Comparison of the Safety and Efficacy of Remimazolam Besylate versus Dexmedetomidine for Patients Undergoing Fiberoptic Bronchoscopy: A Prospective, Randomized Controlled Trial.

Objective: Remimazolam besylate is a novel ultra-short-acting benzodiazepine that is rapidly hydrolyzed to zolpidem propionic acid by tissue lipases. We designed this study to compare the safety and efficacy of remimazolam besylate alfentanil versus dexmedetomidine-alfentanil for fiberoptic bronchoscopy (FB). Methods: One hundred and twenty patients undergoing FB into this prospective randomized controlled trial were divided into two groups. The anesthesia induction consisted of 6 mg/kg/h of remimazolam besylate in the RA group and 0.5 µg/kg of dexmedetomidine in the DA group. 1-2 mg/kg/h of remimazolam besylate or 0.2-0.7 µg/kg/h of dexmedetomidine were administered to maintain during FB. The lowest oxygen saturation, success rate of FB, hemodynamics, time metrics, bronchoscopy feasibility, drug dose requirements, patient and bronchoscopist satisfaction scores, occurrence of intraoperative awareness, number of patients willing to repeat FB with the same sedation regimen, and occurrence and severity of adverse events. Results: The lowest oxygen saturation during the FB was significantly higher in the RA group (P = 0.001). Compared with the variables in the DA group, peripheral oxygen saturation, systolic blood pressure, and diastolic blood pressure were significantly lower at T2 and T3 in the RA group (P < 0.05). Heart rates were significantly higher from T2 to T4 in the DA group (P < 0.05). More patients experienced bradycardia in the DA group (P = 0.041). Compared with time metrics in the DA group, the induction time, fully-alert time, and recovery room-leaving time were all significantly shorter in the RA group (P < 0.05). The bronchoscopy feasibility scores in the RA group were significantly lower at T2, whereas they were lower at T3 in the DA group (P < 0.05). Conclusion: Remimazolam besylate is superior to dexmedetomidine when combined with alfentanil during FB, promoting faster patients' recovery, better operative conditions and respiratory stability with similar rates of occurrence and severity of adverse events.

Corrigendum: Tpr deficiency disrupts erythroid maturation with impaired chromatin condensation in zebrafish embryogenesis.

[This corrects the article DOI: 10.3389/fcell.2021.709923.].

Corrigendum: Mutation of Gemin5 causes defective hematopoietic stem/progenitor cells proliferation in zebrafish embryonic hematopoiesis.

[This corrects the article DOI: 10.3389/fcell.2021.670654.].

TANGO6 regulates cell proliferation via COPI vesicle-mediated RPB2 nuclear entry.

Coat protein complex I (COPI) vesicles mediate the retrograde transfer of cargo between Golgi cisternae and from the Golgi to the endoplasmic reticulum (ER). However, their roles in the cell cycle and proliferation are unclear. This study shows that TANGO6 associates with COPI vesicles via two transmembrane domains. The TANGO6 N- and C-terminal cytoplasmic fragments capture RNA polymerase II subunit B (RPB) 2 in the cis-Golgi during the G1 phase. COPI-docked TANGO6 carries RPB2 to the ER and then to the nucleus. Functional disruption of TANGO6 hinders the nuclear entry of RPB2, which accumulates in the cytoplasm, causing cell cycle arrest in the G1 phase. The conditional depletion or overexpression of TANGO6 in mouse hematopoietic stem cells results in compromised or expanded hematopoiesis. Our study results demonstrate that COPI vesicle-associated TANGO6 plays a role in the regulation of cell cycle progression by directing the nuclear transfer of RPB2, making it a potential target for promoting or arresting cell expansion.

Valsartan attenuates LPS-induced ALI by modulating NF-κB and MAPK pathways.

Background: Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a common respiratory disease characterized by persistent hypoxemia and an uncontrolled inflammatory response. Valsartan, an angiotensin II type 1 receptor antagonist, is clinically used to treat hypertension and has anti-inflammatory and antioxidant effects on gefitinib-induced pneumonia in rats. However, the potential therapeutic effects of valsartan on lipopolysaccharide (LPS)-induced ALI remain unclear. This study investigated the protective role of valsartan in LPS-induced ALI and its underlying mechanisms. Methods: LPS-treated BEAS-2B cells and ALI mouse model were established. BEAS-2B cells were treated with LPS (10 µg/mL) for 24h, with or without valsartan (20, 40, and 80 µM). For ALI mouse models, LPS (5 mg/kg) was administered through intratracheal injection to treat the mice for 24h, and valsartan (10 or 30 mg/kg) was injected intraperitoneally twice 2 h before and 12 h after the LPS injection. Pulmonary functional parameters were examined by an EMKA pulmonary system. Hematoxylin and eosin staining, flow cytometry, CCK-8 assay, qRT-PCR, ELISA, immunofluorescence, Western blotting, and related commercial kits were used to assess the pathological damage to the lungs, neutrophil recruitment in the lung tissue and bronchoalveolar lavage fluid (BALF), cell viability, inflammation, oxidative activity, and mucus production, respectively. Potential mechanisms were further explored using network pharmacology and Western blotting. Results: Valsartan rescued LPS-reduced cell viability of BEAS-2B cells, improved the pulmonary function, ameliorated pathological lung injury in mice with ALI, ameliorated LPS-induced neutrophil recruitment in BALF and lung tissue of mice, attenuated oxidative stress by increasing the level of SOD and decreasing that of MDA and GSSG, inhibited LPS-induced MUC5AC overproduction, decreased the LPS-induced increase in expression of pro-inflammatory cytokines/chemokines including TNF-α, IL-6, IL-1ß, CXCL-1 and CXCL-2, and restored the expression of anti-inflammatory IL-10. Mechanistic studies showed that valsartan inhibits LPS-induced phosphorylation of nuclear factor-kappa B (NF-κΒ) and mitogen-activated protein kinases (MAPKs) including P38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) in both LPS-treated cells and the mouse model of ALI. Conclusion: Valsartan protects against LPS-induced ALI by attenuating oxidative stress, reducing MUC5AC production, and attenuating the inflammatory response that may involve MAPK and NF-κΒ pathways.

TRAIL and Celastrol Combinational Treatment Suppresses Proliferation, Migration, and Invasion of Human Glioblastoma Cells via Targeting Wnt/ß-catenin Signaling Pathway.

OBJECTIVE: To investigate the mechanistic basis for the anti-proliferation and anti-invasion effect of tumor necrosis factor-related apoptosis-induced ligand (TRAIL) and celastrol combination treatment (TCCT) in glioblastoma cells. METHODS: Cell counting kit-8 was used to detect the effects of different concentrations of celastrol (0-16 µmol/L) and TRAIL (0-500 ng/mL) on the cell viability of glioblastoma cells. U87 cells were randomly divided into 4 groups, namely control, TRAIL (TRAIL 100 ng/mL), Cel (celastrol 0.5 µmol/L) and TCCT (TRAIL 100 ng/mL+ celastrol 0.5 µmol/L). Cell proliferation, migration, and invasion were detected by colony formation, wound healing, and Transwell assays, respectively. Quantitative reverse transcription polymerase chain reaction and Western blotting were performed to assess the levels of epithelial-mesenchymal transition (EMT) markers (zona occludens, N-cadherin, vimentin, zinc finger E-box-binding homeobox, Slug, and ß-catenin). Wnt pathway was activated by lithium chloride (LiCl, 20 mol/L) and the mechanism for action of TCCT was explored. RESULTS: Celastrol and TRAIL synergistically inhibited the proliferation, migration, invasion, and EMT of U87 cells (P<0.01). TCCT up-regulated the expression of GSK-3ß and down-regulated the expression of ß-catenin and its associated proteins (P<0.05 or P<0.01), including c-Myc, Cyclin-D1, and matrix metalloproteinase (MMP)-2. In addition, LiCl, an activator of the Wnt signaling pathway, restored the inhibitory effects of TCCT on the expression of ß-catenin and its downstream genes, as well as the migration and invasion of glioblastoma cells (P<0.05 or P<0.01). CONCLUSIONS: Celastrol and TRAIL can synergistically suppress glioblastoma cell migration, invasion, and EMT, potentially through inhibition of Wnt/ß-catenin pathway. This underlies a novel mechanism of action for TCCT as an effective therapy for glioblastoma.

Multi-Responsive Afterglows from Aqueous Processable Amorphous Polysaccharide Films.

Polymer-based room-temperature phosphorescence (RTP) materials, especially polysaccharide-based RTP materials, earn sustained attention in the fields of anti-counterfeiting, data encryption, and optoelectronics owing to their green regeneration, flexibility, and transparency. However, those with both ultralong phosphorescence lifetime and excitation wavelength-dependent afterglow are rarely reported. Herein, a kind of amorphous RTP material with ultralong lifetime of up to 2.52 s is fabricated by covalently bonding sodium alginate (SA) with arylboronic acid in the aqueous phase. The resulting polymer film exhibits distinguished RTP performance with excitation-dependent emissions from cyan to green. Specifically, by co-doping with other fluorescent dyes, further regulation of the afterglow color from cyan to yellowish-green and near-white can be achieved through triplet-to-singlet Förster resonance energy transfer. In addition, the water-sensitive properties of hydrogen bonds endow the RTP property of SA-based materials with water/heat-responsive characteristics. On account of the color-tunable and stimuli-responsive afterglows, these smart materials are successfully applied in data encryption and anti-counterfeiting.

Identification of histone deacetylase inhibitors as neutrophil recruitment modulators in zebrafish using a chemical library screen.

Tissue injury-induced neutrophil recruitment is a prerequisite for the initiation and amplification of inflammatory responses. Although multiple proteases and enzymes involved in post-translational modification (PTM) of proteins regulate leukocyte recruitment, an unbiased functional screen of enzymes regulating inflammatory leukocyte recruitment has yet to be undertaken. Here, using a zebrafish tail fin amputation (TFA) model to screen a chemical library consisting of 295 compounds that target proteases and PTM enzymes, we identified multiple histone deacetylase (HDAC) inhibitors that modulate inflammatory neutrophil recruitment. AR-42, a pan-HDAC inhibitor, was shown to inhibit neutrophil recruitment in three different zebrafish sterile tissue injury models: a TFA model, a copper-induced neuromast damage and mechanical otic vesicle injury (MOVI) model, and a sterile murine peritonitis model. RNA sequencing analysis of AR-42-treated fish embryos revealed downregulation of neutrophil-associated cytokines/chemokines, and exogenous supplementation with recombinant human IL-1ß and CXCL8 partially restored the defective neutrophil recruitment in AR-42-treated MOVI model fish embryos. We thus demonstrate that AR-42 non-cell-autonomously modulates neutrophil recruitment by suppressing transcriptional expression of cytokines/chemokines, thereby identifying AR-42 as a promising anti-inflammatory drug for treating sterile tissue injury-associated diseases.

Synthesis of AgBr/Ti3C2@TiO2 ternary composite for photocatalytic dehydrogenation of 1,4-dihydropyridine and photocatalytic degradation of tetracycline hydrochloride.

In this work, AgBr/Ti3C2@TiO2 ternary composite photocatalyst was prepared by a solvothermal and precipitation method with the aims of introducing Ti3C2 as a cocatalyst and TiO2 as a compositing semiconductor. The crystal structure, morphology, elemental state, functional groups and photoelectrochemical properties were studied by XRD, SEM, TEM, XPS, FI-IR and EIS. The photocatalytic performances of the composites were investigated by the photodehydrogenation of diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (1,4-DHP) and the photodegradation of tetracycline hydrochloride (TCH) under visible light irradiation (λ > 400 nm). The AgBr/Ti3C2@TiO2 composite photocatalyst showed enhanced photocatalytic performance in both photocatalytic reactions. The photocatalytic activity of the composite photocatalyst is dependent on the proportional content of Ti3C2@TiO2. With optimized Ti3C2@TiO2 proportion, the photocatalytic ability of the AgBr/Ti3C2@TiO2 composite was 24.5 times as high as that of Ti3C2@TiO2 for photodehydrogenation of 1,4-DHP and 1.9 times as high as that of pure AgBr for photodegradation of TCH. The enhanced photocatalytic performance of the AgBr/Ti3C2@TiO2 composite should be due to the formation of a p-n heterojunction structure between AgBr and Ti3C2@TiO2 and the excellent electronic properties of Ti3C2, which enhanced the visible light absorption capacity, lowered the internal resistance, speeded up the charge transfer and reduced the recombination efficiency of photo-generated carriers. Mechanism studies showed that superoxide free radical (˙O2-) was the main active species. In addition, the composite photocatalyst also displayed good stability, indicating its reutilization in practical application.

Sfxn5 Regulation of Actin Polymerization for Neutrophil Spreading Depends on a Citrate-Cholesterol-PI(4,5)P2 Pathway.

Cell spreading is an initial and critical step in neutrophil adhesion and migration, leading to neutrophil recruitment to inflammatory tissues. Sideroflexin (Sfxn) family proteins are metabolite transporters located in the mitochondrial membrane. Recombinant SFXN5 protein is a citrate transporter in vitro; however, whether Sfxn5 regulates any cellular behavior or function remains unknown. In this study, we found that small interfering RNA transfection or morpholino injection achieving Sfxn5 deficiency in neutrophils significantly decreased neutrophil recruitment in mice and zebrafish, respectively. Sfxn5 deficiency impaired neutrophil spreading and spreading-associated cellular phenotypes, such as cell adhesion, chemotaxis, and ROS production. Actin polymerization is critical for neutrophil spreading, and we found that actin polymerization in spreading neutrophils was partially inhibited by Sfxn5 deficiency. Mechanistically, we observed that the levels of cytosolic citrate and its downstream metabolic products, acetyl-CoA and cholesterol, were decreased in Sfxn5-deficient neutrophils. The levels of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), a mediator for the regulation of actin polymerization by cholesterol, were reduced in the plasma membrane of Sfxn5-deficient neutrophils. Exogenous supplementation with citrate or cholesterol partially reversed the reduction in PI(4,5)P2 levels, defective neutrophil actin polymerization, and cell spreading. Altogether, we demonstrated that Sfxn5 maintains cytosolic citrate levels and ensures the synthesis of sufficient cholesterol to promote actin polymerization in a PI(4,5)P2-dependent manner during neutrophil spreading, which is essential for the eventual inflammatory recruitment of neutrophils. Our study revealed the importance of Sfxn5 in neutrophil spreading and migration, thus identifying, to our knowledge, for the first time, the physiological cellular functions of the Sfxn5 gene.

Lithium ameliorates Niemann-Pick C1 disease phenotypes by impeding STING/SREBP2 activation.

Niemann-Pick disease type C (NP-C) is a genetic lysosomal disorder associated with progressive neurodegenerative phenotypes. Its therapeutic options are very limited. Here, we show that lithium treatment improves ataxia and feeding phenotypes, attenuates cerebellar inflammation and degeneration, and extends survival in Npc1 mouse models. In addition, lithium suppresses STING activation, SREBP2 processing to its mature form and the expression of the target genes in the Npc1 mice and in Npc1-deficient fibroblasts. Lithium impedes STING/SREBP2 transport from the ER to the Golgi, a step required for STING activation and SREBP2 processing, probably by lowering cytosolic calcium concentrations. This effect of lithium on STING/SREBP2 transport provides a mechanistic explanation for lithium's effects on Npc1 mice. Thus, this study reveals a potential therapeutic option for NP-C patients as well as a strategy to reduce active STING/SREBP2 pathway.

LWJ-M30, a conjugate of DM1 and B6, for the targeted therapy of colorectal cancer with improved therapeutic effects.

Colorectal cancer (CRC) is one of the most prevalent cancers worldwide as well as a significant cause of mortality. The conventional treatment could cause serious side effects and induce drug resistance, recurrence and metastasis of cancers. Hence, specific targeting of cancer cells without affecting the normal tissues is currently an urgent necessity in cancer therapy. The emerging of peptide-drug conjugates (PDC) is regarded as a promising approach to address malignant tumors. LWJ-M30, a conjugate of DM1 and B6 peptide, targeted transferrin receptors (TfRs) on the surface of the CRC cells, showing a powerful anti-cancer effect. LWJ-M30 significantly inhibited the HCT116 cells proliferation and migration in vitro. LWJ-M30 also dramatically decreased the level of polymeric tubulin, while the disruption of microtubules caused the cell cycle to be arrested in the G2/M phase. LWJ-M30 induced the HCT116 cells apoptosis both in vivo and in vitro. The results in vivo demonstrated that LWJ-M30 could inhibit the HCT116 growth without affecting the mouse body weight. Taking these results together, our data indicated that LWJ-M30 could improve the therapeutic effects of DM1 while reducing the systemic toxicity in normal tissues.

Salviae miltiorrhizae Liguspyragine Hydrochloride and Glucose Injection Protects against Myocardial Ischemia-Reperfusion Injury and Heart Failure.

Purpose: Myocardial ischemia-reperfusion (MIR) injury is a common stimulus for cardiac diseases like cardiac arrhythmias and heart failure and may cause high mortality rates. Salviae miltiorrhizae liguspyragine hydrochloride and glucose injection (SGI) has been widely used to treat myocardial and cerebral infarctions in China even though its pharmacological mechanisms are not completely clear. Methods: The protective effect and mechanism of SGI on MIR injury and heart failure were investigated through the H9c2 cell model induced by hypoxia/reoxygenation (H/R) and rapamycin, zebrafish model induced by H/R and isoprenaline, and rat MIR model. Results: SGI significantly reduced the infarct size and alleviated the impairment of cardiac functions in the MIR rat model and H/R zebrafish model and promoted cell viability of cardiomyocyte-like H9c2 cells under H/R condition. Consistently, SGI significantly downregulated the serum level of biomarkers for cardiac damage and attenuated the oxidative damage in the MIR and H/R models. We also found that SGI could downregulate the increased autophagy level in those MIR and H/R models since autophagy can contribute to the injurious effects of ischemia-reperfusion in the heart, suggesting that SGI may alleviate MIR injury via regulating the autophagy pathway. In addition, we demonstrated that SGI also played a protective role in the isoproterenol-induced zebrafish heart failure model, and SGI significantly downregulated the increased autophagy and SP1/GATA4 pathways. Conclusion: SGI may exert anti-MIR and heart failure by inhibiting activated autophagy and the SP1/GATA4 pathway.

Efficacy and safety of ciprofol-remifentanil versus propofol-remifentanil during fiberoptic bronchoscopy: A prospective, randomized, double-blind, non-inferiority trial.

Objective: Ciprofol is a novel 2,6-disubstituted phenol derivative that has improved pharmacokinetic and pharmacodynamic properties compared with propofol. This study was conducted to compare the efficacy and safety of ciprofol-remifentanil versus propofol-remifentanil for patients undergoing fiberoptic bronchoscopy. Methods: Overall, 92 patients undergoing fiberoptic bronchoscopy were included in this prospective, randomized, double-blind, non-inferiority trial and were equally divided into two groups (n = 46 each). Fentanyl (50 µg) was given 2 min before the intravenous infusion of 0.3 mg/kg of ciprofol or 1.2 mg/kg of propofol over a time period of 30 s. During anesthesia maintenance, 0.05-0.2 µg/kg/min of remifentanil combined with one-third to one-fourth of the initial dose of ciprofol or propofol was repeated at 2-min intervals, as required, to maintain a Modified Observer's Assessment of Alertness and Sedation (MOAA/S) scale score <3. The primary outcome was the successful rate of fiberoptic bronchoscopy. Secondary outcomes included demographic characteristics, time metrics, hemodynamics, coughing severity, intubating conditions, lowest oxygen saturation, utilization of study drug doses, number of remedies (lidocaine and vasoactive drugs) used, satisfaction scores of both patients and the endoscopist, occurrence of intraoperative awareness, patients' willing to repeat fiberoptic bronchoscopy, and occurrence and severity of adverse events. Results: The successful completion rate of fiberoptic bronchoscopy was 91.30% (42 of 46; 95% confidence interval [CI]: 82.80%-99.80%) in the ciprofol-remifentanil group and 89.13% (41 of 46; 95% CI: 79.80%-98.50%) in the propofol-remifentanil group. Though the clinically acceptable intubating condition was improved in the ciprofol-remifentanil group, this difference has no clinical statistical difference (p > 0.05). No significant differences were noted between the two groups with respect to time metrics, consumption of fentanyl and remifentanil, or number of remedies (lidocaine and vasoactive drugs). Patients' willingness to repeat fiberoptic bronchoscopy and the satisfaction of both patients and endoscopist were significantly higher in the ciprofol-remifentanil than in the propofol-remifentanil group (p < 0.05). Compared with patients in the propofol-remifentanil group, patients in the ciprofol-remifentanil group had more stable hemodynamics. The lowest oxygen saturation was significantly higher in the ciprofol-remifentanil than in the propofol-remifentanil group (p < 0.05). The numbers of patients who experienced pain on injection in the ciprofol-remifentanil group was significantly lower than the number in the propofol-remifentanil group (p < 0.01). Severity of coughing, clinically acceptable severity of coughing, incidence of intraoperative awareness, and other adverse events were all similar between the two groups (p > 0.05). Only four patients experienced grade 2 adverse events (severe hypotension in one patient in the ciprofol-remifentanil group and three patients in the propofol-remifentanil group; p > 0.05); they were treated with noradrenaline. Conclusion: Ciprofol-remifentanil was non-inferior to propofol-remifentanil with regard to successful sedation for flexible bronchoscopy, when used with pre-intravenous administration of 50 µg of fentanyl. At the same time, patients' willingness to repeat flexible bronchoscopy and the satisfactions were all significantly improved.

The Efficacy and Safety of Ultrasound-Guided, Bi-Level, Erector Spinae Plane Block With Different Doses of Dexmedetomidine for Patients Undergoing Video-Assisted Thoracic Surgery: A Randomized Controlled Trial.

Background: The anesthetic characteristics of ultrasound-guided bi-level erector spinae plane block (ESPB) plus dexmedetomidine (Dex) remain unclear. We compared the efficacy and safety of ultrasound-guided bi-level ESPB plus different doses of Dex in patients undergoing video-assisted thoracic surgery (VATS). Methods: One-hundred eight patients undergoing VATS were randomized into three groups: R group (n = 38, 15 ml of 0.375% ropivacaine with 0.1 mg/kg dexamethasone), RD1 group (n = 38, 15 ml of 0.375% ropivacaine plus 0.5 µg/kg DEX with 0.1 mg/kg dexamethasone) and RD2 group (n = 38, 15 ml of 0.375% ropivacaine plus 1.0 µg/kg DEX with 0.1 mg/kg dexamethasone). The primary outcome was the pain 12 h after surgery. Secondary outcomes included the Prince Henry Hospital Pain Score; hemodynamics; consumption of sufentanil; anesthetized dermatomal distribution; recovery time; rescue analgesia; satisfaction scores of patients and surgeon; quick recovery index; adverse effects; the prevalence of chronic pain and quality of recovery. Results: The visual analog scale (VAS) and the Prince Henry pain score were significantly lower in both the RD1 and RD2 groups during the first 24 h after surgery (P < 0.05). Both VAS with coughing and the Prince Henry pain score were significantly lower in the RD2 group than in the RD1 group 8-24 h after surgery (P < 0.05). Both heart rate and mean arterial pressure were significantly different from T2 to T6 in the RD1 and RD2 groups (P < 0.05). The receipt of remifentanil, propofol, Dex, and recovery time was significantly reduced in the RD2 group (P < 0.05). The requirement for sufentanil during the 8-72 h after surgery, less rescue medication, and total press times were significantly lower in the RD2 group (P < 0.05). The time to the first dose of rescue ketorolac was significantly longer in the RD2 group (P < 0.05). Further, anal exhaust, removal of chest tubes, and ambulation were significantly shorter in the RD2 group (P < 0.05). The incidence of tachycardia, post-operative nausea and vomiting, and chronic pain was significantly reduced in the RD2 group, while the QoR-40 score was significantly higher in the RD2 group (P < 0.05). Conclusions: Pre-operative bi-level, single-injection ESPB plus 1 µg/kg DEX provided superior pain relief and long-term post-operative recovery for patients undergoing VATS. Clinical Trial Registration: http://www.chictr.org.cn/searchproj.aspx.

Tpr Deficiency Disrupts Erythroid Maturation With Impaired Chromatin Condensation in Zebrafish Embryogenesis.

Vertebrate erythropoiesis involves nuclear and chromatin condensation at the early stages of terminal differentiation, which is a unique process to distinguish mature erythrocytes from erythroblasts. However, the underlying mechanisms of chromatin condensation during erythrocyte maturation remain elusive. Here, we reported a novel zebrafish mutant cas7 with erythroid maturation deficiency. Positional cloning showed that a single base mutation in tprb gene, which encodes nucleoporin translocated promoter region (Tpr), is responsible for the disrupted erythroid maturation and upregulation of erythroid genes, including ae1-globin and be1-globin. Further investigation revealed that deficient erythropoiesis in tprb cas7 mutant was independent on HIF signaling pathway. The proportion of euchromatin was significantly increased, whereas the percentage of heterochromatin was markedly decreased in tprb cas7 mutant. In addition, TPR knockdown in human K562 cells also disrupted erythroid differentiation and dramatically elevated the expression of globin genes, which suggests that the functions of TPR in erythropoiesis are highly conserved in vertebrates. Taken together, this study revealed that Tpr played vital roles in chromatin condensation and gene regulation during erythroid maturation in vertebrates.

WO3/Ag2CO3 Mixed Photocatalyst with Enhanced Photocatalytic Activity for Organic Dye Degradation.

The development of an efficient photocatalyst with superior activity under visible light has been regarded as a significant strategy for pollutant degradation and environmental remediation. Herein, a series of WO3/Ag2CO3 mixed photocatalysts with different proportions were prepared by a simple mixing method and characterized by XRD, SEM, TEM, XPS, and DRS techniques. The photocatalytic performance of the WO3/Ag2CO3 mixed photocatalyst was investigated by the degradation of rhodamine B (RhB) under visible light irradiation (λ > 400 nm). The photocatalytic efficiency of the mixed WO3/Ag2CO3 photocatalyst was rapidly increased with the proportion of Ag2CO3 up to 5%. The degradation percentage of RhB by WO3/Ag2CO3-5% reached 99.7% within 8 min. The pseudo-first-order reaction rate constant of WO3/Ag2CO3-5% (0.9591 min-1) was 118- and 14-fold higher than those of WO3 (0.0081 min-1) and Ag2CO3 (0.0663 min-1). The catalytic activities of the mixed photocatalysts are not only higher than those of the WO3 and Ag2CO3 but also higher than that of the WO3/Ag2CO3 composite prepared by the precipitation method. The activity enhancement may be because of the easier separation of photogenerated electron-hole pairs. The photocatalytic mechanism was investigated by free radical capture performance and fluorescence measurement. It was found that light-induced holes (h+) was the major active species and superoxide radicals (·O2 -) also played a certain role in photocatalytic degradation of RhB.

Peptide Hydrogel with Antibacterial Performance Induced by Rare Earth Metal Ions.

Metal ion-induced peptide assembly is an interesting field. As compared to traditional antibacterial Ag+, rare earth metal ions possess the advantage of antibacterial performance with photostability and low toxicity. Herein, a new peptide Fmoc-FFWDD-OH was designed and synthesized, which could form a stable hydrogel induced by rare earth metal ions, including Tb3+, Eu3+, and La3+. The mechanical properties were characterized by rheological measurements, and they exhibited elasticity-dominating properties. Transmission electron microscopy (TEM) images showed a large number of nanoscale fiber structures formed in the hydrogel. Circular dichroism (CD) spectra, Fourier transform infrared (FT-IR) spectra, ThT assays, and X-ray diffraction (XRD) pattern illustrated the formation mechanism of the fiber structure. The rare earth ion-induced peptide hydrogel was proved to possess good antibacterial performance on Escherichia coli (E. coli) with excellent biocompatibility. The introduction of rare earth metal ions may have some potential applications in the biological antibacterial and medical fields.

Drosera-Inspired Dual-Actuating Double-Layer Hydrogel Actuator.

Drosera is a small insectivorous plant whose antennae can fold up, encircle, and prey. The rapid movement of the antennae is achieved by the synergistic effect of a double-layer structure with the antennae contracts on the front and expands on the back. In this work, a drosera-inspired dual-actuating double-layer hydrogel actuator is proposed, in which the temperature-responsive poly(N, N-diethyl acrylamide) (PDEAAm) layer acts as the main actuation layer and a moisture-responsive poly(acrylamide) (PAAm) layer acts as the auxiliary actuation layer. In a water environment with low temperature, both the PAAm and PDEAAm layers absorb water and expand with a swelling property. When the temperature exceeds the lower critical solution temperature of PDEAAm, the PDEAAm layer undergoes a hydrophilic-hydrophobic transition and shrinks rapidly. Therefore, the synergistic effect of the double-layer hydrogel enables the double-layer hydrogel to achieve a large bending angle at high temperature. In addition, when designing and fabricating shape-patterned double-layer hydrogels, complex shape changes can be achieved. Due to the physical and chemical properties, the actuator can be used to grab, transport, and release objects. This drosera-inspired double-layer hydrogel actuator has high practical value, which may provide new insights for the design and manufacture of artificial intelligence materials.

XHL11, a novel selective EGFR inhibitor, overcomes EGFRT790M-mediated resistance in non-small cell lung cancer.

The first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib significantly improved the therapeutic effect in non-small cell lung cancer (NSCLC) patients with EGFR mutation. However, the EGFRT790M mutation occurs and results in acquired resistance. Consequently, mutant selective third-generation EGFR TKIs represented by AZD9291 (Osimertinib) have been developed to offer more effective therapeutic treatment, but the clinical application is limited by the acquired resistance and the high costs. A series of 5-chloropyrimidine-2,4-diamine derivatives were synthesized and screened for in vitro antitumor activity on H1975 and A431 cells. XHL11 showed the strongest antineoplastic activity. Compared to AZD9291, XHL11 suppressed cellular proliferation and colony formation and induced apoptosis in H1975 cells with EGFRL858R/T790M mutation. In addition, XHL11 caused expression changes in EGFR and apoptosis-related pathways. Moreover, oral administration of XHL11 suppressed tumor progression in vivo in a H1975 subcutaneous xenograft model. These data demonstrated that XHL11 might be developed as a promising EGFR TKI for the therapeutic use of NSCLC patients.