Application of Deferoxamine in Tissue Regeneration Attributed to Promoted Angiogenesis.

Deferoxamine, an iron chelator used to treat diseases caused by excess iron, has had a Food and Drug Administration-approved status for many years. A large number of studies have confirmed that deferoxamine can reduce inflammatory response and promote angiogenesis. Blood vessels play a crucial role in sustaining vital life by facilitating the delivery of immune cells, oxygen, and nutrients, as well as eliminating waste products generated during cellular metabolism. Dysfunction in blood vessels may contribute significantly to the development of life-threatening diseases. Anti-angiogenesis therapy and pro-angiogenesis/angiogenesis strategies have been frequently recommended for various diseases. Herein, we describe the mechanism by which deferoxamine promotes angiogenesis and summarize its application in chronic wounds, bone repair, and diseases of the respiratory system. Furthermore, we discuss the drug delivery system of deferoxamine for treating various diseases, providing constructive ideas and inspiration for the development of new treatment strategies.

Intra-Articular Platelet-Rich Plasma Injection After Anterior Cruciate Ligament Reconstruction: A Randomized Clinical Trial.

Importance: Platelet-rich plasma (PRP) has been considered a promising treatment for musculoskeletal disorders. The effects of PRP on clinical outcomes of anterior cruciate ligament reconstruction (ACLR) are controversial. Objective: To compare subjective outcomes and graft maturity in patients undergoing ACLR with and without postoperative intra-articular PRP injection. Design, Setting, and Participants: This surgeon- and investigator-masked randomized clinical trial included patients treated at a national medical center in China who were aged 16 to 45 years and scheduled to undergo ACLR. Participants were enrolled between March 21, 2021, and August 18, 2022, and followed up for 12 months, with the last participant completing follow-up on August 28, 2023. Interventions: Participants were randomized 1:1 to the PRP group (n = 60), which received 3 doses of postoperative intra-articular PRP injection at monthly intervals, or to the control group (n = 60), which did not receive postoperative PRP injection. Both groups had the same follow-up schedule. Main Outcomes and Measures: The primary outcome was the mean score for 4 subscales of the Knee Injury and Osteoarthritis Outcome Score (KOOS4) (range, 0-100, with higher scores indicating better knee function and fewer symptoms) at 12 months postoperatively. Secondary outcomes were patient-reported outcomes, graft maturity (on magnetic resonance imaging), and physical examinations at 3, 6, and 12 months. Results: Among the 120 randomized participants (mean [SD] age, 29.0 [8.0] years; 84 males [70%]), 114 (95%) were available for the primary outcome analysis. The mean KOOS4 scores at 12 months were 78.3 (SD, 12.0; 95% CI, 75.2-81.4) in the PRP group and 76.8 (SD, 11.9; 95% CI, 73.7-79.9) in the control group (adjusted mean between-group difference, 2.0; 95% CI, -2.3 to 6.3; P = .36). Secondary outcomes were not statistically significantly different between the 2 groups except for sports and recreation level and graft maturity at 6 months. Intervention-related adverse events included pain at the injection site and knee swelling after injection. Conclusions and Relevance: In this randomized clinical trial among patients undergoing ACLR, the addition of postoperative intra-articular PRP injection did not result in superior improvement of knee symptoms and function at 12 months compared with no postoperative injection. Further studies are required to determine appropriate indications for PRP in musculoskeletal disorders. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2000040262.

Fibroblast expression of transmembrane protein smoothened governs microenvironment characteristics after acute kidney injury.

The smoothened (Smo) receptor facilitates hedgehog signaling between kidney fibroblasts and tubules during acute kidney injury (AKI). Tubule-derived hedgehog is protective in AKI, but the role of fibroblast-selective Smo is unclear. Here, we report that Smo-specific ablation in fibroblasts reduced tubular cell apoptosis and inflammation, enhanced perivascular mesenchymal cells activities, and preserved kidney function after AKI. Global proteomics of these kidneys identified extracellular matrix proteins, and nidogen-1 glycoprotein in particular, as key response markers to AKI. Intriguingly, Smo was bound to nidogen-1 in cells, suggesting that loss of Smo could impact nidogen-1 accessibility. Phosphoproteomics revealed that the 'AKI protector' Wnt signaling pathway was activated in these kidneys. Mechanistically, nidogen-1 interacted with integrin ß1 to induce Wnts in tubules to mitigate AKI. Altogether, our results support that fibroblast-selective Smo dictates AKI fate through cell-matrix interactions, including nidogen-1, and offers a robust resource and path to further dissect AKI pathogenesis.

T2-weighted imaging-based radiomic-clinical machine learning model for predicting the differentiation of colorectal adenocarcinoma.

BACKGROUND: The study on predicting the differentiation grade of colorectal cancer (CRC) based on magnetic resonance imaging (MRI) has not been reported yet. Developing a non-invasive model to predict the differentiation grade of CRC is of great value. AIM: To develop and validate machine learning-based models for predicting the differentiation grade of CRC based on T2-weighted images (T2WI). METHODS: We retrospectively collected the preoperative imaging and clinical data of 315 patients with CRC who underwent surgery from March 2018 to July 2023. Patients were randomly assigned to a training cohort (n = 220) or a validation cohort (n = 95) at a 7:3 ratio. Lesions were delineated layer by layer on high-resolution T2WI. Least absolute shrinkage and selection operator regression was applied to screen for radiomic features. Radiomics and clinical models were constructed using the multilayer perceptron (MLP) algorithm. These radiomic features and clinically relevant variables (selected based on a significance level of P < 0.05 in the training set) were used to construct radiomics-clinical models. The performance of the three models (clinical, radiomic, and radiomic-clinical model) were evaluated using the area under the curve (AUC), calibration curve and decision curve analysis (DCA). RESULTS: After feature selection, eight radiomic features were retained from the initial 1781 features to construct the radiomic model. Eight different classifiers, including logistic regression, support vector machine, k-nearest neighbours, random forest, extreme trees, extreme gradient boosting, light gradient boosting machine, and MLP, were used to construct the model, with MLP demonstrating the best diagnostic performance. The AUC of the radiomic-clinical model was 0.862 (95%CI: 0.796-0.927) in the training cohort and 0.761 (95%CI: 0.635-0.887) in the validation cohort. The AUC for the radiomic model was 0.796 (95%CI: 0.723-0.869) in the training cohort and 0.735 (95%CI: 0.604-0.866) in the validation cohort. The clinical model achieved an AUC of 0.751 (95%CI: 0.661-0.842) in the training cohort and 0.676 (95%CI: 0.525-0.827) in the validation cohort. All three models demonstrated good accuracy. In the training cohort, the AUC of the radiomic-clinical model was significantly greater than that of the clinical model (P = 0.005) and the radiomic model (P = 0.016). DCA confirmed the clinical practicality of incorporating radiomic features into the diagnostic process. CONCLUSION: In this study, we successfully developed and validated a T2WI-based machine learning model as an auxiliary tool for the preoperative differentiation between well/moderately and poorly differentiated CRC. This novel approach may assist clinicians in personalizing treatment strategies for patients and improving treatment efficacy.

Prevalent arbuscular mycorrhizae in roots and highly variable mycobiome in leaves of epiphytic subtropical fern Ophioderma pendulum.

PREMISE: Endophytic and mycorrhizal fungi are crucial in facilitating plant nutrition acquisition and stress tolerance. In epiphytic habitats, plants face nutrition and water stress, but their roots are mostly nonmycorrhizal and especially lacking in arbuscular mycorrhizal associations. Ophioderma pendulum is an epiphytic fern with a partially mycoheterotrophic lifestyle, likely heavily reliant on symbiotic fungi. To characterize fungal associations in the sporophyte of O. pendulum, we focused on leaves and roots of O. pendulum, seeking to reveal the fungal communities in these organs. METHODS: Roots and leaves from O. pendulum in a subtropical forest were examined microscopically to observe the morphology of fungal structures and determine the percentage of various fungal structures in host tissues. Fungal composition was profiled using metabarcoding techniques that targeted ITS2 of the nuclear ribosomal DNA. RESULTS: Roots were consistently colonized by arbuscular mycorrhizal fungi (Glomeromycota), especially Acaulospora. Unlike previous findings on epiphytic ferns, dark septate endophytes were rare in O. pendulum roots. Leaves were predominantly colonized by Ascomycota fungi, specifically the classes Dothideomycetes (46.88%), Eurotiomycetes (11.51%), Sordariomycetes (6.23%), and Leotiomycetes (6.14%). Across sampling sites, fungal community compositions were similar in the roots but differed significantly in the leaves. CONCLUSIONS: Ophioderma pendulum maintains stable, single-taxon-dominant communities in the roots, primarily featuring arbuscular mycorrhizal fungi, whereas the leaves may harbor opportunistic fungal colonizers. Our study underlines the significance of mycorrhizal fungi in the adaptation of epiphytic ferns.

Water Intake and Adiposity Outcomes among Overweight and Obese Individuals: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Water consumption is believed to be a key factor in weight management strategies, yet the existing literature on the subject yields inconsistent findings. To systematically assess the scientific evidence regarding the effect of water intake on adiposity, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) among overweight and obese populations. METHODS: PubMed and Embase were searched for relevant articles published up to December 2023. The summary weighted mean difference (WMD) and 95% confidence interval (CI) were estimated using the DerSimonian-Laird random-effects model. RESULTS: In this meta-analysis of eight RCTs, interventions to promote water intake or to substitute water for other beverages as compared to the control group resulted in a summary WMD of -0.33 kg (95% CI = -1.75-1.08, I2 = 78%) for body weight, -0.23 kg/m2 (95% CI = -0.55-0.09, I2 = 0%) for body mass index (BMI), and 0.05 cm (95% CI = -1.20-1.30, I2 = 40%) for waist circumference (WC). Among RCTs substituting water for artificially sweetened beverages, summary WMD was 1.82 kg (95% CI = 0.97-2.67, I2 = 0%) for body weight and 1.23 cm (95% CI = -0.03-2.48, I2 = 0%) for WC. Conversely, among RCTs substituting water for sugar-sweetened beverages, summary WMD was -0.81 kg (95% CI = -1.66-0.03, I2 = 2%) for body weight and -0.96 cm (95% CI = -2.06-0.13, I2 = 0%) for WC. CONCLUSIONS: In conclusion, water intake may not significantly impact adiposity among overweight and obese individuals. However, replacing sugar-sweetened beverages with water might offer a modest benefit in inducing weight loss.

FBXO32-mediated degradation of PTEN promotes lung adenocarcinoma progression.

FBXO32, a member of the F-box protein family, is known to play both oncogenic and tumor-suppressive roles in different cancers. However, the functions and the molecular mechanisms regulated by FBXO32 in lung adenocarcinoma (LUAD) remain unclear. Here, we report that FBXO32 is overexpressed in LUAD compared with normal lung tissues, and high expression of FBXO32 correlates with poor prognosis in LUAD patients. Firstly, we observed with a series of functional experiments that FBXO32 alters the cell cycle and promotes the invasion and metastasis of LUAD cells. We further corroborate our findings using in vivo mouse models of metastasis and confirmed that FBXO32 positively regulates LUAD tumor metastasis. Using a proteomic-based approach combined with computational analyses, we found a positive correlation between FBXO32 and the PI3K/AKT/mTOR pathway, and identified PTEN as a FBXO32 interactor. More important, FBXO32 binds PTEN via its C-terminal substrate binding domain and we also validated PTEN as a bona fide FBXO32 substrate. Finally, we demonstrated that FBXO32 promotes EMT and regulates the cell cycle by targeting PTEN for proteasomal-dependent degradation. In summary, our study highlights the role of FBXO32 in promoting the PI3K/AKT/mTOR pathway via PTEN degradation, thereby fostering lung adenocarcinoma progression.

Water intake and obesity: By amount, timing, and perceived temperature of drinking water.

Water intake has been suggested to be associated with weight control, but evidence for optimal water intake in terms of amount, timing, and temperature is sparse. Additionally, genetic predisposition to obesity, which affects satiety and energy expenditure, might interact with water intake in regulating individual adiposity risk. We conducted a cross-sectional study recruiting 172 Korean adults. Information on water intake and lifestyle factors was collected through self-reported questionnaires, and height, weight, and waist circumference (WC) were measured by researchers. The oral buccal swab was performed for genotyping of FTO rs9939609, MC4R rs17782313, BDNF rs6265 and genetic risk of obesity was calculated. Linear regression was performed to estimate mean difference in body mass index (BMI) and WC by water intake and its 95% confidence interval (95% CI). As a sensitivity analysis, logistic regression was performed to estimate odds ratio (OR) of obesity/overweight (BMI of ≥23kg/m2; WC of ≥90cm for men and of ≥80cm for women) and its 95% CI. Drinking >1L/day was significantly associated with higher BMI (mean difference: 0.90, 95% CI 0.09, 1.72) and WC (mean difference: 3.01, 95% CI 0.62, 5.41) compared with drinking ≤1L/day. Independent of total water intake, drinking before bedtime was significantly associated with lower BMI (mean difference: -0.98, 95% CI -1.91, -0.05). The results remained consistent when continuous BMI and WC were analyzed as categorical outcomes. By perceived temperature, drinking >1L/day of cold water was associated with higher BMI and WC compared with drinking ≤1L/day of water at room-temperature. By genetic predisposition to obesity, a positive association between water intake and WC was confined to participants with low genetic risk of obesity (P interaction = 0.04). In conclusion, amount, timing, and perceived temperature of water intake may be associated with adiposity risk and the associations might vary according to genetic predisposition to obesity.

Long-read single-cell RNA sequencing enables the study of cancer subclone-specific genotype and phenotype in chronic lymphocytic leukemia.

Bruton's tyrosine kinase (BTK) inhibitors are effective for the treatment of chronic lymphocytic leukemia (CLL) due to BTK's role in B cell survival and proliferation. Treatment resistance is most commonly caused by the emergence of the hallmark BTKC481S mutation that inhibits drug binding. In this study, we aimed to investigate whether the presence of additional CLL driver mutations in cancer subclones harboring a BTKC481S mutation accelerates subclone expansion. In addition, we sought to determine whether BTK-mutated subclones exhibit distinct transcriptomic behavior when compared to other cancer subclones. To achieve these goals, we employ our recently published method (Qiao et al. 2024) that combines bulk DNA sequencing and single-cell RNA sequencing (scRNA-seq) data to genotype individual cells for the presence or absence of subclone-defining mutations. While the most common approach for scRNA-seq includes short-read sequencing, transcript coverage is limited due to the vast majority of the reads being concentrated at the priming end of the transcript. Here, we utilized MAS-seq, a long-read scRNAseq technology, to substantially increase transcript coverage across the entire length of the transcripts and expand the set of informative mutations to link cells to cancer subclones in six CLL patients who acquired BTKC481S mutations during BTK inhibitor treatment. We found that BTK-mutated subclones often acquire additional mutations in CLL driver genes, leading to faster subclone proliferation. When examining subclone-specific gene expression, we found that in one patient, BTK-mutated subclones are transcriptionally distinct from the rest of the malignant B cell population with an overexpression of CLL-relevant genes.

Magnetic Seizure Therapy vs Modified Electroconvulsive Therapy in Patients With Bipolar Mania: A Randomized Clinical Trial.

Importance: Bipolar mania is a common disabling illness. Electroconvulsive therapy (ECT) is an effective treatment for patients with severe mania, though it is limited by the risk of cognitive adverse effects. Magnetic seizure therapy (MST) as an alternative treatment to ECT for bipolar mania has not yet been reported. Objective: To compare the effectiveness and cognitive adverse effects of MST and ECT in bipolar mania. Design, Setting, and Participants: This randomized clinical trial was conducted at the Shanghai Mental Health Center from July 1, 2017, through April 26, 2021. Forty-eight patients with bipolar mania were recruited and randomly allocated to receive MST or ECT. The data analysis was performed from June 5, 2021, through August 30, 2023. Interventions: Patients completed 2 or 3 sessions of MST or ECT per week for a total of 8 to 10 sessions. The MST was delivered at 100% device output with a frequency of 75 Hz over the vertex. Main Outcomes and Measures: The primary outcomes were reduction of total Young Manic Rating Scale (YMRS) score and response rate (more than 50% reduction of the total YMRS score compared with baseline). An intention-to-treat (ITT) analysis and repeated-measures analyses of variance were conducted for the primary outcomes. Results: Twenty patients in the ECT group (mean [SD] age, 31.6 [8.6] years; 12 male [60.0%]) and 22 patients in the MST group (mean [SD] age, 34.8 [9.8] years; 15 male [68.2%]) were included in the ITT analysis. The response rates were 95.0% (95% CI, 85.4%-100%) in the ECT group and 86.4% (95% CI, 72.1%-100%) in the MST group. The YMRS reduction rate (z = -0.82; 95% CI, -0.05 to 0.10; P = .41) and response rate (χ2 = 0.18; 95% CI, -0.13 to 0.31; P = .67) were not significantly different between the groups. The time-by-group interaction was significant for the language domain (F1,24 = 7.17; P = .01), which was well preserved in patients receiving MST but worsened in patients receiving ECT. No serious adverse effects were reported in either group. Conclusions and Relevance: These findings suggest that MST is associated with a high response rate and fewer cognitive impairments in bipolar mania and that it might be an alternative therapy for the treatment of bipolar mania. Trial Registration: ClinicalTrials.gov Identifier: NCT03160664.

Exact Solution of the Bose-Hubbard Model with Unidirectional Hopping.

A one-dimensional Bose-Hubbard model with unidirectional hopping is shown to be exactly solvable. Applying the algebraic Bethe ansatz method, we prove the integrability of the model and derive the Bethe ansatz equations. The exact eigenvalue spectrum can be obtained by solving these equations. The distribution of Bethe roots reveals the presence of a superfluid-Mott insulator transition at the ground state, and the critical point is determined. By adjusting the boundary parameter, we demonstrate the existence of a non-Hermitian skin effect even in the presence of interaction, but it is completely suppressed for the Mott insulator state in the thermodynamical limit. Our result represents a new class of exactly solvable non-Hermitian many-body systems, which has no Hermitian correspondence and can be used as a benchmark for various numerical techniques developed for non-Hermitian many-body systems.

Paeoniflorin improves ulcerative colitis via regulation of PI3K­AKT based on network pharmacology analysis.

Paeoniflorin (PF) is the primary component derived from Paeonia lactiflora and white peony root and has been used widely for the treatment of ulcerative colitis (UC) in China. UC primarily manifests as a chronic inflammatory response in the intestine. In the present study, a network pharmacology approach was used to explore the specific effects and underlying mechanisms of action of PF in the treatment of UC. A research strategy based on network pharmacology, combining target prediction, network construction, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and molecular docking simulation was used to predict the targets of PF. A total of 288 potential targets of PF and 599 UC-related targets were identified. A total of 60 therapeutic targets of PF against UC were identified. Of these, 20 core targets were obtained by protein-protein interaction network construction. GO and KEGG pathway analyses showed that PF alleviated UC through EGFR tyrosine kinase inhibitor resistance, the IL-17 signaling pathway, and the PI3K/AKT signaling pathway. Molecular docking simulation showed that AKT1 and EGFR had good binding energy with PF. Animal-based experiments revealed that the administration of PF ameliorated the colonic pathological damage in a dextran sulfate sodium-induced mouse model, resulting in lower levels of proinflammatory cytokines including IL-1ß, IL-6, and TNF-α, and higher levels of IL-10 and TGF-ß. PF decreased the mRNA and protein expression levels of AKT1, EGFR, mTOR, and PI3K. These findings suggested that PF plays a therapeutic protective role in the treatment of UC by regulating the PI3K/AKT signaling pathway.

Worldwide productivity and research trend of publications concerning extracellular vesicles role in fibrosis: A bibliometric study from 2013 to 2022.

Background: Fibrosis is a heavy burden on the global healthcare system. Recently, an increasing number of studies have demonstrated that Extracellular vesicles play an important role in intercellular communication under both physiological and pathological conditions. This study aimed to explore the role of extracellular vesicles' in fibrosis using bibliometric methods. Methods: Original articles and reviews related to extracellular vesicles and fibrosis were obtained from the Web of Science Core Collection database on November 9, 2022. VOSviewer was used to obtain general information, including co-institution, co-authorship, and co-occurrence visualization maps. The CiteSpace software was used to analyze citation bursts of keywords and references, a timeline view of the top clusters of keywords and cited articles, and the dual map. R package "bibliometrix" was used to analyze annual production, citation per year, collaboration network between countries/regions, thematic evolution map, and historiography network. Results: In total, 3376 articles related to extracellular vesicles and fibrosis published from 2013 to 2022 were included in this study, with China and the United States being the top contributors. Shanghai Jiao Tong University has the highest number of publications. The main collaborators were Giovanni Camussi, Stefania Bruno, Marta Tepparo, and Cristina Grange. Journals related to molecular, biology, genetics, health, immunology, and medicine tended to publish literature on extracellular vesicles and fibrosis. "Recovery," "heterogeneity," "degradation," "inflammation," and "mesenchymal stem cells" are the keywords in this research field. Literature on extracellular vesicles and fibrosis associated with several diseases, including "kidney disease," "rheumatoid arthritis," and "skin regeneration" may be the latest hot research field. Conclusions: This study provides a comprehensive perspective on extracellular vesicles and fibrosis through a bibliometric analysis of articles published between 2013 and 2022. We identified the most influential countries, institutions, authors, and journals. We provide information on recent research frontiers and trends for scholars interested in the field of extracellular vesicles and fibrosis. Their role in biological processes has great potential to initiate a new upsurge in future research.

Investigating the transcriptomic variances in two phases Ecytonucleospora hepatopenaei (EHP) in Litopenaeus vannamei.

This study explores the transcriptomic differences in two distinct phases of Ecytonucleospora hepatopenaei (EHP) in Litopenaeus vannamei, a crucial aspect in shrimp health management. We employed high-throughput sequencing to categorize samples into two phases, 'Phase A' and 'Phase B', defined by the differential expression of PTP2 and TPS1 genes. Our analysis identified 2057 genes, with 78 exhibiting significant variances, including 62 upregulated and 16 downregulated genes. Enrichment analyses via GO and KEGG pathways highlighted these genes' roles in cellular metabolism, signal transduction, and immune responses. Notably, genes like IQGAP2, Rhob, Pim1, and PCM1 emerged as potentially crucial in EHP's infection process and lifecycle. We hypothesize that these genes may influence trehalose metabolism and glucose provision, impacting the biological activities within EHP during different phases. Interestingly, a lower transcript count in 'Phase A' EHP suggests a reduction in biological activities, likely preparing for host cell invasion. This research provides a foundational understanding of EHP infection mechanisms, offering vital insights for future studies and therapeutic interventions.

A Bayesian framework to study tumor subclone-specific expression by combining bulk DNA and single-cell RNA sequencing data.

Genetic and gene expression heterogeneity is an essential hallmark of many tumors, allowing the cancer to evolve and to develop resistance to treatment. Currently, the most commonly used data types for studying such heterogeneity are bulk tumor/normal whole-genome or whole-exome sequencing (WGS, WES); and single-cell RNA sequencing (scRNA-seq), respectively. However, tools are currently lacking to link genomic tumor subclonality with transcriptomic heterogeneity by integrating genomic and single-cell transcriptomic data collected from the same tumor. To address this gap, we developed scBayes, a Bayesian probabilistic framework that uses tumor subclonal structure inferred from bulk DNA sequencing data to determine the subclonal identity of cells from single-cell gene expression (scRNA-seq) measurements. Grouping together cells representing the same genetically defined tumor subclones allows comparison of gene expression across different subclones, or investigation of gene expression changes within the same subclone across time (i.e., progression, treatment response, or relapse) or space (i.e., at multiple metastatic sites and organs). We used simulated data sets, in silico synthetic data sets, as well as biological data sets generated from cancer samples to extensively characterize and validate the performance of our method, as well as to show improvements over existing methods. We show the validity and utility of our approach by applying it to published data sets and recapitulating the findings, as well as arriving at novel insights into cancer subclonal expression behavior in our own data sets. We further show that our method is applicable to a wide range of single-cell sequencing technologies including single-cell DNA sequencing as well as Smart-seq and 10x Genomics scRNA-seq protocols.

METFORMIN MITIGATES SEPSIS-ASSOCIATED PULMONARY FIBROSIS BY PROMOTING AMPK ACTIVATION AND INHIBITING HIF-1α-INDUCED AEROBIC GLYCOLYSIS.

ABSTRACT: Recent research has revealed that aerobic glycolysis has a strong correlation with sepsis-associated pulmonary fibrosis (PF). However, at present, the mechanism and pathogenesis remain unclear. We aimed to test the hypothesis that the adenosine monophosphate-activated protein kinase (AMPK) activation and suppression of hypoxia-inducible factor 1α (HIF-1α)-induced aerobic glycolysis play a central role in septic pulmonary fibrogenesis. Cellular experiments demonstrated that lipopolysaccharide increased fibroblast activation through AMPK inactivation, HIF-1α induction, alongside an augmentation of aerobic glycolysis. By contrast, the effects were reversed by AMPK activation or HIF-1α inhibition. In addition, pretreatment with metformin, which is an AMPK activator, suppresses HIF-1α expression and alleviates PF associated with sepsis, which is caused by aerobic glycolysis, in mice. Hypoxia-inducible factor 1α knockdown demonstrated similar protective effects in vivo . Our research implies that targeting AMPK activation and HIF-1α-induced aerobic glycolysis with metformin might be a practical and useful therapeutic alternative for sepsis-associated PF.

Biomimetic Hydrogel Containing Copper Sulfide Nanoparticles and Deferoxamine for Photothermal Therapy of Infected Diabetic Wounds.

Inducing cell migration from the edges to the center of a wound, promoting angiogenesis, and controlling bacterial infection are very important for diabetic wound healing. Incorporating growth factors and antibiotics into hydrogels for wound dressing is considered a potential strategy to meet these requirements. However, some present drawbacks greatly slow down their development toward application, such as the short half-life and high price of growth factors, low antibiotic efficiency against drug-resistant bacteria, insufficient ability of hydrogels to promote cell migration, etc. Deferoxamine (DFO) can upregulate the expression of HIF-1α, thus stimulating the secretion of angiogenesis-related endogenous growth factors. Copper sulfide (CuS) nanoparticles possess excellent antibacterial performance combined with photothermal therapy (PTT). Herein, DFO and CuS nanoparticles are incorporated into a biomimetic hydrogel, which mimics the structure and function of the extracellular matrix (ECM), abbreviated as DFO/CuS-ECMgel. This biomimetic hydrogel is expected to be able to promote cell adhesion and migration, be degraded by cell-secreted matrix metalloproteinases (MMPs), and then release DFO and CuS nanoparticles at the wound site to exert their therapeutic effects. As a result, the three crucial requirements for diabetic wound healing, "beneficial for cell adhesion and migration, promoting angiogenesis, effectively killing drug-resistant bacteria," can be achieved simultaneously.

The Value of Minimal Clinically Important Difference, Substantial Clinical Benefit, and Patient-Acceptable Symptomatic State for Commonly Used Patient-Reported Outcomes in Recurrent Patellar Instability Patients After Medial Patellofemoral Ligament Reconstruction and Tibial Tubercle Transfer.

PURPOSE: To identify the minimal clinically important difference (MCID), substantial clinical benefit (SCB) and patient-acceptable symptomatic state (PASS) for commonly used patient-reported outcomes (PROs) in recurrent patellar instability patients after medial patellofemoral ligament reconstruction (MPFLR) and tibial tubercle transfer (TTT), and to determine the impact of potential prognostic factors on the likelihood of achieving these values. METHODS: From April 2015 to February 2021, patients who underwent MPFLR and TTT were retrospectively reviewed. PROs included Kujala, Knee Injury and Osteoarthritis Outcome (KOOS), Lysholm, International Knee Documentation Committee (IKDC), and Tegner score. Relevant anchor questions were provided. A distribution- or anchor-based method was adopted to determine the MCID, SCB, and PASS. Minimal detectable change (MDC) was included to confirm the validity. Univariate regression analyses were conducted to determine the potential prognostic factors. RESULTS: One hundred forty-two patients were included. The MCID were 9.1 (Kujala), 11.1 (Lysholm), 0.9 (Tegner), 9.9 (IKDC), 9.0 (KOOS-Pain), 10.8 (KOOS-Symptoms), 10.0 (KOOS-Activities of Daily Living [ADL]), 17.8 (KOOS-Sports and Recreation [Sports/Rec]), and 12.7 (KOOS-Quality of Life [QoL]). The SCB were 14.5 (Kujala), 12.5 (Lysholm), 1.5 (Tegner), 14.5 (IKDC), 13.9 (KOOS-Pain), 14.3 (KOOS-Symptoms), 18.4 (KOOS-ADL), 47.5 (KOOS-Sports/Rec), and 15.0 (KOOS-QoL). The PASSs were 85.5 (Kujala), 75.5 (Lysholm), 3.5 (Tegner), 73.2 (IKDC), 87.5 (KOOS-Pain), 73.2 (KOOS-Symptoms), 92.0 (KOOS-ADL), 77.5 (KOOS-Sports/Rec), and 53.1 (KOOS-QoL). All SCBs were valid except KOOS-QoL. All MCIDs were valid at the 95% confidence interval (CI) except KOOS scores, the majority of which were valid at the 90% CI. A younger age was an independent prognostic factor of reaching PASS for Lysholm, IKDC, Tegner, and KOOS-ADL score. A higher baseline score was a negative prognostic factor for achieving MCID or SCB but had a slightly positive influence on the achievement of PASS. CONCLUSIONS: This study established the MCID, SCB, and PASS for commonly used PROs and confirmed their validity in recurrent patellar instability patients after MPFLR and TTT. Younger age and lower baseline scores were prognostic factors of achieving MCID and SCB, whereas patients with higher baseline scores were more likely to report satisfaction. LEVEL OF EVIDENCE: Level III, retrospective comparative prognostic trial.

A simple joint detection platform for high-throughput single-cell heterogeneity screening.

Single cell heterogeneity plays an important role in many biological phenomena and distinguishing cells that exhibit certain mutation in sample could benefit clinical diagnose and drug screening. Typical single cell detection methods such as flow cytometry, in-situ hybridization, real-time amplification or sequencing test either protein or nucleic acid as target and usually require specialized instruments. Joint measurement of the both types of targets could be done by combining the above strategies precisely but also unwieldly. Methods for rapidly and parallelly screening single cells with target genotype and antigen is needed. In this study, we describe a gel plate platform to distinguish cell types based on their phenotypes on target gene and antigen with low equipment requirement. Integrated cell lysis and immobilization were done in the gel solidification step, after which antibody hybridization and real-time amplification were sequentially carried out without losing the original loci information of individual single cells so the three types of information of individual single cells could be combined to distinguished cells with expected genotype and phenotype. The easy-to-use gel platform has potential in point-of-care circumstances and single-cell stimulation response that have high requirements on efficiency and simplicity.

Longitudinal Changes in Overall 3D Supraspinatus Muscle Volume and Intramuscular Fatty Infiltration After Arthroscopic Rotator Cuff Repair.

BACKGROUND: There is considerable debate regarding the longitudinal changes in overall rotator cuff (RC) muscle atrophy and intramuscular fatty infiltration (FI) following RC repair. We analyzed the longitudinal changes in overall 3D supraspinatus muscle volume and intramuscular FI (3D FI) to determine the effect of tear size and repair integrity on 3D muscle volume and intramuscular FI. METHODS: Forty-seven patients who underwent arthroscopic RC repair and had 6-point Dixon shoulder magnetic resonance imaging (MRI) preoperatively and 3 and 12 months postoperatively were enrolled. The 3D supraspinatus muscle volume and intramuscular FI were calculated at the 3 time points, and their changes over time were evaluated in the entire cohort as well as according to tear size and repair integrity. The agreement of the difference between time points among the patients was assessed by Bland-Altman analysis. RESULTS: In the cohort as a whole, there were no significant longitudinal changes in the 3D supraspinatus volume (19.65 ± 7.26 to 19.48 ± 7.46 cm 3 , p = 0.911) or 3D FI (17.18% ± 8.85% to 17.30% ± 9.18%, p = 0.977) from preoperatively to the final 12-month time point, overall and in the tear size and repair integrity subgroups. The 3D supraspinatus volume was significantly decreased at 3 months (17.39 ± 6.12 cm 3 , p < 0.001) but then increased again by 12 months (p < 0.001), reaching a value similar to the preoperative level. The 3D FI had a small increase at 3 months (18.18% ± 9.65%, p = 0.097) but subsequently decreased slightly again (p = 0.211), such that there were no significant longitudinal changes. The differences in the 3D supraspinatus volume and FI between these time points showed high agreement among patients. CONCLUSIONS: The overall 3D supraspinatus volume and 3D FI showed no longitudinal change between the preoperative baseline and the 12-month follow-up after arthroscopic RC repair. Tear size and repair integrity had no impact on the longitudinal patterns of muscle volume and intramuscular FI changes. The 3D supraspinatus volume decreased during the first 3 months but recovered to baseline at 12 months postoperatively; 3D FI was relatively stable throughout the 12 months of follow-up after repair. LEVEL OF EVIDENCE: Therapeutic Level II . See Instructions for Authors for a complete description of levels of evidence.