Transcriptional integration of paternal and maternal factors in the Arabidopsis zygote.

In many plants, the asymmetric division of the zygote sets up the apical-basal axis of the embryo. Unlike animals, plant zygotes are transcriptionally active, implying that plants have evolved specific mechanisms to control transcriptional activation of patterning genes in the zygote. In Arabidopsis, two pathways have been found to regulate zygote asymmetry: YODA (YDA) mitogen-activated protein kinase (MAPK) signaling, which is potentiated by sperm-delivered mRNA of the SHORT SUSPENSOR (SSP) membrane protein, and up-regulation of the patterning gene WOX8 by the WRKY2 transcription factor. How SSP/YDA signaling is transduced into the nucleus and how these pathways are integrated have remained elusive. Here we show that paternal SSP/YDA signaling directly phosphorylates WRKY2, which in turn leads to the up-regulation of WOX8 transcription in the zygote. We further discovered the transcription factors HOMEODOMAIN GLABROUS11/12 (HDG11/12) as maternal regulators of zygote asymmetry that also directly regulate WOX8 transcription. Our results reveal a framework of how maternal and paternal factors are integrated in the zygote to regulate embryo patterning.

UFMylation of HRD1 regulates endoplasmic reticulum homeostasis.

Ubiquitin fold modifier 1 is a small ubiquitin-like protein modifier that is essential for embryonic development of metazoans. Although UFMylation has been connected to endoplasmic reticulum homeostasis, the underlying mechanisms and the relevant cellular targets are largely unknown. Here, we show that HRD1, a ubiquitin ligase of ER-associated protein degradation (ERAD), is a novel substrate of UFM1 conjugation. HRD1 interacts with UFMylation components UFL1 and DDRGK1 and is UFMylated at Lys610 residue. In UFL1-depleted cells, the stability of HRD1 is increased and its ubiquitination modification is reduced. In the event of ER stress, the UFMylation and ubiquitination modification of HRD1 is gradually inhibited over time. Alteration of HRD1 Lys610 residue to arginine impairs its ability to degrade unfolded or misfolded proteins to disturb protein processing in ER. These results suggest that UFMylation of HRD1 facilitates ERAD function to maintain ER homeostasis.

CDC48A, an interactor of WOX2, is required for embryonic patterning in Arabidopsis thaliana.

KEY MESSAGE: Interactor of WOX2, CDC48A, is crucial for early embryo patterning and shoot meristem stem cell initiation, but is not required for WOX2 protein turnover or subcellular localization. During Arabidopsis embryo patterning, the WUSCHEL HOMEOBOX 2 (WOX2) transcription factor is a major regulator of protoderm and shoot stem cell initiation. Loss of WOX2 function results in aberrant protodermal cell divisions and, redundantly with its paralogs WOX1, WOX3, and WOX5, compromised shoot meristem formation. To elucidate the molecular basis for WOX2 function, we searched for protein interactors by IP-MS/MS from WOX2-overexpression roots displaying reprogramming toward shoot-like cell fates. Here, we report that WOX2 directly interacts with the type II AAA ATPase molecular chaperone CELL DIVISION CYCLE 48A (CDC48A). We confirmed this interaction with bimolecular fluorescence complementation and co-immunoprecipitation and found that both proteins co-localize in the nucleus. We show that CDC48A loss of function results in protoderm and shoot meristem stem cell initiation defects similar to WOX2 loss of function. We also provide evidence that CDC48A promotes WOX2 activity independently of proteolysis or the regulation of nuclear localization, common mechanisms of CDC48A function in other processes. Our results point to a new role of CDC48A in potentiating WOX2 function during early embryo patterning.

The effect of combined pudendal nerve and spermatic cord block or caudal epidural block on postoperative analgesia after posterior urethroplasty: a randomized trial.

BACKGROUND: Postoperative pain management remains a significant challenge for patients undergoing posterior urethroplasty (PU). In a previous study, we proposed a novel technique of combined pudendal nerve (PN) and spermatic cord (SC) block to manage pain after PU. The present trial was conducted to test the hypothesis that this technique is effective for pain control after PU and provides longer-lasting analgesia than caudal epidural block (CB). METHODS: Sixty patients undergoing PU were randomized into two groups: Group NB received combined PN and SC block, and Group CB received CB. General anesthesia with a laryngeal mask was performed. The primary outcome was the postoperative analgesic duration, and the secondary outcomes included the Numeric Rating Scale (NRS) scores for pain and the number of patients with different motor scores of the lower limb at 3, 6, 12, and 24 h postoperatively. RESULTS: Two patients in Group CB were withdrawn due to block failure. The postoperative analgesic duration was statistically longer in Group NB compared with Group CB (mean difference [95% confidence interval], 115.78 min [17.80, 213.75]; P = 0.021). The NRS scores for pain at 12 and 24 h after surgery were statistically lower in Group NB compared with Group CB. Group NB had statistically more patients with motor score 0 at 3 h postoperatively than Group CB. CONCLUSIONS: PN combined with SC block is an effective technique for postoperative analgesia in PU. This technique can achieve a longer duration of analgesia and lower pain scores, especially 12 h after surgery, than a CB. TRIAL REGISTRATION: This study was registered in the Chinese Clinical Trial Register (registration no. ChiCTR2100042971, registration date on 2/2/2021).

Assessment of emissions and exposure in 3D printing workplaces in Taiwan.

Three-dimensional (3D) printing is an emerging and booming industry in Taiwan. Compared to traditional manufacturing, 3D printing has various advantages, such as advanced customization, additive manufacturing, reduced mold opening time, and reduced consumption of precursors. In this study, the real-time monitoring of particulate matter (PM) and total volatile organic compound (TVOC) emissions from various filaments is investigated using fused deposition modeling with material extrusion technology, a liquid-crystal display, a stereolithography apparatus based on vat photopolymerization technology, and binder jetting for occupational settings. An exposure assessment for nearby workers using the 3D printing process was performed, and improvement measures were recommended. Nine 3D printing fields were measured. The generation rate of ultrafine particles ranged from 1.19 × 1010 to 4.90 × 1012 #/min, and the geometric mean particle size ranged from 30.91 to 55.50 nm. The average concentration of ultrafine particles ranged from 2.31 × 103 to 7.36 × 104 #/cm3, and the PM2.5 and PM10 concentrations in each field ranged from 0.74 ± 0.27 to 12.46 ± 5.61 µg/m3 and from 2.39 ± 0.60 to 30.65 ± 21.26 µg/m3, respectively. The TVOC concentration ranged from 0.127 ± 0.012 to 1.567 ± 0.172 ppm. The respiratory deposition (RDUFPs) dose ranged from 2.02 × 1013 to 5.54 × 1014 nm2/day. Depending on the operating conditions, appropriate control and protective measures should be employed to protect workers' health.

[Effects of different exercise modes on neuromuscular junction and metabolism of skeletal muscle-related proteins in aging rats].

The present study aimed to explore the effects of different exercise modes on neuromuscular junction (NMJ) and metabolism of skeletal muscle-related proteins in aging rats. Ten from 38 male Sprague-Dawley (SD) rats (3-month-old) were randomly selected into young (Y) group, while the rest were raised to 21 months old and randomly divided into elderly control (O), endurance exercise (EN) and resistance exercise (R) groups. After 8 weeks of corresponding exercises training, the gastrocnemius muscles of rats were collected, and the expression of S100B in Schwann cells was detected by immunofluorescence staining. Western blot was used to detect the protein expression levels of agglutinate protein (Agrin), low-density lipoprotein receptor-related protein 4 (Lrp4), muscle- specific kinase protein (MuSK), downstream tyrosine kinase 7 (Dok7), phosphorylated protein kinase B (p-Akt), phosphorylated mammalian target rapamycin (p-mTOR), and phosphorylated forkhead box O1 (p-FoxO1) in rat gastrocnemius muscles. The results showed that, endurance and resistance exercises increased the wet weight ratio of gastrocnemius muscle in the aging rats. The protein expression of S100B in the R group was significantly higher than those in the O and EN groups. Proteins related to NMJ function, including Agrin, Lrp4, MuSK, and Dok7 were significantly decreased in the O group compared with those in the Y group. Resistance exercise up-regulated these four proteins in the aging rats, whereas endurance exercise could not reverse the protein expression levels of Lrp4, MuSK and Dok7. Regarding skeletal muscle-related proteins, the O group showed down-regulated p-Akt, and p-mTOR protein expression levels and up-regulated p-FoxO1 protein expression level, compared to the Y group. Resistance and endurance exercises reversed the changes in p-mTOR and p-FoxO1 protein expression in the aging rats. These findings demonstrate that both exercise modes can enhance NMJ function, increase protein synthesis and reduce the catabolism of skeletal muscle-related proteins in aging rats, with resistance exercise showing a more pronounced effect.

Functional study of the soybean stamen-preferentially expressed gene GmFLA22a in regulating male fertility.

China has a high dependence on soybean imports, yield increase at a faster rate is an urgent problem that need to be solved at present. The application of heterosis is one of the effective ways to significantly increase crop yield. In recent years, the development of an intelligent male sterility system based on recessive nuclear sterile genes has provided a potential solution for rapidly harnessing the heterosis in soybean. However, research on male sterility genes in soybean has been lagged behind. Based on transcriptome data of soybean floral organs in our research group, a soybean stamen-preferentially expressed gene GmFLA22a was identified. It encodes a fasciclin-like arabinogalactan protein with the FAS1 domain, and subcellular localization studies revealed that it may play roles in the endoplasmic reticulum. Take advantage of the gene editing technology, the Gmfla22a mutant was generated in this study. However, there was a significant reduction in the seed-setting rate in the mutant plants at the reproductive growth stage. The pollen viability and germination rate of Gmfla22a mutant plants showed no apparent abnormalities. Histological staining demonstrated that the release of pollen grains in the mutant plants was delayed and incomplete, which may due to the locule wall thickening in the anther development. This could be the reason of the reduced seed-setting rate in Gmfla22a mutants. In summary, our study has preliminarily revealed that GmFLA22a may be involved in regulating soybean male fertility. It provides crucial genetic materials for further uncovering its molecular function and gene resources and theoretical basis for the utilization of heterosis in soybean.

[Mechanism of Mailuo Shutong Pills on posterior limb muscle swelling caused by femoral fracture in rats based on network pharmacology and experimental verification].

This study aims to investigate the mechanism of Mailuo Shutong Pills(MLST) on posterior limb muscle swelling caused by femoral fracture(SCFF) through network pharmacology and animal experiments. The plasma components of MLST were analyzed by LC-MS, and the target and signal pathway of SCFF were predicted by network pharmacology and verified by molecular docking. SCFF model rats were established through animal experiments, and different doses of MLST were administered to detect the degree of limb swelling. Hematoxylin-eosin(HE) staining was used to observe pathological changes in muscle tissue, and interleukin-6(IL-6), interleukin-1ß(interleukin-1ß), and tumor necrosis factor-α(TNF-α) in peripheral blood were determined by enzyme-linked immunosorbent assay(ELISA). The expression of relevant signaling pathways was measured by Western blot. Network pharmacological results showed that MLST and SCFF had a total of 153 disease targets, and the key targets were IL-6, TNF, etc., involving mitogen-activated protein kinase(MAPK) signaling pathway, phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT) signaling pathway, etc. The binding energies of the main components and key targets were lower than-7.0 kcal·mol~(-1), indicating that the network analysis results were reliable. The results of animal experiments showed that MLST could reduce the swelling degree and pathological damage of the posterior limb muscles of SCFF rats compared with the model group. ELISA results showed that MLST could reduce the levels of IL-6, IL-1ß, and TNF-α in the serum of SCFF rats. Western blot results showed that MLST can reduce the expression of p-AKT, p-PI3K, p-NF-κB, p-p38 MAPK, and p-ERK in SCFF rats. MLST may reduce the content of inflammatory factors in serum by regulating the expression of PI3K/AKT and MAPK-related signaling pathway protein and improving posterior limb muscle SCFF in rats.

Two-Dimensional Nonbenzenoid Heteroacene Crystals Synthesized via In-Situ Embedding of Ladder Bipyrazinylenes on Au(111).

Precisely introducing topological defects is an important strategy in nanographene crystal engineering because defects can tune π-electronic structures and control molecular assemblies. The synergistic control of the synthesis and assembly of nanographenes by embedding the topological defects to afford two-dimensional (2D) crystals on surfaces is still a great challenge. By in-situ embedding ladder bipyrazinylene (LBPy) into acene, the narrowest nanographene with zigzag edges, we have achieved the precise preparation of 2D nonbenzenoid heteroacene crystals on Au(111). Through intramolecular electrocyclization of o-diisocyanides and Au adatom-directed [2+2] cycloaddition, the nonbenzenoid heteroacene products are produced with high chemoselectivity, and lead to the molecular 2D assembly via LBPy-derived interlocking hydrogen bonds. Using bond-resolved scanning tunneling microscopy, we determined the atomic structures of the nonbenzenoid heteroacene product and diverse organometallic intermediates. The tunneling spectroscopy measurements revealed the electronic structure of the nonbenzenoid heteroacene, which is supported by density functional theory (DFT) calculations. The observed distinct organometallic intermediates during progression annealing combined with DFT calculations demonstrated that LBPy formation proceeds via electrocyclization of o-diisocyanides, trapping of heteroarynes by Au adatoms, and stepwise elimination of Au adatoms.

Piezoelectric Materials and Sensors for Structural Health Monitoring: Fundamental Aspects, Current Status, and Future Perspectives.

Structural health monitoring technology can assess the status and integrity of structures in real time by advanced sensors, evaluate the remaining life of structure, and make the maintenance decisions on the structures. Piezoelectric materials, which can yield electrical output in response to mechanical strain/stress, are at the heart of structural health monitoring. Here, we present an overview of the recent progress in piezoelectric materials and sensors for structural health monitoring. The article commences with a brief introduction of the fundamental physical science of piezoelectric effect. Emphases are placed on the piezoelectric materials engineered by various strategies and the applications of piezoelectric sensors for structural health monitoring. Finally, challenges along with opportunities for future research and development of high-performance piezoelectric materials and sensors for structural health monitoring are highlighted.

Study on detection of CNVs using human whole genome bisulfite sequencing data.

It has been reported that the aberrant DNA methylation may result in copy number variations (CNVs), and the CNVs may alter the levels of DNA methylation. Whole genome bisulfite sequencing (WGBS) is able to generate the sequencing data of DNAs, and shows the potential ability to detect CNVs. However, the evaluations and performances on the detections of CNVs using WGBS data is still unclear. In this study, five software with different strategies for CNV detections, e.g., BreakDancer, cn.mops, CNVnator, DELLY and Pindel, were selected to explore and benchmark the performances of CNV detections with WGBS data. Based on the real (2.62 billion reads) and simulated (12.35 billion reads) WGBS data of humans, we calculated the number, precision, recall, relative ability, memory usage, and running time of CNV detections by 150 times, and tried to figure out the optimal strategy for CNV detections with WGBS data. Based on the real WGBS data, Pindel detected the most deletions and duplications, CNVnator detected the deletions with the highest precision, cn.mops detected the duplications with the highest precision, Pindel detected the deletions with the highest recall, and cn.mops detected the duplications with the highest recall. Based on the simulated WGBS data, BreakDancer detected the most deletions, and cn.mops detected the most duplications. The CNVnator showed the highest precision and recall for both deletions and duplications. In real and simulated WGBS data, the ability of CNVnator to detect CNVs was likely to overtake that in the whole genome sequencing data. Additionally, DELLY and BreakDancer displayed the lowest peak of memory usage and the lest CPU runtime, while CNVnator expressed the highest peak of memory usage and the most CPU runtime. Taken together, CNVnator and cn.mops showed the excellent performances of CNV detections with WGBS data. These results suggested that it was feasible to detect CNVs using WGBS data, and provided the useful information to further investigate both CNVs and DNA methylation using WGBS data alone.

[Cost-effectiveness analysis of Biyuan Tongqiao Granules combined with Triamcinolone Acetonide Nasal Spray in treatment of chronic rhinosinusitis].

This study aims to evaluate the effectiveness and economic efficiency of Biyuan Tongqiao Granules combined with Triamcinolone Acetonide Nasal Spray in the treatment of chronic rhinosinusitis(CRS). The randomized controlled trial(RCT) of Biyuan Tongqiao Granules combined with Triamcinolone Acetonide Nasal Spray in the treatment of CRS was searched against EMbase, PubMed, Cochrane Library, CNKI, VIP, SinoMed, and Wanfang. The efficacy, nasal mucociliary transport time, and safety of the therapy above in the treatment of CRS were analyzed with single-group rate and Meta-analysis, and the economy and sensitivity were evaluated from the perspective of payer. A total of 9 RCTs were included, including 1 145 patients. Meta-analysis showed that compared with Triamcinolone Acetonide Nasal Spray alone, Biyuan Tongqiao Granules combined with Triamcinolone Acetonide Nasal Spray in the treatment of CRS patients increased the effective rate(RR=1.17, 95%CI[1.11, 1.24], P<0.000 01) and shortened the nasal mucociliary transport time(MD=-3.32, 95%CI[-5.86,-0.78], P=0.01), there was no significant difference in the incidence of adverse reactions between the two groups. The incremental cost-effectiveness analysis showed that the treatment costs of the control group and the observation group were 44.15 yuan and 1 044.96 yuan, respectively. In the Biyuan Tongqiao Granules combined with Triamcinolone Acetonide Nasal Spray treatment group, 75.48 yuan was spent to improve the effective rate of CRS by 1%. The one-way sensitivity analysis indicated the days of treatment, the RR of Biyuan Tongqiao Granules combined with Triamcinolone Acetonide Nasal Spray, the price of unit preparation of Biyuan Tongqiao Granules, and the effective rate of Triamcinolone Acetonide Nasal Spray alone had great influence on the incremental cost-effectiveness ratio. In conclusion, Biyuan Tongqiao Granules combined with Triamcinolone Acetonide Nasal Spray improves the therapeutic effect on CRS. The probabilistic sensitivity analysis showed that when the willingness to pay was greater than 7 920 yuan(less than 0.1 of GDP per capita 8 098 yuan), the combined therapy was economically superior to the control. Due to the limited number of articles published, it is necessary to carry out a real-world clinical trial of Biyuan Tongqiao Gra-nules and Triamcinolone Acetonide Nasal Spray in the treatment of CRS, so as to compare the cost-effectiveness of Biyuan Tongqiao Granules and Triamcinolone Acetonide Nasal Spray.

[Meta-analysis and trial sequential analysis of Chaihuang Granules in treatment of upper respiratory tract infection in children].

This study aimed to evaluate the efficacy and safety of Chaihuang Granules in the treatment of upper respiratory tract infection in children. The databases such as CNKI, Wanfang, VIP, SinoMed, Cochrane Library, PubMed, EMbase, Web of Science, Chinese Clinical Trial Registry, and ClinicalTrials.gov were searched for randomized controlled trial(RCT) of Chaihuang Granules for the treatment of upper respiratory tract infection in children, and supplemented by manual searching of gray literature. Two investigators independently screened the literature, extracted data, and assessed the methodological quality. Meta-analysis was performed using RevMan 5.4 software, trial sequential analysis was conducted using TSA 0.9.5.10 Beta software, and evidence quality evaluation was carried out using GRADE profiler 3.6.1 software. Eighteen RCTs involving 2 459 patients(1 262 in the treatment group and 1 197 in the control group) were included. Meta-analysis showed that compared with conventional therapy alone, Chaihuang Granules significantly improved the total effective rate(RR=1.18, 95%CI[1.15, 1.22], P<0.000 01), reduced the disappearance time of symptoms/signs(MD=-1.39, 95%CI[-1.66,-1.12], P<0.000 01), improved cytokine levels(MD=-2.40, 95%CI[-3.80,-1.00], P=0.000 8), improved humoral immune levels(MD=0.75, 95%CI[0.60, 0.90], P<0.000 01), and reduced the recurrence rate(MD=-2.11, 95%CI[-2.98,-1.25], P<0.000 01). However, the incidence of adverse reactions was not increased(RR=0.94, 95%CI[0.59, 1.49], P=0.78). Subgroup analysis showed that:(1) both Chaihuang Granules used alone(RR=1.19, 95%CI[1.11, 1.27], P<0.000 01) and in combination with other therapies(RR=1.18, 95%CI[1.14, 1.22], P<0.000 01) effectively improved the total effective rate.(2) In terms of symptoms/signs disappearance time, Chaihuang Granules effectively reduced the duration of fever(MD=-1.18, 95%CI[-1.78,-0.58], P=0.000 1), cough with sputum(MD=-1.82, 95%CI[-2.38,-1.25], P<0.000 01), cough(MD=-1.31, 95%CI[-1.89,-0.74], P<0.000 01), sore throat(MD=-1.57, 95%CI[-2.25,-0.89], P<0.000 01), and lung rales(MD=-1.49, 95%CI[-2.06,-0.92], P<0.000 01).(3) Regarding cytokine levels, Chaihuang Gra-nules effectively improved the levels of interleukin(IL)-2(MD=-0.94, 95%CI[-1.16,-0.72], P<0.000 01), IL-6(MD=-4.71, 95%CI[-6.39,-3.03], P<0.000 01), and tumor necrosis factor-α(TNF-α)(MD=-2.07, 95%CI[-2.43,-1.71], P<0.000 01).(4) In terms of cellular immune levels, Chaihuang Granules effectively improved the levels of CD3~+(MD=4.11, 95%CI[1.53, 6.69], P=0.002), CD4~+(MD=4.21, 95%CI[1.69, 6.73], P=0.001), CD8~+(MD=-2.65, 95%CI[-3.93,-1.37], P<0.000 1), and CD4~+/CD8~+(MD=0.25, 95%CI[0.14, 0.37], P<0.000 1).(5) In terms of humoral immune levels, Chaihuang Granules effectively improved the levels of IgA(MD=0.44, 95%CI[0.23, 0.64], P<0.000 1), IgM(MD=0.31, 95%CI[0.15, 0.46], P=0.000 1), and IgG(MD=2.02, 95%CI[1.60, 2.43], P<0.000 01). Trial sequential analysis showed that the cumulative Z-curve of the total effective rate crossed the boundary value, further confirming its clinical efficacy. The GRADE evidence quality evaluation showed that the evidence quality of the above outcome indicators was low or very low, and the recommendation strength was weak. Compared to conventional therapy alone, Chaihuang Granules can effectively improve the total effective rate of treatment, alle-viate symptoms and signs of upper respiratory tract infection in children, improve inflammatory conditions, enhance immune function, and reduce the recurrence rate. Due to the limited quality of the included studies, high-quality RCT is still needed to provide evidence support for the above conclusions.

[Meta-analysis and trial sequential analysis of Compound Qinlan Oral Liquid in treatment of acute upper respiratory tract infection].

This study aims to evaluate the efficacy and safety of Compound Qinlan Oral Liquid in the treatment of acute upper respiratory tract infection. Computer-based online searching of CNKI, VIP, SinoMed, Wanfang, ChiCTR, ClinicalTrials.gov, Cochrane Library, PubMed, EMbase, and Web of Science was performed to retrieve the randomized controlled trial(RCT) regarding Compound Qinlan Oral Liquid in the treatment of acute upper respiratory tract infection. In addition, manual searching of gray literature was conducted. After two evaluators independently selected articles, extracted data, and evaluated the quality of methodology included in the studies, Meta-analysis was carried out in RevMan 5.4 and trial sequential analysis(TSA) in TSA 0.9.5.10 Beta. GRADE profiler 3.6.1 was employed to evaluate the evidence quality. A total of 21 RCTs were included in this study, involving 2 651 patients(1 330 patients in the observation group and 1 321 patients in the control group). Meta-analysis showed that compared with conventional western medicine alone, Compound Qinlan Oral liquid improved the total response rate(RR=1.15, 95%CI[1.12, 1.19], P<0.000 01) without increasing the incidence of adverse reactions(RR=0.77, 95%CI[0.47, 1.25], P=0.16). The results of subgroup analysis are described as follows:(1) Compared with conventional western medicine alone, Compound Qinlan Oral Liquid improved the total response rate(RR=1.10, 95%CI[1.05, 1.14], P<0.000 01) and shortened the time to symptom relief(SMD=-0.76, 95%CI[-1.02,-0.51], P<0.000 01). There was no significant difference in the incidence of adverse reactions between the two groups(RR=1.16, 95%CI[0.54, 2.47], P=0.71).(2) Compared with conventional western medicine alone, Compound Qinlan Oral Liquid + conventional western medicine improved the total response rate(RR=1.20, 95%CI[1.15, 1.25], P<0.000 01), decreased traditional Chinese medicine(TCM) syndrome scores(MD=-0.58, 95%CI[-0.75,-0.41], P<0.000 01), shortened the time to symptom relief(SMD=-2.44, 95%CI[-3.09,-1.80], P<0.000 01) and physical sign improvement(MD=-2.57, 95%CI[-4.11,-1.04], P=0.001), lowered the serum levels of inflammatory cytokines(SMD=-2.16, 95%CI[-2.61,-1.70], P<0.000 01), improved respiratory function indicators(SMD=1.48, 95%CI[1.00, 1.96], P<0.000 01), and enhanced the humoral immunity(MD=0.94, 95%CI[0.69, 1.18], P<0.000 01). There was no significant difference in the incidence of adverse reactions between the two groups(RR=0.57, 95%CI[0.29, 1.09], P=0.09). TSA showed that the cumulative Z curve of total response rate crossed the traditional threshold and TSA threshold, further confirming the clinical efficacy of Compound Qinlan Oral Liquid. The GRADE graded the evidence of the above outcome indicators as low or extremely low, and yielded weak recommendation. Compared with conventional western medicine alone, Compound Qinlan Oral Liquid can improve the total effective rate and reduce the time to symptom relief. The combination of Compound Qinlan Oral Liquid and conventional western medicine can improve the total response rate, mitigate the symptoms and improve the physical signs, reduce inflammation, and improve respiratory function and immunity of the patients with acute upper respiratory tract infection. In view of the limited number and quality of the included studies, the above conclusions still require high-quality RCT to provide evidence support.

Lenvatinib with or without immune checkpoint inhibitors for patients with unresectable hepatocellular carcinoma in real-world clinical practice.

BACKGROUND: Lenvatinib is regarded as the first-line therapy for patients with unresectable hepatocellular carcinoma (HCC). This study assessed the efficacy and safety of lenvatinib with or without immune checkpoint inhibitors (ICIs) in patients with unresectable HCC. METHODS: In this multicentric retrospective study, patients with unresectable HCC who treated with lenvatinib with or without ICIs would be enrolled. Overall survival, progression-free survival, objective response rate, and disease control rate were calculated to assess the antitumor response. RESULTS: Between January 2019 and August 2020, 65 patients received lenvatinib plus ICIs while other 45 patients received lenvatinib. The baseline characteristics were comparable between the two groups. Lenvatinib plus ICIs provided significantly higher overall survival (hazard ratio = 0.47, 95% CI 0.26-0.85; p = 0.013) and progression-free survival (hazard ratio = 0.35, 95% CI 0.20-0.63; p < 0.001) than lenvatinib monotherapy. Moreover, patients with lenvatinib plus ICIs had significantly higher objective response rate (41.5% vs 20.0%, p = 0.023) and disease control rate (72.3% vs 46.7%, p = 0.009) per RECIST v1.1 than those with lenvatinib. No treatment-related deaths were observed. Grade 3 or greater adverse events occurring in 10% or more of patients in either treatment group were hypertension [13 (20.0%) of 65 patients treated with lenvatinib plus ICIs vs 8 (17.8%) of 45 patients treated with lenvatinib], and palmar-plantar erythrodysesthesia [seven (10.8%) vs two (4.4%)]. CONCLUSIONS: In this real-world study, lenvatinib combined with ICIs showed significantly promising efficacy and manageable safety than lenvatinib alone in patients with unresectable HCC.

Characteristics of purified anti-ß2GPI IgG N-glycosylation associate with thrombotic, obstetric and catastrophic antiphospholipid syndrome.

OBJECTIVE: Anti-ß-2 glycoprotein I (anti-ß2GPI) antibodies, defined as primary pathogenic antibody in antiphospholipid syndrome (APS). It has been reported that IgG Fc N-glycosylation affects IgG effector, we aim to investigate the association of Fc glycosylation profiles of purified anti-ß2GP1 IgG with clinical features of APS. METHODS: We purify anti-ß2GPI IgG and total IgG from 82 APS patients including nine catastrophic antiphospholipid syndrome (CAPS) patients, as well as total IgG from 103 healthy controls to quantitatively analyse all detectable Fc N-glycanforms of all IgG subclasses with Multiple Reaction Monitoring (MRM) method based on UPLC-ESI-QqQ mass spectrometry. RESULTS: Both purified anti-ß2GPI IgG and APS total IgG showed altered N-glycan profiles when compared with healthy control (HC) IgG. Anti-ß2GPI IgG presented with lower galactosylation, increased bisection and core fucosylation compared with APS total IgG and HC IgG. We found higher galactosylation of aß2GPI IgG2 in thrombotic APS compared with the obstetric APS, and lower galactosylation of aß2GPI IgG2 associated with late pregnancy morbidity. Moreover, low galactosylation of all anti-ß2GPI IgG subclasses, increased bisection and core fucosylation of anti-ß2GPI IgG1/2 were strongly associated with CAPS and triple positivity of antiphospholipid antibodies (aPLs). CONCLUSION: We comprehensively characterize the N-Glycans landscape of both anti-ß2GP1 and total IgG in APS. Altered N-glycan profiles of anti-ß2GPI IgG enables enabled the antibodies with proinflammatory properties. Furthermore, we associated levels of IgG Fc-glycosylation with clinical features antiphospholipid syndrome. These findings could increase our understanding of anti-ß2GPI antibody mediated mechanisms in APS and be used to develop diagnostics and new target treatments.

Guest-Induced Planar-Chiral Pillar[5]arene Surface for Selectively Adsorbing Protein Based on Host-Guest Chemistry.

In living systems, the adsorption of a protein on biointerfaces is a universal phenomenon, such as the specific binding of an antibody and antigen, which plays an important role in body growth and life maintenance. The exploration of a protein-selective adsorption on the biointerface is of great significance for understanding the life process and treatment in vitro. Herein, on the basis of biomimetic strategies, we fabricated a planar-chiral NH2-pillar[5]arene modified silicon surface (pR-/pS-NP5 surfaces) for a highly enantioselective adsorption of protein by taking advantage of the guest-induced planar chirality of pillar[5]arenes. Results from practical experiments and theoretical calculations show that the pR-NP5 surface possesses a high adsorption capacity and chiral selectivity for bovine serum albumin (BSA). Moreover, it was identified that the guest-induced chiral effect the generation and amplification of planar chirality, which was much beneficial for enhancing the interaction between planar-chiral pillar[5]arene host and BSA. The binding capacity of pR-NP5 and BSA is stronger than that of pS-NP5, thus promoting the chiral selective adsorption of BSA. This work affords a deeper understanding of the chiral influence of protein adsorption on biointerfaces and meanwhile provides a new perspective for chiral-sensing applications.

Clinical implications and biological features of a novel postoperative recurrent HCC classification: A multi-centre study.

BACKGROUND & AIMS: The multiplicity of hepatocellular carcinoma (HCC) recurrence patterns is the most important determinant of patients' postsurgical survival. A systematic HCC recurrence classification is needed to help prevent and treat postoperative HCC recurrence in the era of precision medicine. METHODS: A total of 1319 patients with recurrent HCC from four hospitals were enrolled and divided into a development cohort (n = 916), internal validation cohort (n = 225) and external validation cohort (n = 178). A comprehensive study of patients' clinicopathological factors and biological features was conducted. RESULTS: Four subtypes of recurrence were identified, which integrated recurrence features, survival, effects on systemic and liver function and potential therapeutics after recurrence: type I (solitary-intrahepatic oligorecurrence); type II (multi-intrahepatic oligorecurrence); type III (progression recurrence) and type IV (hyper-progression recurrence). Type III~IV recurrence indicated exceptionally poor prognosis. Subsequently, two nomogram models were established for type III~IV recurrence prediction, and both demonstrated excellent predictive performance and applicability of pre and postoperative strategy formulation. Multiple biological analyses revealed that HCC cases with type III~IV recurrence were characterized by enrichment in p53 mutations, CCND1 amplification, high proliferation/metastasis potential, inactive metabolism and immune exhaustion features. Over-expression of high mobility group protein 2 (HMGA2) enhanced the highly malignant behaviour of HCC through multiple molecular pathways, making it a potential prognostic predictor and therapeutic target. CONCLUSIONS: This 'recurrent HCC classification' has important potential value in identifying patients with surgical benefit, predicting postsurgical survival and guiding treatment strategies. Multidimensional biological insights also increased knowledge of factors associated with HCC recurrence.

A C-type lectin containing two carbohydrate recognition domains participates in the antibacterial response by regulating the JNK pathway and promoting phagocytosis.

C-type lectins (CTLs) are important immune-related molecules in crustaceans. However, the immunologic mechanism by which CTLs eliminate invading pathogens is still unclear. In this study, we studied the antimicrobial mechanism of a CTL containing two carbohydrate recognition domains (DClec). After Aeromonas hydrophila challenge, several antimicrobial peptides (ALF1, ALF4, ALF5 and lys-i2) were upregulated. The transcript levels of ALF1, ALF4 and ALF5 were downregulated after A. hydrophila challenge in groups with DClec interference or inhibition compared with the control group. Similar results were obtained after c-Jun N-terminal kinase (JNK) interference. This finding indicates that DClec might regulate the JNK signalling pathway and subsequently adjust antimicrobial peptide (AMP) expression. Additionally, we found that DClec was secreted into the hemolymph. Recombinant protein DClec (rDClec) agglutinated gram-positive or gram-negative bacteria. Both rDClec and the native DClec in hemolymph bound to different bacteria. In this process, Ca2+ promoted the rDClec bacterial binding ability. After DClec interference, the phagocytosis ability of hemocytes was lower than that of the control group. Therefore, DClec can facilitate bacterial elimination by promoting AMPs expression and hemocyte phagocytosis.

Dezocine relieves the postoperative hyperalgesia in rats through suppressing the hyper-action of Akt1/GSK-3ß pathway.

The relieving role of dezocine in pain after surgery was previously reported, while the potential mechanism was not completely clear. Therefore, the current research probed into the regulatory mechanism of dezocine in pain after surgery. A postoperative pain model was established by performing plantar incision surgery on the juvenile Sprague-Dawley rats. After the rats were treated with dezocine or SC79 (Akt1 activator), the paw withdrawal threshold and paw withdrawal latency of rats were detected to evaluate the mechanical allodynia and thermal hyperalgesia. After the plantar tissue, dorsal root ganglions, and spinal cord of rats were collected, the expressions of Akt1, p-Akt1, GSK-3ß, and p-GSK-3ß in the tissues were determined by western blot to evaluate the activation state of the Akt1/GSK-3ß pathway. After surgery, the paw withdrawal threshold and paw withdrawal latency of rats were lessened, whereas the ratios of p-Akt1/Akt1 and p-GSK-3ß/GSK-3ß were augmented in rat plantar tissue, dorsal root ganglions, and spinal cord. After treatment with dezocine alone, the paw withdrawal threshold and paw withdrawal latency of postoperative rats were elevated, but ratios of p-Akt1/Akt1 and p-GSK-3ß/GSK-3ß were reduced. After co-treatment with dezocine and SC79, SC79 reversed the effects of dezocine on elevating the paw withdrawal threshold and paw withdrawal latency, and reducing the ratios of p-Akt1/Akt1 and p-GSK-3ß/GSK-3ß in postoperative rats. Dezocine ameliorated the postoperative hyperalgesia in rats via repressing the hyper-action of Akt1/GSK-3ß pathway.