Self-renewal and differentiation of adult stem cells are tightly regulated partly through configuration of chromatin structure by chromatin remodelers. Using knockout mice, we here demonstrate that bromodomain PHD finger transcription factor (BPTF), a component of the nucleosome remodeling factor (NURF) chromatin-remodeling complex, is essential for maintaining the population size of hematopoietic stem/progenitor cells (HSPCs), including long-term hematopoietic stem cells (HSCs). Bptf-deficient HSCs are defective in reconstituted hematopoiesis, and hematopoietic-specific knockout of Bptf caused profound defects including bone marrow failure and anemia. Genome-wide transcriptome profiling revealed that BPTF loss caused downregulation of HSC-specific gene-expression programs, which contain several master transcription factors (Meis1, Pbx1, Mn1, and Lmo2) required for HSC maintenance and self-renewal. Furthermore, we show that BPTF potentiates the chromatin accessibility of key HSC "stemness" genes. These results demonstrate an essential requirement of the chromatin remodeler BPTF and NURF for activation of "stemness" gene-expression programs and proper function of adult HSCs.

To evaluate the diagnostic performance of donor-derived plasma cell-free DNA (cfDNA) in discriminating antibody-mediated rejection (ABMR) or de novo donor-specific antibodies (DSA) without histological lesions in kidney allograft recipients.

Gallbladder carcinoma (GBC) is a rare gastrointestinal malignancy with poor prognosis. Adequate pre-treatment prediction of survival is essential for risk stratification and patient selection for aggressive surgery or adjuvant therapeutic strategy. Whole blood cell count (WBCC) derived indexes are broadly used as prognosticative biomarkers in various cancer types, but their utility in GBC needs to be validated.

Overweight and obese (OW/OB) adults are at increased risk of hypertension due to visceral adipose tissue (VAT) inflammation. In this study, we explored gene level differences in the VAT of hypertensive and normotensive OW/OB patients. VAT samples obtained from six OW/OB adults (three hypertensive, three normotensive) were subjected to transcriptome sequencing analysis. Gene set enrichment analysis was conducted for all gene expression data to identify differentially expressed genes (DEGs) with |log2 (fold change)| ≥ 1 and q < 0.05. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment analyses were performed on the DEGs, and hub genes were identified by constructing a protein-protein interaction (PPI) network. The proposed hub genes were validated using quantitative real-time PCR in ten other samples from five hypertensive and five normotensive patients. In addition, we performed ROC analysis and Spearman correlation analysis. A total of 84 DEGs were identified between VAT samples from OW/OB patients with and without hypertension, among which 21 were significantly upregulated and 63 were significantly downregulated. Bioinformatics analysis revealed that spleen function was related to hypertension in OW/OB adults. Meanwhile, PPI network analysis identified the following top 10 hub genes: CD79A, CR2, SELL, CD22, IL7R, CCR7, TNFRSF13C, CXCR4, POU2AF1, and JAK3. Through qPCR verification, we found that CXCR4, CD22, and IL7R were statistically significant. qPCR verification suggested that RELA was statistically significant. However, qPCR verification indicated that NFKB1 and KLF2 were not statistically significant. These hub genes were mainly regulated by the transcription factor RELA. The AUC of ROC analysis for CXCR4, IL7R, and CD22 was 0.92. What is more, VAT CXCR4 and CD22 were positively related to RELA relative expression levels. Taken together, our research demonstrates that CXCR4, IL7R, and CD22 related to VAT in hypertensive OW/OB adults could serve as future therapeutic targets.

Brain metastasis (BM) is a significant risk factor for survival and prognosis in non-small cell lung cancer (NSCLC). While surgical resection and radiotherapy are the primary treatment modalities, the overall prognosis in NSCLC patients with BM remains poor, and all therapies lead to adverse events. East Asian herbal medicine (EAHM) has broad prospects as an adjuvant treatment, but its efficacy and safety remain controversial. We propose to conduct a systematic review and meta-analysis to summarize the clinical efficacy and safety of EAHM for the treatment of NSCLC with BMs and to identify specific herbs that can improve the prognosis.

With the emergence of COVID-19, social distancing detection is a crucial technique for epidemic prevention and control. However, the current mainstream detection technology cannot obtain accurate social distance in real-time. To address this problem, this paper presents a first study on smartphone-based social distance detection technology based on near-ultrasonic signals. Firstly, according to auditory characteristics of the human ear and smartphone frequency response characteristics, a group of 18 kHz-23 kHz inaudible Chirp signals accompanied with single frequency signals are designed to complete ranging and ID identification in a short time. Secondly, an improved mutual ranging algorithm is proposed by combining the cubic spline interpolation and a two-stage search to obtain robust mutual ranging performance against multipath and NLoS affect. Thirdly, a hybrid channel access protocol is proposed consisting of Chirp BOK, FDMA, and CSMA/CA to increase the number of concurrencies and reduce the probability of collision. The results show that in our ranging algorithm, 95% of the mutual ranging error within 5 m is less than 10 cm and gets the best performance compared to the other traditional methods in both LoS and NLoS. The protocol can efficiently utilize the limited near-ultrasonic channel resources and achieve a high refresh rate ranging under the premise of reducing the collision probability. Our study can realize high-precision, high-refresh-rate social distance detection on smartphones and has significant application value during an epidemic.

Diabetic nephropathy (DN) is prevalent in patients with diabetes. N6-methyladenosine (m6A) methylation has been found to cause modification of nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing (NLRP) 3, which is involved in cell pyroptosis and inflammation. WTAP is a key gene in modulating NLRP3 m6A.

The grid-connected inverter is the key to ensure stable, reliable, safe, and efficient operation of the power generation system; the quality of the grid-connected output current waveform directly affects the performance of the entire power generation system. To improve the anti-interference performance and reduce the output current harmonic content of the grid-connected inverter, an improved control strategy that combined repetitive control (RC) and auto disturbance rejection control (ADRC) is designed in this paper. Firstly, decoupled the ADRC to realize the individual adaptation between tracking performance parameters and anti-interference performance parameters of the controller, through which the difficulty of adjusting parameters is reduced. Secondly, the control approach is devised by adding RC to ADRC. To demonstrate the effectiveness of the proposed method in this paper, detailed experimental studies are conducted using proportional integral control, traditional ADRC, and the proposed method under normal power grids, weak power grids, and periodic disturbances. And dynamic performance simulation experiment is done to verify the dynamic performance of the self-disturbance rejection controller before and after the addition of RC links. The results indicated the effectiveness and feasibility of the proposed method. Finally, after simulation, the steady state and dynamic performance are conducted on a hardware testing platform. The impacts of the obtained results indicate the effectiveness and feasibility of the control algorithm proposed, the ability to suppress intermediate frequency disturbances is improved, the bandwidth of the auto disturbance rejection controller is expanded, and the harmonic content of the output current is depressed.

Pharmacological therapies are promising interventions to slow down aging and reduce multimorbidity in the elderly. Studies in animal models are the first step toward translation of candidate molecules into human therapies, as they aim to elucidate the molecular pathways, cellular mechanisms, and tissue pathologies involved in the anti-aging effects. Trametinib, an allosteric inhibitor of MEK within the Ras/MAPK (Ras/Mitogen-Activated Protein Kinase) pathway and currently used as an anti-cancer treatment, emerged as a geroprotector candidate because it extended lifespan in the fruit fly Drosophila melanogaster. Here, we confirm that trametinib consistently and robustly extends female lifespan, and reduces intestinal stem cell (ISC) proliferation, tumor formation, tissue dysplasia, and barrier disruption in guts in aged flies. In contrast, pro-longevity effects of trametinib are weak and inconsistent in males, and it does not influence gut homeostasis. Inhibition of the Ras/MAPK pathway specifically in ISCs is sufficient to partially recapitulate the effects of trametinib. Moreover, in ISCs, trametinib decreases the activity of the RNA polymerase III (Pol III), a conserved enzyme synthesizing transfer RNAs and other short, non-coding RNAs, and whose inhibition also extends lifespan and reduces gut pathology. Finally, we show that the pro-longevity effect of trametinib in ISCs is partially mediated by Maf1, a repressor of Pol III, suggesting a life-limiting Ras/MAPK-Maf1-Pol III axis in these cells. The mechanism of action described in this work paves the way for further studies on the anti-aging effects of trametinib in mammals and shows its potential for clinical application in humans.

Background: Kanglaite injection (KLTI) is a traditional Chinese medicine (TCM) preparation with anti-tumor activity, which has been used to treat malignant tumors in China. The purpose of this study was to evaluate the efficacy and safety of intrapleural infusion with KLTI in the treatment of malignant pleural effusion (MPE). Methods: Randomized controlled trials (RCTs) on the efficacy and safety of intrathoracic infusion with KLTI in the treatment of MPE were searched from the PubMed, EMBASE, the Cochrane Library, CNKI, VIP, Wanfang and CBM databases. The primary outcome was objective remission rate (ORR). Secondary outcomes included quality of life (QOL) and incidence of adverse events (AEs). The Stata15.1 software and RevMan5.3 software were used to calculate risk ratios (RR) at 95% confidence intervals (CI) and conduct the meta-analysis. Results: This meta-analysis included 20 RCTs, involving 1,291 patients. The ORR of intrapleural infusion with KLTI + chemotherapy drugs in the treatment of MPE was higher than that of chemotherapy alone (RR) 1.23; 95%CI; 1.11-1.36, I 2 = 0%, z = 3.876, p = 0.000]. When KLTI is combined with cisplatin or KLTI 200 ml is used in every time, it is more advantageous to improve ORR. Moreover, compared with intrapleural infusion of chemotherapy drugs alone, KLTI combined with chemotherapy drugs significantly improved the QOL of patients with MPE (RR 1.28; 95%CI; 1.70-1.53, I 2 = 0%, z = 2.70, p = 0.007). In addition, the participation of KLTI reduced the gastrointestinal reaction (RR 0.79; 95% CI; 0.66-0.96; I 2 = 0%, z = 2.37, p = 0.018) and renal damage (RR 0.468; 95% CI; 0.23-0.945, I 2 = 0%, z = 2.11, p = 0.035) caused by chemotherapy drugs, but did not increase other adverse reactions (p > 0.05). Conclusion: The efficacy and safety of traditional chemotherapy drugs plus KLTI was superior to traditional chemotherapy drugs alone via intrapleural injection in controlling MPE, which suggested that KLTI can be used to treat MPE. However, a more rigorous RCT should be designed and completed before it is widely recommended.

Although radiation therapy (RT) improves locoregional recurrence and overall survival in breast cancer (BC), it is not yet clear whether RT affects the risk of patients with BC developing second esophageal cancer (SEC). We enrolled patients with BC as their first primary cancer from nine registries in the Surveillance, Epidemiology, and End Results (SEER) database between 1975 and 2018. Fine-Gray competing risk regressions were assessed to determine the cumulative incidence of SECs. The standardized incidence ratio (SIR) was used to compare the prevalence of SECs among BC survivors to that in the general population of the US. Kaplan-Meier survival analysis was applied to calculate the 10-year overall survival (OS) and cancer-specific survival (CSS) rates for SEC patients. Among the 523,502 BC patients considered herein, 255,135 were treated with surgery and RT, while 268,367 had surgery without radiotherapy. In a competing risk regression analysis, receiving RT was associated with a higher risk of developing an SEC in BC patients than that in the patients not receiving RT (P = .003). Compared to the general population of the US, the BC patients receiving RT showed a greater incidence of SEC (SIR, 1.52; 95% confidence interval [CI], 1.34-1.71, P < .05). The 10-year OS and CSS rates of SEC patients after RT were comparable to those of the SEC patients after no RT. Radiotherapy was related to an increased risk of developing SECs in patients with BC. Survival outcomes for patients who developed SEC after RT were similar to those after no RT.

Cells migrate by adapting their leading-edge behaviors to heterogeneous extracellular microenvironments (ECMs) during cancer invasions and immune responses. Yet it remains poorly understood how such complicated dynamic behaviors emerge from millisecond-scale assembling activities of protein molecules, which are hard to probe experimentally. To address this gap, we establish a spatiotemporal "resistance-adaptive propulsion" theory based on the interactions between Arp2/3 complexes and polymerizing actin filaments and a multiscale dynamic modeling system spanning from molecular proteins to the cell. We quantitatively find that cells can accurately self-adapt propulsive forces to overcome heterogeneous ECMs via a resistance-triggered positive feedback mechanism, dominated by polymerization-induced actin filament bending and the bending-regulated actin-Arp2/3 binding. However, for high resistance regions, resistance triggers a negative feedback, hindering branched filament assembly, which adapts cellular morphologies to circumnavigate the obstacles. Strikingly, the synergy of the two opposite feedbacks not only empowers the cell with both powerful and flexible migratory capabilities to deal with complex ECMs but also enables efficient utilization of intracellular proteins by the cell. In addition, we identify that the nature of cell migration velocity depending on ECM history stems from the inherent temporal hysteresis of cytoskeleton remodeling. We also show that directional cell migration is dictated by the competition between the local stiffness of ECMs and the local polymerizing rate of actin network caused by chemotactic cues. Our results reveal that it is the polymerization force-regulated actin filament-Arp2/3 complex binding interaction that dominates self-adaptive cell migrations in complex ECMs, and we provide a predictive theory and a spatiotemporal multiscale modeling system at the protein level.

The therapeutic effectiveness of the empirical and unselected use of oral rehydration salts (ORS) on postural tachycardia syndrome (POTS) is not satisfactory in children. Therefore, looking for suitable predictors of the therapeutic effects of ORS before treatment is extremely necessary to implement individualised treatment for paediatric patients with POTS.

Previous studies have implicated the role of CD146 and its soluble form (sCD146) in the pathogenesis of inflammatory diseases. However, the association between CD146 and acute rejection in kidney transplant patients remains unexplored. In this study, fifty-six patients with biopsy-proved rejection or non-rejection and 11 stable allograft function patients were retrospectively analyzed. Soluble CD146 in plasma was detected in peripheral blood by enzyme linked immunosorbent assay (ELISA), and local CD146 expression in graft biopsy was detected by immunohistochemistry. We found that plasma soluble CD146 in acute rejection recipients was significantly higher than in stable patients without rejection, and the biopsy CD146 staining in the rejection group was higher than that of the non-rejection group. Multivariate analysis demonstrated soluble CD146 as an independent risk factor of acute rejection. The area under the receiver operating characteristic curve (AUC) of sCD146 for AR diagnosis was 0.895, and the optimal cut-off value was 75.64 ng/ml, with a sensitivity of 87.8% and a specificity of 80.8%, which was better than eGFR alone (P = 0.02496). Immunohistochemistry showed CD146 expression in glomeruli was positively correlated with the Banff-g score, and its expression in tubules also had a positive relationship with the Banff-t score. Therefore, soluble CD146 may be a potential biomarker of acute rejection. Increased CD146 expression in the endothelial or tubular epithelial cells may imply that endothelial/epithelial dysfunction is involved in the pathogenesis of immune injury.

Enhancer of zeste homolog 2 (EZH2) and related EZH1 control gene expression and promote tumorigenesis via methylating histone H3 at lysine 27 (H3K27). These methyltransferases are ideal therapeutic targets due to their frequent hyperactive mutations and overexpression found in cancer, including hematopoietic malignancies. Here, we characterized a set of small molecules that allow pharmacologic manipulation of EZH2 and EZH1, which include UNC1999, a selective inhibitor of both enzymes, and UNC2400, an inactive analog compound useful for assessment of off-target effect. UNC1999 suppresses global H3K27 trimethylation/dimethylation (H3K27me3/2) and inhibits growth of mixed lineage leukemia (MLL)-rearranged leukemia cells. UNC1999-induced transcriptome alterations overlap those following knockdown of embryonic ectoderm development, a common cofactor of EZH2 and EZH1, demonstrating UNC1999's on-target inhibition. Mechanistically, UNC1999 preferentially affects distal regulatory elements such as enhancers, leading to derepression of polycomb targets including Cdkn2a. Gene derepression correlates with a decrease in H3K27me3 and concurrent gain in H3K27 acetylation. UNC2400 does not induce such effects. Oral administration of UNC1999 prolongs survival of a well-defined murine leukemia model bearing MLL-AF9. Collectively, our study provides the detailed profiling for a set of chemicals to manipulate EZH2 and EZH1 and establishes specific enzymatic inhibition of polycomb repressive complex 2 (PRC2)-EZH2 and PRC2-EZH1 by small-molecule compounds as a novel therapeutics for MLL-rearranged leukemia.

To investigate the efficacy and safety of bone marrow-derived mesenchymal stem cells (BM-MSCs) on chronic active antibody-mediated rejection (cABMR) in the kidney allograft.

Introduction: Until now, there is no clinically approved specific medicine to treat COVID-19. Prior systematic reviews (SRs) have shown that traditional Chinese medicine (TCM) reduces the number of patients with severe disease and time to fever clearance, promotes clinical effectiveness, and improves chest images and the negativity rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acid test. Few SRs arrived at a definitive conclusion, and more randomized controlled trials (RCTs) were published. We conducted this study to summarize the latest evidence of TCM in COVID-19. Methods: Eight online databases were searched from December 2019 to July 2020, updated to March 2021. Only RCTs evaluating the clinical efficacy and safety of TCM in the treatment of COVID-19 were included. Primary outcomes were clinical cure and the negativity of the SARS-CoV-2 nucleic acid test. Secondary outcomes included clinical deterioration, ARDS, mechanical ventilation, death, time to fever clearance, duration of hospitalization, and chest imaging improvement. Safety outcomes included adverse events and serious adverse events during treatment. Two reviewers selected the included articles, assessed the risk of bias, and extracted data independently and in duplicate. Results: A total of 25 RCTs involving 2222 participants were selected in the systematic review, and seven RCTs were included in the meta-analysis. The results showed that TCM plus routine treatment was significantly better than routine treatment alone in clinical cure (risk ratio [RR] = 1.20, 95% confidence interval (CI) [1.04, 1.38], P = 0.01) and chest image improvement (RR = 1.22, 95% CI [1.07, 1.39], P = 0.01) and could reduce clinical deterioration (RR = 0.39, 95% CI [0.18, 0.86], P = 0.02), ARDS (RR = 0.28, 95% CI [0.11, 0.69], P = 0.01), mechanical ventilation (RR = 0.30, 95% CI [0.12, 0.77], P = 0.01), or death rate (RR = 0.28, 95% CI [0.09, 0.84], P = 0.02). No significant difference between TCM and routine treatment in the negativity of SARS-CoV-2 nucleic acid test (RR = 1.08, 95% CI [0.94, 1.23], P = 0.29) was observed. Finally, there was no overall significant difference in the incidence of adverse events between the two groups. The summary of evidence showed moderate confidence of a benefit of 11.8% in clinical cure and 14.0% in chest image improvement and a reduction of 5.9% in clinical deterioration, 25.4% in ARDS, 18.3% in mechanical ventilation, and 4.5% in death with TCM plus routine treatment compared to routine treatment alone in patients with COVID-19. A low confidence of a benefit of 5.4% in the negativity of SARS-CoV-2 nucleic acid test was also observed. Conclusions: Synethized evidence of 21 outcomes in 8 RCTs showed moderate certainty that TCM treatment plus routine treatment may promote a clinical cure and chest image improvement compared to routine treatment alone while reducing clinical deterioration, development of ARDS, use of mechanical ventilation, and death in patients with COVID-19. TCM treatment plus routine treatment may not promote the negativity of the SARS-CoV-2 nucleic acid test compared to routine treatment alone. TCM treatment was found to be safe for patients with COVID-19.

Non-small-cell lung cancer (NSCLC) is usually diagnosed at an advanced stage, and chemotherapy is the main treatment for this disease. Kanglaite injections (KLTi) have been widely used for the treatment of cancer in China. KLTi combined with chemotherapy could improve the short-term efficacy, quality of life, and performance status for NSCLC compared with chemotherapy alone. This trial aims to assess the long-term efficacy and safety of KLTi in combination with chemotherapy for the treatment of advanced NSCLC.

Hepatic ischemia-reperfusion (IR) injury remains a common issue lacking effective strategy and validated pharmacological targets. Here, using an unbiased metabolomics screen, this study finds that following murine hepatic IR, liver 3-hydroxyanthranilic acid (3-HAA) and quinolinic acid (QA) decline while kynurenine and kynurenic acid (KYNA) increase. Kynurenine aminotransferases 2, functioning at the key branching point of the kynurenine pathway (KP), is markedly upregulated in hepatocytes during ischemia, shifting the kynurenine metabolic route from 3-HAA and QA to KYNA synthesis. Defects in QA synthesis impair de novo nicotinamide adenine dinucleotide (NAD) biosynthesis, rendering the hepatocytes relying on the salvage pathway for maintenance of NAD and cellular antioxidant defense. Blocking the salvage pathway following IR by the nicotinamide phosphoribosyltransferase inhibitor FK866 exacerbates liver oxidative damage and enhanced IR susceptibility, which can be rescued by the lipid peroxidation inhibitor Liproxstatin-1. Notably, nicotinamide mononucleotide administration once following IR effectively boosts NAD and attenuated IR-induced oxidative stress, inflammation, and cell death in the murine model. Collectively, the findings reveal that metabolic rewiring of the KP partitions it away from NAD synthesis in hepatic IR pathophysiology, and provide proof of concept that NAD augmentation is a promising therapeutic measure for IR-induced liver injury.

While additive manufacturing (AM) has facilitated the production of complex structures, it has also highlighted the immense challenge inherent in identifying the optimum AM structure for a given application. Numerical methods are important tools for optimization, but experiment remains the gold standard for studying nonlinear, but critical, mechanical properties such as toughness. To address the vastness of AM design space and the need for experiment, we develop a Bayesian experimental autonomous researcher (BEAR) that combines Bayesian optimization and high-throughput automated experimentation. In addition to rapidly performing experiments, the BEAR leverages iterative experimentation by selecting experiments based on all available results. Using the BEAR, we explore the toughness of a parametric family of structures and observe an almost 60-fold reduction in the number of experiments needed to identify high-performing structures relative to a grid-based search. These results show the value of machine learning in experimental fields where data are sparse.