Association of parathyroid hormone with risk of hypertension and type 2 diabetes: a dose-response meta-analysis.

BACKGROUND: Despite an increase in parathyroid hormone (PTH) has been reported to be associated with a higher risk of hypertension and type 2 diabetes (T2D), the comprehensive evaluation of the dose-response relationship between PTH and hypertension and T2D remains ambiguous. Therefore, a dose-response meta-analysis was performed to quantitatively investigate this association. METHODS: PubMed, Web of Science, and Embase were systematically searched up to May 2023. Random-effect models were used to estimate the summary odds ratios (ORs) and 95% confidence intervals (CIs). Restricted cubic splines were used to model the dose-response association. RESULTS: Ten articles (including 13 studies) were identified, with a total of 11,878 cases and 51,234 participants in the meta-analysis. Of these studies, eight (five cohort and three cross-sectional) studies investigated the association of PTH with hypertension; five (two cohort and three cross-sectional) studies assessed the association of PTH with T2D. The results showed a positive relationship between PTH and the risk of hypertension (OR,1.24, 95% CI: 1.16-1.33). We found a linear association between PTH and hypertension (Pnon-linearity= 0.222). In the dose-response analysis, the risk of hypertension increased 5% for every 10 pg/ml increase in PTH (OR,1.05, 95% CI: 1.02-1.08). The pooled OR of T2D risk for a 10 pg/ml increase in PTH was 1.00 (95% CI: 0.98-1.02). CONCLUSIONS: Elevated PTH is associated with an increased risk of hypertension. However, the evidence of the association between PTH and T2D is limited, and more well-designed studies need to be explored.

Scavenger receptor-AI targeted theranostic nanoparticles for regression of atherosclerotic plaques via ABCA1 modulation.

ATP-binding cassette transporter A1 (ABCA1) plays a crucial role in atherosclerotic formation through mediated cholesterol efflux in macrophage-derived foam cells. In this study, a scavenger receptors AI (SR-AI) targeted theranostic nanoparticles was constructed for atherosclerosis regression via ABCA1 activation in foam cells. ABCA1-upregulator 5242331 and IR780 were encapsulated in PLGA-PEG micelles which were conjugated with SR-AI targeting peptide (PP1) to formulate the nanoparticles (SAU-NPs). Immunostaining revealed that SR-AI was highly expressed both in macrophage foam cells and in atherosclerotic plaque of ApoE-/- mice. The SAU-NPs have shown more active targeting to plaque lesion with higher stability compared with non-SR-AI targeted nanoparticles. The transformation from macrophage to foam cells was inhibited by SAU-NPs carried 5242331. Cholesterol deposition was effectively reduced in foam cells by SAU-NPs through activating the LXRα-ABCA1/ABCG1/SR-BI pathway. In conclusion, theranostic SAU-NPs which carried ABCA1-upregulator 5242331 exert beneficial effects on atherosclerosis regression via LXRα activation.

Empowered But Isolated: A Qualitative Research on Experiences of Family Caregivers of Patients With Acute Heart Failure in China.

BACKGROUND: Family caregivers play crucial roles in the self-management of patients with heart failure (HF). However, little is known about caregiving experiences of Chinese family caregivers during acute HF. OBJECTIVE: The aim of this study was to describe Chinese family caregivers' experiences in symptom management and care-seeking during acute HF. METHODS: This is an exploratory, qualitative study using the Consolidated Criteria for Reporting Qualitative Research guidelines. Data were collected through semistructured interviews and analyzed with thematic analysis. FINDINGS: A total of 21 family caregivers of patients with acute HF were enrolled in this study. "Empowered but isolated" was identified as the overarching theme during data analysis, including 3 themes and 6 subthemes: (1) "Responsible symptom managers: leading the home-based symptom management," including 2 subthemes, "Proxy in symptom management" and "Only knowing the surface, instead of the truth"; (2) "Powerless anchors: care-seeking is a torturous journey," including 2 subthemes, "Facing discrepancies in care-seeking" and "Seeing a doctor is the last choice"; (3) "Carrying the weight forward: responsibility combing with emotional burnout," including 2 subthemes, "Living on tenterhooks" and "Submitting to fate." CONCLUSIONS: In this study, we described Chinese family caregivers' experiences in symptom management and care-seeking during acute HF. Although empowered as proxy, they were also isolated bearing a great burden, receiving insufficient support from patients, family, and the medical system.

Selection of rice and maize varieties with low cadmium accumulation and derivation of soil environmental thresholds in karst.

Cadmium (Cd) is considered the primary dietary toxic element. Previous studies have demonstrated significant differences in heavy metal accumulation among crop species. However, this information in karst areas with low heavy metal activity is missing. In this study, the uptake and accumulation characteristics of cadmium in soil-crop samples of group 504 in the core karst region of East Asia were analyzed. Cadmium low-accumulating maize and rice were screened using cluster and Pareto analytic methods. In addition, a new method, the species-sensitive distribution model (SSD), was proposed, which could be used to estimate the environmental threshold for cadmium in regional cropland. The results showed that both maize and rice soils in the research area were contaminated with varying degrees of cadmium. The total concentrations of cadmium ω(T-Cd) in maize and rice fields are 0.18-1.32 and 0.20-4.42 mg kg-1, respectively. The ω(T-Cd) of heavy metals in maize kernels and rice grains is 0.002-0.429 and 0.003-0.393 mg kg-1, respectively. The bioaccumulation factor (BCF) of cadmium in maize ranged from 0.0079 to 0.9701, with a coefficient of variation of 1.71; the BCF of cadmium in rice ranged from 0.0074 to 0.1345, with a coefficient of variation of 0.99. According to cluster and Pareto analyses, the maize crop varieties with low cadmium accumulation suitable for local cultivation were screened as JHY809, JDY808, AD778, SN3H and SY13, and the rice varieties were DMY6188, GY725, NY6368, SY451 and DX4103. In addition, the environmental cadmium threshold ranges of 0.30-10.05 mg kg-1 and 0.89-24.39 mg kg-1 for maize and rice soils, respectively, were deduced in this study. This threshold will ensure that 5-95% of maize and rice will not be contaminated with cadmium in the soil.

Characteristics of workplace violence, responses and their relationship with the professional identity among nursing students in China: a multicenter cross-sectional study.

BACKGROUND: Nursing students are one of the most vulnerable groups suffering from workplace violence. This study aimed to investigate the workplace violence incidence of Chinese nursing students during clinical practice, to describe the characteristics of violence and students' responses and to analyse the relationship between the experience of workplace violence and professional identity. METHODS: A cross-sectional study was conducted among 954 nursing students in ten universities in China through convenience sampling. Workplace violence was surveyed through Hospital Workplace Violence Questionnaire for Nursing Students. Students' professional identity was measured by Professional Identity Questionnaire for Nursing Students. Statistical methods included descriptive statistics, chi-square test, independent-samples t-test, analysis of variance and linear regression analysis. RESULTS: It was found that the incidence of workplace violence among nursing students was 42.98%. The violent incidents ranking from high to low were: verbal abuse, threat, physical attack, sexual harassment, and gathering disturbance. The majority of the nursing students chose to avoid the conflict during the incident. 86.34% of the students didn't report the incidents. More than half of the victims developed post-traumatic stress disorder after the incidents. Regression analysis results showed that workplace violence experience (ß = - 0.076, P < 0.05) was a significantly negative predictor of professional identity. CONCLUSIONS: Chinese nursing students were exposed to physical and psychological violence during clinical practice with insufficient coping solutions and psychological adjustment. The professional identity of the nursing students was significantly associated with the experience of workplace violence.

Dynamic Effect of Organic Fertilizer Application on Rice Growth, Soil Physicochemical Properties and Cd Activity Exposed to Excess Cd.

To investigate the dynamic effects of organic fertilizer application on the agronomic traits of rice (Oryza sativa L.), soil physicochemical properties and soil Cd activity under excess cadmium (Cd) exposure, this study was conducted to simulate a paddy system under different organic fertilizer application rates using exogenous spiked Cd soil as the test soil and conducting a rice pot experiment. The obtained results showed that the application of organic fertilizer increased the number of rice tillers, rice plant height, total grain number and total grain weight at maturity in all treated soils, while it decreased the concentration of Cd in brown rice. The application of organic fertilizer increased the organic matter (OM), redox potential and electrical conductivity of all treated soils but decreased the pH and TCLP-extractable Cd of all treated soils. There was a significant or highly significant negative correlation (p < 0.05 or p < 0.01) between soil TCLP-extractable Cd and soil OM throughout the experimental period, implying that soil OM may be an important factor influencing the changes in Cd activity in soil. In addition, our experiment also examined in detail the dynamic change process of the abovementioned indicators throughout the experimental period and observed that the dynamic change process of soil Cd activity could be described as a trend of first decreasing and then gradually increasing throughout the rice reproductive period.

Characteristics of Clinical Trials relating to COVID-19 registered at ClinicalTrials.gov.

WHAT IS KNOWN AND OBJECTIVE: Since the beginning of the COVID-19 outbreak in China in December 2019, the epidemic has continued to spread globally. Despite continuous reports of clinical trials being launched, no studies have yet systematically summarized and analysed their characteristics. Our objective is to do this by reviewing trials registered at ClinicalTrials.gov. METHODS: We searched the ClinicalTrials.gov database and retrieved all clinical trials on COVID-19 registered up to and including 3 April 2020. We summarized the characteristics of the trials, presenting the results of all trials, all intervention trials and drug intervention (including vaccines and traditional Chinese medicine) trials. RESULTS AND DISCUSSION: We identified 306 COVID-19-related clinical trials. Seven of the studies had been withdrawn, leaving 299 active trials. Of the trials, 28.8% were planned to be conducted in Asia, 26.8% in Europe and 18.7% in North America. Most (73.0%) proposed trials expected to recruit fewer than 500 people, and only 22.1% of the studies included children (aged <18 years). About two-thirds (67.2%) of the studies were funded by the own resources of medical or research institutions. Of intervention trials, 73.9% used random allocation, and 73.4% used parallel assignment. Only 36.7% of the intervention trials used blinding. In terms of drug trials, 147 trials were drug intervention studies, covering 80 conventional drugs and seven traditional Chinese medicine drugs. Antiviral drugs and antimalarial drugs were the most commonly studied drugs with 52 and 45 trials registered, respectively. Five registered clinical trials were on vaccines. WHAT IS NEW AND CONCLUSION: A large number of COVID-19-related trials have been registered within the first 4 months since the first infection was reported. These involve a large number of different drugs, the most common being antiviral drugs and antimalarial drugs. More attention should be paid to adequate blinding in future trials.

Direct Single Molecule Imaging of Enhanced Enzyme Diffusion.

Recent experimental results have shown that enzymes can diffuse faster when they are in the presence of their reactants (substrate). This faster diffusion has been termed enhanced diffusion. Fluorescence correlation spectroscopy (FCS), which has been employed as the only method to make these measurements, relies on analyzing the fluctuations in fluorescence intensity to measure the diffusion coefficient of particles. Recently, artifacts in FCS measurements due to its sensitivity to environmental conditions have been evaluated, calling prior enhanced diffusion results into question. It behooves us to adopt complementary and direct methods to measure the mobility of enzymes. Herein, we use a technique of direct single molecule imaging to observe the diffusion of individual enzymes in solution. This technique is less sensitive to intensity fluctuations and deduces the diffusion coefficient directly based on the trajectory of the enzyme. Our measurements recapitulate that enzyme diffusion is enhanced in the presence of its substrate and find that the relative increase in diffusion of a single enzyme is even higher than those previously reported using FCS. We also use this complementary method to test if the total enzyme concentration affects the relative increase in diffusion and if the enzyme oligomerization state changes during its catalytic turnover. We find that the diffusion increase is independent of the total concentration of enzymes and the presence of substrate does not change the oligomerization state of enzymes.

Activation of melatonin receptor 2 but not melatonin receptor 1 mediates melatonin-conferred cardioprotection against myocardial ischemia/reperfusion injury.

Accumulated pieces of evidence have proved the beneficial effects of melatonin on myocardial ischemia/reperfusion (MI/R) injury, and these effects were largely dependent on melatonin membrane receptor activation. In humans and other mammals, there are two types of melatonin receptors, including the melatonin receptor 1 (MT1, melatonin receptor 1a or MTNR1A) and melatonin receptor 1 (MT2, melatonin receptor 1b or MTNR1B) receptor subtypes. However, which receptor mediates melatonin-conferred cardioprotection remains unclear. In this study, we employed both loss-of-function and gain-of-function approaches to reveal the answer. Mice (wild-type; MT1 or MT2 silencing by in vivo minicircle vector; and those overexpressing MT1 or MT2 by in vivo AAV9 vector) were exposed to MI/R injury. Both MT1 and MT2 were present in wild-type myocardium. MT2, but not MT1, was essentially upregulated after MI/R Melatonin administration significantly reduced myocardial injury and improved cardiac function after MI/R Mechanistically, melatonin treatment suppressed MI/R-initiated myocardial oxidative stress and nitrative stress, alleviated endoplasmic reticulum stress and mitochondrial injury, and inhibited myocardial apoptosis. These beneficial actions of melatonin were absent in MT2-silenced heart, but not the MT1 subtype. Furthermore, AAV9-mediated cardiomyocyte-specific overexpression of MT2, but not MT1, mitigated MI/R injury and improved cardiac dysfunction, which was accompanied by significant amelioration of oxidative stress, endoplasmic reticulum stress, and mitochondrial dysfunction. Mechanistically, MT2 protected primary cardiomyocytes against hypoxia/reoxygenation injury via MT2/Notch1/Hes1/RORα signaling. Our study presents the first direct evidence that the MT2 subtype, but not MT1, is a novel endogenous cardiac protective receptor against MI/R injury. Medications specifically targeting MT2 may hold promise in fighting ischemic heart disease.

High KIF2A expression predicts unfavorable prognosis in diffuse large B cell lymphoma.

Kinesin family member 2A (KIF2A), a conserved motor protein, plays a critical role in the pathogenesis and prognosis of several malignant tumors. The aim of the present study was to investigate KIF2A expression in diffuse large B cell lymphoma (DLBCL), evaluate the association between KIF2A expression and the clinical parameters of the disease, and determine its prognostic value. KIF2A expression was evaluated in 134 DLBCL and 57 reactive hyperplasia samples using immunohistochemistry on a tissue microarray. The correlations between KIF2A expression with clinical parameters and prognosis were estimated using univariate and multivariate analyses. The expression of KIF2A was significantly higher in DLBCL tissue samples compared with those from subjects with reactive hyperplasia (P=0.002). Furthermore, increased expression of KIF2A protein in DLBCL was related to Ann Arbor stage (P=0.027) and international prognostic index (IPI) score (P=0.01). The survival analysis showed that KIF2A expression (P=0.016), serum LDH level (P=0.049), and IPI score (P<0.001) were independent prognostic markers for DLBCL. Our findings also confirmed that downregulating KIF2A expression decreased tumor cell viability, accompanied by downregulation of pAKT levels. Taken together, these data provide the first evidence that increased KIF2A expression predicts poor prognosis in patients with DLBCL, and a rationale for treatment of DLBCL by targeting KIF2A.

MEF-UNet: An end-to-end ultrasound image segmentation algorithm based on multi-scale feature extraction and fusion.

Ultrasound image segmentation is a challenging task due to the complexity of lesion types, fuzzy boundaries, and low-contrast images along with the presence of noises and artifacts. To address these issues, we propose an end-to-end multi-scale feature extraction and fusion network (MEF-UNet) for the automatic segmentation of ultrasound images. Specifically, we first design a selective feature extraction encoder, including detail extraction stage and structure extraction stage, to precisely capture the edge details and overall shape features of the lesions. In order to enhance the representation capacity of contextual information, we develop a context information storage module in the skip-connection section, responsible for integrating information from adjacent two-layer feature maps. In addition, we design a multi-scale feature fusion module in the decoder section to merge feature maps with different scales. Experimental results indicate that our MEF-UNet can significantly improve the segmentation results in both quantitative analysis and visual effects.

Advances in the isolation, cultivation, and identification of gut microbes.

The gut microbiome is closely associated with human health and the development of diseases. Isolating, characterizing, and identifying gut microbes are crucial for research on the gut microbiome and essential for advancing our understanding and utilization of it. Although culture-independent approaches have been developed, a pure culture is required for in-depth analysis of disease mechanisms and the development of biotherapy strategies. Currently, microbiome research faces the challenge of expanding the existing database of culturable gut microbiota and rapidly isolating target microorganisms. This review examines the advancements in gut microbe isolation and cultivation techniques, such as culturomics, droplet microfluidics, phenotypic and genomics selection, and membrane diffusion. Furthermore, we evaluate the progress made in technology for identifying gut microbes considering both non-targeted and targeted strategies. The focus of future research in gut microbial culturomics is expected to be on high-throughput, automation, and integration. Advancements in this field may facilitate strain-level investigation into the mechanisms underlying diseases related to gut microbiota.

Development and validation of the self-volume management behaviour questionnaire for patients with chronic heart failure.

AIMS: We aim to develop and validate a questionnaire on the behaviour of self-volume management of patients with chronic heart failure. METHODS AND RESULTS: Based on the specific situation theory of heart failure self-care, the items of this questionnaire were formed through literature review and expert consultation. Content validity is judged by expert consultation. Item analysis was used for further filter entries. Cronbach's alpha and retest were used for reliability. Exploratory factor analysis and confirmatory factor analysis were used to test the structural validity. The questionnaire finally contained 3 subscales and 22 items. The Cronbach's α was between 0.732 and 0.797. The reliability of the retest was between 0.983 and 0.998. In expert consultation, the I-CVI of each item was 0.92-1, and the S-CVI of each subscale was 0.99, 1.00, and 0.99. In exploratory factor analysis, each subscale has two factors. In confirmatory factor analysis, the model fits of the three subscales were good: χ2/df < 3, RMSEA < 0.08, CFI > 0.9, TLI > 0.9, and SRMR < 0.05. CONCLUSIONS: The study has shown that the questionnaire on the behaviour of self-volume management of patients with chronic heart failure has good reliability and validity. It can be used as an evaluation tool for evaluating the self-volume management behaviour of patients with chronic heart failure.

[Mechanism of electroacupuncture regulating nuclear factor-κB pathway to improve the dedifferentiation of pancreatic ß-cells in rats with T2DM].

OBJECTIVE: To observe the effects of electroacupuncture (EA) on the expression of serum interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and the pancreatic nuclear factor-κB (NF-κB) pathway in type 2 diabetes mellitus (T2DM) rats, and to explore the possible mechanism by which EA improving the dedifferentiation of pancreatic ß-cells in the treatment of T2DM. METHODS: Among 18 SPF-grade male Wistar rats, 6 rats were randomly selected as the control group, and the remaining 12 rats were fed with high-sugar and high-fat diet combined with intraperitoneal injection of 2% streptozotocin solution (35 mg/kg) to establish T2DM model. After successful modeling, the 12 rats were randomly divided into a model group and an EA group, with 6 rats in each group. The EA group received EA at bilateral "Zusanli" (ST 36), "Sanyinjiao" (SP 6), "Weiwanxiashu" (EX-B 3), and "Pishu" (BL 20), with continuous wave, frequency of 15 Hz, current intensity of 2 mA, for 20 min each time, once a day, 6 times a week, for a total of 6 weeks. Fasting blood glucose (FBG) levels were measured before modeling and before and after intervention. After intervention, ELISA was used to detect the serum fasting insulin (FINS), IL-1ß and TNF-α levels, and the ß-cell function index (HOMA-ß) and insulin resistance index (HOMA-IR) were calculated; HE staining was used to observe the morphology of the pancreatic islets; Western blot was used to detect the protein expression of pancreatic forkhead box protein O1 (FoxO1), pancreatic and duodenal homeobox 1 (PDX-1), neurogenin 3 (NGN3), and NF-κB p65. RESULTS: After intervention, the FBG in the model group was higher than that in the control group (P<0.01), and the FBG in the EA group was lower than that in the model group (P<0.01). Compared with the control group, the model group had increased levels of serum FINS, IL-1ß, TNF-α, and HOMA-IR (P<0.01), and decreased HOMA-ß (P<0.01), reduced protein expression of pancreatic FoxO1 and PDX-1 (P<0.01), and increased protein expression of pancreatic NGN3 and NF-κB p65 (P<0.01, P<0.05). Compared with the model group, the EA group had lower serum FINS, IL-1ß, TNF-α levels, and HOMA-IR (P<0.01), higher HOMA-ß (P<0.05), increased protein expression of pancreatic FoxO1 and PDX-1 (P<0.01, P<0.05), and decreased protein expression of pancreatic NGN3 and NF-κB p65 (P<0.01, P<0.05). The control group's pancreatic islets showed no obvious abnormalities; the model group's pancreatic islets were irregular in shape and had unclear boundaries with the surrounding area, with immune cell infiltration, reduced ß-cell nuclei, disordered arrangement of islet cells, and increased intercellular spaces; the EA group showed improvements in islet morphology, immune cell infiltration, ß-cell nuclei count, and the arrangement and spacing of islet cells approaching normal. CONCLUSION: EA could lower the blood glucose levels in T2DM rats, alleviate chronic inflammatory responses in the islets, and improve the dedifferentiation of pancreatic ß-cells, which may be related to the inhibition of pancreatic NF-κB pathway expression.

Care-seeking delay of patients with heart failure in China: a mixed-method study.

AIM: This study aims to explore the duration and influencing factors of care-seeking delay among patients with heart failure (HF) in China. METHODS AND RESULTS: A convergent mixed method containing a cross-sectional study and two parts of qualitative studies was designed, following the STROBE and COREQ guidelines. Convenience sampling was applied to recruit patients with HF from two general hospitals from December 2021 to December 2022. Purposive sampling was used to enrol healthcare professionals from two general hospitals and two community hospitals from June to November 2022. Among the 258 patients with HF in the cross-sectional study, the median duration of care-seeking delay was 7.5 days. The result integration indicated that the delay duration was influenced by the dyspnoea symptom burden, the oedema symptom burden, and the depression status. The lower dyspnoea symptom burden, the higher oedema symptom burden, and the higher depression score were related to the prolonged care-seeking delay duration. The duration was also affected by the COVID-19 pandemic, level of support from medical system, and the symptom management abilities of the caregivers. The COVID-19 pandemic, low level of support from medical system, and limited symptom management abilities of caregivers were related to the prolonged care-seeking delay duration. CONCLUSIONS: Care-seeking delay among patients with HF needs attention in China. The duration of care-seeking delay of patients with HF was influenced by the dyspnoea symptom burden, the oedema symptom burden, and depression status, as well as the COVID-19 pandemic, level of support from medical system, and the symptom management abilities of the caregivers.

Correlation Between Serum 1,25(OH)2D3, Serum Phosphorus, and Parathyroid Hormone and Parathyroid Function After Central Lymph Node Dissection in Patients with Papillary Thyroid Carcinoma.

This work was to demonstrate the relationship between serum 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), serum phosphorus (SP), and parathyroid hormone (PTH) and parathyroid function after central lymph node dissection (CLND) in patients with papillary thyroid carcinoma (PTC). 200 PTC patients after CLND were included, who were rolled into a control group (CG) (n = 89 cases without hypoparathyroidism) and an observation group (OG) (n = 111 cases with complicated hypoparathyroidism). The 1,25(OH)2D3, SP, and PTH levels were detected, and the diagnostic effect of these indicators was assessed. The serum PTH levels of patients in CG after surgery were normal relative to those before surgery, while the serum PTH of patients in OG was relatively lower. 1,25(OH)2D3 concentration of patients in OG was also inferior to CG, while the SP level was superior (P < 0.05). Hypoparathyroidism was positively correlated with serum PTH (r = 0.382) and 1,25(OH)2D3 (r = 0.321) and negatively correlated with SP (r = - 0.211). The area under the curve (AUC) (0.893), sensitivity (90.83%), and specificity (94.77%) of the joint diagnosis of 1,25(OH)2D3 + SP + PTH were greatly superior to those of the single diagnosis and the pairwise diagnosis with the three indicators (P < 0.05). Hypoparathyroidism in patients with PTC after CLND surgery was positively correlated with 1,25(OH)2D3 and PTH and negatively correlated with SP concentration. In addition, the combination diagnosis of 1,25(OH)2D3, PTH, and SP worked well.

Cluster of Differentiation-44-Targeting Prussian Blue Nanoparticles Onloaded with Colchicine for Atherosclerotic Plaque Regression in a Mice Model.

Atherosclerosis management heavily relies on the suppression of the inflammatory response of macrophages. Colchicine's potent anti-inflammatory properties make it a promising candidate for secondary prevention against cardiovascular disease. However, its high toxicity and numerous adverse effects limit its clinical use. To address this, there is an urgent need for specific drug delivery systems to boost the level of accumulation of colchicine within atherosclerotic plaques. In this study, the cluster of differentiation-44 receptor was verified to be overexpressed in inflammatory macrophages within plaques both in vitro and in vivo. Subsequently, a Prussian blue-based nanomedical loading system with hyaluronic acid (HA) coating was constructed, and its effects were observed on the atherosclerosis regression. Colchicine and Cy5.5 were encapsulated within Prussian blue nanoparticles through self-assembly, followed by conjugation with hyaluronic acid to create col@PBNP@HA. The formulated col@PBNP@HA displayed a cubic shape and scattered distribution. Importantly, col@PBNP@HA demonstrated specific cellular uptake into lipopolysaccharide-stimulated macrophages. In vitro experiments showed that col@PBNP@HA more effectively inhibited expression of inflammatory factors and scavenged reactive oxygen species compared with the control group, which were treated with colchicine. Furthermore, col@PBNP@HA exhibited its specific and higher accumulation in aortic plaque analysis via fluorescence imaging of aortas. After 4 weeks, administration of col@PBNP@HA resulted in significant atherosclerosis regression in the mice model, with therapeutic effects superior to those of free colchicine. Similar to colchicine, col@PBNP@HA inhibited the secretion of inflammation factors and scavenged ROS through the regulation of the toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (Myd88)/nuclear factor kappa-B (NF-κB) and peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) signaling pathway. In summary, col@PBNP@HA demonstrated specific targeting ability to inflammatory plaques and exerted beneficial effects on atherosclerosis regression through TLR4/Myd88/NF-κB and PGC-1α modulation.

Myosin-I Synergizes with Arp2/3 Complex to Enhance Pushing Forces of Branched Actin Networks.

Myosin-Is colocalize with Arp2/3 complex-nucleated actin networks at sites of membrane protrusion and invagination, but the mechanisms by which myosin-I motor activity coordinates with branched actin assembly to generate force are unknown. We mimicked the interplay of these proteins using the "comet tail" bead motility assay, where branched actin networks are nucleated by Arp2/3 complex on the surface of beads coated with myosin-I and the WCA domain of N-WASP. We observed that myosin-I increased bead movement efficiency by thinning actin networks without affecting growth rates. Remarkably, myosin-I triggered symmetry breaking and comet-tail formation in dense networks resistant to spontaneous fracturing. Even with arrested actin assembly, myosin-I alone could break the network. Computational modeling recapitulated these observations suggesting myosin-I acts as a repulsive force shaping the network's architecture and boosting its force-generating capacity. We propose that myosin-I leverages its power stroke to amplify the forces generated by Arp2/3 complex-nucleated actin networks.