP-independent molecular chaperones that protect insects from heat stress damage. In order to explore the role of sHSPs in the thermotolerance of H. cunea, five novel sHSP genes of H. cunea were cloned, including an orthologous gene (HcHSP21.4) and four species-specific sHSP genes (HcHSP18.9, HcHSP20.1, HcHSP21.5, and HcHSP29.8). Bioinformatics analysis showed that the proteins encoded by these five HcHSPs contained typical α-crystallin domains. Quantitative real-time PCR analysis revealed the ubiquitous expression of all HcHSPs across all developmental stages of H. cunea, with the highest expression levels in pupae and adults. Four species-specific HcHSPs were sensitive to high temperatures. The expression levels of HcHSPs were significantly up-regulated under heat stress and increased with increasing temperature. The expression levels of HcHSPs in eggs exhibited an initial up-regulation in response to a temperature of 40 °C. In other developmental stages, the transcription of HcHSPs was immediately up-regulated at 30 °C or 35 °C. HcHSPs transcripts were abundant in the cuticle before and after heat shock. The expression of HcHSP21.4 showed weak responses to heat stress and constitutive expression in the tissues tested. These results suggest that most of the HcHSPs are involved in high-temperature response and may also have functions in the normal development and reproduction of H. cunea.

Transcranial magneto-acoustic stimulation improves spatial memory and modulates hippocampal neural oscillations in a mouse model of Alzheimer's disease.

Introduction: In our study, we applied transcranial magneto-acoustic stimulation (TMAS), a technique based on focused ultrasound stimulation within a static magnetic field, in the APP/PS1 mouse model of Alzheimer's disease (AD) to explore the feasibility of TMAS on improving AD related spatial memory deficits and abnormal neural oscillations. Methods: The mice treated with TMAS once daily for 21 days. We recorded local field potential signals in the hippocampal CA1 region of the mice after TMAS treatment with in-vivo electrophysiology and evaluated the neural rehabilitative effect of TMAS with sharp-wave ripple (SWR), gamma oscillations during SWRs, and phase-amplitude coupling (PAC). The spatial memory function of the mice was examined by the Morris water maze (MWM) task. Results: We found that TMAS improved the performance of MWM related spatial cognitive functions compared with AD group. Furthermore, our results implied that TMAS alleviated abnormalities in hippocampal SWRs, increased slow gamma power during SWRs, and promoted theta-slow gamma phase-amplitude coupling. These findings suggest that TMAS could have a positive influence on spatial memory through the modulation of neural oscillations. Discussion: This work emphasizes the potential of TMAS to serve as a non-invasive method for Alzheimer's disease rehabilitation and promote the application of TMAS for the treatment of more neurological and brain aging diseases in the future.

A novel ratiometric fluorescent probe with high selectivity for lysosomal nitric oxide imaging.

Nitric oxide (NO) plays critical roles in both physiology and pathology, serving as a significant signaling molecule. Recent investigations have uncovered the pivotal role of lysosome as a critical organelle where intracellular NO exists and takes function. In this study, we developed a novel ratiometric fluorescent probe called XL-NO and modified it with a morpholine unit, which followed the intramolecular charge transfer (ICT) mechanism. The probe could detect lysosomal nitric oxide with high selectivity and sensitivity. The probe XL-NO contained a secondary amine moiety that could readily react with NO in lysosomes, leading to the formation of the N-nitrosation product. The N-nitroso structure enhanced the capability in push-pull electron, which obviously led to the change of fluorescence from 621 nm to 521 nm. In addition, XL-NO was discovered to have some evident advantages, such as significant ratiometric signal (I521/I621) change, strong anti-interference ability, good biocompatibility, and a low detection limit (LOD = 44.3 nM), which were crucial for the detection of lysosomal NO. To evaluate the practical application of XL-NO, NO imaging experiments were performed in both living cells and zebrafish. The results from these experiments confirmed the feasibility and reliability of XL-NO for exogenous/endogenous NO imaging and lysosome targeting.

Mitigating phospholipid peroxidation of macrophages in stress-induced tumor microenvironment by natural ALOX15/PEBP1 complex inhibitors.

BACKGROUND: The intricate interactions between chronic psychological stress and susceptibility to breast cancer have been recognized, yet the underlying mechanisms remain unexplored. Danzhi Xiaoyao Powder (DZXY), a traditional Chinese medicine (TCM) formula, has found clinical utility in the treatment of breast cancer. Macrophages, as the predominant immune cell population within the tumor microenvironment (TME), play a pivotal role in orchestrating tumor immunosurveillance. Emerging evidence suggests that lipid oxidation accumulation in TME macrophages, plays a critical role in breast cancer development and progression. However, a comprehensive understanding of the pharmacological mechanisms and active components of DZXY related to its clinical application in the treatment of stress-aggravated breast cancer remains elusive. PURPOSE: This study sought to explore the plausible regulatory mechanisms and identify the key active components of DZXY contributing to its therapeutic efficacy in the context of breast cancer. METHODS: Initially, we conducted an investigation into the relationship between the phagocytic capacity of macrophages damaged by psychological stress and phospholipid peroxidation using flow cytometry and LC-MS/MS-based phospholipomics. Subsequently, we evaluated the therapeutic efficacy of DZXY based on the results of the tumor size, tumor weight, the phospholipid peroxidation pathway and phagocytosis of macrophage. Additionally, the target-mediated characterization strategy based on binding of arachidonate 15-lipoxygenase (ALOX15) to phosphatidylethanolamine-binding protein-1 (PEBP1), including molecular docking analysis, microscale thermophoresis (MST) assay, co-immunoprecipitation analysis and activity verification, has been further implemented to reveal the key bio-active components in DZXY. Finally, we evaluated the therapeutic efficacy of isochlorogenic acid C (ICAC) based on the results of tumor size, tumor weight, the phospholipid peroxidation pathway, and macrophage phagocytosis in vivo. RESULTS: The present study demonstrated that phospholipid peroxides, as determined by LC-MS/MS-based phospholipidomics, triggered in macrophages, which in turn compromised their capacity to eliminate tumor cells through phagocytosis. Furthermore, we elucidate the mechanism behind stress-induced PEBP1 to form a complex with ALOX15, thereby mediating membrane phospholipid peroxidation in macrophages. DZXY, demonstrates potent anti-breast cancer therapeutic effects by disrupting the ALOX15/PEBP1 interaction and inhibiting phospholipid peroxidation, ultimately enhancing macrophages' phagocytic capability towards tumor cells. Notably, ICAC emerged as a promising active component in DZXY, which can inhibit the ALOX15/PEBP1 interaction, thereby mitigating phospholipid peroxidation in macrophages. CONCLUSION: Collectively, our findings elucidate stress increases the susceptibility of breast cancer by driving lipid peroxidation of macrophages and suggest the ALOX15/PEBP1 complex as a promising intervention target for DZXY.

Adjuvant therapy in completely resected, EGFR-mutant non-small cell lung cancer: a comparative analysis of treatment efficacy between EGFR-TKI and anti-PD-1/PD-L1 immunotherapy.

The IMpower010 and KEYNOTE-091 trials have demonstrated the benefit of adjuvant immunotherapy (IO) after chemotherapy (C+IO) in resected non-small cell lung cancer (NSCLC), including those with epidermal growth factor receptor gene (EGFR) mutation. Meanwhile, several studies have reported that EGFR-tyrosine kinase inhibitor (EGFR-TKI) may prolong disease-free survival (DFS) in these patients. However, there is currently a lack of head-to-head comparison between these two adjuvant therapy strategies. Therefore, we designed a comparative analysis of their efficacy to inform clinical decision-making by assessing DFS as the primary outcome. The results of direct meta-analysis indicated that EGFR-TKI reduced the risk of recurrence and/or death in completely resected NSCLC (HREGFR-TKI/chemo = 0.41, 95% CI: 0.23 to 0.74, p=0.003), while C+IO did not significantly improve DFS compared with chemotherapy alone (HRC+IO/chemo=0.68, 95% CI: 0.31 to 1.50, p=0.338). Indirect comparison suggested that EGFR-TKI has a trend to prolong DFS compared with C+IO (HR EGFR-TKI/C+IO = 0.60, 95% CI: 0.23 to 1.61, p=0.312), while the third-generation TKI (3rd-TKI) osimertinib significantly outperformed C+IO (HR3rd-TKI/C+IO = 0.29, 95% CI: 0.12 to 0.70, p=0.006). In conclusion, osimertinib rather than immunotherapy should be regarded as the preferred adjuvant therapy in completely resected, EGFR-mutant NSCLC.

A ferroptosis-targeting ceria anchored halloysite as orally drug delivery system for radiation colitis therapy.

Radiation colitis is the leading cause of diarrhea and hematochezia in pelvic radiotherapy patients. This work advances the pathogenesis of radiation colitis from the perspective of ferroptosis. An oral Pickering emulsion is stabilized with halloysite clay nanotubes to alleviate radiation colitis by inhibiting ferroptosis. Ceria nanozyme grown in situ on nanotubes can scavenge reactive oxygen species, and deferiprone was loaded into the lumen of nanotubes to relieve iron stress. These two strategies effectively inhibit lipid peroxidation and rescue ferroptosis in the intestinal microenvironment. The clay nanotubes play a critical role as either a medicine to alleviate colitis, a nanocarrier that targets the inflamed colon by electrostatic adsorption, or an interfacial stabilizer for emulsions. This ferroptosis-based strategy was effective in vitro and in vivo, providing a prospective candidate for radiotherapy protection via rational regulation of specific oxidative stress.

Efficacy and safety of PD-1 inhibitors combined with chemotherapy as first-line therapy for advanced esophageal cancer: A systematic review and network meta-analysis.

BACKGROUND: Different clinical trials for advanced esophageal cancer have investigated diverse immuno-oncology combinational treatment in first-line setting, but the optimal choice has not been identified. METHODS: We used PubMed, Embase, and Cochrane Library databases for systematic retrieval. The primary endpoint was overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and treatment-related adverse events (AEs) between immune checkpoint inhibitors combined with chemotherapy and chemotherapy. RESULTS: A total of five phase-III randomized controlled trials involving 3,163 patients met the inclusion criteria. Significantly improved OS (HR: 0.69, 95% CI: 0.62-0.76, P＜0.001), PFS (HR: 0.62, 95% CI: 0.55-0.70, P < 0.001) and ORR (RR: 1.41, 95% CI: 1.23-1.62, P＜0.001) were observed when programmed death 1 (PD-1) inhibitor was added to chemotherapy. Toripalimab plus chemotherapy achieved the best OS benefit than any other treatment examined (HR: 0.58, 95% CI: 0.43-0.78). The longest PFS was founded in both sintilimab-chemotherapy and camrelizumab-chemotherapy combination (HR: 0.56, 95% CI: 0.46-0.68). Patients treated with nivolumab-chemotherapy got the best ORR improvement as compared to other combinations (RR: 1.73, 95% CI:1.40-2.14). Camrelizumab-chemotherapy and pembrolizumab-chemotherapy caused a relatively lower incidence of grade ≥ 3 AEs than other immunotherapy combination regimens. Subgroup analyses suggested significant OS advantage in programmed death-ligand 1(PD-L1) tumor-positive score (TPS) ≥ 10% groups and obviously longer PFS in PD-L1 combined positive score (CPS) ≥ 10 groups. CONCLUSIONS: In advanced esophageal cancer, PD-1 inhibitors combined with chemotherapy as first-line therapy have better survival outcomes than chemotherapy with greater but manageable toxicity. Toripalimab-chemotherapy showed the best OS benefit over chemotherapy, while sintilimab-chemotherapy and camrelizumab-chemotherapy generated the best PFS. The highest ORR improvement was founded in patients receiving nivolumab plus chemotherapy.

Maternal diets have effects on intestinal mucosal flora and susceptibility to colitis of offspring mice during early life.

OBJECTIVES: Intestinal flora is considered closely related to the occurrence of inflammatory bowel disease (IBD). This study aimed to discover whether diverse diet conditions during early life lead to different intestinal flora structure and impact different susceptibility to IBD. METHODS: We performed a randomized, controlled trial to investigate the relationship between maternal diet, intestinal flora, and susceptibility of IBD in offspring mice. We treated the maternal mice with different dietary conditions (maternal high fat, high protein, or normal diet, and offspring continued maternal diets or changed to normal diet), and then extracted bacterial meta-genomic DNA from the intestinal mucosa of the offspring during the early life and adult stages. We amplified and sequenced the conserved gene v3-v4 of the bacterial 16 S ribosomal RNA. After dextran sulphate sodium intervention, we evaluated the susceptibility to intestinal inflammation with hematoxylin and eosin stains and disease activity index scores. RESULTS: The number of species and alpha diversity of weaning mice (3 wk old) fed a maternal high-protein diet were significantly lower than those of the control diet group (P < 0.05). Among adult (8 wk old) offspring rats, the alpha diversity of mice that continued on a high-protein diet remained significantly decreased (P < 0.05). In addition, 12 kinds of weak bacteria were found in weaning mice fed a maternal high-protein diet compared with the control group. Offspring that continued in the maternal high-protein group had increased disease activity index and pathologic scores after weaning. CONCLUSIONS: In general, our study shows that a maternal high-protein diet during early life can negatively regulate the intestinal flora diversity of offspring mice. A high-protein diet during early life led to higher susceptibility of IBD in offspring rats.

Leveraging the multivalent p53 peptide-MdmX interaction to guide the improvement of small molecule inhibitors.

Overexpressed Mdm2 and its 7homolog MdmX impair p53 activity in many cancers. Small molecules mimicking a p53 peptide can effectively inhibit Mdm2 but not MdmX. Here, we show a strategy for improving lead compounds for Mdm2 and MdmX inhibition based on the multivalency of the p53 peptide. Crystal structures of MdmX complexed with nutlin-3a, a strong Mdm2 inhibitor but a weak one for MdmX, reveal that nutlin-3a fits into the ligand binding pocket of MdmX mimicking the p53 peptide. However, due to distinct flexibility around the MdmX ligand binding pocket, the structures are missing many important intermolecular interactions that exist in the MdmX/p53 peptide and Mdm2/nultin-3a complexes. By targeting these flexible regions, we identify allosteric and additive fragments that enhance the binding affinity of nutlin-3a for MdmX, leading to potent Mdm2/MdmX inhibitors with anticancer activity. Our work provides a practical approach to drug design for signal transduction therapy.

Psychosomatic Disorders in Patients with Gastrointestinal Diseases: Single-Center Cross-Sectional Study of 1186 Inpatients.

OBJECTIVE: To investigate the prevalence of anxiety and depression in hospitalized patients in the Department of Gastroenterology and to explore the risk factors affecting psychosomatic conditions in patients with digestive disorders. METHODS: Patients hospitalized with gastrointestinal diseases were enrolled by the Department of Gastroenterology of Xiangya Hospital of Central South University from November 2017 to June 2018 and completed a cross-sectional questionnaire survey. According to anxiety/nonanxiety, depression/nondepression, the subjects were divided into two groups, respectively, and the risk factors of anxiety/depression were analyzed. RESULTS: A total of 1186 patients were included in this study. The overall detection rate was 20.74% for anxiety symptoms alone, 31.78% for depressive symptoms alone, 13.99% for both anxiety and depressive symptoms, and 38.53% for either depression or anxiety symptoms. The prevalence of anxiety symptoms was higher in female than in male patients and inversely correlated with levels of education. There was no significant difference in the detection rate of anxiety and depression between patients with functional and organic digestive diseases. Sleep quality and quality of life were inversely correlated with the severity of anxiety and depression. Notably, among the patients with abnormal psychological conditions, only 7.6% of them were willing to receive psychological treatment. Gender, sleep quality, and life quality are independent risk factors for anxiety and depression symptoms for inpatients with gastrointestinal diseases. CONCLUSION: Paying more attention to the education level, sleep quality, and quality of life in patients with gastrointestinal diseases will help doctors to identify the risk of psychological abnormalities and improve medical care.

Development and validation of predictive models for Crohn's disease patients with prothrombotic state: a 6-year clinical analysis.

BACKGROUND: Crohn's disease (CD) is a chronic idiopathic inflammatory disease. Studies show that multiple risk factors during disease progression can lead to a prothrombotic state (PTS), which predisposes the patient to thrombosis. Therefore, predicting PTS can help identify patients at risk of thrombosis. The aim of our study was to classify CD patients through D-dimer levels, and construct a prediction model for PTS. METHODS: The clinical and laboratory data parameters were extracted from a retrospective observational cohort. The factors significantly associated with PTS were determined by univariate analysis, and the importance rankings were calculated. Two multivariate models were then constructed using these factors to predict PTS in CD using logistic regression and random forest analysis. RESULTS: A total of 744 CD patients were included in the study, of which 116 were in PTS. The significant PTS-related factors were older patients, isolated colonic involvement, penetrating behavior, fever symptom, disease activity, abdominal surgery, lymphocyte counts, hematocrit levels, erythrocyte sedimentation rate, C-reactive protein, hematocrit, mean corpuscular volume levels and albumin. Multivariate logistic regression and random forest models predicted PTS with the accuracy of 89.73% and 90.63% respectively, and the corresponding AUC were 0.76 and 0.84. CONCLUSIONS: Two predictive models based on clinical and laboratory variables accurately identified CD patients with PTS with high precision.

Assessment of sarcopenia as a predictor of poor overall survival for advanced non-small-cell lung cancer patients receiving salvage anti-PD-1 immunotherapy.

BACKGROUND: Sarcopenia, which is defined as the loss of skeletal muscle mass, has been identified as a poor prognostic factor for cancer patients. This study sought to elucidate the effects of sarcopenia on the outcomes of advanced non-small cell lung cancer (NSCLC) patients receiving salvage anti-programmed death-1 (PD-1) immunotherapy. METHODS: In total, 105 NSCLC patients receiving second-line anti-PD-1 immunotherapy at the Sun Yat-sen University Cancer Center between January 2015 and December 2017 were enrolled in this study, and detailed patient data were collected. Available lumbar computed tomography images of the patients were analyzed to determine the total skeletal muscle cross-section area. The efficacy of the predictive and prognostic role of sarcopenia in progression-free survival (PFS) and overall survival (OS) was analyzed using the Kaplan-Meier method, and the risk factors were analyzed using Cox analyses. RESULTS: We found that patients with sarcopenia receiving salvage anti-PD-1 immunotherapy had significantly worse PFS (2.67 vs. 7.96 months; P<0.001) and OS (9.08 vs. 21.84 months; P<0.001) than their non-sarcopenic counterparts. We also found that sarcopenia was associated with the neutrophil-to-lymphocyte ratio (NLR) (P=0.041), and that the NLR acts as a predictor of OS. CONCLUSIONS: Sarcopenia was associated with a poor prognosis in advanced NSCLC patients receiving salvage anti-PD-1 immunotherapy. Further research needs to be conducted to identify more biomarkers and the patients most likely to benefit from immunotherapy.