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Extracellular vesicles (EVs) are nanoparticles that include exosomes, microvesicles, and apoptotic bodies; they interact with target cell surface receptors and transport contents, including mRNA, proteins, and enzymes into the cytoplasm of target cells to function. The biological fingerprints of EVs practically mirror those of the parental cells they originated from. In the bone remodeling microenvironment, EVs could act on osteoblasts to regulate the bone formation, promote osteoclast differentiation, and regulate bone resorption. Therefore, there have been many attempts wherein EVs were used to achieve targeted therapy in bone-related diseases. Periodontitis, a common bacterial infectious disease, could cause severe alveolar bone resorption, resulting in tooth loss, whereas research on periodontal bone regeneration is also an urgent question. Therefore, EVs-related studies are important for periodontal bone remodeling. In this review, we summarize the current knowledge of mesenchymal stem cell-EVs involved in periodontal bone remodeling and explore the functional gene expression through a comparative analysis of transcriptomic content.

Malignant intestinal obstruction refers to intestinal obstruction caused by advanced primary tumors or secondary metastatic malignant tumors. Because surgical treatment cannot significantly improve the life cycle, non-surgical treatment is mostly used to improve the symptoms of intestinal obstruction; transanal intestinal obstruction catheter and transnasal intestinal obstruction catheter are palliative therapies for decompression and drainage. Transanal intestinal obstruction catheter is mostly used for rectal and left colon obstruction. Transnasal intestinal obstruction catheter is mostly used for small intestinal obstruction. The two catheters are generally used alone according to the site of obstruction and clinical manifestations, and there are few reports on the combined use of the two catheters. We try to use the two catheters to treat patients with complex conditions and explore a better treatment strategy for malignant intestinal obstruction.Retrospective analysis From January 2016 to April 2022, 14 patients with advanced cancer were diagnosed as malignant intestinal obstruction by imaging data and clinical manifestations. Under the premise of no improvement in the symptoms of placement of a catheter, nasal ileus catheter combined with transanal ileus catheter was used for common decompression and drainage. The efficacy of combined catheterization was evaluated by comparing the differences in imaging data before and after catheterization, as well as analyzing the degree of relief and prognosis of intestinal obstruction symptoms; of intestinal obstruction symptoms was completely relieved in 4 of 14 patients combined catheterization, and spontaneous defecation and exhaust could be performed; intestinal obstruction symptoms were significantly relieved in 3 patients, reexamination of image air-fluid level was reduced by more than 70%, abdominal distension and abdominal pain were significantly relieved, and intermittent defecation and exhaust could be performed; intestinal obstruction symptoms were relieved in 3 patients, reexamination of image air-fluid level was reduced by 20-50%, abdominal distension and abdominal pain were relieved, and defecation and exhaust could not be performed; intestinal obstruction symptoms were not relieved in 4 patients.Combined application of transanal ileus catheter and transnasal ileus catheter decompression and drainage can be used as a palliative treatment to relieve the symptoms of malignant ileus.

Normal early erythropoiesis depends on the precise regulation of protein expression and phosphorylation modification. Dysregulation of protein levels or modification contributes to erythroid disorders. To date, the dynamics of protein phosphorylation profiling across human erythroid development is not fully understood. Here, we characterized quantitative proteomic and phosphoproteomic profiling by tandem mass-tagging technology. We systemically built phospho-expression profiling and expression clusters of 11 414 phosphopeptides for human early erythropoiesis. The standardization methods for multitier integrative analyses revealed multiple functional modules of phosphoproteins (e.g., regulation of the G2/M transition) and active phosphorylated signalling (e.g., cell cycle-related pathways). Our further analysis revealed that CDK family members were the main kinases that phosphorylate substrates in erythroid progenitors and identified that CDK9 played an important role in the proliferation of erythroid progenitors. Collectively, our phosphoproteomic profiling, integrative network analysis and functional studies define landscapes of the phosphoproteome and reveal signalling pathways that are involved in human early erythropoiesis. This study will serve as a valuable resource for further investigations of phosphatase and kinase functions in human erythropoiesis and erythroid-related diseases.

To evaluate whether admission systolic blood pressure (SBP) is associated with the choice of initial antiplatelet therapy for minor stroke. Eligible patients retrospectively gathered from 2010 to 2018. Finally, 1312 of 1494 patients were divided into three groups: aspirin monotherapy (AM, n = 538, 41.0%), dual antiplatelet therapy with aspirin and load-clopidogrel (clopidogrel loading dose of 300 mg on the first day, DAPT-ALC, n = 474, 35.6%), and dual antiplatelet therapy with aspirin and unload-clopidogrel (clopidogrel 75 mg daily with no loading dose, DAPT-AUC, n = 300, 22.9%). The mean ± SD age of final patients was 62.0 ± 12.7 years old; 903 (70.9%) participants were male. Patients in the DAPT-ALC group were more likely to be younger, to arrive earlier, and to have a lower proportion of intracerebral hemorrhage than those in the AM group. DAPT-AUC group patients were more like to have a history of acute myocardial infarction and less likely to have a history of ICH than the AM group (4.7% vs. 1.7% and .3% vs. 2.6%, p .05). Overall, there was a likely "S-shaped" association between the selection of the DAPT-ALC or DAPT-AUC scheme and admission systolic blood pressure (P for nonlinearity = .012). Compared with the SBP 140 mmHg group, the SBP ≥ 180 mmHg group was more likely to be given DAPT-AUC (OR = 2.92 [1.62-5.26], p .001) than DAPT-ALC. Our findings support that admission SBP is associated with the choice of initial antiplatelet, especially when the SBP was greater than or equal to 180 mmHg.

Subsequent vascular events are common after acute ischemic stroke during hospitalization. This study aimed to analyze the effectiveness of combination therapy with clopidogrel and aspirin among mild-to-moderate ischemic stroke patients treated within 72 h on the basis of a high-intensity dose of statins.In a retrospective and multicenter cohort study, acute (within 72 h of onset) mild-to-moderate stroke patients were divided into aspirin and clopidogrel-aspirin groups on the basis of a high-intensity dose of statin therapy. The primary outcome was compound vascular events during hospitalization. Cox's proportional hazards model was used to assess differences, with the study center as a random effect.Among the 506 patients meeting the eligibility criteria, all subjects received a high-intensity dose of statins, including 20 mg rosuvastatin or 40 mg atorvastatin while in the hospital. In an unadjusted analysis, compound vascular events occurred in 7.2% of patients in the clopidogrel-aspirin group compared with 13.7% of those in the aspirin group (p = 0.022). In a Cox proportional hazards regression analysis, clopidogrel-aspirin was associated with a lower risk of compound vascular events (hazard ratio [95% CI], 0.47 [0.25-0.87]; p = 0.017) and ischemic vascular events (p = 0.008). Moderate and severe hemorrhage occurred in four patients (1.07%) in the clopidogrel-aspirin group and three patients (2.30%) in the aspirin group (p = 0.626).In this study based on high-intensity statin therapy, clopidogrel-aspirin reduced the risk of compound vascular events and did not increase the risk of hemorrhage during patients' hospitalization after mild-to-moderate ischemic stroke within 72 h.

Postoperative cognitive dysfunction (POCD) remains one of the most common complications following anesthesia and surgery (AS) in the elderly population. Calcium-mediated mitochondrial injury has been proved to induce cognitive impairment in a variety of neurologic diseases. In the current study we determined whether electro-acupuncture (EA) pretreatment ameliorated AS-induced POCD in aged rats, as well as the underlying mechanism. Eighty SD rats (18 months, male) were randomly assigned into four groups (n = 20): C, C + EA, POCD and EA + POCD. Rats in Group POCD and EA + POCD were subjected to exploratory laparotomy under sevoflurane anesthesia. Rats of Group C + EA and EA + POCD received a 5-day EA stimulation at Hegu, Neiguan and Zusanli acupoints before AS. At 3rd day after AS, open field test along with Morris water maze test were employed to examine the cognitive function of aged rats. Then hippocampal tissues were stripped and hippocampal neuronal amount, expression level of cleaved caspase-9 level, cytochrome c (Cyt C), cleaved caspase-3 level, Bcl-2, Bax, ROS expression level, apoptosis rate, mitochondrial membrane potential (MMP), cytosolic calcium concentration ([Ca

Patients with minor stroke suffer a substantial risk of further recurrences, especially in the first two weeks. We aimed to develop and validate a prognostic nomogram to predict in-hospital stroke recurrence among patients with acute minor stroke.A total of 1326 patients with minor non-cardiac stroke (NIHSS) ≤5) from three centers were divided into development cohort (1016 patients from two centers) and validation cohort (310 patients from another center). Recurrent stroke was defined as a new ischemic stroke. A logistic regression model was employed to develop the nomogram to predict in-hospital stroke recurrence in patients with minor stroke using demographic, medical and imaging information. We then validated the nomogram externally. The predictive discrimination and calibration of the nomogram were assessed in the development and validation cohorts by area under the curve (AUC) and calibration plots.During a median length of stay of 12 days, stroke recurrence occurred in 34 patients (3.3%). Predictors of in-hospital recurrence included prior history of transient ischemic attack, baseline NIHSS score, multiple infarctions, and carotid stenosis. The clinical and imaging-based nomogram B demonstrated adequate calibration and discrimination (AUC = 0.777), which was validated among 273 patients in a separate validation cohort (AUC = 0.753). Our clinical-imaging based nomogram was determined to be superior to the clinical-based nomogram and the RRE90 score in terms of discrimination.A prognostic nomogram that integrates clinical and imaging information to predict the in-hospital risk of stroke recurrence among patients after acute minor stroke was constructed and validated externally. The nomogram demonstrated adequate calibration and discrimination in both the development and validation cohort.

In this study, a positively charged near-infrared fluorescent probe (TPA-P+) was constructed by connecting a pyridine cation with triphenylamine and successfully used for the detection of heparin. The probe has the following characteristics: (1) TPA-P+ exhibited both AIE and TICT characteristics. (2) TPA-P+ could detect heparin by the introduction of a pyridine cation into TPA-P+, which increased the electrostatic interaction between the probe and heparin. (3) The probe has high sensitivity and good selectivity towards heparin and responds quickly. (4) Heparin detection using TPA-P+ was verified by protamine and was found to be reversible and effective. (5) The fluorescence intensity of TPA-P+ has good linearity with heparin concentration in the range of 0-16.0 μg mL

Bacteria and their derivatives (membrane vesicles, MVs) exhibit great advantages for targeting hypoxic tumor cores, strong penetration ability and activating immune responses, holding great potential as auspicious candidates for therapeutic and drug-delivery applications. However, the safety issues and low therapeutic efficiency by single administration still need to be solved. To further optimize their performance and to utilize their natural abilities, scientists have strived to modify bacteria with new moieties on their surface while preserving their advantages. The aim of this review is to give a comprehensive overview of a non-genetic engineering modification strategy that can be used to optimize the bacteria with nanomaterials and the design strategy that can be used to optimize MVs for better targeted therapy. Here, the advantages and disadvantages of these processes and their applicability for the development of bacteria-related delivery system as antitumor therapeutic agents are discussed. The prospect and the challenges of the above targeted delivery system are also proposed.

Background Studies on the anti-wrinkle effects of retinol have been widely reported, but there are few reports on the infraorbital dark circles reducing effects. Objective To evaluate the efficiency and tolerance of one novel formulation containing supramolecular retinol plus acmella oleracea extract in Chinese urban eye skin. Methods Thirty-three women with dark circles and visible fine wrinkles around the eyes, aged 20-45 years, were enrolled and instructed to use the formula for 6 weeks. Instrumental measures and subject assessment were obtained at baseline and at 3-week intervals. Results After 6 weeks, Mexameter MX18 results demonstrated a statistically significant 13.8% decrease in MI (melanin index) value, and Colorimeter CL400 results demonstrated a statistically significant 0.5% increase in L* (lightness) value, which proved the efficacy of reducing dark circles. Primos-Lite data showed that the wrinkles parameters of Ra, the wrinkle area %, and number of the wrinkles under the eyes and crow's feet revealed significant reduction to varying degrees. Cutometer results showed that R2 value increased significantly by 13.0%, indicating the benefits of firmer skin. In addition, subject assessment revealed that at the end of 6 weeks, the eye skin was noticeably improved. Conclusions By clinical evaluation and subject assessment, the novel formulation containing supramolecular retinol plus acmella oleracea extract can effectively diminish the collective signs of stressed urban eye skin for Chinese female in terms of dark circles, fine wrinkles, and sagging skin with good tolerance.

Disordered chromatin remodeling regulation has emerged as an essential driving factor for cancers. Imitation switch (ISWI) family are evolutionarily conserved ATP-dependent chromatin remodeling complexes, which are essential for cellular survival and function through multiple genetic and epigenetic mechanisms. Omics sequencing and a growing number of basic and clinical studies found that ISWI family members displayed widespread gene expression and genetic status abnormalities in human cancer. Their aberrant expression is closely linked to patient outcome and drug response. Functional or componential alteration in ISWI-containing complexes is critical for tumor initiation and development. Furthermore, ISWI-non-coding RNA regulatory networks and some non-coding RNAs derived from exons of ISWI member genes play important roles in tumor progression. Therefore, unveiling the transcriptional regulation mechanism underlying ISWI family sparked a booming interest in finding ISWI-based therapies in cancer. This review aims at describing the current state-of-the-art in the role of ISWI subunits and complexes in tumorigenesis, tumor progression, immunity and drug response, and presenting deep insight into the physiological and pathological implications of the ISWI transcription machinery in cancers.

Psoriasis is currently an incurable skin disorder mainly driven by a chronic inflammatory response. We found that subcutaneous application of umbilical cord- derived mesenchymal stem/stromal cells (MSCs) primed by IFN-γ and TNF-α, referred to as MSCs-IT, exhibited remarkable therapeutic efficacy on imiquimod (IMQ)-induced psoriasis-like inflammation in mice. Neutrophil infiltration, a hallmark of psoriasis, was significantly reduced after treatment with MSCs-IT. We further demonstrated that the effects of MSCs-IT were mediated by tumor necrosis factor (TNF) stimulating gene-6 (TSG-6), which was greatly upregulated in MSCs upon IFN-γ and TNF-α stimulation. MSCs transduced with TSG-6 siRNA lost their therapeutic efficacy while recombinant TSG-6 applied alone could also reduce neutrophil infiltration and alleviate the psoriatic lesions. Furthermore, we demonstrated that TSG-6 could inhibit neutrophil recruitment by decreasing the expression of CXCL1, which may be related to the reduced level of STAT1 phosphorylation in the keratinocytes. Thus, blocking neutrophil recruitment by MSCs-IT or TSG-6 has potential for therapeutic application in human psoriasis.

Background: Arterial stiffness index (ASI) is a potential risk factor for cerebrovascular and cardiometabolic diseases, but the causal links between them are inconclusive. The aim is to evaluate the causal effects of ASI on cerebrovascular and cardiometabolic diseases by Mendelian randomization (MR). Methods: Two-sample MR analysis was performed to infer causal links. Genetic variants significantly associated with ASI were extracted. The inverse variance weighted method was used for estimating the effects. Sensitivity analysis was performed to test heterogeneity or pleiotropy. Results: MR analysis indicated an effect of genetically predicted ASI on the risk of ischemic stroke (IS) of all causes (OR = 1.894, 95% CI 1.210–2.965, p = 0.005). No links were identified between genetically predicted ASI and other cerebrovascular or cardiometabolic diseases (all p > 0.05). Subgroup analysis of IS etiologies found a suggestive association between genetically predicted ASI and large artery atherosclerosis stroke (LAS) (OR = 3.726, 95% CI 1.230–11.286, p = 0.020). There were no effects of ASI on IS due to cardioembolism or small vessel occlusion. Conclusion: The current MR analysis suggested that genetically predicted ASI was associated with higher risk of IS of all causes. The results and the underlying pathways or mechanisms between ASI and IS needs further investigation.

To compare image quality and diagnostic accuracy of arterial stenosis in low-dose lower-extremity CT angiography (CTA) between adaptive statistical iterative reconstruction-V (ASIR-V) and deep learning image reconstruction (DLIR) algorithms.46 patients undergoing low-dose lower-extremity CTA were enrolled. Images were reconstructed using ASIR-V (blending factor of 50% (AV-50) and 100% (AV-100)) and DLIR (medium (DL-M), and high (DL-H)). CT values and standard deviation of the aorta, psoas, popliteal artery, popliteal and ankle muscles were measured. The edge-rise distance and edge-rise slope were calculated. The degrees of granularity and edge blurring were assessed using a 5-point scale. The stenosis degrees were measured on the four reconstructions, and their mean square errors against that of digital subtraction angiography were calculated and compared.For both ASIR-V and DLIR, higher reconstruction intensity generated lower noise and higher signal-to-noise ratio and contrast-to-noise ratio values. The standard deviation values in AV-100 images were significantly lower than other reconstructions. The two DLIR image groups had higher edge-rise slope and lower edge-rise distance (DL-M:1.79 ± 0.37 mm and DL-H:1.82 ± 0.38 mmDLIR images had higher image quality ratings with lower image noise and sharper vessel walls in low-dose lower-extremity CTA, and DL-H provides the best overall image quality and highest accuracy in diagnosing artery stenoses.DLIR provides high-quality images with sharper edges compared to ASIR-V during low-dose CTA of lower extremity arteries, and DLIR (high) provides the best overall image quality and highest accuracy in diagnosing artery stenoses among all reconstruction algorithms (ASIR-V and DLIR). ASIR-V with blending factor of 100% has the strongest noise reduction ability among all reconstruction algorithms (ASIR-V and DLIR); however, it generates the most blurred images.

Pyolysin (PLO) is secreted by Trueperella pyogenes as a water-soluble monomer after forming transmembrane β-barrel channels in the cell membrane by binding cholesterol. Two significantly conserved residues at domain 1 of PLO are mutated, which provides novel evidence of a relationship between conformational change and interaction with the cell membrane and uncovers the pore formation mechanism of the cholesterol-dependent cytolysin (CDC) family. Moreover, PLO is a special member of the CDCs, which the percentage of sequence identities between PLO and other CDC members is from 31% to 45%, while others are usually from 40% to 70%. It is important to understand that at very low sequence identities, models can be different in the pathogenic mechanisms of these CDC members, which are dedicated to a large number of Gram-positive bacterial pathogens. Our studies, for the first time, located and mutated two different highly conserved structural sites in the primary structure critical for PLO structure and function that proved the importance of these sites. Together, novel and repeatable observations into the pore formation mechanism of CDCs are provided by our findings.

Protein neddylation is catalyzed by a neddylation activating enzyme (NAE, E1), an E2 conjugating enzyme, and an E3 ligase. In various types of human cancers, the neddylation pathway is abnormally activated. Our previous study validated that the neddylation E2 UBE2F is a promising therapeutic target in lung cancer. Although the NAE inhibitor MLN4924/pevonedistat is currently under clinical investigation as an anti-cancer agent, there are no small molecules available that selectively target UBE2F. Here, we report, for the first time, the discovery, via structure-based virtual screen and chemical optimization, of such a small molecule, designated as HA-9104. HA-9104 binds to UBE2F, reduces its protein levels, and consequently inhibits cullin-5 neddylation. Blockage of cullin-5 neddylation inactivates cullin-RING ligase-5 (CRL5) activity, leading to accumulation of the CRL5 substrate, NOXA, to induce apoptosis. Moreover, HA-9104 appears to form the DNA adduct via its 7-azaindole group to induce DNA damage and G2/M arrest. Biologically, HA-9104 effectively suppresses the growth and survival of lung cancer cells and confers radiosensitization in both in vitro cell culture and in vivo xenograft tumor models. In summary, we discovered a small molecule, designated HA-9104, that targets the UBE2F-CRL5 axis with anti-cancer activity alone or in combination with radiation.

Human glioma is a kind of common and fatal intracranial tumor. Therefore, exploring effective drug targets for glioma is the main task of basic and clinical research. This study investigated the role of ubiquitin protein ligase E3 module N-recognition 5 (UBR5) in glioma and the underlying mechanism. First, TCGA datasets were employed to analyze the expression of

Hematopoietic stem cells (HSCs) and lineage committed hematopoietic progenitor cells (HPCs) undergo profound shifts in gene expression during neonatal and juvenile stages of life. Temporal changes in HSC/HPC gene expression underlie concomitant changes in self-renewal capacity, lineage biases and hematopoietic output. Moreover, they can modify disease phenotypes. For example, childhood leukemias have distinct driver mutation profiles relative to adult leukemias, and they may arise from distinct cells of origin. The putative relationship between neonatal HSC/HPC ontogeny and childhood blood disorders highlights the importance of understanding how, at a mechanistic level, HSCs transition from fetal to adult transcriptional states. In this perspective piece, we summarize recent work showing that the transition is uncoordinated and imprecisely timed. We discuss implications of these findings, including mechanisms that might enable neonatal HSCs and HPCs to acquire adult-like properties over a drawn-out period of time, in lieu of precise gene regulatory networks. The transition from fetal to adult transcriptional programs coincides with a pulse of type I interferon signaling that activates many genes associated with the adult-like state. This pulse may sensitize HSCs/HPCs to mutations that drive leukemogenesis shortly after birth. If we can understand how developmental switches modulate HSC and HPC fate after birth – both under normal circumstances and in the setting of disease-causing mutations – we can potentially reprogram these switches to treat or prevent childhood leukemias.

T cell receptor excision circles (TRECs) are small circularized DNA elements produced during rearrangement of T cell receptor (TCR) genes. Because TRECs are fairly stable, do not replicate during mitosis, and are not diluted during division of naïve T cells (Dion et al. [1]), they are suitable for assessing the number of newly formed T cells (Ping and Denise [2]). In this study, we detected TRECs in 521 healthy Chinese children aged 0-18 years in different clinical settings. The TRECs decrease with aging and show lower levels in preterm and low birth weight (BW) babies compared to those in full-term infants, while the preterm babies can also show comparable levels of TRECs when they have a gestation age (GA)-matched BW. We found a strong correlation between TRECs and peripheral CD4 naïve T cell numbers, which was age-related. We also analyzed the TRECs in different PIDs. Since T cell defects vary in PIDs, TREC levels change inconsistently. For example, in Wiskott-Aldrich syndrome (WAS), combining the level of TREC with lymphocyte subsets can help to distinguish subtypes of disease.Conclusion: We established the reference value range for TRECs by evaluating children below 18 years old in China, which could be used to screen for PIDs during early life. What is Known: • The TREC levels are decreased with age, and there is a positive correlation between TRECs and the numbers of naïve T cells. What is New: • This is the largest study to determine TREC reference levels in healthy Chinese pediatric, we provide solid data showing a correlation between CD4 naïve T cell counts and TREC levels according to age. We point out the GA matched BW is need to be considered during the SCID newborn screening. We are the first group showed that TREC levels can help clinician distinguish different WAS phenotype.

Research on the roles of the bacteria in tumor development and progression is a rapidly emerging field. Increasing evidence links bacteria with the modification of the tumor immune microenvironment, which greatly influences the antitumor response. In view of the individual immune effects of various bacteria in various tumors, developing personalized bacteria-modulating therapy may be a key to successful antitumor treatment. This review emphasizes the critical role of the bacteria in immune regulation, including both the tumor bacteria and gut bacteria. Aiming at tumor-related bacteria, we focus on various precise modulation strategies and discuss their impact and potential for tumor suppression. Finally, engineered bacteria with tumor-targeting ability could achieve precise delivery of various payloads into tumors, acting as a precision tool. Therefore, a precise tumor-related bacteria therapy may be a promising approach to suppress the development of tumors, as well as an adjuvant therapy to improve the antitumor efficacy of other approaches. KEY POINTS: • The mini-review updates the knowledge on complex effect of bacteria in TME. • Insight into the interaction and adjustment of bacteria in gut for TME. • Prospects and limitations of bacteria-related personalized therapy in the clinical anticancer therapy.

Pyroptosis is a relatively newly discovered programmed cell death accompanied by an inflammatory response. In the classical view, pyroptosis is mediated by caspases-1,-4,-5,-11 and executed by GSDMD, however, recently it was demonstrated that caspase-3 and-8 also participate in the process of pyroptosis, by cleaving GSDMD/E and GSDMD respectively. Different from autophagy and apoptosis, many pores are formed on the cell membrane during pyroptosis, which makes the cell membrane lose its integrity, eventually leading to the release of cytokines interleukin(IL)-1β and IL-18. When the body is infected with pathogens or exposed to some stimulations, pyroptosis could play an immune defense role. It is found that pyroptosis exists widely in infectious and inflammatory respiratory diseases such as acute lung injury, bronchial dysplasia, chronic obstructive pulmonary disease, and asthma. Excessive pyroptosis may accompany airway inflammation, tissue injury, and airway damage, and induce an inflammatory reaction, leading to more serious damage and poor prognosis of respiratory diseases. This review summarizes the relationship between pyroptosis and related respiratory diseases.

Tuberous sclerosis complex (TSC) is a rare disease that threatens multiple organs in the human body. TSC‑associated renal angiomyolipoma (TSC‑RAML) has potentially life‑threatening complications and a generally poor prognosis. The present study aimed to find plasma proteomic diagnostics and disease‑associated markers, and explore the tumor microenvironment using multi‑omics. To achieve this goal, the plasma proteomics as well as tissue proteomics, bulk and single‑cell RNA transcriptome from patients with TSC‑RAML were examined and analyzed. The results suggested that plasma proteins such as MMP9 and C‑C motif chemokine ligand 5 were able to differentiate TSC‑RAML from sporadic angiomyolipoma and renal cyst. A correlation analysis revealed that plasma proteomics were associated with lymphangioleiomyomatosis, TSC‑RAML grading and whole‑body disease burden. Tissue proteomics of participants with TSC‑RAML revealed disturbed small molecule catabolic process, mitochondrial matrix component and actin binding function. Bulk and single‑cell RNA sequencing suggested a greater number of tumor‑like cells, fibroblasts and mononuclear macrophages within the tumor microenvironment. The above results indicated that TSC‑RAML exhibited a characteristic and disease‑associated plasma proteomic profile. The unique microenvironment, made up of fibroblasts and mono‑macrophages, may promote tumorigenesis and TSC‑RAML progression.

International audience; Bloom syndrome protein (BLM) is a conserved RecQ family helicase involved in the maintenance of genome stability. BLM has been widely recognized as a genome "caretaker" that processes structured DNA. In contrast, our knowledge of how BLM behaves on single-stranded (ss) DNA is still limited. Here, we demonstrate that BLM possesses the intrinsic ability for phase separation and can co-phase separate with ssDNA to form dynamically arrested protein/ssDNA co-condensates. The introduction of ATP potentiates the capability of BLM to condense on ssDNA, which further promotes the compression of ssDNA against a resistive force of up to 60 piconewtons. Moreover, BLM is also capable of condensing replication protein A (RPA)- or RAD51-coated ssDNA, before which it generates naked ssDNA by dismantling these ssDNA-binding proteins. Overall, our findings identify an unexpected characteristic of a DNA helicase and provide a new angle of protein/ssDNA co-condensation for understanding the genomic instability caused by BLM overexpression under diseased conditions.

BackgroundPrevious prediction models of osteosarcoma have not focused on survival in patients undergoing surgery, nor have they distinguished and compared prognostic differences among amputation, radical and local resection. This study aimed to establish and validate the first reliable prognostic nomogram to accurately predict overall survival (OS) after surgical resection in patients with osteosarcoma. On this basis, we constructed a risk stratification system and a web-based nomogram.MethodsWe enrolled all patients with primary osteosarcoma who underwent surgery between 2004 and 2015 in the Surveillance, Epidemiology, and End Results (SEER) database. In patients with primary osteosarcoma after surgical resection, univariate and multivariate cox proportional hazards regression analyses were utilized to identify independent prognostic factors and construct a novel nomogram for the 1-, 3-, and 5-year OS. Then the nomogram's predictive performance and clinical utility were evaluated by the concordance index (C-index), receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA).ResultThis study recruited 1,396 patients in all, with 837 serving as the training set (60%) and 559 as the validation set (40%). After COX regression analysis, we identified seven independent prognostic factors to develop the nomogram, including age, primary site, histological type, disease stage, AJCC stage, tumor size, and surgical method. The C-index indicated that this nomogram is considerably more accurate than the AJCC stage in predicting OS [Training set (HR: 0.741, 95% CI: 0.726–0.755) vs. (HR: 0.632, 95% CI: 0.619–0.645); Validation set (HR: 0.735, 95% CI: 0.718–0.753) vs. (HR: 0.635, 95% CI: 0.619–0.652)]. Moreover, the area under ROC curves, the calibration curves, and DCA demonstrated that this nomogram was significantly superior to the AJCC stage, with better predictive performance and more net clinical benefits.ConclusionThis study highlighted that radical surgery was the first choice for patients with primary osteosarcoma since it provided the best survival prognosis. We have established and validated a novel nomogram that could objectively predict the overall survival of patients with primary osteosarcoma after surgical resection. Furthermore, a risk stratification system and a web-based nomogram could be applied in clinical practice to assist in therapeutic decision-making.

The oocyte

Abstract Macrolide antibiotics are one of the most commonly used broad-spectrum antibiotics. They have an inhibitory effect on a variety of respiratory pathogens; besides, they have non-anti-infective effects, including anti-inflammatory, regulating airway secretion, immune regulation, and other effects. A growing number of studies have shown that the non-anti-infective effects of macrolides have important and potential value in the treatment of pediatric chronic airway diseases; the therapy was described as “long-term, low-dose usage”; unfortunately, there is no guideline or consensus that applies to children. To better carry out the mechanism and clinical research of non-anti-infective effect and promote its rational use in children, the authors summarize the evidence of the usage of long-term, low-dose macrolide antibiotic therapy (LLMAT) in the treatment of chronic airway diseases in children and the progress in recent years. Impact This review summarizes the evidence (mostly in recent 5 years) of the usage of long-term, low-dose macrolide antibiotic therapy in the treatment of chronic airway diseases. The recent studies and guidelines support and enrich the point that long-term, low-dose macrolide antibiotic therapy has potential benefit for children with severe asthma, CF, non-CF bronchiectasis, and BO, which provides clinical references and is of clinical interest. Long-term, low-dose macrolide antibiotic therapy has good safety, and no serious events have been reported; however, potential cardiac side effects and macrolide resistance should be clinically noted.

Pancreatic cancer is a common malignant tumor worldwide. Extensive studies have been conducted on the functional role of long noncoding RNAs in pancreatic cancer. In this study, long intergenic nonprotein coding RNA 173 (LINC00173) was highly expressed in pancreatic cancer tissues. In vitro functional experiments showed that LINC00173 overexpression inhibited the proliferation and invasion of pancreatic cancer cells and promoted cell apoptosis in MIA PaCa-2 and PANC-1 cells. RNA sequencing analysis and Western blot assays demonstrated that LINC00173 reduced the expression of sphingosine kinase 1 (SPHK1) and then inhibited the protein expression of activated phospho-protein kinase B (AKT) and NF-κB. In vivo functional assays also revealed that LINC00173 inhibited the growth of pancreatic cancer xenografts, repressed cell proliferation, promoted cell apoptosis, and inhibited SPHK1 expression. The combined results of this study indicate that LINC00173 inhibits pancreatic cancer progression by repressing SPHK1 expression. Improving LINC00173 may represent a therapeutic strategy for pancreatic cancer in the future.

The underlying mechanism of orphan nuclear receptor estrogen-related receptor α (ERRα) in breast cancer was investigated by identifying its interaction partners using mass spectrometry. F-box and leucine-rich repeat protein 10 (FBXL10), which modulates various physiological processes, may interact with ERRα in breast cancer. Here, we investigated the interaction between FBXL10 and ERRα, and their protein expression and correlation in breast cancer. Mechanical studies revealed that FBXL10 stabilized ERRα protein levels by reducing its poly-ubiquitylation and promoting its mono-ubiquitylation. The reporter gene assay and examination of ERRα target genes validated the increased transcriptional activity of ERRα due to its increased protein levels by FBXL10. FBXL10 also increased ERRα enrichment at the promoter region of its target genes. Functionally, FBXL10 facilitated the ERRα/peroxisome proliferator-activated receptor gamma coactivator 1 β (PGC1β)-mediated proliferation and tumorigenesis of breast cancer cells in vitro and in vivo. Our results uncovered a molecular mechanism linking the mono-ubiquitylation and protein stability of ERRα to functional interaction with FBXL10. Moreover, a novel regulatory axis of FBXL10 and ERRα regulating the proliferation and tumorigenesis of breast cancer cells was established.

Objective To determine whether revision laparoscopic Kasai portoenterostomy (RLKPE) is a viable treatment option for patients with biliary atresia (BA) who had undergone initially successful laparoscopic Kasai portoenterostomy (ILKPE). Methods The medical records of 312 patients with nonsyndromic BA who had undergone ILKPE between May 2009 and May 2017 were retrospectively reviewed. The patients were divided into three groups according to their outcomes after ILKPE: group A: 25 patients who had undergone RLKPE; group B: 203 patients who had undergone ILKPE and required no further surgical intervention; group C: 84 patients with failed ILKPE who had either died or required liver transplantation for survival. The 3-year and 5-year survival with native liver (SNL) rates were compared between groups A and B and between groups A and C. Among the 25 patients in group A, the perioperative data of RLKPE were compared with those of ILKPE. Results Of the 312 patients who had undergone ILKPE, 228 reached the normal bilirubin concentration range within 6 months postoperatively. Among them, 25 patients with a sudden cessation of bile flow had undergone RLKPE. Adequate biliary drainage, as evidenced by normalized conjugated bilirubin levels, was achieved in 80% of patients who had undergone RLKPE. The perioperative variables, including the operative time, blood loss, rate of conversion to open surgery and complications of RLKPE, were not significantly different between RLKPE and ILKPE. The 3-year and 5-year SNL rates in patients after RLKPE were 64.0% and 52.0%, respectively, which were not significantly different from the corresponding rates of 86.2% and 73.9%, respectively, in patients after unrevised ILKPE (P > 0.05). Conclusion Our data demonstrated that RPLKE is a viable and effective treatment option in patients with sudden cessation of bile drainage after ILKPE. RPLKE can delay the need for liver transplantation, yielding encouraging medium-term patient outcomes.

This article proposes a Bayesian method to acquire the estimation of human impedance and motion intention in a human-robot collaborative task. Combining with the prior knowledge of human stiffness, estimated stiffness obeying Gaussian distribution is obtained by Bayesian estimation, and human motion intention can be also estimated. An adaptive impedance control strategy is employed to track a target impedance model and neural networks are used to compensate for uncertainties in robotic dynamics. Comparative simulation results are carried out to verify the effectiveness of estimation method and emphasize the advantages of the proposed control strategy. The experiment, performed on Baxter robot platform, illustrates a good system performance.

Background Methylxanthine, including caffeine citrate and aminophylline, is the most common pharmacologic treatment for apnea of prematurity. However, due to the lack of high-quality evidence, there are no clear recommendations or guidelines on how to choose between caffeine and aminophylline. Objective This meta-analysis aimed to assess the comparative efficacy and safety of caffeine and aminophylline for apnea of prematurity, and provide reliable evidence for clinical medication in the treatment for apnea of prematurity. Methods PubMed, Scopus, Embase, EBSCO, Web of Science, and Cochrane databases were systematically searched from May 1975 to June 2022. Results Ten studies including a total of 923 preterm infants were evaluated. Our results showed that there was no significant difference in the effective rate of 1-3days between caffeine and aminophylline (OR 1.05, 95%CI: 0.40–2.74, P = 0.914). However, for side effects such as tachycardia (OR 0.22, 95%CI: 0.13–0.37, P<0.001) and feeding intolerance (OR 0.40, 95%CI: 0.23–0.70, P = 0.001), the incidence rate was lower in the caffeine group compared with the aminophylline group. No significant difference was found in hyperglycemia (OR 0.45, 95%CI: 0.19–1.05, P = 0.064). Conclusion This meta-analysis reveals that caffeine citrate and aminophylline have similar therapeutic effectiveness on respiratory function, but caffeine has fewer side effects and should be considered first for treatment.

White-coat hypertension (WCH) is associated with increased cardiovascular risks. To investigate the relationship between WCH and left ventricular hypertrophy (LVH), the authors recruited 706 participants who underwent anthropometric measurements, blood laboratory analysis, 24h ambulatory blood pressure monitoring (ABPM), and echocardiography. The authors defined WCH as elevated office BP but normal ABPM over 24h, daytime, and nighttime periods. The authors compared the proportion of LVH between the true normotension (NT) and the WCH population, and further assessed the associations between BP indexes and LVH in the two groups, respectively. The proportion of LVH was significantly higher in the WCH group than in NT participants (19.70% vs. 13.12%, P = .036). In the NT group, 24h SBP, 24h PP, daytime SBP, daytime PP and SD of nighttime SBP were associated with LVH after adjustment for demographic and blood biochemical data (all P .05). In the WCH population, LVH was associated with 24h SBP, nighttime SBP, nighttime MAP, and office SBP after adjustment (all P .05). However, on forward logistic regression analysis with all the BP indexes listed above, only 24h SBP (OR = 1.057, 1.017-1.098, P .001) in the NT group, and nighttime MAP (OR = 1.114, 1.005-1.235, P .05) and office SBP (OR = 1.067, 1.019-1.117, P .001) in the WCH group were still significantly associated with LVH. Our study suggests that the proportion of LVH is higher in WCH patients than in the NT population. Furthermore, elevated nighttime MAP and office SBP may play critical roles in the development of LVH in the WCH population.

BackgroundObesity is conventionally considered a risk factor for multiple metabolic diseases, such as dyslipidemia, type 2 diabetes, hypertension, and cardiovascular disease (CVD). However, not every obese patient will progress to metabolic disease. Phlegm-dampness constitution (PDC), one of the nine TCM constitutions, is considered a high-risk factor for obesity and its complications. Alterations in the gut microbiota have been shown to drive the development and progression of obesity and metabolic disease, however, key microbial changes in obese patients with PDC have a higher risk for metabolic disorders remain elusive.MethodsWe carried out fecal 16S rRNA gene sequencing in the present study, including 30 obese subjects with PDC (PDC), 30 individuals without PDC (non-PDC), and 30 healthy controls with balanced constitution (BC). Metagenomic functional prediction of bacterial taxa was achieved using PICRUSt.ResultsObese individuals with PDC had higher BMI, waist circumference, hip circumference, and altered composition of their gut microbiota compared to non-PDC obese individuals. At the phylum level, the gut microbiota was characterized by increased abundance of Bacteroidetes and decreased levels of Firmicutes and Firmicutes/Bacteroidetes ratio. At the genus level, Faecalibacterium, producing short-chain fatty acid, achieving anti-inflammatory effects and strengthening intestinal barrier functions, was depleted in the PDC group, instead, Prevotella was enriched. Most PDC-associated bacteria had a stronger correlation with clinical indicators of metabolic disorders rather than more severe obesity. The PICRUSt analysis demonstrated 70 significantly different microbiome community functions between the two groups, which were mainly involved in carbohydrate and amino acid metabolism, such as promoting Arachidonic acid metabolism, mineral absorption, and Lipopolysaccharide biosynthesis, reducing Arginine and proline metabolism, flavone and flavonol biosynthesis, Glycolysis/Gluconeogenesis, and primary bile acid biosynthesis. Furthermore, a disease classifier based on microbiota was constructed to accurately discriminate PDC individuals from all obese people.ConclusionOur study shows that obese individuals with PDC can be distinguished from non-PDC obese individuals based on gut microbial characteristics. The composition of the gut microbiome altered in obese with PDC may be responsible for their high risk of metabolic diseases.

The global rise of antimicrobial resistance (AMR) that increasingly invalidates conventional antibiotics has become a huge threat to human health. Although nanosized antibacterial agents have been extensively explored, they cannot sufficiently discriminate between microbes and mammals, which necessitates the exploration of other antibiotic-like candidates for clinical uses. Herein, two-dimensional boron nitride (BN) nanosheets are reported to exhibit antibiotic-like activity to AMR bacteria. Interestingly, BN nanosheets had AMR-independent antibacterial activity without triggering secondary resistance in long-term use and displayed excellent biocompatibility in mammals. They could target key surface proteins (e.g., FtsP, EnvC, TolB) in cell division, resulting in impairment of Z-ring constriction for inhibition of bacteria growth. Notably, BN nanosheets had potent antibacterial effects in a lung infection model by P. aeruginosa (AMR), displaying a 2-fold increment of survival rate. Overall, these results suggested that BN nanosheets could be a promising nano-antibiotic to combat resistant bacteria and prevent AMR evolution.

CD81 deficiency is an extremely rare primary immunodeficiency disease characterized by severe and recurrent infections, IgA-related nephropathy, and profound hypogammaglobulinemia. Only one patient has been reported so far, and the pathogenesis remains unclear. Here, we identified a new case of CD81 deficiency and described its pathogenesis.We analyzed the clinical, genetic, and immunological features of the patient with CD81 deficiency, and explored the pathogenesis of her antibody deficiencies.The major manifestation of this patient was unexpectedly not recurrent infections but IgA nephropathy with aberrant serum galactose-deficient IgA1. Whole-exome sequencing revealed novel biallelic mutations in CD81 gene that abolished the surface expression of CD81. B cells from the patient lack membrane CD19 and showed reduced switched memory B cells and transitional B cells. Decreased expression of key molecules pY and pBTK in BCR signaling were demonstrated by confocal microscopy. RNA sequencing revealed that genes associated with BCR signaling and immunoglobulins were downregulated in CD81-deficient B cells. In addition, the patient showed increased frequency of T follicular helper cells that biased to Th1-like subsets.We reported the second patient with CD81 deficiency in the world and illustrated aberrant BCR signaling in the patient, therefore helping to unravel the mechanism of antibody deficiency in CD81-deficient patients.

Bovine mastitis seriously affects bovine health and dairy product quality.

Although an increasing number of patients benefit from immunotherapy and targeted therapies, melanoma remains incurable with increasing incidence. Drug repositioning and repurposing is an alternative strategy to discover and develop novel anticancer drugs or combined therapeutic regimens. In this study, we demonstrated that albendazole (ABZ), an Food and Drug Administration (FDA)-approved broad-spectrum antiparasitic agent, significantly inhibits the proliferation of melanoma cells in vitro and in vivo. RNA sequencing and flow cytometry analysis revealed that ABZ arrests melanoma cells at the G2/M phase of the cell cycle and induces cell apoptosis. More importantly, the CDK4/6 inhibitor palbociclib, as a member of the first and only class of highly specific CDK inhibitors approved for cancer treatment to date, showed significant synergistic effects with ABZ treatment in melanoma cells and mouse models. Taken together, we revealed a previously unappreciated function of ABZ in antimelanoma proliferation by inducing cell cycle arrest and apoptosis and provided a novel combined therapeutic regimen of ABZ plus CDK4/6 inhibitor treatment in melanoma.

Microbial infection and the limitation of tissue regeneration are main obstacles to chronic wound healing. Herein, a biofunctional hydrogel is prepared to simultaneously kill bacteria efficiently and promote would healing. First, a rose bengal/polypyrrole hybrid poly(vinyl alcohol) hydrogel (RB/PPy PVA HD) is synthesized and its antibacterial property is investigated under coirradiation of 550 nm visible light and 808 near-infrared light. The hydrogel exhibits excellent antibacterial activity within 10 min below 45 °C in vitro due to the synergistic effect of photothermal and photodynamic antibacterial therapy. Next, the recombined human epidermal growth factor (rhEGF) is physically absorbed on the surface of the porous hydrogel to form a RB/PPy/rhEGF hybrid PVA HD (rhEGF/RB/PPy PVA HD). The introduction of rhEGF enables the hydrogel to promote fibroblast proliferation and collagen secretion. Furthermore, the in vivo results indicate that the rhEGF/RB/PPy PVA HD can control infection effectively and promote wound healing significantly.

Meningococcal meningitis caused by Neisseria meningitidis is a reportable infectious disease in China, due to the high incidence of meningitis in the era before the availability of vaccines. The disease incidence was markedly reduced after meningococcal vaccination was introduced in the 1980s. Currently, there are polysaccharide, conjugate, and combined vaccine formulations against meningococcal meningitis in the Chinese market, almost all of which are produced by domestic manufacturers. It is necessary to further enhance national meningococcal surveillance to improve the level of prevention and control of meningococcus. However, the immune efficacy and persistence of immunity of vaccines should be monitored. More importantly, additional investments should be made to develop serogroup B meningococcal vaccines.

Objectives: Lung cancer was one of the most common malignancies around the world. It has great significance in to search for the mechanism of occurrence and development of lung cancer. LIM Domain Binding protein 2 (LDB2) belongs to the LIM-domain binding family, it can be used as a binding protein that combined with other transcription factors to form the transcription complex for regulating the expression of target genes. The expression of microRNA-96-5p (miR-96-5p) has been investigated in various tumors. The aim of this study is to investigate the potential role of LDB2 and miR-96-5p in lung cancer. Methods: Real-time quantitative PCR was applied to detect the expression of LDB2 and miR-96-5p. The proliferation, invasion, and metastasis of H1299 cells were analyzed by CCK8, transwell, and wound healing assay after LDB2 or miR-96-5p transfection. Luciferase activities assay and western blot were used to reveal the targeted regulation between LDB2 and miR-96-5p. Results: Here the authors found LDB2 was down-regulated in lung cancer tissues and negatively correlated with miR-96-5p expression, it could promote or inhibit the proliferation, invasion and metastasis of H1299 cells after LDB2 knockdown or overexpression and regulate the expression of cyclinD1, MMP9, Bcl-2, and Bax via ERK1/2 signaling pathway. Furthermore, miR-96-5p exerted its function by directly binding to 3′-UTR of LDB2 and regulating expression of LDB2. miR-96-5p could promote the proliferation, invasion, and metastasis of H1299 cells. Conclusion: These findings demonstrate that LDB2 can act as a new regulator to inhibit cell proliferation, invasion, and metastasis via the ERK1/2 signaling pathway, and miR-96-5p may be a potential promising molecular by targeting LDB2 in lung cancer.

We enhanced the sample throughput of microplate-based photothermal detection by using a semicylindrical prism to expand a point laser source to a long beam for illuminating multiple wells. Coupled with four epoxy-coated thermocouples in alignment with wells on a 96-well microplate, four parallel immunoassays of C-reaction protein (CRP) with antibody-conjugated gold nanoparticles can be simultaneously performed. The sample throughput is further increased by mounting the Styrofoam-enclosed microplate onto a translational/elevator stage so that immunoassays and thermocouple rinse/drying cycles can be implemented in a programmed fashion. The automated assay with three rinse/drying cycles takes only 34.5 min for four samples or 8.62 min/sample, whereas the manual mode with a single thermocouple and a point light source requires at least 66 min for just one sample. With careful calibration of the energy distribution of the expanded laser beam and controllable immersion of the thermocouples, excellent well-to-well (RSD = 1.3%) and cycle-to-cycle (RSD = 4.0%) reproducibility can be attained. The temperature changes can be correlated with the CRP concentration by the Langmuir isotherm, and the low limit of detection, 0.52 ng/mL or 4.33 pM, is well below the plasma CRP levels of both healthy people (

Skin is the largest organ of the human body. Skin wound is one of the most common forms of wound. Mesenchymal stromal cells (MSCs) have been used to aid skin wound healing via their paracrine factors. Because the secretome of MSCs can be greatly enriched and amplified by treatment with IFN‐γ and TNF‐α (IT), we here tested whether supernatant derived from MSCs pretreated with IT, designated as S‐MSCs‐IT, possesses improved wound healing effect by using a murine model of cutaneous excision, S‐MSCs‐IT was found to be more potent in promoting angiogenesis, constricting collagen deposition and accelerating wound closure than control supernatant (S‐MSCs) during the healing of skin wound. VEGFC, but not VEGFA, was greatly upregulated by IT and was found to be a key factor in mediating the improved wound healing effect of S‐MSCs‐IT. Our results indicate that the beneficial paracrine effect of MSCs on wound healing can be enhanced by pretreatment with inflammatory cytokines. IT treatment may represent a new strategy for optimizing the therapeutic effect of MSCs on skin injuries., TNF‐α and IFN‐γ stimulation upregulates the expression of VEGFC in mesenchymal stromal cells, which acts on endothelial cells and promotes angiogenesis, thus accelerating skin wound healing.

Colorectal cancer (CRC) is a deadly disease with a poor prognosis. Lidocaine is preferred by surgical procedures due to the excellent anesthesia. Circular RNA integrin alpha FG-GAP repeat containing 2 (circITFG2) has been recognized as a momentous participator in CRC progression. The specific role of circITFG2 was further studied in this research. Quantitative real-time PCR (qRT-PCR) was devoted to examining the expression of circITFG2, microRNA-1204 (miR-1204) and SOCS2 mRNA in CRC cells. Western blot was used to determine SOCS2 protein expression in CRC cells. Cell viability, colony formation and apoptosis were detected by cell counting kit-8 (CCK-8) assay, colony formation assay and flow cytometry assay respectively. Cell migration and invasion were tested by wound healing assay and transwell assay. Dual-luciferase reporter system, RNA pull down and RNA-binding protein immunoprecipitation (RIP) assays were applied to verify the combination between miR-1204 and circITFG2 or SOCS2. CircITFG2 was strikingly downregulated; however, lidocaine treatment induced a significant increase in the expression of circITFG2 and SOCS2 and a decrease in miR-1204 expression in CRC cells. Meanwhile, SOCS2 protein expression was upregulated by lidocaine treatment or miR-1204 silence in CRC cells and downregulated by circITFG2 knockdown or miR-1204 overexpression in lidocaine-treated CRC cells. CircITFG2 knockdown or miR-1204 overexpression abolished lidocaine-induced inhibition in proliferation, metastasis and promotion in apoptosis in CRC cells. CircITFG2 overexpression, SOCS3 overexpression or lidocaine treatment suppressed proliferation, metastasis and facilitated apoptosis in CRC cells. CircITFG2 sponged miR-1204 to regulate SOCS3 expression in lidocaine-treated CRC cells. Lidocaine hindered CRC progression by circITFG2/miR-1204/SOCS2 axis. This finding might beat a path in improving CRC therapy.

Deoxynivalenol (DON) is a ubiquitous trichothecene mycotoxin in food. DON and its modified forms can cross the placental barrier and influence the foetus' health. Limited information is available on exposure of dietary DON intake of pregnant women in China recently. We estimated the exposure of dietary DON intake of pregnant women in a large sample size (n = 2534) from China. The total DON (tDON) and free DON (fDON) biomarkers in urine were detected by liquid chromatography-tandem mass spectrometry. The mean concentration of tDON was 34.8 ng/mg creatinine, and the fDON was 15.9 ng/mg creatinine. The estimated exposure of dietary DON intake was 0.96-1.91 μg/kg bw/day, and the difference in exposure of DON between the first and second trimesters was statistically insignificant. Approximately 26%-60% of individuals exceeded the provisional maximum tolerable daily intake (PMTDI). The age, pre-pregnancy BMI, and the sampling seasons may be the risk factor for the occurrence of exceeding PMTDI. This survey is the first exposure biomarker for DON in a large sample size from pregnant women in China. We found that the dietary DON exposure in pregnant women was relatively high and particular concern should be paid to the DON exposure during pregnancy.

Although thermal proteome profiling (TPP) acts as a popular modification-free approach for drug target deconvolution, some key problems are still limiting screening sensitivity. In the prevailing TPP workflow, only the soluble fractions are analyzed after thermal treatment, while the precipitate fractions that also contain abundant information of drug-induced stability shifts are discarded; the sigmoid melting curve fitting strategy used for data processing suffers from discriminations for a part of human proteome with multiple transitions. In this study, a precipitate-supported TPP (PSTPP) assay was presented for unbiased and comprehensive analysis of protein-drug interactions at the proteome level. In PSTPP, only these temperatures where significant precipitation is observed were applied to induce protein denaturation and the complementary information contained in both supernatant fractions and precipitate fractions was used to improve the screening specificity and sensitivity. In addition, a novel image recognition algorithm based on deep learning was developed to recognize the target proteins, which circumvented the problems that exist in the sigmoid curve fitting strategy. PSTPP assay was validated by identifying the known targets of methotrexate, raltitrexed, and SNS-032 with good performance. Using a promiscuous kinase inhibitor, staurosporine, we delineated 99 kinase targets with a specificity up to 83% in K562 cell lysates, which represented a significant improvement over the existing thermal shift methods. Furthermore, the PSTPP strategy was successfully applied to analyze the binding targets of rapamycin, identifying the well-known targets, FKBP1A, as well as revealing a few other potential targets.

Ferroptosis is a nonapoptotic iron-dependent cell death pathway with a significant clinical potential, but its translation is impeded by lack of tumor-specific ferroptosis regulators and aberrant tumor iron metabolism. Herein, we report a combinational strategy based on clinically tested constituents to selectively induce ferroptosis in metabolically reprogrammed tumor cells through cooperative GPX4-inhibition and ferritinophagy-enabled Fe2+ reinforcement. Azido groups were first introduced on tumor cells using biocompatible long-circulating self-assemblies based on polyethylene glycol-disulfide-N-azidoacetyl-d-mannosamine via metabolic glycoengineering. The azido-expressing tumor cells could specifically react with dibenzocyclooctyne-modified disulfide-bridged nanoassemblies via bioorthogonal click reactions, where the nanoassemblies were loaded with ferroptosis inducer RSL3 and ferritinophagy initiator dihydroartemisinin (DHA) and could release them in a bioresponsive manner. DHA-initiated ferritinophagy could degrade intracellular ferritin to liberate stored iron species and cooperate with the RSL3-mediated GPX4-inhibition for enhanced ferroptosis therapy. This tumor-specific ferroptosis induction strategy provides a generally applicable therapy with enhanced translatability, especially for tumors lacking targetable endogenous receptors. National Research Foundation (NRF) This study is financially supported by the National Natural Science Foundation of China (32122048, 11832008, 92059107, and 51825302), the Chongqing Graduate Scientific Research and Innovation Program (cYB20047 and cYS20043), the Fundamental Research Funds for the Central Universities (2021CDJLXB001, 2021CDJZYJH-002, and 2020CDJYGZL009), the Chongqing Outstanding Young Talent Supporting Program (cstc2021ycjh-bgzxm0124), the Returning Overseas Scholar Innovation Program (CX2018062, CX2021098, and CX2020045), the Natural Science Foundation of Chongqing Municipal Government (cstc2020jcyj-msxmX0834 and cstc2021jcyj-jqX0022), and the Singapore National Research Foundation Investigatorship (NRF-NRFI2018-03) and Competitive Research Programme (CRP26-2021-0058).

This paper is written to observe the clinical effects of “neuromuscular electrical stimulation in the prevention of deep venous thrombosis of lower extremities after anterior cruciate ligament reconstruction” in our department. Data from March 2018 to March 2021 was selected including 187 males and 91 females. They were randomly divided into experimental groups and control groups. The experimental group adopted DVT general prevention + basic physical prevention + NMES and the control group adopted DVT general prevention + basic physical prevention. The VAS score, the content of blood D-dimer, the circumference of the affected knee, and results of DVT color ultrasound screening were studied in each group on the first day before operation and the fourth day after the operation. Results obtained showed that there were no significant differences in the baseline characteristics of the two groups of patients, such as gender composition, age, and so on P > 0.05 . The VAS scores, blood D-dimer content, and knee circumference of each group on the day before and on the fourth day after surgery were observed. Diameter and DVT color Doppler ultrasound screening results were superior to the control group in the test group and the difference was statistically significant P < 0.05 . It was concluded that NMES can effectively reduce the pain, knee swelling, and incidence of DVT in patients after ACL reconstruction. It is a simple and effective intervention therapy to prevent the occurrence of DVT.

Objective. To explore the effect of nursing in operating room combined with intraoperative heat preservation intervention on preventing incision infection and improving hemodynamics in patients with anterior cruciate ligament (ACL) injury and reconstruction under knee arthroscopy. Methods. About 200 patients with knee arthroscopic ACL reconstruction in our hospital from January 2019 to July 2021 were enrolled. The patients were randomly assigned into two groups: the control group and the study group. The former group received nursing care in the operating room operating room and the latter group received nursing care in operating room combined with intraoperative heat preservation intervention. Nursing satisfaction, incidence of incision infection, knee joint VAS score, knee joint range of motion, knee joint Lysholm score, and hemodynamic indexes were compared. Results. First of all, we compared the nursing satisfaction, the study group was very satisfied in 78 cases, satisfactory in 20 cases, and general in 2 cases, and the satisfaction rate was 100.00%, while in the control group, 445 cases were very satisfied, 20 cases were satisfied, 15 cases were general, and 8 cases were dissatisfied. The satisfaction rate was 82.00%. The nursing satisfaction of the study group was higher compared to the control group ( P < 0.05 ). Secondly, we compared the incidence of incision infection. The incidence of incision infection in the study group was lower compared to the control group ( P < 0.05 ). With regard to the knee joint VAS score, the knee joint VAS score of the study group was lower compared to the control group at 2 weeks, 4 weeks, 8 weeks, and 12 weeks after operation ( P < 0.05 ). In terms of the range of motion of the knee joint, the range of motion of the knee joint in the study group was higher compared to the control group at 2 weeks, 4 weeks, 8 weeks, and 12 weeks after operation ( P < 0.05 ). Regarding the knee joint Lysholm score, the knee joint Lysholm score of the study group was higher compared to the control group at 2 weeks, 4 weeks, 8 weeks, and 12 weeks after operation ( P < 0.05 ). Finally, we compared the hemodynamic indexes. Before nursing, there exhibited no significant difference ( P > 0.05 ). During and after nursing, the indexes of HR and MAP in the study group fluctuated little ( P < 0.05 ). Conclusion. During the perioperative period of patients with ACL injury and reconstruction under knee arthroscopy, standardized and necessary operating room combined with intraoperative thermal insulation intervention measures should be given, attention should be paid to the management of operating room, and intraoperative thermal insulation intervention should be strengthened. It includes preoperative visit, psychological nursing of patients, strict application of antibiotics before operation, monitoring of air quality in operating room, disinfection and sterilization of surgical instruments, shortening operation time, maintaining body temperature during operation, and paying attention to hand hygiene of medical staff. It plays a supervisory role in promoting the attention of medical staff to the prevention of wound infection, which is beneficial to the healing of surgical wounds of patients. It plays a positive role in enhancing hemodynamic indexes. Comprehensive nursing intervention on the risk factors of each link can effectively prevent postoperative wound infection and strengthen the prognosis and quality of life of patients.

Cytokines produced by immune cells have been demonstrated to act on muscle stem cells (MuSCs) and direct their fate and behavior during muscle repair and regeneration. Nevertheless, it is unclear whether and how MuSCs can also in turn modulate the properties of immune cells. Here, we showed that in vitro expanded MuSCs exhibited a potent anti‐inflammatory effect when infused into mice suffering from inflammatory bowel disease (IBD). Supernatant conditioned by MuSCs similarly ameliorated IBD. This beneficial effect of MuSCs was not observed when macrophages were depleted. The MuSC supernatant was found to greatly attenuate the expression of inflammatory cytokines but increase the expression of programmed death‐ligand 1 in macrophages treated with lipopolysaccharide and interferon gamma. Further analysis revealed that MuSCs produce a large amount of insulin‐like growth factor‐2 (IGF‐2) that instructs maturing macrophages to undergo oxidative phosphorylation and thus acquire anti‐inflammatory properties. Interestingly, the IGF‐2 production by MuSCs is much higher than by mesenchymal stem cells. Knockdown or neutralization of IGF‐2 abrogated the anti‐inflammatory effects of MuSCs and their therapeutic efficacy on IBD. Our study demonstrated that MuSCs possess a strong anti‐inflammatory property and the bidirectional interactions between immune cells and MuSCs have important implications in muscle‐related physiological and pathological conditions., Immune cells are known to direct the fate of muscle stem cells (MuSCs) during tissue repair and regeneration. MuSCs can also act on maturing macrophages and confer them with anti‐inflammatory properties via insulin‐like growth factor‐2, thus ameliorating dextran sulfate sodium‐induced colitis.

Fibrosis is characterized by fibroblast activation, extracellular matrix (ECM) accumulation and infiltration of inflammatory cells that sometimes leads to irreversible organ dysfunction. Considerable evidence now indicates that inflammation plays a critical role in the initiation and progression of organ fibrosis. S100A4 protein, a ubiquitous member of the S100 family, has recently been discovered as a potential factor implicated in fibrotic diseases. S100A4 protein is released at inflammatory site and has a certain biological function to promote cell motility, invasion, ECM remodelling, autophagy and angiogenesis. In addition, extracellular S100A4 is also a potential causation of inflammatory processes and induces the release of cytokines and growth factors under different pathological conditions. Elevated S100A4 level in patients’ serum closely correlates with disease activity in several fibrotic diseases and serves as a useful biomarker for diagnosis and monitoring disease progression. Analyses of knockout mouse models have identified a functional role of extracellular S100A4 protein in fibrotic diseases, suggesting that suppressing its expression, release or function might be a promising therapeutic strategy. This review will focus on the role of extracellular S100A4 as a key regulator of pro‐inflammatory signalling pathways and its relative biological processes involved in the pathogenesis of fibrosis.