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Motivation Catastrophic transitions are ubiquitous in the dynamic progression of complex biological systems; that is, a critical transition at which complex systems suddenly shift from one stable state to another occurs. Identifying such a critical point or tipping point is essential for revealing the underlying mechanism of complex biological systems. However, it is difficult to identify the tipping point since few significant differences in the critical state are detected in terms of traditional static measurements. Results In this study, by exploring the dynamic changes in gene cooperative effects between the before-transition and critical states, we presented a model-free approach, the directed-network rank score (DNRS), to detect the early-warning signal of critical transition in complex biological systems. The proposed method is applicable to both bulk and single-cell RNA-sequencing (scRNA-seq) data. This computational method was validated by the successful identification of the critical or pre-transition state for both simulated and six real datasets, including three scRNA-seq datasets of embryonic development and three tumor datasets. In addition, the functional and pathway enrichment analyses suggested that the corresponding DNRS signaling biomarkers were involved in key biological processes. Availability and implementation The source code is freely available at https://github.com/zhongjiayuan/DNRS. Supplementary information Supplementary data are available at Bioinformatics online.

Data from trials investigating the effects and risks of endovascular thrombectomy for the treatment of stroke due to basilar-artery occlusion are limited.We conducted a multicenter, prospective, randomized, controlled trial of endovascular thrombectomy for basilar-artery occlusion at 36 centers in China. Patients were assigned, in a 2:1 ratio, within 12 hours after the estimated time of basilar-artery occlusion to receive endovascular thrombectomy or best medical care (control). The primary outcome was good functional status, defined as a score of 0 to 3 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]), at 90 days. Secondary outcomes included a modified Rankin scale score of 0 to 2, distribution across the modified Rankin scale score categories, and quality of life. Safety outcomes included symptomatic intracranial hemorrhage at 24 to 72 hours, 90-day mortality, and procedural complications.Of the 507 patients who underwent screening, 340 were in the intention-to-treat population, with 226 assigned to the thrombectomy group and 114 to the control group. Intravenous thrombolysis was used in 31% of the patients in the thrombectomy group and in 34% of those in the control group. Good functional status at 90 days occurred in 104 patients (46%) in the thrombectomy group and in 26 (23%) in the control group (adjusted rate ratio, 2.06; 95% confidence interval [CI], 1.46 to 2.91, P0.001). Symptomatic intracranial hemorrhage occurred in 12 patients (5%) in the thrombectomy group and in none in the control group. Results for the secondary clinical and imaging outcomes were generally in the same direction as those for the primary outcome. Mortality at 90 days was 37% in the thrombectomy group and 55% in the control group (adjusted risk ratio, 0.66; 95% CI, 0.52 to 0.82). Procedural complications occurred in 14% of the patients in the thrombectomy group, including one death due to arterial perforation.In a trial involving Chinese patients with basilar-artery occlusion, approximately one third of whom received intravenous thrombolysis, endovascular thrombectomy within 12 hours after stroke onset led to better functional outcomes at 90 days than best medical care but was associated with procedural complications and intracerebral hemorrhage. (Funded by the Program for Innovative Research Team of the First Affiliated Hospital of USTC and others; ATTENTION ClinicalTrials.gov number, NCT04751708.).

The infusion of chimeric antigen receptor (CAR) T cells that target specific tumor-associated antigens is a promising strategy that has exhibited encouraging results in clinical trials. However, few studies have focused on the effectiveness and safety of CD20 CAR T cells in rituximab-refractory/relapsed (R/R) B-cell non-Hodgkin lymphoma (B-NHL) patients, particularly those treated with rituximab for a short time. This prospective study aimed to assess the effectiveness and toxicity of CD20 CAR T cells in R/R B-NHL patients previously treated with rituximab.The authors conducted a prospective, single-center phase I study on the effectiveness and toxicity of CD20 CAR T cells in rituximab-treated R/R B-NHL patients (no. ChiCTR2000036350). A total of 15 patients with R/R B-NHL were enrolled between November 21, 2017, and December 1, 2021.An overall response rate of 100% was shown in enrolled patients, with 12 (80%) achieving complete remission and three (20%) achieving partial remission for the best response. The median follow-up time was 12.4 months. Progression-free survival and overall survival were not yet reached by the data cutoff day. No patient developed grade 4 cytokine release syndrome, and only one patient had immune effector cell-associated neurotoxicity syndrome.All enrolled B-NHL patients who were previously R/R to rituximab achieved different degrees of clinical response with tolerable toxicities. Notably, patients who had received rituximab within 3 months had a poorer prognosis.

The microbes and metabolomics of microbiota dysbiosis in the gut in the different phases of hepatitis B virus (HBV) infection are not fully understood.To investigate the specific gut microbiota and metabolites of the immune-tolerant (IT) and immune-active (IA) phases of chronic hepatitis B (CHB).Clinical fecal samples from healthy individuals and patients in the IT and IA phases of HBV infection were collected. Next, non-target metabolomics, bioinformatics, and 16S rDNA sequencing analyses were performed.A total of 293 different metabolites in 14 phyla, 22 classes, 29 orders, 51 families, and 190 genera were identified. The four phyla ofThese findings provide observational evidence of compositional alterations of the gut microbiome and some related metabolites in patients with IT-phase or IA-phase HBV infection. Further studies should investigate whether microbiota modulation can facilitate the progression of CHB and the cause-effect relationship between the gut microbiota and CHB.

Precision medicine demands the best application of multiple unambiguous biomarkers to bring uniform decisions in disease prognosis. The remarkable development of heterogeneous immunoassay greatly promotes precision medicine when combined with the biomarker combination strategy. Nevertheless, the cumbersome washing steps in heterogeneous immunoassay have inevitably compromised the accuracy because of the sample losses and nature change of the matrix, challenging the further exploration of a more facile and lower limit-of-detection analysis. The new methodologies with high throughputs and specificity are never out of date to provide simultaneous evaluations and uniform decisions on multiple analytes through a simple process. Herein, we propose a new wash-free immunoassay, named differential assay, for multiplexed biomarker monitoring. The method is based on counting the number difference of unbound nanoparticle tags before and after immunoreactions from a solid support (i.e., magnetic microsphere) by single-particle inductively coupled plasma mass spectrometry (sp-ICP-MS), discarding the tedious washing steps. We primarily explore the proof-of-concept proposal within two types (sandwich and competitive assay), demonstrating the good feasibility for further facile clinical practice. To provide efficient multiplexed evaluations, we synthesized PtNPs with four diameters and screened the most suitable size for efficient differential immunoassay. The wash-free strategy was successfully utilized in simultaneous serological biomarker (CA724, CA199, and CEA) evaluation, with results in good accordance with those measured by the clinical routine method. Potentially, the proposed differential bioassay can be regarded as a more facile and valuable tool in malignancy prognosis and cancer recurrence monitoring.

Bipolar disorder (BD) is increasingly being regarded as a dysconnection syndrome. Functional integration among the three core brain networks - executive control network (ECN), salience network (SN), and default mode network (DMN) - is abnormal in patients with BD; however, the causal relationship among the three networks in BD is largely unknown. It is also unclear whether patients with BD in different mood states show distinct effective connectivity patterns during rest.Resting-state fMRI data were collected from 65 patients with BD and 85 healthy controls. Spectral dynamic causal modeling was applied to investigate the effective connectivity difference of the three brain networks between all patients with BD and healthy controls and between patients who were in euthymic mood state (euthymic BD) and depressed mood state (depressed BD).Compared with healthy controls, all patients with BD showed altered effective connectivity within and between the ECN and SN and from these two networks to the DMN. Compared with patients with depressed BD, patients with euthymic BD showed increased excitatory effects within the ECN and decreased inhibitory effects from the SN to the ECN and DMN.These results further confirmed that patients with BD show abnormal functional integration within and among the three core brain networks, and exhibit similar and different effective connectivity patterns in different mood states. Abnormal effective connectivity has the potential to be a critical index for diagnosing BD and differentiating between BD patients with different mood states.

It is thought to be an effective technique to handle the problem of educational data explosion and lack of information by identifying potential relationships between data and directing decision-makers through the extraction, transformation, analysis, and modeling of educational data. Based on this, this research constructs a data analysis model for education evaluation using the K-means clustering technique in DM. The weight of each index of students’ comprehensive quality is calculated using AHP, and the value of the weight is used to determine whether the index is the important feature of analysis system mining. Improved sampling technology is used to deal with the representation of large-scale data sets; a sample partition clustering technique is proposed as a general framework. The best accuracy of this method, according to experimental data, is 95.6 percent, which is 12.1 percent greater than Mi cluster algorithm and 6.8 percent higher than DRCluster algorithm. The K-means clustering analysis technology is used to analyze students’ comprehensive evaluation data in this paper, with the goal of determining the regularity of data implication, accurately diagnosing learning problems, and providing the foundation for developing effective student management strategies.

Objective. This study aims to observe the changes in pupil diameter (PD) after anesthesia with different doses of sufentanil with the ultrasound method and observe whether pupil contraction is correlated with hemodynamic changes and bispectral index (BIS) values. Methods. A total of 124 patients between the ages of 18–65 with ASA I–II undergoing general anesthesia for surgery were enrolled in the study. According to the sufentanil dose initially injected, they were randomly divided into groups P, S1, S2, and S3, with 31 cases in each group. Group P was injected with normal saline. Group S1 was injected with 0.2 μg/kg of sufentanil. Group S2 was injected with 0.4 μg/kg of sufentanil. Group S3 was injected with 0.6 μg/kg of sufentanil. Following propofol administration and eye closure, the pupil diameter (PD) of the patients in the four groups was observed and measured by ultrasound after the loss of consciousness (T1) and within 3 min after the sufentanil injection at an interval of 30 s (30 s (T2), 1 min (T3), 1 min 30 s (T4), 2 min (T5), 2 min 30 s (T6), and 3 min (T7)). PD, systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and BIS values at T1–T7 were recorded. Results. The ultrasonic method was used to observe that different doses of sufentanil could make the patients’ pupils contract. During anesthesia induction, the changes in PD have a positive correlation with SBP, DBP, HR, and BIS values. Conclusion. Ultrasound can become a new noninvasive method to monitor pupil changes during general anesthesia, and ultrasonic observation of pupil changes has great potential for individualized analgesia management in the perioperative period.

Prostate cancer ranks among the most commonly diagnosed malignancies for men and has become a non-negligible threat for public health. Interplay between inflammatory factors and cancer cells renders inflammatory tissue environment as a predisposing condition for cancer development. The Hippo pathway is a conserved signaling pathway across multiple species during evolution that regulates tissue homeostasis and organ development. Nevertheless, whether Hippo pathway regulates cancer-related inflammatory factors remains elusive. Here, we show that high cell density-mediated activation of the Hippo pathway blunts STAT3 activity in prostate cancer cells. Hippo pathway component MST2 kinase phosphorylates STAT3 at T622, which is located in the SH2 domain of STAT3. This phosphorylation blocks the SH2 domain in one STAT3 molecule to bind with the phosphorylated Y705 site in another STAT3 molecule, which further counteracts IL6-induced STAT3 dimerization and activation. Expression of a nonphosphorylatable STAT3 T622A mutant enhances STAT3 activity and IL6 expression at high cell density and promotes tumor growth in a mice xenograft model. Our findings demonstrate that STAT3 is a novel phosphorylation substrate for MST2 and thereby highlight a regulatory cascade underlying the crosstalk between inflammation and the Hippo pathway in prostate cancer cells.

This study aimed to compare the behavior of rat bone marrow mesenchymal stem cells and rabbit auricle blastema cells implanted in non-cellular gingival tissue scaffold of human. In this regard, the tissues obtained from gingival surgeries in the dental clinic were de-cellulated using two detergents of sodium dodecyl sulfate and triton 100-X. After washing and sterilization, they were used as a scaffold for culture with bone marrow mesenchymal stem cells of rats. Using light and electron microscopy, these scaffolds were examined before and after 1, 2, and 4 weeks of cell culture. Also, the prepared three-dimensional scaffold was placed in the blastema ring obtained from the rabbit earlobe punch. The samples were evaluated 1, 2, and 4 weeks after culture based on histology techniques. The results showed that the study of scaffolds by electron microscopy showed preserving the epithelium matrix and the collagen fibers in the tissue. Structures similar to the epithelium were created in both samples. In addition, induction of cellular secretion was observed in scaffold cells migrating to the scaffold. In general, scaffolds made from human gums can be a good platform for studying cellular behaviors. Of course, further experiments to determine the nature of differentiated cells can help advance our knowledge of matrix cell interactions.

Soft-tissue sarcoma (STS) is a rare solid malignant tumor with numerous histologic subtypes. Current studies on targeted therapy for STS are in preclinical and early-phase trials. Genomic differences largely influence the prognosis of patients even with the same subtype. To investigate the genomic alterations (GAs) and the potential of targeted therapy in STS, we analyzed the genomic landscape, the therapeutic GAs, and biomarkers of immunotherapy in Chinese STS patients.Targeted sequencing covering 425 genes was performed, from which we obtained the results of tissue samples from 351 Chinese STS patients of all ages covering different histologic subtypes. Bioinformatics analysis of altered genes with nonsynonymous mutations, copy-number variations, and gene fusions were performed. OncoKB therapeutic GAs and relevant biomarkers including TMB, MSI, and HRD were further examined for potential targeted therapy.In total, 2743 GAs were identified in 330 genes with a median of 6 (1-38) per case. The top 11 frequently altered genes were: TP53, MCL1, MDM2, CDK4, MYC, CDKN2A, GNAS, RB1, ATRX, CDKN2B, and FGFR1. OncoKB defined therapeutic GAs were found in 23 genes in 43% of the patients. In general, 9.4% of the patients had high-TMB, 2.8% had MSI, and 13.7% had HRD. A significant difference in the percentage of patients with OncoKB therapeutic GAs were observed between the most frequent two subtypes, leiomyosarcoma and liposarcoma. Altogether, 54% of the patients had the potential to respond to a targeted therapy.This study indicated the potential efficacy of targeted therapy on many STS patients, and also provided insight for novel precision therapy. The clinical efficacy of combining targeted therapy and immunotherapy can be further investigated.

Genetic studies have identified Alzheimer's disease (AD)-associated SNPs in TOMM40 and PVRL2 genes, but the underlying mechanisms remain unknown. We examined their associations and interactions with AD risk and plasma biomarkers among Chinese older adults. This population-based study included 4876 participants. TOMM40(rs2075650) and PVRL2(rs6859) polymorphisms were detected using multiple-polymerase chain reaction amplification. Plasma Aβ40, Aβ42, and t-tau concentrations were measured using SIMOA in a subsample (n = 1257). AD was diagnosed following the international criteria. Data were analyzed using multiple logistic and general linear models. AD was diagnosed in 182 participants. The multiadjusted odds ratio of AD was 6.24 (95% CI 1.73-22.48) for TOMM40GG, 1.47 (0.89-2.42) for PVRL2AA, and 12.87 (3.97-41.73) for having both risk alleles (P

Yu Qin,1,2,* Rui Liu,1,2,* Yongxiang Wang,1– 3 Jiyou Tang,4 Lin Cong,1– 3 Juan Ren,1,2 Shi Tang,1– 3 Yifeng Du1– 3 1Department of Neurology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 2Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China; 3Shandong Provincial Clinical Research Center for Neurological Diseases, Jinan, Shandong, People’s Republic of China; 4Department of Neurology, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yifeng Du; Shi Tang, Department of Neurology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, No. 324 Jingwuweiqi Road, Jinan, Shandong, 250021, People’s Republic of China, Tel +86 531 68776354 ; +86-18678780912, Fax +86 531 68776354, Email duyifeng2013@163.com; tangshi@sdfmu.edu.cnPurpose: To investigate the cross-sectional associations of self-reported sleep characteristics with cardiovascular diseases (CVDs) and cardiovascular multimorbidity in older adults living in rural Eastern China.Patients and Methods: This population-based study included 4618 participants (age ≥ 65 years; 56.5% women) living in rural Eastern China. In March–September 2018, data were collected through interviews, clinical examinations, neuropsychological testing, and laboratory tests. Sleep parameters were assessed using the Pittsburgh Sleep Quality Index, Epworth Sleepiness Score, and Berlin questionnaire. Coronary heart disease (CHD), heart failure (HF), and stroke were defined according to in-person interviews, clinical and neurological examinations, and electrocardiogram examination. Data were analyzed using logistic regression and restricted cubic spline regression.Results: CHD was diagnosed in 991 participants, HF in 135 participants, and stroke in 696 participants. The multivariable-adjusted odds ratio (OR) of CHD was 1.27 (95% CI, 1.09– 1.49) for sleep duration ≤ 6 hours/night (vs > 6– 8 hours/night), 1.40 (1.20– 1.62) for poor sleep quality, and 1.22 (1.04– 1.43) for high risk for obstructive sleep apnea (OSA). The OR of HF was 2.16 (1.38– 3.39) for sleep duration > 8 hours/night, and 1.76 (1.22– 2.54) for high risk for OSA. In addition, the OR of stroke was 1.23 (1.04– 1.46) for poor sleep quality, 1.32 (1.01– 1.72) for excessive daytime sleepiness, and 1.42 (1.19– 1.70) for high risk for OSA. The associations of poor sleep with cardiovascular multimorbidity (≥ 2 CVDs) were stronger than that of sleep problems with a single CVD.Conclusion: Extreme sleep duration, high risk for OSA, and other sleep problems were associated with CVDs, especially cardiovascular multimorbidity.Keywords: sleep, coronary heart disease, heart failure, stroke, cardiovascular multimorbidity

The renal artery is often involved in aortic dissection, leading to kidney ischaemia and renal dysfunction. However, some patients with aortic dissection with combined renal artery involvement do not show clinical renal dysfunction. This study aimed to analyse the relationship between renal artery involvement and renal function.Data and images were collected from 79 patients (Group A), in Beijing Anzhen hospital between January 2015 and December 2017, who had type A aortic dissection, in order to analyse the relationship between renal artery involvement and serum creatinine. In order to further analyse the relationship between renal artery involvement and single kidney function, data from 27 patients (Group B) with aortic dissection from August 2018 to October 2018 were collected. Renal dynamic imaging was conducted, and clinical and image data were recorded.Results showed that patients with one partially occluded renal artery had higher variance of serum creatinine after surgery compared with patients with one false-lumen renal artery (5.8±22.7 μmol/L vs -18.7±22.7 μmol/L; p=0.003). The glomerular filtration rate of a single kidney that had a partially occluded renal artery was lower than that of a single kidney with a normal renal artery (37.77±9.57 vs 42.73±10.54; p=0.04).A partially occluded renal artery in aortic dissection was associated with impaired renal function after surgery, even though patients did not present high serum creatinine. More attention should be paid to those experiencing aortic dissection.

Acute myocardial infarction (AMI) is a severe and even fatal cardiovascular disease. The effect of transcription factors on AMI is intensively explored. Our experiment attempts to probe the role of Sox9 in cardiomyocyte apoptosis after AMI. AMI cell model was established in AC16 cells by hypoxia treatment. Cell viability and apoptosis were assessed. Then, the levels of BAX, Bcl-2, Sox9, miR-223-3p, and MEF2C were detected. The binding relation between Sox9 and miR-223-3p and between miR-223-3p and MEF2C was verified. The expression of miR-223-3p was upregulated using the miR-223-3p mimic, and collaborative experiments were conducted as si-Sox9 or si-MEF2C was transfected into cells to inhibit the expression of Sox9 or MEF2C. Sox9 was highly expressed in cardiomyocyte apoptosis after hypoxia, while Sox9 silencing protected hypoxia-treated cardiomyocytes from apoptosis by enhancing cell viability, quenching apoptosis, and reducing activity of caspase-3 and caspase-9. Essentially, Sox9 bound to the miR-223-3p promoter region to upregulate its expression. miR-223-3p targeted MEF2C transcription. miR-223-3p overexpression and MEF2C silencing could counteract the suppressive role of Sox9 silencing in hypoxia-treated cardiomyocyte apoptosis. Sox9 exacerbated hypoxia-induced cardiomyocyte apoptosis by promoting miR-223-3p expression and inhibiting MEF2C transcription.

Objective. To explore the application effect of a whole-process seamless nursing model based on the smart healthcare mode in the perioperative period of patients undergoing hematoma removal. Methods. In this retrospective study, 50 patients with hematoma removal admitted to our hospital from August 2018 to August 2019 were included as the control group (CG), while 50 patients with hematoma removal admitted to our hospital from September 2019 to September 2020 were included as the experimental group (EG). During the period of hematoma removal, CG received routine perioperative nursing, while EG received the whole-process seamless nursing model based on the smart healthcare mode. The perioperative indexes, hemodynamic indexes, and the incidence of postoperative complications were compared between the two groups, and the incidence of nursing staff’s work omissions in different periods was analyzed. Results. Notable differences were observed in surgical time, intraoperative blood loss, hematoma clearance rates, length of ICU stay, hospitalization time, removal time of ventricular drainage tube, and cerebral edema volume at 1 week after surgery between EG and CG (P

Background: Few studies have examined occurrence and progression of cognitive impairment, no dementia (CIND) in rural China. Objective: To determine the prevalence and incidence of CIND in rural-dwelling Chinese older adults, and to examine risk and protective factors associated with progression to CIND and dementia. Methods: This population-based study included 2,781 dementia-free participants (age≥65 years) who were examined at baseline (2014) and followed in 2018. Demographic, epidemiological, clinical, and neuropsychological data were collected following a structured questionnaire. We defined CIND according to subjective cognitive complaints and the age- and education-specific Mini-Mental State Examination (MMSE) score. Data were analyzed with the multinomial logistic regression models. Results: The overall prevalence of CIND was 10.54% and the incidence was 28.26 per 1,000 person-years. CIND at baseline was associated with the multi-adjusted odds ratio (OR) of 2.06 (95% confidence interval = 1.23–3.47) for incident dementia. Multinomial logistic regression analysis suggested that compared with no CIND, the multi-adjusted OR of incident CIND was 2.21 (1.51–3.23) for women and 0.62 (0.38–0.99) for high social support, whereas the multi-adjusted OR of incident dementia was 1.14 (1.09–1.18) for older age, 0.29 (0.16–0.53) for high education, and 2.91 (1.47–5.74) for having a stroke history. Conclusion: CIND affects over one-tenth of older adults living in rural communities of western Shandong province. People with CIND are twice as likely to progress to dementia as people without CIND. Female sex, low education, stroke history, and low social support are associated with an increased risk of progression from normal cognition to CIND or dementia.

Colorectal cancer (CRC) continues to be one of the most malignant cancers with a high mortality rate to date. Promoting the radio‐responsiveness of CRC is of great importance for local control and prognosis. In this study, we examined the roles of exosomal microRNA‐19b (miR‐19b) in CRC radioresistance. The regulatory role of miR‐19b in CRC stem cells and radiotherapy‐resistant cells was determined using miRNA microarray analysis, and its prognostic value was probed using the TCGA database. It was found that miR‐19b was overexpressed in CRC tissues, which indicated a poor prognosis. CRC‐derived exosomes (EXOs) enhanced the radio‐resistance and stemness properties of CRC cells via delivery of miR‐19b in vitro and in vivo. FBXW7 was identified as a putative target of miR‐19b. On the contrary, reintroduction of FBXW7 reversed the effects of miR‐19b on radioresistance and stemness properties. Furthermore, the Wnt/β‐catenin pathway activity was elevated in CRC cells upon EXOs treatment, decreased after miR‐19b downregulation, and increased again after FBXW7 downregulation. These results suggest that miR‐19b inhibition could enhance the efficacy of radiotherapy while reducing the stemness properties, thus presenting a promising strategy for sensitizing CRC cells to radiotherapy.

This study aimed to investigate the performance of handmade tri-leaflet expanded polytetrafluoroethylene (ePTFE) conduits in the absence of a suitable homograft.Patients who underwent right ventricular outflow tract reconstruction with tri-leaflet ePTFE conduits or homografts between December 2016 and August 2020 were included. The primary endpoint was the incidence of moderate or severe conduit stenosis (≥ 36 mmHg) and/or moderate or severe insufficiency. The secondary endpoint was the incidence of severe conduit stenosis (≥ 64 mmHg) and/or severe insufficiency.There were 102 patients in the ePTFE group and 52 patients in the homograft group. The median age was younger [34.5 (interquartile range: 20.8-62.8) vs. 60.0 (interquartile range: 39.3-81.0) months, P = 0.001] and the median weight was lower [13.5 (10.0-19.0) vs. 17.8 (13.6-25.8) kg, P = 0.003] in the ePTFE group. The conduit size was smaller (17.9 ± 2.2 vs. 20.5 ± 3.0 mm, P 0.001) and the conduit Z score was lower (1.48 ± 1.04 vs. 1.83 ± 1.05, P = 0.048) in the ePTFE group. There was no significant difference in the primary endpoints (log rank, P = 0.33) and secondary endpoints (log rank, P = 0.35). Multivariate analysis identified lower weight at surgery [P = 0.01; hazard ratio: 0.75; 95% confidence interval (CI) 0.59-0.94] and homograft conduit use (P = 0.04; hazard ratio: 8.43; 95% CI 1.14-62.29) to be risk factors for moderate or severe conduit insufficiency. No risk factors were found for moderate or severe conduit stenosis or conduit dysfunction on multivariate analysis.Handmade tri-leaflet ePTFE conduits showed acceptable early and midterm outcomes in the absence of a suitable homograft, but a longer follow-up is needed.

Atherosclerosis (AS) is a chronic inflammatory disease characterized by abnormal lipid metabolism. Foam cell formation is also known as an early event of AS. Cholesterol efflux is a process whereby cholesterol is excreted from foam cells through transporters, which serves as one of the effective regulatory mechanisms to prevent AS. Autophagy is a biodegradable mechanism, and lipophagy is a special form of autophagy that selectively degrades lipids. Cholesterol efflux is regulated by several mechanisms. Moreover, numerous studies have shown that autophagy is also process whereby cholesterol efflux is regulated. In early studies, scholars found that cholesterol efflux is related to autophagy. Subsequent studies have shown that various targeted molecules can induce autophagy and promote the expression of cholesterol transporters (such as LXRα, ABCA1, and ABCG1) through specific signaling pathways. Several novel treatments for AS use these small molecules as entry points for research and development based on autophagy. However, this autophagy-dependent cholesterol efflux involves many different molecular mechanisms. This not only indicates that cholesterol efflux is the result of multiple factors, but also that autophagy, which mediates cholesterol efflux, is a complex physiological mechanism. Through a literature review, we found that the role of autophagy in cholesterol efflux is related to cell type and is regulated by both the level of autophagy and the mechanism that triggers autophagy. In this review, we aim to discuss the role of autophagy in cholesterol efflux from many aspects based on recent relevant studies to aid in the treatment of AS.

Background The amygdala is vital in processing psychological stress and predicting vulnerability or resilience to stress-related disorders. This study aimed to build the link between functional magnetic resonance imaging data obtained before the stress event and the subsequent stress-related depressive symptoms. Methods Neuroimaging data obtained before the coronavirus disease 2019 pandemic from 39 patients with major depressive disorder (MDD) and 61 health controls (HCs) were used in this study. The participants were divided retrospectively into four groups in accordance with the severity of depressive symptoms during the pandemic: remitted patients, non-remitted patients, depressed HCs (HCd) and non-depressed HCs (HCnd). Seed-based resting-state functional connectivity (rsFC) analyses of the amygdala and its subregions, including the centromedial (CM), the basolateral and the superficial (SF), were performed. Results Vulnerability to depression was suggested by decreased rsFC between the left CM amygdala and the bilateral lingual gyrus in the HCd group compared with the HCnd group, and decreased rsFC of the left CM or right SF amygdala with the precuneus and the postcentral gyrus in the HCd group compared with patients with MDD. No evidence supported the rsFC of the amygdala or its subregions as a biomarker for the resilience of patients with MDD to stress under antidepressant treatment. Limitations Smaller sample size and no longitudinal neuroimaging data. Conclusions Our findings suggested that the rsFC of amygdala subregions may represent a neurobiological marker of vulnerability to depression following stress.

Nucleic acid amplification strategies have successfully dominated ultrasensitive bioassays, but they sometimes bring high time-consumption, multi-step operation, increased contamination risk, and mismatch-related inaccuracy. We proposed a nucleic acid amplification-free method called the AuNPs-tagging based CRISPR-Cas12a bioassay platform. The signal amplification was realized by integrating the self-amplification effect of CRISPR-Cas12a with the enhancement effect of the large number of detectable atoms inside each gold nanoparticle. The proposed method achieved a low LOD of 1.05 amol in 40 min for HIV-related DNA.

Cancer cells frequently use fructose as an alternative energy and carbon source, to fuel glycolysis and support the synthesis of various biomacromolecules. Glut5 is the only fructose-specific transporter, which lacks the ability to transport other carbohydrates such as glucose and galactose. Interplay between inflammatory factors and cancer cells renders inflammatory tissue environment as a predisposing condition for cancer development. Nevertheless, how inflammatory factors coordinate with fructose metabolism to facilitate tumor growth remains largely elusive. Here we show that treatment with IL-6 activates fructose uptake and fructolysis in oral squamous cell carcinoma (OSCC) cells and prostate cancer cells. Mechanistic study shows that transcription factor STAT3 associates with Glut5 promoter region and enhances Glut5 transcription in response to IL-6 treatment. Knockdown of Glut5 abolished IL-6-induced fructose uptake and utilization of fructose, and compromises IL-6-elicited tumor cell proliferation. Further, positive correlation between Glut5 and IL-6 expression is observed in multiple cancers. Our findings demonstrate a regulatory cascade underlying the crosstalk between inflammation and fructose metabolism in cancer cells, and highlights Glut5 as a novel oncogenic factor.

Alcohol-associated liver disease (ALD) encompasses a wide range of pathologies from simple steatosis to cirrhosis and hepatocellular carcinoma and is a global health problem. Currently, there are no effective pharmacological treatments for ALD. We have previously demonstrated that aging exacerbates the pathogenesis of ALD, but the underlying mechanisms are still poorly understood. Cellular repressor of E1A-stimulated genes 1 protein (CREG1) is a recently identified small glycoprotein that has been implicated in aging process by promoting cellular senescence and activating stress kinases. Thus, the current study aimed to explore the role of aging associated CREG1 in ALD pathogenesis and CREG1 as a potential therapeutic target. Hepatic and serum CREG1 protein levels were elevated in ALD patients. Elevation of hepatic CREG1 protein and mRNA was also observed in a mouse model of Gao-binge alcohol feeding. Genetic deletion of the

Background Adipocytes and their products, adipocytokines, play important roles in the generation and development of multiple myeloma (MM). Studies have demonstrated some adipocytokines to be associated with MM, although those results are controversial. Therefore, we conducted a meta-analysis to verify the association of adipocytokines with MM. Methods We performed a systematic retrieval of literature published prior to 26 October 2021. Standardized mean difference (SMD) with a 95% confidence interval (CI) was calculated to evaluate pooled effects. Subgroup analysis and meta-regression analysis were conducted to detect sources of heterogeneity. Sensitivity analysis was performed to evaluate the stability of the study. Publication bias was assessed by funnel plots and Egger’s linear regression test. Results Ten eligible studies with 1269 MM patients and 2158 controls were included. The pooled analyses indicated that circulating leptin levels of MM patients were significantly higher than control levels (SMD= 0.87, 95%CI: 0.33 to 1.41), while the circulating adiponectin levels in MM patients were significantly lower than controls with a pooled SMD of -0.49 (95%CI: -0.78 to -0.20). The difference of circulating resistin levels were not significant between MM patients and controls (SMD= -0.08, 95%CI: -0.55 to 0.39). Subgroup analysis and meta-regression analysis found that sample size, age, and sex were possible sources of heterogeneity. Sensitivity analysis demonstrated our pooled results to be stable. Conclusion Decreased circulating adiponectin and increased leptin levels were associated with the occurrence and development of MM. Adiponectin and leptin may be potential biomarkers and therapeutic targets for MM.

In this paper, we propose a multiresidual module convolutional neural network-based method for athlete pose estimation in sports game videos. The network firstly designs an improved residual module based on the traditional residual module. Firstly, a large perceptual field residual module is designed to learn the correlation between the athlete components in the sports game video within a large perceptual field. A multiscale residual module is designed in the paper to better solve the inaccuracy of the pose estimation due to the problem of scale change of the athlete components in the sports game video. Secondly, these three residual modules are used as the building blocks of the convolutional neural network. When the resolution is high, the large perceptual field residual module and the multiscale residual module are used to capture information in a larger range as well as at each scale, and when the resolution is low, only the improved residual module is used. Finally, four multiresidual module convolutional neural networks are used to form the final multiresidual module stacked convolutional neural network. The neural network model proposed in this paper achieves high accuracy of 89.5% and 88.2% on the upper arm and lower arm, respectively, so the method in this paper reduces the influence of occlusion on the athlete’s posture estimation to a certain extent. Through the experiments, it can be seen that the proposed multiresidual module stacked convolutional neural network-based method for athlete pose estimation in sports game videos further improves the accuracy of athlete pose estimation in sports game videos.

The outcomes, therapeutic strategies, and risk factors of congenital corrected transposition of great arteries (ccTGA) unoperated before adulthood are unclear.From October 2009 to January 2018, 117 adult ccTGA patients, classified into ccTGA with intact ventricular septum, ventricular septum defect, and pulmonary valve or subpulmonary outflow tract stenosis (PS) groups, were reviewed. Statistical analysis was performed with SPSS 19.0 (IBM, Armonk, NY).At the first visit, no patients suffered operation. The PS group had the least systemic atrioventricular valve regurgitation and the greatest systemic ventricular ejection fraction. All 49 patients underwent surgery. From the first visit to last follow-up, systemic ventricular ejection fraction of unoperated ccTGA decreased significantly. In the intact ventricular septum group, patients receiving systemic atrioventricular valve replacement/valvuloplasty had a significantly increased systemic ventricular ejection fraction and statistically more freedom from death and transplant than unoperated. In the ventricular septum defect group the late systemic ventricular ejection fraction of operated patients was not statistically different from their basic data at first visit. In the PS group patients receiving physiologic repair had significantly decreased systemic ventricular ejection fractions. Severe systemic atrioventricular valve regurgitation, physiologic repair, and systemic ventricular dysfunction (ejection fraction40%) were risk factors for mortality, transplant, and congestive heart failure.PS protects against systemic atrioventricular valve regurgitation and ventricular dysfunction. Systemic atrioventricular valve replacement/valvuloplasty improved systemic ventricular function for ccTGA with an intact ventricular septum. Physiologic repair was not ideal for ccTGA with PS. Severe systemic atrioventricular valve regurgitation and systemic ventricular dysfunction were associated with suboptimal outcomes.

OBJECTIVES To assess the effectiveness of an eye-tracking-based test (ETBT) to measure eye deviation angle vs. a manual prism alternating cover test (PACT) in children with strabismus. DESIGN The prospective, masked, cross-sectional study included 95 children aged 1.8 years and older. Eye deviation was tested twice by each of ETBT and PACT. Each subject underwent four strabismus measurements, two by the ETBT and two by PACT. In each test, subjects were fixated on accommodative targets at 50 cm, with habitual optical correction allowed. Masked examiners compared the manual PACT results with those of the ETBT. RESULTS There was a high correlation (about 90%) between the ETBT and PACT. Repeatability of ETBT was higher than that of PACT (correlation coefficients of 0.99 and 0.91 respectively, p

Background Humans can recognize the physical properties of objects by touching them, even when vision is unavailable. Tactile perception is important for humans in interacting with the environment. The triangular ridged textures are usually added to surface to improve the grip reliability of products, but the sharp edge of triangular ridge induces sharp and uncomfortable feeling. Materials and methods To study the effect of the edge shape of triangular ridged texture on brain activity, functional magnetic resonance imaging technique was used to obtain the blood oxygen level-dependent (BOLD) signal of subjects during the touching of textured surfaces. Samples with sharp, round, and flat shape ridged textures were chosen as the tactile stimulus. Results The contralateral postcentral gyrus, the precentral gyrus, the inferior parietal lobule, and the supramarginal gyrus, corresponding with the functional regions of the primary somatosensory cortex (SI), the secondary somatosensory cortex (SII), and the primary motor cortex (MI) were related to the perception of three shape ridged textures. The main brain activation located in the postcentral gyrus and the SI. The tactile information of three shape ridged textures was received by Brodmann area (BA) 3 of the SI, and then inputted to BA 2 of the SI, the further tactile discrimination of shape of ridged textures was involved in BA40 of the SII. The intensity, the areas, and the percent signal change (PSC) of brain activation that were evoked by different shape ridged textures were related to the geometric structures of the ridged textures. The more complex the geometric structures of texture are, the larger the intensity, the area, and the PSC in brain activation are. The negative BOLD responses of the ipsilateral sensory cortex that were evoked by the flat ridged texture indicated the ipsilateral neuronal inhibition within the sensory systems. The bilateral precuneus, the superior parietal gyrus, and the inferior parietal gyrus, corresponding with the functional areas of the SII (BA40) and the SSA(BA7), were involved in the tactile discriminate of the differences in shapes of ridged textures. The differences in brain activation were related to the differences in geometric structures of the ridged texture. The larger the differences in geometric structure of texture are, the larger the differences in brain activation are. This study revealed the activated location of brain related to the tactile stimulation of different edge shape of ridged textures and the relationship between the geometric structures of ridged texture and brain activities. This research contributes to optimize surface tactile characteristics on products, especially effective surface textures design for good grip.

Purpose Interstitial brachytherapy based on phosphorus-32 (P-32) has an established role as a minimally invasive treatment modality for patients with cystic craniopharyngioma. However, reporting on long-term outcomes with toxicity profiles for large cohorts is lacking in the literature. The purpose of this study is therefore to evaluate the long-term visual, endocrinal, and neurocognitive functions in what is the largest patient series having received this treatment to date. Methods and Materials We retrospectively evaluated 90 patients with cystic craniopharyngiomas who were treated with stereotactic intracavitary brachytherapy between 1998 and 2010. Colloidal activity of injected radioisotope P-32 was based on an even distribution within the tumor. After treatment, patients were followed-up for a minimum of 5 years and over a mean of 121 months (60-192 months) to assess radiographic and clinical responses. Results The 90 patients included in our study cohort underwent a total of 108 stereotactic surgical procedures for 129 craniopharyngioma-related cysts. Of the included tumors, 65 (72.2%) were associated with a single cyst, 15 (16.7%) were associated with 2 cysts, and 10 (11.1%) tumors had developed septations with 3 to 4 cysts. Stereotactic cyst puncture and content aspiration were used to drain a mean cyst fluid volume of 21.4 mL (1.0-55.0 mL). Each cyst was then instilled for interstitial brachytherapy with colloidal P-32 solution. Based on radiographic follow-up assessments, 56 cysts (43.4%) showed resolution and/or nonrecurrence, which was classified as a complete response to treatment; 47 cysts (36.4%) showed a partial response; and 5 cysts (3.9%) displayed a stable appearance. Treatment resulted in immediate and clinically significant vision improvement in 54 of 63 (86%) symptomatic patients, and this improvement was maintained. Progression-free survival rates at 5 and 10 years were 95.5% and 84.4%, respectively. Conclusions P-32–based interstitial brachytherapy can play an effective role in managing patients with cystic craniopharyngiomas. It can be considered a valid alternative to surgery in select patients with a favorable toxicity profile and long-term clinical outcomes.

Background Cognitive behavioural therapy (CBT) is considered an effective first-line treatment for obsessive-compulsive disorder (OCD). However, the neural basis of CBT for OCD has not yet been elucidated. The role of the amygdala in OCD and its functional coupling with the cerebral cortex have received increasing attention, and may provide new understanding of the neural basis of CBT for OCD. Methods We acquired baseline resting-state functional MRI (fMRI) scans from 45 unmedicated patients with OCD and 40 healthy controls; we then acquired another wave of resting-state fMRI scans from the patients with OCD after 12 weeks of CBT. We performed seed-based resting-state functional connectivity analyses of the amygdala subregions to examine changes in patients with OCD as a result of CBT. Results Compared to healthy controls, patients with OCD showed significantly increased resting-state functional connectivity at baseline between the left basolateral amygdala and the right middle frontal gyrus, and between the superficial amygdala and the right cuneus. In patients with OCD who responded to CBT, we found decreased resting-state functional connectivity after CBT between the amygdala subregions and the visual association cortices and increased resting-state functional connectivity between the amygdala subregions and the right inferior parietal lobe. Furthermore, these changes in resting-state functional connectivity were positively associated with changes in scores on the compulsion or obsession subscales of the Yale-Brown Obsessive-Compulsive Scale. Limitations Because of the lack of a second scan for healthy controls after 12 weeks, our results may have been confounded by other variables. Conclusion Our findings yield insights into the pathophysiology of OCD; they also reveal the potential neural changes elicited by CBT, and thus have implications for guiding effective treatment strategies with CBT for OCD.

Reminiscence therapy (RT) relieves mental disorders and improves quality of life (QoL) in some cancer survivors, but in postoperative cervical cancer patients, its effect is unclear. This study aimed to assess the impact of reminiscence therapy involved care (RTIC) and usual care (UC) on anxiety, depression, QoL, and survival in postoperative cervical cancer patients. In this randomized control study, 152 eligible postoperative cervical cancer patients were randomized as 1:1 ratio into RTIC (N = 76) and UC (N = 76) groups: the former received routine care and RT, while the latter only received routine care for 12 months. Anxiety, depression, and QoL were evaluated from baseline (month (M) 0) to M12, respectively. Patients were continuously followed up to M36 for overall survival (OS) calculation. HADS-Anxiety score from M6 to M12 was decreased; both HADS-Depression score from M9 to M12 and depression rate at M12 were reduced in RTIC group compared with UC group (all P

BACKGROUND Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Early diagnosis and timely treatment are essential for effective cancer control and have been widely analyzed in childhood cancer. However, few studies have described the time to diagnosis and treatment in children with ALL. This study investigated delays in diagnosis and treatment initiation and their impact on survival. METHODS This retrospective cohort study included 419 patients aged 0 to 14 years at a tertiary hospital between 2011 and 2015. The optimal cutoff values for delays were determined by X-tile software. The Kaplan-Meier method and Cox regression models were used to evaluate the impact of delays on survival. RESULTS The median diagnosis, treatment, and total delays were 21 (interquartile range [IQR]: 11-35), 4 (IQR: 2-7), and 26 (IQR: 16-43) days, respectively. The results of multivariate analyses showed that diagnosis delay, risk stratification, and minimal residual disease level were independent predictors for treatment outcome in childhood ALL. CONCLUSIONS These findings suggested that a longer time to diagnosis negatively affected the clinical outcome of childhood ALL. Reducing the time to diagnosis could help to improve survival in these patients.

The abuse of antibiotics in modern life and aquaculture has become a worldwide problem. Trace amounts of antibiotics discharged into natural water are increased in organisms through bioaccumulation and ultimately harm human health. Herein, we report a metal-tagged CRISPR/Cas12a bioassay and apply it to an ultrasensitive and highly selective evaluation of antibiotics bioaccumulation in wild fish samples. We integrated an element-tagging report probe and collateral cleavage activity of CRISPR/Cas12a. With the recognition and capture of target kanamycin by a "locked-activated" system, the activator strand was subsequently released to activate the collateral cleavage activity of Cas12a, followed by the cleavage of free Tm-Rep. After SA-MB capture, the biotin terminal was modified, and the uncleaved probe of Tm-Rep was removed. The acidized supernate containing the element tag fragment could be directly detected with 169Tm isotope monitoring by inductively coupled plasma mass spectrometry (ICPMS). With CRISPR/Cas12a biosensing and metal isotope detection by ICPMS, ultrasensitive and fast antibiotics analysis was realized with multiplex detection potential. Taking kanamycin as a modal analyte, a limit of detection as low as 4.06 pM was provided in a 30 min detection workflow. Besides, the bioaccumulation effect of kanamycin in a wild fish sample was also evaluated using the proposed strategy. We investigated the geographical distribution with Pseudorasbora parva samples collected in four different locations along a 600 km stretch of the Yangtze River. In addition, the bioaccumulation kinetics of antibiotics was evaluated in serum, muscle, and liver tissues of Pseudorasbora parva with 7 days of continuous feeding in a kanamycin-enriched environment.

The balance between endothelial nitric oxide (NO) synthase (eNOS) activation and production of reactive oxygen species (ROS) is very important for NO homeostasis in liver sinusoidal endothelial cells (LSECs). Overexpression of cyclooxygenase‐2 (COX‐2), a major intravascular source of ROS production, has been observed in LSECs of cirrhotic liver. However, the links between low NO bioavailability and COX‐2 overexpression in LSECs are unknown. This study has confirmed the link between low NO bioavailability and COX‐2 overexpression by COX‐2‐dependent PGE2‐EP2‐ERK1/2‐NOX1/NOX4 signalling pathway in LSECs in vivo and in vitro. In addition, the regulation of COX‐2‐independent LKB1‐AMPK‐NRF2‐HO‐1 signalling pathway on NO homeostasis in LSECs was also elucidated. The combinative effects of celecoxib on diminishment of ROS via COX‐2‐dependent and COX‐2‐independent signalling pathways greatly decreased NO scavenging. As a result, LSECs capillarisation was reduced, and endothelial dysfunction was corrected. Furthermore, portal hypertension of cirrhotic liver was ameliorated with substantial decreasing hepatic vascular resistance and great increase of portal blood flow. With the advance understanding of the mechanisms of LSECs protection, celecoxib may serve as a potential therapeutic candidate for patients with cirrhotic portal hypertension.

Aberrant glucose metabolism and elevated O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) are hallmarks of hepatocellular carcinoma (HCC). Loss of phosphoenolpyruvate carboxykinase 1 (PCK1), the major rate-limiting enzyme of hepatic gluconeogenesis, increases hexosamine biosynthetic pathway (HBP)-mediated protein O-GlcNAcylation in hepatoma cell and promotes cell growth and proliferation. However, whether PCK1 deficiency and hyper O-GlcNAcylation can induce HCC metastasis is largely unknown. Here, gain- and loss-of-function studies demonstrate that PCK1 suppresses HCC metastasis in vitro and in vivo. Specifically, lysine acetyltransferase 5 (KAT5), belonging to the MYST family of histone acetyltransferases (HAT), is highly modified by O-GlcNAcylation in PCK1 knockout hepatoma cells. Mechanistically, PCK1 depletion suppressed KAT5 ubiquitination by increasing its O-GlcNAcylation, thereby stabilizing KAT5. KAT5 O-GlcNAcylation epigenetically activates TWIST1 expression via histone H4 acetylation, and enhances MMP9 and MMP14 expression via c-Myc acetylation, thus promoting epithelial-mesenchymal transition (EMT) in HCC. In addition, targeting HBP-mediated O-GlcNAcylation of KAT5 inhibits lung metastasis of HCC in hepatospecific Pck1-deletion mice. Collectively, our findings demonstrate that PCK1 depletion increases O-GlcNAcylation of KAT5, epigenetically induces TWIST1 expression and promotes HCC metastasis, and link metabolic enzyme, post-translational modification (PTM) with epigenetic regulation.

During the pathogensis of rheumatoid arthritis (RA), activated RA fibroblast-like synoviocytes (RA-FLSs) combines similar proliferative features as tumor and inflammatory features as osteoarthritis, which eventually leads to joint erosion. Therefore, it is imperative to research and develop new compounds, which can effectively inhibit abnormal activation of RA-FLSs and retard RA progression. Neohesperidin (Neo) is a major active component of flavonoid compounds with anti-inflammation and anti-oxidant properties. In this study, the anti-inflammation, anti-migration, anti-invasion, anti-oxidant and apoptosis-induced effects of Neo on RA-FLSs were explored to investigate the underlying mechanism. The results suggested that Neo decreased the levels of interleukin IL-1β, IL-6, IL-8, TNF-α, MMP-3, MMP-9 and MMP-13 in FLSs. Moreover, Neo blocked the activation of the MAPK signaling pathway. Furthermore, treatment with Neo induced the apoptosis of FLSs, and inhibited the migration of FLSs. It was also found that Neo reduced the accumulation of reactive oxygen species (ROS) induced by TNF-α. Taken together, our results highlighted that Neo may act as a potential and promising therapeutic drug for the management of RA.

The association between gut microbiome and chronic metabolic disease including polycystic ovary syndrome (PCOS), is well documented, however, the relationship between the gut microbiota and serum metabolites remains unknown. In this study, untargeted metabolomics together with a 16S rRNA gene sequencing tool was used to detect small molecule serum metabolites and the gut microbiome. We identified 15 differential metabolites between PCOS patients and the healthy control. Lysophosphatidylcholine (LPC) (18:2, 20:3, 18:1, P-16:0, 17:0, 15:0, 18:3, 20:4), phosphatidylcholine(PC), ganglioside GA2 (d18:1/16:0) and 1-linoleoylglycerophosphocholine were increased in the PCOS group, and the concentrations of phosphoniodidous acid, bilirubin, nicotinate beta-d-ribonucleotide and citric acid were decreased in the PCOS group, suggesting a lipid metabolism and energy metabolism disorder in the PCOS patients. The diversity of gut microbiota in PCOS group was lower than that in healthy controls. Escherichia/Shigella, Alistipes and an unnamed strain 0319_6G20 belonging to Proteobacteria were important distinguishing genera (LDA > 3.5) in PCOS. Prevotella_9 was positively correlated with phosphoniodidous acid, nicotinate beta-d-ribonucleotide and citric acid concentrations, and negatively correlated with the concentration of LPC (20:3) and 1-linoleoylglycerophosphocholine; Roseburia was negatively correlated with LPC concentration (20:4), while the characteristic genus 0319_6G20 of PCOS was positively correlated with LPC concentration (20:3) (COR > 0.45). SF-36 in the PCOS group was significantly lower than that in the healthy control (HC) group, which was associated with the presence of Escherichia-Shigella and Alistipes. Our finding demonstrated the correlation between the gut microbiota and serum metabolites in PCOS, and therefore characteristic gut microbiota and metabolites may play an important role in the insulin resistance and the mood changes of PCOS patients.

The risk factors for cardiovascular and cerebrovascular diseases in young and middle-aged people have not yet been determined. We conducted a meta-analysis to find the risk factors for cardiovascular and cerebrovascular diseases, in order to provide guidance for the prevention of diseases in the young and middle-aged population.We searched PubMed, Embase, Cochrane Library from the establishment of the database to Mar 2022. We included case-control or cohort studies reporting risk factors for cardiovascular and cerebrovascular disease in young and middle-aged adults. We excluded repeated publication, research without full text, incomplete information or inability to conduct data extraction and animal experiments, reviews and systematic reviews. STATA 15.1 was used to analyze the data.The pooled results indicated that increased systolic blood pressure was significantly associated with increased risk of any stroke, ischemic stroke and hemorrhagic stroke. Body Mass Index (BMI), current smoking, hypertension, and diabetes were significantly associated with increased risk of any stroke and ischemic stroke. Atrial fibrillation was only significantly associated with increased risk of any stroke. Increased total cholesterol was significantly associated with an increased risk of ischemic stroke, whereas increased triglycerides were significantly associated with a decreased risk of ischemic stroke. In addition, increased hypertension was also significantly associated with an increased risk of acute coronary syndrome.Our pooled results show that BMI, current smoking, atrial fibrillation, hypertension, systolic blood pressure, and total cholesterol can be used as risk factors for cardiovascular and cerebrovascular diseases in young people, while triglycerides can be used as protective factors for cardiovascular and cerebrovascular diseases in young and middle-aged adults.

Lumbar disc herniation (LDH) is the main cause of low back pain and/or radiculopathy. Currently, epidural intervention is a widely used and effective conservative treatment method for managing low back and radicular pain caused by LDH.To explore the effectiveness of different epidural injection approaches in adult patients with lumbosacral radicular pain.Systematic review and network meta-analysis (NMA).An electronic literature search was performed in the Pubmed, Embase, Cochrane Library, and Web of Science databases. Two authors independently performed data extraction and quality assessment. A Bayesian random effects model was conducted to incorporate the estimates of direct and indirect treatment comparisons and rank the interventions in order. Effect estimates from Bayesian NMA were presented as mean difference (MD) with 95% credible intervals (CrI).This NMA assessed caudal (C), interlaminar (IL), transforaminal (TF) and parasagittal interlaminar (PIL) epidural injection approaches for lumbosacral radicular pain from 7 trials. A statistically significant treatment difference for pain relief was reported for midline interlaminar (MIL) vs PIL (MD, 1.16; 95%CrI, 0.31-2.06), MIL vs TF (MD, 1.12; 95%CrI, 0.51-1.85), C vs TF (MD, 1.07; 95%CrI, 0.01-2.18) in short-term follow-up and MIL vs TF (MD, 1.8; 95% CrI, 0.3-3.48) in intermediate-term follow-up. For functional improvement, a statistically significant difference was observed with MIL vs PIL (MD, 9.9; 95% CrI, 0.64-19.94) and MIL vs TF (MD, 1.08; 95% CrI, 1.08-17.08) in short-term follow-up. Moreover, the PIL approach and TF appeoach were ranked in the top 2 for pain relief and functional improvement, both in short-term and intermediate-term follow-up.1) The number of studies included was small; 2) some treatments lacked direct comparisons; 3) only scores from the visual analog scale for pain and the Oswestry Disability Index were included in the result; 4) important outcomes, such as complications, were not included.In short-term and intermediate-term follow-up, the PIL approach has the highest probability for pain relief and functional improvement.

Five caged polycyclic polyprenylated acylphloroglucinols including an unprecedented octahydro-2,5-methanoindene skeleton (1) were discovered from

The binding of the spike glycoprotein (S protein) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to angiotensin-converting enzyme 2 (ACE2) is the main pathway that leads to serious coronavirus disease 2019 (COVID-19) infection. In the biomedical applications of various nanomaterials, black phosphorus nanosheets (BP) have been receiving increasing attention owing to their excellent characteristics. In this study, the biological effect of BP on the interaction between the S protein and ACE2 was investigated by molecular dynamics simulations. The results indicated that the ACE2 could be quickly and stably adsorbed on the BP surface by non-specific binding and retain its structural integrity. Compared with the case without BP, the interaction of the S protein bound to ACE2 adsorbed on the BP surface was greatly weakened, including hydrogen bonds, salt bridges, and van der Waals forces. This study not only reveals that BP could effectively obstruct the binding of S protein and ACE2, which may provide a potential and reasonable drug carrier to further enhance the curative effect of inhibitors against SARS-CoV-2 infection, but also presents a novel interference mechanism for protein-protein interactions caused by nanomaterials.

Upper airway collapsibility after anaesthesia induction may be associated with unpredictable difficult airway. However, most works on airway anatomy are tended to morphological description before anaesthesia. This study aimed to evaluate the changes of upper airway after anaesthesia induction and using pre-anesthetic ultrasound measurements to predict Difficult Laryngoscopy (DL). We included 104 eligible subjects with complete data, who were performed tracheal intubations under general anaesthesia in the study. The upper airway changes before and after anaesthesia induction were determined by seven neck ultrasound measurements, included as follow: (1) Distance from skin to under surface of Tongue (DT), (2) Thickness of the thickest part of Tongue body (TT), (3) Hyoid Mental Distance (HMD), (4) Depth of Hyoid (DH), (5) Width of Hyoid (WH), (6) Distance from Skin to Epiglottis (DSE), (7) Depth of the anterior combination of the Vocal Cords (DVC). DL was evaluated with Cormack–Lehane (CL). Data regarding HMD [from 45.3 (42.4–48.5) to 41.1 (38.5–44.9) mm], DH [from 8.7 (6.6–10.9) to 7.0 (5.3–9.1) mm], DSE [from 20.1 (16.6–22.5) to 19.5 (16.5–21.6) mm] and the DVC [from 7.1 (5.7–8.3) to 6.8 (5.7–7.9) mm] were decreased (P P > 0.05) after anaesthesia induction. Additionally, when cut-off value of DSE was 21.25 mm before anaesthesia, it may be better predicted to DL [sensitivity 80.0% (95% CI: 60.7–91.6%) and specificity 83.8% (95% CI: 73.0–91.0%)]. The upper airway after induction showed the propensity of collapsibility by ultrasound measurements. Compared with other indicators, the DSE assessed by ultrasound might be considered to a valuable predictor of DL.Trial registration: The study was registered in ClinicalTrials.gov on 23th Jan 2019, ChiCTR1900021123.

Background Plexiform lesions, which have a dynamic appearance in structure and cellular composition, are the histological hallmark of severe pulmonary arterial hypertension in humans. The pathogenesis of the lesion development remains largely unknown, although it may be related to local inflammation and dysfunction in early progenitor endothelial cells (eEPCs). We tested the hypothesis that eEPCs contribute to the development of plexiform lesions by differentiating into macrophages in the setting of chronic inflammation. Methods The eEPC markers CD133 and VEGFR-2, macrophage lineage marker mannose receptor C-type 1 (MRC1), TNFα and nuclear factor erythroid 2-related factor 2 (Nrf2) in plexiform lesions in a broiler model were determined by immunohistochemistry. eEPCs derived from peripheral blood mononuclear cells were exposed to TNFα, and macrophage differentiation and angiogenic capacity of the cells were evaluated by phagocytotic and Matrigel plug assays, respectively. The role of Nrf2 in eEPC-to-macrophage transition as well as in MRC1 expression was also evaluated. Intratracheal installation of TNFα was conducted to determine the effect of local inflammation on the formation of plexiform lesions. Results Cells composed of the early lesions have a typical eEPC phenotype whereas those in more mature lesions display molecular and morphological characteristics of macrophages. Increased TNFα production in plexiform lesions was observed with lesion progression. In vitro studies showed that chronic TNFα challenge directed eEPCs to macrophage differentiation accompanied by hyperactivation of Nrf2, a stress-responsive transcription factor. Nrf2 activation (Keap1 knockdown) caused a marked downregulation in CD133 but upregulation in MRC1 mRNA. Dual luciferase reporter assay demonstrated that Nrf2 binds to the promoter of MRC1 to trigger its expression. In good agreement with the in vitro observation, TNFα exposure induced macrophage differentiation of eEPCs in Matrigel plugs, resulting in reduced neovascularization of the plugs. Intratracheal installation of TNFα resulted in a significant increase in plexiform lesion density. Conclusions This work provides evidence suggesting that macrophage differentiation of eEPCs resulting from chronic inflammatory stimulation contributes to the development of plexiform lesions. Given the key role of Nrf2 in the phenotypic switching of eEPCs to macrophages, targeting this molecular might be beneficial for intervention of plexiform lesions.

Motivation The identification of drug–target interactions (DTIs) plays a vital role for in silico drug discovery, in which the drug is the chemical molecule, and the target is the protein residues in the binding pocket. Manual DTI annotation approaches remain reliable; however, it is notoriously laborious and time-consuming to test each drug–target pair exhaustively. Recently, the rapid growth of labelled DTI data has catalysed interests in high-throughput DTI prediction. Unfortunately, those methods highly rely on the manual features denoted by human, leading to errors. Results Here, we developed an end-to-end deep learning framework called CoaDTI to significantly improve the efficiency and interpretability of drug target annotation. CoaDTI incorporates the Co-attention mechanism to model the interaction information from the drug modality and protein modality. In particular, CoaDTI incorporates transformer to learn the protein representations from raw amino acid sequences, and GraphSage to extract the molecule graph features from SMILES. Furthermore, we proposed to employ the transfer learning strategy to encode protein features by pre-trained transformer to address the issue of scarce labelled data. The experimental results demonstrate that CoaDTI achieves competitive performance on three public datasets compared with state-of-the-art models. In addition, the transfer learning strategy further boosts the performance to an unprecedented level. The extended study reveals that CoaDTI can identify novel DTIs such as reactions between candidate drugs and severe acute respiratory syndrome coronavirus 2-associated proteins. The visualization of co-attention scores can illustrate the interpretability of our model for mechanistic insights. Availability Source code are publicly available at https://github.com/Layne-Huang/CoaDTI.

Radiation-induced oral mucositis is the most common complication for patients who receive head/neck radiotherapy. Nicotinamide adenine dinucleotide (NAD

Background Mesenchymal stem/stromal cells (MSCs) acquire immunosuppressive capacity only in an inflammatory microenvironment. This can be recapitulated in vitro by treating MSCs with inflammatory cytokines TNFα and IFNγ, which induce indoleamine 2,3-dioxygenase (IDO) and TNF-stimulated gene-6 (TSG-6). However, the signaling pathways downstream of the cytokines remain to be elucidated. Methods Inflammatory bowel disease (IBD) mouse model was established by subjecting mice to dextran sulfate sodium (DSS) in drinking water for 7 days. Human UC-MSCs were pretreated with TNF-α and IFN-γ for 24 h and were then infused intravenously at day 2 of DSS administration. Colon tissues were collected for length measurement and histopathological examination. The serum level of IL-6 in mice was measured by enzyme-linked immunosorbent assay. Real-time PCR and Western blot were used to examine the mRNA level and protein expression. MSCs overexpressing constitutive active AKT or dominant negative AKT were generated and were analyzed. The glycolysis level of the MSCs was measured using Extracellular Flux Analyzer. 2-NBDG was used to monitor the uptake of glucose by MSCs. Results TNFα and IFNγ treatment led to rapid consumption of glucose and metabolic skewing toward glycolysis in MSCs, which was required for the therapeutic efficacy of MSCs on IBD. Blockade of glycolysis in MSCs inhibited the expression of immunomodulatory molecules, IDO and TSG-6, as well as the therapeutic effect on IBD. Moreover, PI3K-AKT signaling axis was rapidly activated and was required for the skewing toward glycolysis induced by TNFα and IFNγ. MSCs expressing dominant negative AKT were compromised in their therapeutic efficacy on IBD. Conclusion The glycolysis-dependent anti-inflammatory property of MSCs conferred by inflammatory cytokines is mediated by PI3K-AKT signaling pathway.