RIP1 kinase inactivation protects against LPS-induced acute respiratory distress syndrome in mice.

Acute respiratory distress syndrome (ARDS) is characterized by lung tissue oedema and inflammatory cell infiltration, with limited therapeutic interventions available. Receptor-interacting protein kinase 1 (RIPK1), a critical regulator of cell death and inflammation implicated in many diseases, is not fully understood in the context of ARDS. In this study, we employed RIP1 kinase-inactivated (Rip1K45A/K45A) mice and two distinct RIPK1 inhibitors to investigate the contributions of RIP1 kinase activity in lipopolysaccharide (LPS)-induced ARDS pathology. Our results indicated that RIPK1 kinase inactivation, achieved through both genetic and chemical approaches, significantly attenuated LPS-induced ARDS pathology, as demonstrated by reduced polymorphonuclear neutrophil percentage (PMN%) in alveolar lavage fluid, expression of inflammatory and fibrosis-related factors in lung tissues, as well as histological examination. Results by tunnel staining and qRT-PCR analysis indicated that RIPK1 kinase activity played a role in regulating cell apoptosis and inflammation induced by LPS administration in lung tissue. In summary, employing both pharmacological and genetic approaches, this study demonstrated that targeted RIPK1 kinase inactivation attenuates the pathological phenotype induced by LPS inhalation in an ARDS mouse model. This study enhances our understanding of the therapeutic potential of RIPK1 kinase modulation in ARDS, providing insights for the pathogenesis of ARDS.

Dual CTLA-4 and PD-1 checkpoint blockade using CS1002 and CS1003 (nofazinlimab) in patients with advanced solid tumors: A first-in-human, dose-escalation, and dose-expansion study.

BACKGROUND: This study investigated the safety and efficacy of an anti-CTLA-4 monoclonal antibody (CS1002) as monotherapy and in combination with an anti-PD-1 monoclonal antibody (CS1003) in patients with advanced/metastatic solid tumors. METHODS: The phase 1 study involved phase 1a monotherapy dose-escalation (part 1) and phase 1b combination therapy dose escalation (part 2) and expansion (part 3). Various dosing schedules of CS1002 (0.3, 1, or 3 mg/kg every 3 weeks, or 3 mg/kg every 9 weeks) were evaluated with 200 mg CS1003 every 3 weeks in part 3. RESULTS: Parts 1, 2, and 3 included a total of 13, 18, and 61 patients, respectively. No dose-limiting toxicities or maximum tolerated doses were observed. Treatment-related adverse events (TRAEs) were reported in 30.8%, 83.3%, and 75.0% of patients in parts 1, 2, and 3, respectively. Grade ≥3 TRAEs were experienced by 15.4%, 50.0%, and 18.3% of patients in each part. Of 61 patients evaluable for efficacy, 23 (37.7%) achieved objective responses in multiple tumor types. Higher objective response rates were observed with conventional and high-dose CS1002 regimens (1 mg/kg every 3 weeks or 3 mg/kg every 9 weeks) compared to low-dose CS1002 (0.3 mg/kg every 3 weeks) in microsatellite instability-high/mismatch repair-deficient tumors, melanoma, and hepatocellular carcinoma (50.0% vs. 58.8%, 14.3% vs. 42.9%, and 0% vs. 16.7%). CONCLUSION: CS1002, as monotherapy, and in combination with CS1003, had a manageable safety profile across a broad dosing range. Promising antitumor activities were observed in patients with immune oncology (IO)-naive and IO-refractory tumors across CS1002 dose levels when combined with CS1003, supporting further evaluation of this treatment combination for solid tumors. PLAIN LANGUAGE SUMMARY: CS1002 is a human immunoglobulin (Ig) G1 monoclonal antibody that blocks the interaction of CTLA-4 with its ligands and increases T-cell activation/proliferation. CS1003, now named nofazinlimab, is a humanized, recombinant IgG4 monoclonal antibody that blocks the interaction between human PD-1 and its ligands. In this original article, we determined the safety profile of CS1002 as monotherapy and in combination with CS1003. Furthermore, we explored the antitumor activity of the combination in anti-programmed cell death protein (ligand)-1 (PD-[L]1)-naive microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) pan tumors, and anti-PD-(L)1-refractory melanoma and hepatocellular carcinoma (HCC). CS1002 in combination with CS1003 had manageable safety profile across a broad dosing range and showed promising antitumor activities across CS1002 dose levels when combined with CS1003. This supports further assessment of CS1002 in combination with CS1003 for the treatment of solid tumors.

Bimodal DNA self-origami material with nucleic acid function enhancement.

BACKGROUND: The design of DNA materials with specific nanostructures for biomedical tissue engineering applications remains a challenge. High-dimensional DNA nanomaterials are difficult to prepare and are unstable; moreover, their synthesis relies on heavy metal ions. Herein, we developed a bimodal DNA self-origami material with good biocompatibility and differing functions using a simple synthesis method. We simulated and characterized this material using a combination of oxDNA, freeze-fracture electron microscopy, and atomic force microscopy. Subsequently, we optimized the synthesis procedure to fix the morphology of this material. RESULTS: Using molecular dynamics simulation, we found that the bimodal DNA self-origami material exhibited properties of spontaneous stretching and curling and could be fixed in a single morphology via synthesis control. The application of different functional nucleic acids enabled the achievement of various biological functions, and the performance of functional nucleic acids was significantly enhanced in the material. Consequently, leveraging the various functional nucleic acids enhanced by this material will facilitate the attainment of diverse biological functions. CONCLUSION: The developed design can comprehensively reveal the morphology and dynamics of DNA materials. We thus report a novel strategy for the construction of high-dimensional DNA materials and the application of functional nucleic acid-enhancing materials.

Plasticizer acetyl triethyl citrate (ATEC) induces lipogenesis and obesity.

Environmental chemicals, such as plasticizers, have been linked to increased rates of obesity, according to epidemiological studies. Acetyl triethyl citrate (ATEC) is a plasticizer that is commonly utilized in pharmaceutical products and food packaging as a non-phthalate alternative. Due to its direct contact with the human body and high leakage rate from the polymers, assessment of the potential risk of ATEC exposure at environmentally relevant low doses to human health is needed. Male C57BL/6 J mice were fed diets containing ATEC at doses of either 0.1 or 10 µg/kg per day in a period of 12 weeks to mimic the real exposure environment. The findings suggest that in C57BL/6 J mice, ATEC exposure resulted in increased body weight gain, body fat percentage, and benign hepatocytes, as well as adipocyte size. Consistent with in vivo models, ATEC treatment obviously stimulated the increase of intracellular lipid load in both mouse and human hepatocytes. Mechanically, ATEC induced the transcriptional expression of genes involved in de novo lipogenesis and lipid uptake. Using both enzyme inhibitor and small interfering RNA (siRNA) transfection, we found that stearoyl-coenzyme A desaturase 1 (SCD1) played a significant role in ATEC-induced intracellular lipid accumulation. This study for the first time provided initial evidence suggesting the obesogenic and fatty liver-inducing effect of ATEC at low doses near human exposure levels, and ATEC might be a potential environmental obesogen and its effect on human health need to be further evaluated.

Transmission risk of asymptomatic SARS-CoV-2 infection: a systematic review and meta-analysis.

Background: Global evidence on the transmission of asymptomatic SARS-CoV-2 infection needs to be synthesized. Methods: A search of 4 electronic databases (PubMed, EMBASE, Cochrane Library, and Web of Science databases) as of January 24, 2021 was performed. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Studies which reported the transmission rate among close contacts with asymptomatic SARS-CoV-2 cases were included, and transmission activities occurred were considered. The transmission rates were pooled by zero-inflated beta distribution. The risk ratios (RRs) were calculated using random-effects models. Results: Of 4923 records retrieved and reviewed, 15 studies including 3917 close contacts with asymptomatic indexes were eligible. The pooled transmission rates were 1.79 per 100 person-days (or 1.79%, 95% confidence interval [CI] 0.41%-3.16%) by asymptomatic index, which is significantly lower than by presymptomatic (5.02%, 95% CI 2.37%-7.66%; p<0.001), and by symptomatic (5.27%, 95% CI 2.40%-8.15%; p<0.001). Subgroup analyses showed that the household transmission rate of asymptomatic index was (4.22%, 95% CI 0.91%-7.52%), four times significantly higher than non-household transmission (1.03%, 95% CI 0.73%-1.33%; p=0.03), and the asymptomatic transmission rate in China (1.82%, 95% CI 0.11%-3.53%) was lower than in other countries (2.22%, 95% CI 0.67%-3.77%; p=0.01). Conclusions: People with asymptomatic SARS-CoV-2 infection are at risk of transmitting the virus to their close contacts, particularly in household settings. The transmission potential of asymptomatic infection is lower than symptomatic and presymptomatic infections. This meta-analysis provides evidence for predicting the epidemic trend and promulgating vaccination and other control measures. Registered with PROSPERO International Prospective Register of Systematic Reviews, CRD42021269446; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=269446.

Research trends of acupuncture therapy on stress urinary incontinence from 1992 to 2022: A bibliometric analysis.

Background: Stress urinary incontinence (SUI), the most prevalent type of urinary incontinence disorder, has aroused increasing attention among societies since it has caused much inconvenience in daily life. In addition to conventional conservative treatments like medication and pelvic floor muscle training, acupuncture is now frequently advised. However, a bibliometric analysis of the trend of SUI therapies is still lacking. Objectives: This article was carried out using CiteSpace (6.3.1) software to research the use of acupuncture therapy on SUI worldwide over the past 30 years (since the database's inception). Methods: All related articles included were retrieved from the Web of Science Core Collection. CiteSpace (6.3.1) software was used to analyze the number of publications, countries and institutions, authors and cited authors, and burst keywords to assess the hotspots and trends over the previous three decades. And Microsoft Office Excel 2019 was also used for sorting data and generating tables. Results: The articles were retrieved on August 31, 2022. A total of 108 records with publication dates ranging from 1992 to 2022 were discovered. The annual number of publications generally increased. In the aspect of publication regions, the USA ranked first in centrality, but China had the largest number of publications. The China Academic of Chinese Medical Sciences, Beijing University of Chinese Medicine, and Shanghai University of Traditional Chinese Medicine were the top 3 institutions, according to the institution map. Liu Z (Liu ZS) was the most productive author, and Chen Y ranked first in the centrality. The article published by Liu Z (Liu ZS) in 2017 was the most cited reference. "Bladder neck suspension", "electrical stimulation" and "acupuncture" were popular therapies mentioned among the top ten hot topics. The keywords "therapy", "postprostatectomy incontinence", "muscle", "cell therapy", and "symptom" ranked in the top five on citation burst. The four frontier topics were "efficacy", "symptom", "cell therapy", and "medical technology". Conclusion: This study illustrated that the application of acupuncture on SUI had an increasing acceptance worldwide. Recent research has concentrated mainly on acupuncture and electroacupuncture, however, there is still not enough literature on these topics. The valuable information was provided for acupuncture researchers to identify prospects including potential collaborators, cooperation institutions, hot themes, and research frontiers.

D-LMBmap: a fully automated deep-learning pipeline for whole-brain profiling of neural circuitry.

Recent proliferation and integration of tissue-clearing methods and light-sheet fluorescence microscopy has created new opportunities to achieve mesoscale three-dimensional whole-brain connectivity mapping with exceptionally high throughput. With the rapid generation of large, high-quality imaging datasets, downstream analysis is becoming the major technical bottleneck for mesoscale connectomics. Current computational solutions are labor intensive with limited applications because of the exhaustive manual annotation and heavily customized training. Meanwhile, whole-brain data analysis always requires combining multiple packages and secondary development by users. To address these challenges, we developed D-LMBmap, an end-to-end package providing an integrated workflow containing three modules based on deep-learning algorithms for whole-brain connectivity mapping: axon segmentation, brain region segmentation and whole-brain registration. D-LMBmap does not require manual annotation for axon segmentation and achieves quantitative analysis of whole-brain projectome in a single workflow with superior accuracy for multiple cell types in all of the modalities tested.

A first-in-human phase 1 study of nofazinlimab, an anti-PD-1 antibody, in advanced solid tumors and in combination with regorafenib in metastatic colorectal cancer.

BACKGROUND: We assessed nofazinlimab, an anti-PD-1 antibody, in solid tumors and combined with regorafenib in metastatic colorectal cancer (mCRC). METHODS: This phase 1 study comprised nofazinlimab dose escalation (phase 1a) and expansion (phase 1b), and regorafenib dose escalation (80 or 120 mg QD, days 1-21 of 28-day cycles) combined with 300-mg nofazinlimab Q4W (part 2a) to determine safety, efficacy, and RP2D. RESULTS: In phase 1a (N = 21), no dose-limiting toxicity occurred from 1 to 10 mg/kg Q3W, with 200 mg Q3W determined as the monotherapy RP2D. In phase 1b (N = 87), 400-mg Q6W and 200-mg Q3W regimens were found comparable. In part 2a (N = 14), both regimens were deemed plausible RP2Ds. Fatigue was the most frequent treatment-emergent adverse event (AE) in this study. Any-grade and grade 3/4 nofazinlimab-related AEs were 71.4% and 14.3%, 56.3% and 5.7%, and 57.1% and 21.4% in phases 1a, 1b, and part 2a, respectively. ORRs were 14.3% and 25.3% in phases 1a and 1b, respectively. In part 2a, no patients had radiological responses. CONCLUSIONS: Nofazinlimab monotherapy was well tolerated and demonstrated preliminary anti-tumor activity in multiple tumor types. Regorafenib plus nofazinlimab had a manageable safety profile but was not associated with any response in mCRC. CLINICAL TRIAL REGISTR ATION: Clinicaltrials.gov (NCT03475251).

Hydrophilic nanofibers with aligned topography modulate macrophage-mediated host responses via the NLRP3 inflammasome.

Successful biomaterial implantation requires appropriate immune responses. Macrophages are key mediators involved in this process. Currently, exploitation of the intrinsic properties of biomaterials to modulate macrophages and immune responses is appealing. In this study, we prepared hydrophilic nanofibers with an aligned topography by incorporating polyethylene glycol and polycaprolactone using axial electrospinning. We investigated the effect of the nanofibers on macrophage behavior and the underlying mechanisms. With the increase of hydrophilicity of aligned nanofibers, the inflammatory gene expression of macrophages adhering to them was downregulated, and M2 polarization was induced. We further presented clear evidence that the inflammasome NOD-like receptor thermal protein domain associated protein 3 (NLRP3) was the cellular sensor by which macrophages sense the biomaterials, and it acted as a regulator of the macrophage-mediated response to foreign bodies and implant integration. In vivo, we showed that the fibers shaped the implant-related immune microenvironment and ameliorated peritendinous adhesions. In conclusion, our study demonstrated that hydrophilic aligned nanofibers exhibited better biocompatibility and immunological properties.

Quantification and Distribution of Thiols in Fermented Grains of Sauce-Aroma Baijiu Production Process.

Five volatile thiol compounds (methanethiol, ethanethiol, 2-mercapto-1-ethanol, 2-furfurylthiol, and 2-methyl-3-furanethiol) in fermented grains of sauce-aroma baijiu were determined using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The samples were pre-treated using a modified QuEChERS method. 4,4'-Dithiodipyridine (DTDP) derivatization reaction improved the detectability and stability of volatile thiol compounds. From the end of the first round to the end of the seventh round of fermentation and different fermentation states from the fifth round of fermented grains of the sauce-aroma baijiu production process were analyzed. The results showed that the concentrations of methanethiol (67.64-205.37 µg/kg), ethanethiol (1.22-1.76 µg/kg), 2-furfurylthiol (0.51-3.03 µg/kg), and 2-methyl-3-furanthiol (1.70-12.74 µg/kg) were increased with the number of fermentation rounds. Methanethiol, 2-furfurylthiol, and 2-methyl-3-furanthiol increased during fermentation and distillation in the fifth round. Fermentation and distillation were important stages for their widespread production. After distillation, there were still a large number of volatile thiol compounds in the fermented grains. The thermal reaction was of great significance in the formation of these thiols.

Arthritic Microenvironment-Dictated Fate Decisions for Stem Cells in Cartilage Repair.

The microenvironment and stem cell fate guidance of post-traumatic articular cartilage regeneration is primarily the focus of cartilage tissue engineering. In articular cartilage, stem cells are characterized by overlapping lineages and uneven effectiveness. Within the first 12 weeks after trauma, the articular inflammatory microenvironment (AIME) plays a decisive role in determining the fate of stem cells and cartilage. The development of fibrocartilage and osteophyte hyperplasia is an adverse outcome of chronic inflammation, which results from an imbalance in the AIME during the cartilage tissue repair process. In this review, the sources for the different types of stem cells and their fate are summarized. The main pathophysiological events that occur within the AIME as well as their protagonists are also discussed. Additionally, regulatory strategies that may guide the fate of stem cells within the AIME are proposed. Finally, strategies that provide insight into AIME pathophysiology are discussed and the design of new materials that match the post-traumatic progress of AIME pathophysiology in a spatial and temporal manner is guided. Thus, by regulating an appropriately modified inflammatory microenvironment, efficient stem cell-mediated tissue repair may be achieved.

A green and facile one-step hydration method based on ZIF-8-PDA to prepare melamine composite sponges with excellent hydrophobicity for oil-water separation.

Frequent crude oil spills and illegal discharges of industrial organic pollutants cause serious damage to the ecological environment and considerable loss of valuable resources. Therefore, there is an urgent need to develop efficient strategies to separate and recover oils or reagents from sewage. Herein, a green, facile and rapid one-step hydration method was applied to obtain the composite sponge (ZIF-8-PDA@MS) that monodispersed zeolitic imidazolate framework-8 nanoparticles with high porosity and large specific surface area were firmly loaded onto the melamine sponge by ligand exchange and the self-assembly of dopamine. The water contact angle of ZIF-8-PDA@MS with multiscale hierarchical porous structure could reach 162°, which remained stable over a long period of time and a wide pH range. ZIF-8-PDA@MS displayed excellent adsorption capacities (up to 85.45-168.95 g⋅g-1), and could be reused at least 40 times. Besides, ZIF-8-PDA@MS exhibited remarkable photothermal effect. Simultaneously, Silver nanoparticle-immobilized composite sponges were also prepared via in-situ reduction of silver ions to inhibit bacterial contamination. The composite sponge developed in this work can be used not only for the treatment of industrial sewage, but also for the emergency response of large-scale marine oil spill accidents, which has inestimable practical value for water decontamination.

Assessment of lipid metabolism-disrupting effects of non-phthalate plasticizer diisobutyl adipate through in silico and in vitro approaches.

Diisobutyl adipate (DIBA), as a novel non-phthalate plasticizer, is widely used in various products. However, little effort has been made to investigate whether DIBA might have adverse effects on human health. In this study, we integrated an in silico and in vitro strategy to assess the impact of DIBA on cellular homeostasis. Since numerous plasticizers could activate peroxisome proliferator-activated receptor γ (PPARγ) pathway to interrupt metabolism systems, we first utilized molecular docking to analyze interaction between DIBA and PPARγ. Results indicated that DIBA had strong affinity with the ligand-binding domain of PPARγ (PPARγ-LBD) at Histidine 499. Afterwards, we used cellular models to investigate in vitro effects of DIBA. Results demonstrated that DIBA exposure increased intracellular lipid content in murine and human hepatocytes, and altered transcriptional expression of genes related to PPARγ signaling and lipid metabolism pathways. At last, target genes regulated by DIBA were predicted and enriched for Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Protein-protein interaction (PPI) network and transcriptional factors (TFs)-genes network were established accordingly. Target genes were enriched in Phospholipase D signaling pathway, phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) and Epidermal growth factor receptor (EGFR) signaling pathway which were related to lipid metabolism. These findings suggested that DIBA exposure might disturb intracellular lipid metabolism homeostasis via targeting PPARγ. This study also demonstrated that this integrated in silico and in vitro methodology could be utilized as a high throughput, cost-saving and effective tool to assess the potential risk of various environmental chemicals on human health.

The Efficacy of Electroacupuncture in the Treatment of Knee Osteoarthritis: A Systematic Review and Meta-Analysis.

This study aims to evaluate the comparative efficacy of electroacupuncture (EA) and analgesics in treating knee osteoarthritis (KOA) and provide evidence-based medical support for EA for the treatment of KOA. Randomized controlled trials from January 2012 to December 2021 are included in electronic databases. The Cochrane risk of bias tool for randomized trials is used to assess the risk of bias in the included studies, while the Grading of Recommendations, Assessment, Development and Evaluation is used to assess the quality of evidence. Statistical analyses are performed using Review Manager V5.4. There are 1616 patients from 20 clinical studies, including 849 patients in the treatment group and 767 patients in the control group. The effective rate in the treatment group is significantly higher than in the control group (p < 0.00001). In the treatment group, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) stiffness scores are significantly improved as compared to the control group (p < 0.0001). However, EA is similar to analgesics in improving visual analog scale scores and WOMAC subitems such as pain and joint function. EA is effective in treating KOA because it can significantly improve clinical symptoms and quality of life in KOA patients.

Transcriptomic Study on the Lungs of Broilers with Ascites Syndrome.

Although broiler ascites syndrome (AS) has been extensively studied, its pathogenesis remains unclear. The lack of cardiopulmonary function in broilers causes relative hypoxia in the body; hence, the lung is the main target organ of AS. However, the transcriptome of AS lung tissue in broilers has not been studied. In this study, an AS model was successfully constructed, and lung tissues of three AS broilers and three healthy broilers were obtained for RNA sequencing (RNA-seq) and pathological observation. The results showed that 614 genes were up-regulated and 828 genes were down-regulated in the AS group compared with the normal group. Gene Ontology (GO) functional annotation revealed the following up-regulated genes: FABP4, APLN, EIF2AK4, HMOX1, MMP9, THBS1, TLR4, BCL2; and down-regulated genes: APELA, FGF7, WNT5A, CDK6, IL7, IL7R, APLNR. These genes have attracted much attention in cardiovascular diseases such as pulmonary hypertension. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that multiple metabolic processes were enriched, indicating abnormal lung metabolism of AS in broilers. These findings elucidate the potential genes and signal pathways in the lungs of broilers with AS and provide a potential target for studying the pathogenesis and preventing AS.

Controllable CO2 Reduction or Hydrocarbon Oxidation Driven by Entire Solar via Silver Quantum Dots Direct Photocatalysis.

The current solar-chemical-industry based on semiconductor photocatalyst is impractical. Metal catalysts are extensively employed in thermal- and electro-catalysis industries, but unsuitable for direct-driven photocatalysis. Herein, silver quantum dots (Ag-QDs) are synthesized on support via an in situ photoreduction method, and in situ photocatalysis temperature programmed dynamics chemisorption desorption analyses are designed to demonstrate that Ag-QDs should be the actual photocatalytic sites. The surface plasmon resonance of Ag-QDs could harvests entire visible solar, and the plasmon-driven charge-transfer exhibits opposite directions at the interface when supports are different. Consequently, Ag-QDs could be alternatively regulated as oxidation or reduction active centers. Furthermore, Ag-QDs excite electron tunneling transfer with adsorbate, which does not generate high-energy free-radical intermediates. As a result, the efficiencies of hydrocarbon photooxidation and CO2 photoreduction are improved in several orders of magnitude. Evidently, the Ag-QDs direct photocatalytic technology greatly promotes solar-chemical-industry applications.

Risk of SARS-CoV-2 reinfection: a systematic review and meta-analysis.

This meta-analysis aims to synthesize global evidence on the risk of reinfection among people previously infected with SARS-CoV-2. We systematically searched PubMed, Scopus, Embase and Web of Science as of April 5, 2021. We conducted: (1) meta-analysis of cohort studies containing data sufficient for calculating the incidence rate of SARS-CoV-2 reinfection; (2) systematic review of case reports with confirmed SARS-CoV-2 reinfection cases. The reinfection incidence was pooled by zero-inflated beta distribution. The hazard ratio (HR) between reinfection incidence among previously infected individuals and new infection incidence among infection-naïve individuals was calculated using random-effects models. Of 906 records retrieved and reviewed, 11 studies and 11 case reports were included in the meta-analysis and the systematic review, respectively. The pooled SARS-CoV-2 reinfection incidence rate was 0.70 (standard deviation [SD] 0.33) per 10,000 person-days. The incidence of reinfection was lower than the incidence of new infection (HR = 0.12, 95% confidence interval 0.09-0.17). Our meta-analysis of studies conducted prior to the emergency of the more transmissible Omicron variant showed that people with a prior SARS-CoV-2 infection could be re-infected, and they have a lower risk of infection than those without prior infection. Continuing reviews are needed as the reinfection risk may change due to the rapid evolution of SARS-CoV-2 variants.

Lipid nanoparticle-assisted miR29a delivery based on core-shell nanofibers improves tendon healing by cross-regulation of the immune response and matrix remodeling.

Inferior healing and peritendinous adhesions are the major clinical problems following Achilles tendon injury, leading to impaired motor function and an increased risk of re-rupture. These complications are presumed to be inextricably linked to inflammation and fibroscar formation. Here, microRNA29a is identified as a promising therapeutic target for tendon injury through the cross-regulation of the immune response and matrix remodeling. MiR29a-LNPs were successfully prepared by microfluidic technology. They are then loaded into the core-shell nanofibers to achieve local delivery in the injured tendon, where the shell layer is composed of PELA for anti-adhesion. Our studies reveal that miR29a regulates collagen synthesis and NF-κB activation in tenocytes, and promotes macrophage polarization by inhibiting the inflammasome pathway. In vivo studies of the Achilles tendon-rupture model indicate the best repair in the miR29a group, as evidenced by superior collagen composition and alignment, higher mechanical strength, and better functional recovery. In conclusion, a functionalized anti-adhesive membrane that promotes nascent tendon matrix remodeling and improves the regenerative immune microenvironment is developed for the treatment of tendon injury.

Research on electroacupuncture parameters for knee osteoarthritis based on data mining.

BACKGROUND: Knee osteoarthritis, a common degenerative joint disease, has been widely treated by electroacupuncture in recent years. However, there are too many parameters of the treatment currently, resulting in various applications in clinical practice. This study aims to summarize the optimal stimulation parameters of electroacupuncture for knee osteoarthritis in clinical studies by applying data mining techniques. METHODS: Four databases including Pubmed, Cochrane Library, Embase, and Web of Science were searched for clinical studies on electroacupuncture treating knee osteoarthritis from 2012 to 2021. A database was established by Microsoft Excel 2020 and analyzed by R Version 4.1.1. RESULTS: Forty-six articles were included according to the established criteria. The most used electroacupuncture stimulation parameters were 0.30 mm × 40 mm needle, continuous wave, low frequency of current (mainly 2 Hz), stimulation duration for 30 min per treatment, and frequency of treatment for once a day. Eighteen acupoints were mentioned and the most used ones include Dubi (ST35), Liangqiu (ST34), Neixiyan (EX-LE4), Xuehai (SP10), Yanglingquan (GB34), and Yinlingquan (SP9), and those most generally used acupoints are closely arranged on the Stomach Channel of Foot Yangming. Cluster analysis showed two groups, one for obligatory acupoints and one for adjunctive ones. The association analysis showed the most supported acupoint pair was Liangqiu (ST34) and Xuehai (SP10). CONCLUSIONS: Continuous wave, low frequency of current (2 Hz), 30-min stimulation, and local acupoint selection are frequently used for electroacupuncture treating knee osteoarthritis. Due to the limitations of this study, further research and more standardized, multi-centered, and large-sample clinical trials should be conducted to provide more convincing evidence.

TRPC6 interacted with KCa1.1 channels to regulate the proliferation and apoptosis of glioma cells.

Malignant glioma is the most aggressive and deadliest brain malignancy. TRPC6 and KCa1.1, two ion channels, have been considered as potential therapeutic targets for malignant glioma treatment. TRPC6, a Ca2+-permeable channel, plays a vital role in promoting tumorigenesis and the progression of glioma. KCa1.1, a large-conductance Ca2+-activated channel, is also involved in growth and migration of glioma. However, the underlying mechanism by which these two ion channels promote glioma progression was unclear. In our study, we found that TRPC6 upregulated the expression of KCa1.1, while the immunoprecipitation analysis also showed that TRPC6 interacts with KCa1.1 channels in glioma cells. The currents of KCa1.1 recorded by the whole-cell patch clamp technique were increased by TRPC6 in glioma cells, suggesting that TRPC6 can provide a Ca2+ source for the activation of KCa1.1 channels. It was also suggested that TRPC6 regulates the proliferation and apoptosis of glioma cells through KCa1.1 channels in vitro. Therefore, C6-bearing glioma rats were established to validate the results in vitro. After the administration of paxilline (a specific inhibitor of KCa1.1 channels), TRPC6-dependent growth of glioma was inhibited in vivo. We also found that TRPC6 enhanced co-expression with KCa1.1 in glioma. These all suggested that TRPC6/KCa1.1 signal plays a role in promoting the growth of glioma. Our results provided new evidence for TRPC6 and KCa1.1 as potential targets for glioma treatment.