miRNA-21-5p is an important contributor to the promotion of injured peripheral nerve regeneration using hypoxia-pretreated bone marrow-derived neural crest cells.

JOURNAL/nrgr/04.03/01300535-202501000-00035/figure1/v/2024-05-14T021156Z/r/image-tiff Our previous study found that rat bone marrow-derived neural crest cells (acting as Schwann cell progenitors) have the potential to promote long-distance nerve repair. Cell-based therapy can enhance peripheral nerve repair and regeneration through paracrine bioactive factors and intercellular communication. Nevertheless, the complex contributions of various types of soluble cytokines and extracellular vesicle cargos to the secretome remain unclear. To investigate the role of the secretome and extracellular vesicles in repairing damaged peripheral nerves, we collected conditioned culture medium from hypoxia-pretreated neural crest cells, and found that it significantly promoted the repair of sensory neurons damaged by oxygen-glucose deprivation. The mRNA expression of trophic factors was highly expressed in hypoxia-pretreated neural crest cells. We performed RNA sequencing and bioinformatics analysis and found that miR-21-5p was enriched in hypoxia-pretreated extracellular vesicles of neural crest cells. Subsequently, to further clarify the role of hypoxia-pretreated neural crest cell extracellular vesicles rich in miR-21-5p in axonal growth and regeneration of sensory neurons, we used a microfluidic axonal dissociation model of sensory neurons in vitro, and found that hypoxia-pretreated neural crest cell extracellular vesicles promoted axonal growth and regeneration of sensory neurons, which was greatly dependent on loaded miR-21-5p. Finally, we constructed a miR-21-5p-loaded neural conduit to repair the sciatic nerve defect in rats and found that the motor and sensory functions of injured rat hind limb, as well as muscle tissue morphology of the hind limbs, were obviously restored. These findings suggest that hypoxia-pretreated neural crest extracellular vesicles are natural nanoparticles rich in miRNA-21-5p. miRNA-21-5p is one of the main contributors to promoting nerve regeneration by the neural crest cell secretome. This helps to explain the mechanism of action of the secretome and extracellular vesicles of neural crest cells in repairing damaged peripheral nerves, and also promotes the application of miR-21-5p in tissue engineering regeneration medicine.

Negative family expressiveness and adolescents' externalizing problems: Respiratory sinus arrhythmia as a moderator and anger regulation as a mediator.

Family environment, emotion regulation and biological sensitivity have been shown to be associated with adolescents' externalizing problem behaviours. However, findings regarding respiratory sinus arrhythmia (RSA) reactivity are mixed and sometimes contradictory. This study aims to clarify the roles of RSA reactivity and anger regulation in the relationship between negative family expressiveness (NFE) and adolescents' externalizing behaviour by measuring RSA reactivity during the Parent-Adolescent Interaction Task (PAIT), designed to simulate a naturalistic negative family environment. In this study, 125 Chinese adolescents (M = 13.95 years, SD = 0.95; 48% male) completed questionnaires assessing negative family expressiveness, anger regulation and externalizing problems. Additionally, we collected electrocardiogram and respiration data during both the resting period and a 10-min PAIT. Results showed that anger regulation mediated the relationship between NFE and externalizing problem behaviours. Moreover, adolescents' RSA reactivity moderated this mediation effect, even after controlling for baseline RSA. Greater RSA suppression potentially indicated greater susceptibility, with the relationship between NFE and anger regulation being more pronounced in adolescents with greater RSA suppression compared to those with lesser RSA suppression. These findings highlight the importance of considering physiological systems, especially within the context of adverse family environments, when studying the relationships with externalizing problems.

MAFLD-related hepatocellular carcinoma: Exploring the potent combination of immunotherapy and molecular targeted therapy.

Hepatocellular carcinoma (HCC) is a common cause of cancer-related mortality and morbidity globally, and with the prevalence of metabolic-related diseases, the incidence of metabolic dysfunction-associated fatty liver disease (MAFLD) related hepatocellular carcinoma (MAFLD-HCC) continues to rise with the limited efficacy of conventional treatments, which has created a major challenge for HCC surveillance. Immune checkpoint inhibitors (ICIs) and molecularly targeted drugs offer new hope for advanced MAFLD-HCC, but the evidence for the use of both types of therapy in this type of tumour is still insufficient. Theoretically, the combination of immunotherapy, which awakens the body's anti-tumour immunity, and targeted therapies, which directly block key molecular events driving malignant progression in HCC, is expected to produce synergistic effects. In this review, we will discuss the progress of immunotherapy and molecular targeted therapy in MAFLD-HCC and look forward to the opportunities and challenges of the combination therapy.

Unveiling the Role of Electric Double-Layer in Sulfur Catalysis for Batteries.

The metal-catalyzed sulfur reaction in lithium-sulfur (Li-S) batteries usually suffers from the strong binding of sulfur species to the catalyst surface, which destroys the electric double layer (EDL) region there. This causes rapid catalyst deactivation because it prevents the desorption of sulfur species and mass transport through the EDL is hindered. This work introduces a competitive adsorption factor (fsulfur) as a new indicator to quantify the competitive adsorption of sulfur species in the EDL and proposes an alloying method to change it by strengthening the p-d hybridization of alloying metals with electrolyte solvents. A cobalt-zinc alloy catalyst with a moderate fsulfur lowers the activation energy of the rate-limiting step of the conversion of lithium polysulfides to lithium sulfide, giving a platform capacity proportion that is 96% of the theoretical value and has a greatly improved anti-passivation ability, especially at high sulfur loadings and lean electrolyte conditions (a low E/S ratio of 5 µL mgS -1). A pouch cell using this approach has a high energy density of up to 464 Wh kg-1. Such a competitive adsorption indicator and alloying strategy offer a new guideline for catalyst design and a practical electrocatalysis solution for Li-S batteries.

Aqueous Extract of Wolfberry Alleviates Aging-Related Skeletal Muscle Dysfunction by Modulating PRRs Signaling Pathways and Enhancing DNA Repair.

Aging can lead to a series of degenerative changes in skeletal muscle, which would negatively impact physical activity and the quality of life of the elderly. Wolfberry contains numerous bioactive substances. It's vital to further explore the mechanisms underlying its healthy effects on skeletal muscle function during aging progress. This study discusses the benefits and mechanisms of aqueous extract of wolfberry (AEW) to protect skeletal muscle from aging-related persistent DNA damage based on its anti-inflammatory activity. It is found that AEW improves muscle mass, strength, and endurance, modulates the expression of Atrogin-1, MyH, and MuRF-1, and decreases oxidative stress and inflammation levels in aging mice, which is consistent with the in vitro results. Mechanistically, AEW inhibits the pattern recognition receptors (PRRs) pathway induced by inflammatory gene activation, suggesting its potential in response to DNA damage. AEW is also observed to mitigate chromatin decompaction. Network pharmacology is conducted to analyze the potential targets of AEW in promoting DNA repair. In conclusion, the study shows the anti-aging effects of AEW on skeletal muscle by promoting DNA repair and reducing the transcriptional activity of inflammatory factors. AEW intake may become a potential strategy for strengthening skeletal muscle function in the elderly.

Decellularized Matrices for the Treatment of Tissue Defects: from Matrix Origin to Immunological Mechanisms.

Decellularized matrix transplantation has emerged as a promising therapeutic approach for repairing tissue defects, with numerous studies assessing its safety and efficacy in both animal models and clinical settings. The host immune response elicited by decellularized matrix grafts of natural biological origin plays a crucial role in determining the success of tissue repair, influenced by matrix heterogeneity and the inflammatory microenvironment of the wound. However, the specific immunologic mechanisms underlying the interaction between decellularized matrix grafts and the host immune system remain elusive. This article reviews the sources of decellularized matrices, available decellularization techniques, and residual immunogenic components. It focuses on the host immune response following decellularized matrix transplantation, with emphasis on the key mechanisms of Toll-like receptor, T-cell receptor, and TGF-ß/SMAD signaling in the stages of post-transplantation immunorecognition, immunomodulation, and tissue repair, respectively. Furthermore, it highlights the innovative roles of TLR10 and miR-29a-3p in improving transplantation outcomes. An in-depth understanding of the molecular mechanisms underlying the host immune response after decellularized matrix transplantation provides new directions for the repair of tissue defects.

l-Carnitine relieves cachexia-related skeletal muscle fibrosis by inducing deltex E3 ubiquitin ligase 3L to negatively regulate the Runx2/COL1A1 axis.

BACKGROUND: Cancer cachexia-induced skeletal muscle fibrosis (SMF) impairs muscle regeneration, alters the muscle structure and function, reduces the efficacy of anticancer drugs, diminishes the patient's quality of life and shortens overall survival. RUNX family transcription factor 2 (Runx2), a transcription factor, and collagen type I alpha 1 chain (COL1A1), the principal constituent of SMF, have been linked previously, with Runx2 shown to directly modulate COL1A1 mRNA levels. l-Carnitine, a marker of cancer cachexia, can alleviate fibrosis in liver and kidney models; however, its role in cancer cachexia-associated fibrosis and the involvement of Runx2 in the process remain unexplored. METHODS: Female C57 mice (48 weeks old) were inoculated subcutaneously with MC38 cells to establish a cancer cachexia model. A 5 mg/kg dose of l-carnitine or an equivalent volume of water was administered for 14 days via oral gavage, followed by assessments of muscle function (grip strength) and fibrosis. To elucidate the interplay between the deltex E3 ubiquitin ligase 3L(DTX3L)/Runx2/COL1A1 axis and fibrosis in transforming growth factor beta 1-stimulated NIH/3T3 cells, a suite of molecular techniques, including quantitative real-time PCR, western blot analysis, co-immunoprecipitation, molecular docking, immunofluorescence and Duolink assays, were used. The relevance of the DTX3L/Runx2/COL1A1 axis in the gastrocnemius was also explored in the in vivo model. RESULTS: l-Carnitine supplementation reduced cancer cachexia-induced declines in grip strength (>88.2%, P < 0.05) and the collagen fibre area within the gastrocnemius (>57.9%, P < 0.05). At the 5 mg/kg dose, l-carnitine also suppressed COL1A1 and alpha-smooth muscle actin (α-SMA) protein expression, which are markers of SMF and myofibroblasts. Analyses of the TRRUST database indicated that Runx2 regulates both COL1A1 and COL1A2. In vitro, l-carnitine diminished Runx2 protein levels and promoted its ubiquitination. Overexpression of Runx2 abolished the effects of l-carnitine on COL1A1 and α-SMA. Co-immunoprecipitation, molecular docking, immunofluorescence and Duolink assays confirmed an interaction between DTX3L and Runx2, with l-carnitine enhancing this interaction to promote Runx2 ubiquitination. l-Carnitine supplementation restored DTX3L levels to those observed under non-cachectic conditions, both in vitro and in vivo. Knockdown of DTX3L abolished the effects of l-carnitine on Runx2, COL1A1 and α-SMA in vitro. The expression of DTX3L was negatively correlated with the levels of Runx2 and COL1A1 in untreated NIH/3T3 cells. CONCLUSIONS: This study revealed a previously unrecognized link between Runx2 and DTX3L in SMF and demonstrated that l-carnitine exerted a significant therapeutic impact on cancer cachexia-associated SMF, potentially through the upregulation of DTX3L.

Early detection of multiple endocrine neoplasia type 1: A case report.

BACKGROUND: Multiple endocrine neoplasias (MENs) are a group of hereditary diseases involving multiple endocrine glands, and their prevalence is low. MEN type 1 (MEN1) has diverse clinical manifestations, mainly involving the parathyroid glands, gastrointestinal tract, pancreas and pituitary gland, making it easy to miss the clinical diagnosis. CASE SUMMARY: We present the case of a patient in whom MEN1 was detected early. A middle-aged male with recurrent abdominal pain and diarrhea was admitted to the hospital. Blood tests at admission revealed hypercalcemia and hypophosphatemia, and emission computed tomography of the parathyroid glands revealed a hyperfunctioning parathyroid lesion. Gastroscopy findings suggested a duodenal bulge and ulceration. Ultrasound endoscopy revealed a hypoechoic lesion in the duodenal bulb. Further blood tests revealed elevated levels of serum gastrin. Surgery was performed, and pathological analysis of the surgical specimens revealed a parathyroid adenoma after parathyroidectomy and a neuroendocrine tumor after duodenal bulbectomy. The time from onset to the definitive diagnosis of MEN1 was only approximately 1 year. CONCLUSION: For patients who present with gastrointestinal symptoms accompanied by hypercalcemia and hypophosphatemia, clinicians need to be alert to the possibility of MEN1.

Preoperative albumin-bilirubin score predicts short-term outcomes and long-term prognosis in colorectal cancer patients undergoing radical surgery.

BACKGROUND: The albumin-bilirubin (ALBI) score is a serum biochemical indicator of liver function and has been proven to have prognostic value in a variety of cancers. In colorectal cancer (CRC), a high ALBI score tends to be associated with poorer survival. AIM: To investigate the correlation between the preoperative ALBI score and outcomes in CRC patients who underwent radical surgery. METHODS: Patients who underwent radical CRC surgery between January 2011 and January 2020 at a single clinical center were included. The ALBI score was calculated by the formula (log10 bilirubin × 0.66) + (albumin × -0.085), and the cutoff value for grouping patients was -2.8. The short-term outcomes, overall survival (OS), and disease-free survival (DFS) were calculated. RESULTS: A total of 4025 CRC patients who underwent radical surgery were enrolled in this study, and there were 1908 patients in the low ALBI group and 2117 patients in the high ALBI group. Cox regression analysis revealed that age, tumor size, tumor stage, ALBI score, and overall complications were independent risk factors for OS; age, tumor stage, ALBI score, and overall complications were identified as independent risk factors for DFS. CONCLUSION: A high preoperative ALBI score is correlated with adverse short-term outcomes, and the ALBI score is an independent risk factor for OS and DFS in patients with CRC undergoing radical surgery.

Protocol for analyzing arginase I expression in tumor-associated myeloid-derived suppressor cells from murine colon cancer using flow cytometry.

Arginase1 (ARG1) is a metabolic enzyme that is highly expressed in tumor-associated myeloid-derived suppressor cells (MDSCs) and causes the dysfunction of tumor-reactive T cells. Here, we present a protocol for detecting ARG1 expression in tumor MDSCs from a murine model of colon cancer using flow cytometry. We describe steps for tumor tissue processing, antibody staining, and data acquisition. We then detail procedures for identifying MDSC subsets and detecting ARG1 expression using a precise gating strategy. For complete details on the use and execution of this protocol, please refer to Zhang et al.1.

Unraveling the gut microbiota's role in salt-sensitive hypertension: current evidences and future directions.

The gut microbiota plays a pivotal role in both maintaining human health and in the pathogenesis of diseases. Recent studies have brought to light the significant correlation between gut microbiota and hypertension, particularly focusing on its role in the development and advancement of SSH, a subtype characterized by elevated blood pressure in response to high salt consumption. The complexity of SSH's etiology is notable, with dysbiosis of the gut microbiome identified as a crucial contributing factor. The gut microbiota participates in the occurrence and development of SSH by affecting the host's immune system, metabolic function, and neuromodulation. Investigations have demonstrated that the gut microbes regulate the development of SSH by regulating the TH17 axis and the activity of immune cells. Moreover, microbial metabolites, such as short-chain fatty acids, are implicated in blood pressure regulation and affect the development of SSH. There is evidence to show that the composition of the gut microbiome can be altered through prebiotic interventions so as to prevent and treat SSH. This review aims to concisely sum up the role of gut microbiota in SSH and to discuss pertinent therapeutic strategies and clinical implications, thereby providing a valuable reference for further research and clinical practice in this area.

A single-centre study on abnormal antinuclear antibodies in children caused by intravenous infusion of gamma globulin.

Objective: To clarify the impact of intravenous infusion of gamma globulin (IVIg) on antinuclear antibodies (ANAs) in children. Methods: A retrospective analysis was performed on the data of children with nonspecific autoantibody-related diseases whose antinuclear antibody (ANA) and autoantibody profiles were detected in our hospital from January to March 2022. A total of 108 patients with a clear history of IVIg infusion within 28 days composed the IVIg group, and 1201 patients without a history of IVIg infusion composed the non-IVIg group. Results: All patients in the IVIg group had either positive ANAs or positive autoantibodies. Anti-SSA, anti-Ro52 and anti-AMA Mi2 were the top three autoantibodies in the IVIg group. The proportions of patients who were positive for either of these three autoantibodies in the IVIg group were significantly greater than those in the non-IVIg group (all P<0.5). Spearman correlation analysis revealed that the signal intensities of anti-SSA and anti-Ro52 were negatively correlated with the number of days of ANA detection after IVIg infusion (P<0.05). Multiple logistic analyses revealed that a greater total dosage of IVIg, greater IVIg per kilogram of body weight, and fewer ANA detection days after IVIg infusion were independent risk factors for positive anti-SSA and anti-Ro52 results. Conclusions: It is recommended that if rheumatic diseases are suspected, ANA detection should be carried out beforeIVIg infusion. But for patients who are positive for at least one of these three autoantibodies after IVIg infusion, doctors should first consider adoptive antibodies.

Observation of dynamic non-Hermitian skin effects.

Non-Hermitian physics has emerged as a new paradigm that profoundly changes our understanding of non-equilibrium systems, introducing novel concepts such as exceptional points, spectral topology, and non-Hermitian skin effects (NHSEs). Most existing studies focus on non-Hermitian eigenstates, whereas dynamic properties have been discussed only recently, and the dynamic NHSEs are not yet confirmed in experiments. Here, we report the experimental observation of non-Hermitian skin dynamics using tunable one-dimensional nonreciprocal double-chain mechanical systems with glide-time symmetry. Remarkably, dynamic NHSEs are observed with various behaviors in different dynamic phases, which can be understood via the generalized Brillouin zone and the related concepts. Moreover, the observed dynamic NHSEs, amplifications, bulk unidirectional wave propagation, and boundary wave trapping provide promising ways to manipulate waves in a controllable and robust way. Our findings open a new pathway toward non-Hermitian dynamics, which will fertilize the study of non-equilibrium phases of matter.

Endmember extraction and abundance estimation algorithm based on double-compressed sampling.

Based on double-compressed sampling, a hyperspectral spectral unmixing algorithm (SU_DCS) is proposed, which could directly complete the endmember extraction and abundance estimation. On the basis of the linear mixed model (LMM), we designed spatial and spectral sampling matrices, obtained spatial and spectral measurement data, and constructed a joint unmixing model containing endmember and abundance information. By using operator separation and Lagrangian multiplier algorithm, the endmember matrix, abundance matrix and remixing image can be quickly obtained by matrix operation. The parameters of the unmixing algorithm, including regularization parameter, convergence threshold and spatial sampling rate, are determined using synthetic simulated hyperspectral data. The proposed algorithm is applied to two kinds of real hyperspectral data, with or without ground truth, in order to verify the effectiveness and reliability of the algorithm. Firstly, we provide the performance of the algorithm on real datasets without ground truth. Compared with algorithm VCA_FCLS and algorithm CPPCA_VCA_FCLS, the endmember spectral curve extracted by the proposed SU_DCS is almost consistent with that obtained by VCA_FCLS, and is more smooth than that of obtained by CPPCA_VCA_FCLS. Additionally, the abundance estimation map estimated by the SU_DCS has consistency with the results obtained by VCA_FCLS. Moreover, the proposed SU_DCS has higher peak signal-to-noise ratio (PSNR) for remixing images with higher computational efficiency. Secondly, we provide the performance of the proposed algorithm on four real datasets with ground truth, including dataset Cuprite, dataset Samson, dataset Jasper and dataset Urban. We provide the results of endmember extraction and abundance estimation from the compressed data under different sampling rate conditions. The extracted endmember maintains good consistency with the true spectral curves, and the estimated abundance map can also maintain good spatial consistency with the ground truth. The comparison results with other four comparative algorithms also indicate that the proposed algorithm can obtain relatively accurate endmembers and abundance information from compressed data, the reliability and validity of the proposed algorithm have been proved. In summary, the main innovation of the proposed algorithm is that it can extract endmembers and estimate abundance with high accuracy from a small amount of measurement data.

Signal mining and gender differences analysis of adverse events in NMIBC treatment with gemcitabine and BCG bladder instillation based on the FAERS database.

OBJECTIVE: To explore safety differences and perform a gender-based analysis of adverse events related to gemcitabine and Bacillus Calmette-Guérin (BCG) vaccine using the U.S. FDA Adverse Event Reporting System (FAERS) database. METHODS: Using the Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR) methods, adverse events associated with gemcitabine and BCG were mined from FAERS database reports spanning from Q1 2004 to Q3 2023. RESULTS: The study extracted 37,855 reports with gemcitabine and 5,455 reports with BCG as the primary suspected drugs. Adverse events were more prevalent in males (male-to-female ratio: gemcitabine 1.10, BCG 4.25). Differences in high-frequency adverse events among the top 20 signals were detected for both drugs. Both drugs affected similar organ systems, including potential pulmonary, ocular, and renal toxicity, with gemcitabine showing a broader range of adverse events. Gender analysis revealed fewer adverse reactions to gemcitabine in females, while males had fewer adverse reactions to BCG. CONCLUSION: Differences in high-frequency adverse events between gemcitabine and BCG, including some not listed on drug labels, were observed. Both drugs affect similar organ systems, with gemcitabine showing a broader range of adverse events. Gender differences in adverse events were notable.

Physicians' knowledge, attitudes, and practices regarding fibromyalgia: A systematic review and meta-analysis of cross-sectional studies.

BACKGROUND: The diagnosis, etiology, and optimal management of fibromyalgia remains contentious. This uncertainty may result in variability in clinical management. We conducted a systematic review and meta-analysis of cross-sectional studies examining physicians' knowledge, attitudes, and practices regarding fibromyalgia. METHODS: We searched MEDLINE, Embase, and PubMed from inception to February 2023 for cross-sectional surveys evaluating physicians' attitudes toward, and management of, fibromyalgia. Pairs of independent reviewers conducted article screening, data extraction, and risk of bias assessment in duplicate. We used random-effects meta-analysis to pool proportions for items reported by more than one study and the Grading of Recommendations Assessment, Development, and Evaluation approach to summarize the certainty of evidence. RESULTS: Of 864 citations, 21 studies (8904 participants) were eligible for review. Most physicians endorsed fibromyalgia as a distinct clinical entity (84%; 95% confidence interval [CI], 74-92), and half (51%; 95% CI, 40-62) considered fibromyalgia a psychosocial condition. Knowledge of formal diagnostic criteria for fibromyalgia was more likely among rheumatologists (69%, 95% CI, 45-89) versus general practitioners (38%, 95% CI, 24-54) (P = .04). Symptom relief was endorsed as the primary management goal by most physicians (73%, 95% CI, 52-90). Exercise, physiotherapy, antidepressants, nonsteroidal anti-inflammatory drugs, and non-opioid analgesics were most endorsed for management of fibromyalgia, but with wide variability between surveys. Opioids and most complementary and alternative interventions (e.g., homeopathy, chiropractic, and massage) received limited endorsement. CONCLUSION: There is moderate certainty evidence to suggest that physicians are divided regarding whether fibromyalgia is a biomedical or psychosocial disorder. Physicians typically prioritize symptom relief as the primary goal of management, and often endorse management with exercise, non-opioid analgesics, nonsteroidal anti-inflammatory drugs, antidepressants, and physiotherapy (moderate to high certainty evidence); however, important practice variation exists.

An insoluble cellulose nanofiber with robust expansion capacity protects against obesity.

An imbalance between energy intake and energy expenditure predisposes obesity and its related metabolic diseases. Soluble dietary fiber has been shown to improve metabolic homeostasis mainly via microbiota reshaping. However, the application and metabolic effects of insoluble fiber are less understood. Herein, we employed nanotechnology to design citric acid-crosslinked carboxymethyl cellulose nanofibers (CL-CNF) with a robust capacity of expansion upon swelling. Supplementation with CL-CNF reduced food intake and delayed digestion rate in mice by occupying stomach. Besides, CL-CNF treatment mitigated diet-induced obesity and insulin resistance in mice with enhanced energy expenditure, as well as ameliorated inflammation in adipose tissue, intestine and liver and reduced hepatic steatosis, without any discernible signs of toxicity. Additionally, CL-CNF supplementation resulted in enrichment of probiotics such as Bifidobacterium and decreased in the relative abundances of deleterious microbiota expressing bile salt hydrolase, which led to increased levels of conjugated bile acids and inhibited intestinal FXR signaling to stimulate the release of GLP-1. Taken together, our findings demonstrate that CL-CNF administration protects mice from diet-induced obesity and metabolic dysfunction by reducing food intake, enhancing energy expenditure and remodeling gut microbiota, making it a potential therapeutic strategy against metabolic diseases.

Acidic biofilm microenvironment-responsive ROS generation via a protein nanoassembly with hypoxia-relieving and GSH-depleting capabilities for efficient elimination of biofilm bacteria.

Reactive oxygen species (ROS) are widely considered to the effective therapeutics for fighting bacterial infections especially those associated with biofilm. However, biofilm microenvironments including hypoxia, limited H2O2, and high glutathione (GSH) level seriously limit the therapeutic efficacy of ROS-based strategies. Herein, we have developed an acidic biofilm microenvironment-responsive antibacterial nanoplatform consisting of copper-dopped bovine serum albumin (CBSA) loaded with copper peroxide (CuO2) synthesized in situ and indocyanine green (ICG). The three-in-one nanotherapeutics (CuO2/ICG@CBSA) are capable of releasing Cu2+ and H2O2 in a slightly acidic environment, where Cu2+ catalyzes the conversion of H2O2 into hydroxyl radical (•OH) and consumes the highly expressed GSH to disrupt the redox homeostasis. With the assistance of an 808 nm laser, the loaded ICG not only triggers the production of singlet oxygen (1O2) by a photodynamic process, but also provides photonic hyperpyrexia that further promotes the Fenton-like reaction for enhancing •OH production and induces thermal decomposition of CuO2 for the O2-self-supplying 1O2 generation. The CuO2/ICG@CBSA with laser irradiation demonstrates photothermal-augmented multi-mode synergistic bactericidal effect and is capable of inhibiting biofilm formation and eradicating the biofilm bacteria. Further in vivo experiments suggest that the CuO2/ICG@CBSA can effectively eliminate wound infections and accelerate wound healing. The proposed three-in-one nanotherapeutics with O2/H2O2-self-supplied ROS generating capability show great potential in treating biofilm-associated bacterial infections. STATEMENT OF SIGNIFICANCE: Here, we have developed an acidic biofilm microenvironment-responsive nanoplatform consisting of copper-dopped bovine serum albumin (CBSA) loaded with copper peroxide (CuO2) synthesized in situ and indocyanine green (ICG). The nanotherapeutics (CuO2/ICG@CBSA) are capable of releasing Cu2+ and H2O2 in an acidic environment, where Cu2+ catalyzes the conversion of H2O2 into •OH and consumes the overexpressed GSH to improve oxidative stress. With the aid of an 808 nm laser, ICG provides photonic hyperpyrexia for enhancing •OH production, and triggers O2-self-supplying 1O2 generation. CuO2/ICG@CBSA with laser irradiation displays photothermal-augmented multi-mode antibacterial and antibiofilm effect. Further in vivo experiments prove that CuO2/ICG@CBSA effectively eliminates wound infection and accelerates wound healing. The proposed three-in-one nanotherapeutics show great potential in treating biofilm-associated bacterial infections.

Cataract Surgery and Incidence of Retinal Vascular Occlusion: Population-Based Cohort Study Using a Target Trial Emulation Framework.

BACKGROUND: Previous studies suggested an association between cataract surgery and retinal vascular occlusion. However, the association may be attributable to detection bias because postoperative monitoring may be more frequent for those who receive cataract surgery than for those who do not. DESIGN: Population-based cohort study using target trial emulation framework. METHODS: We included patients with cataract aged 50 years and older receiving cataract surgery or non-surgical interventions identified from the Taiwan National Health Insurance Research Database between 2003 and 2018, matched by propensity score. The primary outcome was retinal vascular occlusion. Cox proportional hazards models were used to compare surgery and control groups. Additional analyses were restricted to patients who had undergone fundoscopic examination within 6 months prior to cataract surgery to address the issue of detection bias. RESULTS: We included 577,129 cataract surgery and control pairs. We found the hazard ratio (HR) for retinal vascular occlusion after cataract surgery was 1.23 (95% confidence interval (CI): 1.17-1.29), compared with the control group. Secondary outcome analyses yielded similar results for retinal artery occlusion (HR: 1.13, 95% CI: 1.02-1.26) and retinal vein occlusion (HR: 1.26, 95% CI: 1.20-1.33). However, no risk of retinal vascular occlusion was observed among patients who had received fundoscopic examinations (HR: 1.06, 95% CI: 0.98-1.15) at baseline. CONCLUSIONS: Our study underscored the importance of conducting complete baseline fundoscopic examinations before cataract surgery to clarify whether postoperative conditions are due to patients' underlying diseases or unintended complications of cataract surgery.

[Molecular biological identification of a case with A223B subtype].

OBJECTIVE: To study the molecular basis for a proband with A subtype B of the ABO blood group and explore the influence of amino acid variant on the activity of glycosyltransferase (GT). METHODS: A proband who had presented at the First Affiliated Hospital of Zhengzhou University on July 2, 2020 was selected as the study subject. Serological identification of the ABO blood groups of the proband and her family members were performed by gel card and test tube methods. The ABO gene of the proband was identified by PCR-sequence specific primers (PCR-SSP) and DNA sequencing. A 3D molecular homologous model was constructed to predict the impact of the variant on the stability of α-(1→3)-D-N-acetylgalactosamine transferase (GTA). RESULTS: The red blood cells of the proband, her mother and two younger brothers showed weak agglutination with anti-A and strong agglutination with anti-B. The sera showed 1~2+ agglutination with Ac and no agglutination with Bc. Based on the serological characteristics, the proband was identified as AwB subtype. Pedigree analysis suggested that the variant was inherited from her mother. The blood group of the proband was identified as A223B type by PCR-SSP. ABO gene sequencing analysis showed that the proband has harbored heterozygous variants of c.297A>G, c.467C>T, c.526C>G, c.657C>T, c.703G>A, c.796C>A, c.803G>C, c.930G>A and c.1055insA. Based on the results of clone sequencing, it was speculated that the genotype was ABO*A223/ABO*B.01. There were c.467C>T and c.1055insA variants compared with ABO*A1.01, and c.1055insA variant compared with ABO*A1.02. Homologous modeling showed that the C-terminal of A223 GT was significantly prolonged, and the local amino acids and hydrogen bond network have changed. CONCLUSION: Above results revealed the molecular genetics mechanism of A223B subtype. The c.1055insA variant carried by the proband may affect the enzymatic activity of GTA and ultimately lead to weakening of A antigen.