Tailored UPRE2 variants for dynamic gene regulation in yeast.

Genetic elements are foundational in synthetic biology serving as vital building blocks. They enable programming host cells for efficient production of valuable chemicals and recombinant proteins. The unfolded protein response (UPR) is a stress pathway in which the transcription factor Hac1 interacts with the upstream unfolded protein response element (UPRE) of the promoter to restore endoplasmic reticulum (ER) homeostasis. Here, we created a UPRE2 mutant (UPRE2m) library. Several rounds of screening identified many elements with enhanced responsiveness and a wider dynamic range. The most active element m84 displayed a response activity 3.72 times higher than the native UPRE2. These potent elements are versatile and compatible with various promoters. Overexpression of HAC1 enhanced stress signal transduction, expanding the signal output range of UPRE2m. Through molecular modeling and site-directed mutagenesis, we pinpointed the DNA-binding residue Lys60 in Hac1(Hac1-K60). We also confirmed that UPRE2m exhibited a higher binding affinity to Hac1. This shed light on the mechanism underlying the Hac1-UPRE2m interaction. Importantly, applying UPRE2m for target gene regulation effectively increased both recombinant protein production and natural product synthesis. These genetic elements provide valuable tools for dynamically regulating gene expression in yeast cell factories.

Large valley polarization and the valley-dependent Hall effect in a Janus TiTeBr monolayer.

Ferrovalley materials hold great promise for implementation of logic and memory devices in valleytronics. However, there have so far been limited ferrovalley materials exhibiting significant valley polarization and high Curie temperature (TC). Using first-principles calculations, we predict that the TiTeBr monolayer is a promising ferrovalley candidate. It exhibits intrinsic ferromagnetism with TC as high as 220 K. It is indicated that an out-of-plane alignment of magnetization demonstrates a valley polarization up to 113 meV in the topmost valence band, as further verified by perturbation theory considering both the spin polarization and spin-orbit coupling. Under an in-plane electric field, the valley-dependent Berry curvature results in the anomalous valley Hall effect (AVHE). Moreover, under a suitable in-plane biaxial strain, the TiTeBr monolayer transforms into a Chern insulator with a nonzero Chern number, yet retains its ferrovalley characters and thus the emergent quantum anomalous valley Hall effect (QAVHE). Our study indicates that the TiTeBr monolayer is a promising ferrovalley material, and it provides a platform for investigating the valley-dependent Hall effect.

Performance Enhancement of Tin-Based Perovskite Photodetectors through Bifunctional Cesium Fluoride Engineering.

Tin halide perovskites are rising as promising candidates for next-generation optoelectronic materials due to their good optoelectronic properties and relatively low toxicity. However, the high defect density and the easy oxidation of Sn2+ have limited their optoelectronic performance. Herein, we report the treatment of the FASnI3 (formamidinium tin, FA) perovskite film by a bifunctional cesium fluoride (CsF) additive, which improves the film quality and significantly enhances the photoelectric performance. The responsivity of the perovskite-based photodetector (PD) with an optimal CsF concentration of 15% is over 60 times larger than that of the PD without CsF. It indicates that both the Cs substitution and the fluoride anion additive from CsF inhibit the oxidation of Sn2+, optimize the crystal growth, and passivate the defects, demonstrating the dual roles of the CsF additive in improving the photoelectric performance. This work offers valuable insights into the additive selection for developing high-quality tin-based perovskite films and devices.

Optimizing the Biosynthesis of Dihydroquercetin from Naringenin in Saccharomyces cerevisiae.

Dihydroquercetin (DHQ), known for its varied physiological benefits, is widely used in the food, chemical, and pharmaceutical industries. However, the efficiency of the DHQ synthesis is significantly limited by the substantial accumulation of intermediates during DHQ biosynthesis. In this study, DHQ production was achieved by integrating genes from various organisms into the yeast chromosome for the expression of flavanone-3-hydroxylase (F3H), flavonoid-3'-hydroxylase, and cytochrome P450 reductase. A computer-aided protein design approach led to the development of optimal F3H mutant P221A, resulting in a 1.67-fold increase in DHQ yield from naringenin (NAR) compared with the control. Subsequently, by analysis of the enzyme reaction and optimization of the culture medium composition, 637.29 ± 20.35 mg/L DHQ was synthesized from 800 mg/L NAR. This corresponds to a remarkable conversion rate of 71.26%, one of the highest reported values for DHQ synthesis from NAR to date.

Electric properties of the twelve-fold vortex structure in hexagonal manganites.

Hexagonal manganites, as a functional ferroelectric (FE) material, receive considerable attention due to their improper ferroelectricity and topological vortex structures. This family exhibits three low-symmetry states accompanied by distinct vortex domain structures. In addition to the FEP63cmand anti-FE (AFE)P-3c1 states accompanied by dual six-fold vortex structures, there is another FEP3c1 state accompanied by a twelve-fold vortex structure. The responses of FE materials to external stimuli, such as external electric fields, are the core ingredients in the physics of FEs and are significant for technological applications. Under external electric fields, the responses of FE materials are determined by special FE domain structures. The electric properties of the FEP63cmand AFEP-3c1 states are very different. However, the electric properties of the FEP3c1 state, which only stabilizes in Ga-substituted In(Mn, Ga)O3, are unclear. The present work studies the electric properties of the FEP3c1 state. The electric-field-driven transition of the FEP3c1 state is found to follow two sequences, i.e. (1) twelve-foldP3c1 → nine-foldP3c1 +P63cm→ three-foldP63cm, and (2) twelve-foldP3c1 → six-foldP3c1 → three-foldP63cm. The variation of average polarization withEfor the FEP3c1 state with the second transition sequence manifests as an unusual triple-hysteresis loop, different from the usual single-hysteresis loop of FE materials. The results are related to the coexistence of the FE and non-FE domain walls in the FEP3c1 state. Furthermore, it is found that the FEP3c1 state at substitution concentration 0.39 exhibits the highest dielectric response. The results advance our understanding of topological vortex structures in hexagonal manganites.

De Novo Pterostilbene Production from Glucose Using Modular Coculture Engineering in Escherichia coli.

Pterostilbene, a derivative of resveratrol, is of increasing interest due to its increased bioavailability and potential health benefits. Sustainable production of pterostilbene is important, especially given the challenges of traditional plant extraction and chemical synthesis methods. While engineered microbial cell factories provide a potential alternative for pterostilbene production, most approaches necessitate feeding intermediate compounds. To address these limitations, we adopted a modular coculture engineering strategy, dividing the pterostilbene biosynthetic pathway between two engineered E. coli strains. Using a combination of gene knockout, atmospheric and room-temperature plasma mutagenesis, and error-prone PCR-based whole genome shuffling to engineer strains for the coculture system, we achieved a pterostilbene production titer of 134.84 ± 9.28 mg/L from glucose using a 1:3 inoculation ratio and 0.1% dimethyl sulfoxide supplementation. This represents the highest reported de novo production titer. Our results underscore the potential of coculture systems and metabolic balance in microbial biosynthesis.

POU5F1 promotes the proliferation, migration, and invasion of gastric cancer cells by reducing the ubiquitination level of TRAF6.

POU5F1 plays an important role in maintaining the cancer stem cell (CSC) -like properties of gastric cancer (GC) cells. The impact of POU5F1 on the proliferation and metastasis of GC was examined, along with the potential of ATRA as a specific therapeutic agent for GC. The dysregulation of POU5F1 expression in GC tissues was analyzed using public databases and bioinformatics techniques, and the disparity in POU5F1 expression between normal gastric tissues and GC tissues was further assessed through western blot, RT-qPCR, and immunohistochemistry. The present study aimed to investigate the impact of POU5F1 on the proliferation, migration, and invasion of GC cells through both in vivo and in vitro experiments. Additionally, the effects of ATRA on the proliferation, migration, and invasion of GC cells were examined using in vivo and in vitro approaches. Our findings revealed a significant upregulation of POU5F1 in GC tissues, which was found to be associated with a poorer prognosis in patients with GC. Moreover, POU5F1 was observed to enhance the proliferation, migration, and invasion of GC cells in vitro, as well as promote subcutaneous tumor growth and lung metastasis of GC cells in vivo. The overexpression of POU5F1 mechanistically triggers the process of Epithelial-mesenchymal transition (EMT) by down-regulating E-Cadherin and up-regulating N-Cadherin and VIM. POU5F1 hinders the ubiquitination of TRAF6 through negative regulation of TRIM59, thereby facilitating the activation of the NF-κB pathway. Furthermore, the administration of ATRA effectively impedes the proliferation, migration, and invasion of GC cells by suppressing the expression of POU5F1. The upregulation of POU5F1 elicits EMT, fosters the initiation of the NF-κB signaling pathway in GC cells, and stimulates the proliferation, invasion, and metastasis of GC cells. All-trans retinoic acid (ATRA) can impede these POU5F1-induced effects, thereby potentially serving as an adjunctive therapeutic approach for GC.

Macroscopic Piezoelectricity of Halide Perovskite Single Crystals and Their Highly Sensitive Self-Powered X-ray Detectors.

The FAxMA1-xPbI3 single crystal has excellent semiconductor photoelectric performance and good stability; however, there have been conflicting opinions regarding its macroscopic piezoelectricity. Here, the FAxMA1-xPbI3 (x = 0-0.1) single crystals (FAx SCs) exhibit a high macroscopic piezoelectric d33 coefficient of over 10 pC/N. The single crystal transforms from a tetragonal ferroelectric phase to a cubic paraelectric phase at x = 0.1-0.125. Furthermore, the fully polarized MAPbI3 and FA0.05 SCs were applied to prepare self-powered X-ray detectors with vertical structures. The sensitivity of the detector reaches 5.1 × 104 µC·Gy-1·cm-2 under a 0 V bias voltage, and its detection limit is as low as 50 nGy/s. This work provides an approach to designing self-powered and high-quality detectors with piezoelectric semiconductors.

Personalized radiomics signature to screen for KIT-11 mutation genotypes among patients with gastrointestinal stromal tumors: a retrospective multicenter study.

OBJECTIVES: Gastrointestinal stromal tumors (GISTs) carrying different KIT exon 11 (KIT-11) mutations exhibit varying prognoses and responses to Imatinib. Herein, we aimed to determine whether computed tomography (CT) radiomics can accurately stratify KIT-11 mutation genotypes to benefit Imatinib therapy and GISTs monitoring. METHODS: Overall, 1143 GISTs from 3 independent centers were separated into a training cohort (TC) or validation cohort (VC). In addition, the KIT-11 mutation genotype was classified into 4 categories: no KIT-11 mutation (K11-NM), point mutations or duplications (K11-PM/D), KIT-11 557/558 deletions (K11-557/558D), and KIT-11 deletion without codons 557/558 involvement (K11-D). Subsequently, radiomic signatures (RS) were generated based on the arterial phase of contrast CT, which were then developed as KIT-11 mutation predictors using 1408 quantitative image features and LASSO regression analysis, with further evaluation of its predictive capability. RESULTS: The TC AUCs for K11-NM, K11-PM/D, K11-557/558D, and K11-D ranged from 0.848 (95% CI 0.812-0.884), 0.759 (95% CI 0.722-0.797), 0.956 (95% CI 0.938-0.974), and 0.876 (95% CI 0.844-0.908), whereas the VC AUCs ranged from 0.723 (95% CI 0.660-0.786), 0.688 (95% CI 0.643-0.732), 0.870 (95% CI 0.824-0.918), and 0.830 (95% CI 0.780-0.878). Macro-weighted AUCs for the KIT-11 mutant genotype ranged from 0.838 (95% CI 0.820-0.855) in the TC to 0.758 (95% CI 0.758-0.784) in VC. TC had an overall accuracy of 0.694 (95%CI 0.660-0.729) for RS-based predictions of the KIT-11 mutant genotype, whereas VC had an accuracy of 0.637 (95%CI 0.595-0.679). CONCLUSIONS: CT radiomics signature exhibited good predictive performance in estimating the KIT-11 mutation genotype, especially in prediction of K11-557/558D genotype. RS-based classification of K11-NM, K11-557/558D, and K11-D patients may be an indication for choice of Imatinib therapy.

Engineering P-Fe2O3-CoP nanosheets for overall freshwater and seawater splitting.

Tailoring surface composition and coordinative environment of catalysts in a nano-meter region often influence their chemical performance. It is reported that CoP exhibits a low dissociation ability of H-OH, originating from the poor desorption of intermediate species. Herein, we provide a feasible method to construct P-Fe2O3-CoP nanosheets through a gas-phase phosphorization process. P doping induces the formation of interfacial structure between Fe2O3 and CoP and the generation of defective structures. The resulting P-Fe2O3-CoP nanosheets afford high freshwater/seawater oxidation activity (250/270 mV@10 mA/cm2) in 1 mol/L (M) KOH, which is even lower than commercial RuO2. Compared with CoP||CoP, P-Fe2O3||P-Fe2O3, and Co3O4||Co3O4, the assembled P-Fe2O3-CoP||P-Fe2O3-CoP exhibits the superior water/seawater electrolysis performance with 1.61/1.65 V@10 mA/cm2. The synergistic effect of P doping, defective structure, and heterojunction leads to high water oxidation efficiency and water splitting efficiency.

Development and validation of a preoperative nomogram for predicting the surgical difficulty of laparoscopic colectomy for right colon cancer: a retrospective analysis.

BACKGROUND: In laparoscopic right hemicolectomy for right colon cancer, complete mesocolic excision is a standard procedure that involves extended lymphadenectomy and blood vessel ligation. This study aimed to establish a nomogram to facilitate evaluation of the surgical difficulty of laparoscopic right hemicolectomy based on preoperative parameters. MATERIALS AND METHODS: The preoperative clinical and computed tomography-related parameters, operative details, and postoperative outcomes were analyzed. The difficulty of laparoscopic colectomy was defined using the scoring grade reported by Escal et al . with modifications. Multivariable logistic analysis was performed to identify parameters that increased the surgical difficulty. A preoperative nomogram to predict the surgical difficulty was established and validated. RESULTS: A total of 418 consecutive patients with right colon cancer who underwent laparoscopic radical resection at a single tertiary medical center between January 2016 and May 2022 were retrospectively enrolled. The patients were randomly assigned to a training data set ( n =300, 71.8%) and an internal validation data set ( n =118, 28.2%). Meanwhile, an external validation data set with 150 consecutive eligible patients from another tertiary medical center was collected. In the training data set, 222 patients (74.0%) comprised the non-difficulty group and 78 (26.0%) comprised the difficulty group. Multivariable analysis demonstrated that adipose thickness at the ileocolic vessel drainage area, adipose area at the ileocolic vessel drainage area, adipose density at the ileocolic vessel drainage area, presence of the right colonic artery, presence of type III Henle's trunk, intra-abdominal adipose area, plasma triglyceride concentration, and tumor diameter at least 5 cm were independent risk factors for surgical difficulty; these factors were included in the nomogram. The nomogram incorporating seven independent predictors showed a high C-index of 0.922 and considerable reliability, accuracy, and net clinical benefit. CONCLUSIONS: The study established and validated a reliable nomogram for predicting the surgical difficulty of laparoscopic colectomy for right colon cancer. The nomogram may assist surgeons in preoperatively evaluating risk and selecting appropriate patients.

Stretchable and self-healable hydrogel artificial skin.

Hydrogels have emerged as promising materials for the construction of skin-like mechanical sensors. The common design of hydrogel-based artificial skin requires a dielectric sandwiched between two hydrogel layers for capacitive sensing. However, such a planar configuration limits the sensitivity, stretchability and self-healing properties. Here, we report the design of single-layer composite hydrogels with bulk capacitive junctions as mechanical sensors. We engineer dielectric peptide-coated graphene (PCG) to serve as homogenously dispersed electric double layers in hydrogels. Any mechanical motions that alter the microscopic distributions of PCG in the hydrogels can significantly change the overall capacitance. We use peptide self-assembly to render strong yet dynamic interfacial interactions between the hydrogel network and graphene. The resulting hydrogels can be stretched up to 77 times their original length and self-heal in a few minutes. The devices can effectively sense strain and pressure in both air and aqueous environments, providing tremendous opportunities for next-generation iontronics.

Significant Interfacial Dielectric Relaxation of Covalently Bonded Ice-Hydrogels.

Hydrogels are composed of a three-dimensional network of cross-linked hydrophilic polymer chains and large amounts of water. The physicochemical properties of the polymer-water interface in hydrogels draw our attention. Due to the complex structure of hydrogel systems, it is still a challenge to investigate the interfacial layer properties of hydrogels through experiments. In this work, we investigate the properties of the covalently bonded chitosan-based ice-hydrogels interfacial layer by dielectric relaxation spectroscopy (DRS) techniques in the presence of avoided electrode polarization. The DRS data exhibit that the polymer-water interfacial layer has a strong dielectric signal response, which indicates that a large number of polar electric dipoles or polar molecules may be contained in the interfacial layer. The variable temperature dielectric relaxation behavior of a series of chitosan-base ice-hydrogels showed that the value of dielectric activation energy for different water contents is about 180 kJ/mol, which is much larger than that of the polymer and ice phases, suggesting a strong coupling of polar electric dipoles within the interfacial layer. This work demonstrates the important role of the polymer-water interface in covalently bonded hydrogels, which will provide assistance in the design and application of covalently bonded hydrogels.

Facile Benzylic Alkylation of Arenes with Alcohols by Catalysis with Spirocyclic NHC IrIII Pincer Complex.

A facile benzylic alkylation of indenes and other arenes was developed from readily available primary and secondary alcohols using our newly investigated CCC pincer IrIII catalyst (SNIr-H). Excellent regioselectivity and yield (89 %) of the C3-alkylated indenes were obtained. Additionally, the challenging sp2 C-alkylation was readily accomplished. This method could be utilized for the synthesis of the analogs of a histamine H1 receptor antagonist and the functional material template molecule, indeno[2,1-a]indene. A hemilabile IrIII -dihydride intermediate was proposed based on control experiments and previous density functional theory (DFT) calculations for the borrowing hydrogen mechanism and is key to the success of this IrIII catalyst in the reduction of unactivated multi-substituted olefin intermediates.

Clinical Application of Indocyanine Green Fluorescence Technology in Laparoscopic Radical Gastrectomy.

Background: This study aimed to observe the application and evaluate the feasibility and safety of indocyanine green (ICG) fluorescence technology in laparoscopic radical gastrectomy (LRG). Methods: Patients who underwent LRG & D2 lymphadenectomy at Qilu Hospital of Shandong University were included between January 2018 and August 2019. According to whether endoscopic injection of ICG was performed, patients were assigned to the ICG group (n=107) and the control group (n=88). The clinicopathologic features, retrieved lymph nodes, postoperative recovery, and follow-up data were compared between the two groups. Results: Baseline characteristics are comparable. The ICG group had a significantly larger number of lymph nodes retrieved (49.55 ± 12.72 vs. 44.44 ± 10.20, P<0.05), shorter total operation time (min) (198.22 ± 13.14 vs. 202.50 ± 9.91, P<0.05), shorter dissection time (min) (90.90 ± 5.34 vs. 93.74 ± 5.35, P<0.05) and less blood loss (ml) (27.51 ± 12.83 vs. 32.02 ± 17.99, P<0.05). The median follow-up time was 29.0 months (range 1.5-43.8 months), and there was no significant difference between the ICG group and the control group in 2-year OS (87.8% vs. 82.9%, P>0.05) or DFS (86.0% vs. 80.7%, P>0.05). Conclusions: ICG fluorescence technology in laparoscopic radical gastrectomy has advantages in LN dissection, operation time, and intraoperative blood loss. The 2-year OS and 2-year DFS rates between the two groups were comparable. In conclusion, ICG fluorescence technology is feasible and safe.

Objective follow-up after transection of uterine round ligament during laparoscopic repair of inguinal hernias in women: assessment of safety and long-term outcomes.

BACKGROUND: Whether to preserve the uterine round ligament during laparoscopic inguinal hernia repair in women is controversial. In this study, we aimed to compare outcomes of uterine round ligament preservation versus transection during such surgery and to explore the impact and long-term outcomes of transecting the round ligament. METHODS: The study cohort comprised 419 women who had undergone laparoscopic inguinal hernia repair in Beijing Chaoyang Hospital and Qilu Hospital from January 2013 to January 2020; 393 (93.8%) of whom were successfully followed up. Patient characteristics and technical details of the operative procedure were collected and analyzed retrospectively. Early and late postoperative follow-up data, complications, especially symptoms related to retroflexed uterus, and fertility outcomes, were collected by a single follow-up nurse who was blinded to the operative procedure. RESULTS: There were 218 women (239 sides) in the uterine round ligament preservation group and 175 (182 sides) in the transection group. The patients in the preservation group were younger (45.9 vs. 53.6 years, p = 0.000), and had lower American Society of Anesthesiologists scores (p = 0.000). The median follow-up times in the preservation and transection groups were 41.8 ± 24.2 and 42.7 ± 24.6 months, respectively (p = 0.692). Compared with the transection group, the preservation group had longer operative times for repair of both primary and recurrent hernias. Intraoperative bleeding, length of hospital stay, development of seromas, recurrence rate, incidence of postoperative pain at the first and third postoperative months, and time of last outpatient visit were similar in the two groups. There were more premenopausal patients in the preservation group; however, we found no evidence that transection of the round ligament affected subsequent pregnancy or childbirth. Moreover, we identified no differences in dyspareunia, dysmenorrhea, chronic pelvic pain, or uterine prolapse. CONCLUSION: Transection of the round ligament during laparoscopic inguinal hernia repair in women does not increase the incidence of dyspareunia, dysmenorrhea, chronic pelvic pain, or uterine prolapse, whereas it has the advantage of reducing the operation time.

Non-closure of the Free Peritoneal Flap During Laparoscopic Hernia Repair of Lower Abdominal Marginal Hernia: A Retrospective Analysis.

Background: During lower abdominal marginal hernia repair, the peritoneal flap is routinely freed to facilitate mesh placement and closed to conclude the procedure. This procedure is generally called trans-abdominal partial extra-peritoneal (TAPE). However, the necessity of closing the free peritoneal flap is still controversial. This study aimed to investigate the safety and feasibility of leaving the free peritoneal flap in-situ. Methods: A retrospective review was conducted on 68 patients (16 male, 52 female) who underwent laparoscopic hernia repair between June 2014 and March 2021. Patients were diagnosed as the lower abdominal hernia and all required freeing the peritoneal flap during the operation. Patients were divided into 2 groups: one group was TAPE group with the closed free peritoneal flap, another group left the free peritoneal flap unclosed. Analyses were performed to compare both intraoperative parameters and postoperative complications. Results: There were no significant differences in demographic, comorbidity, hernia characteristics and ASA classification. The intra-operative bleeding volume, visceral injury, hospital stay, urinary retention, visual analog scale (VAS) score, dysuria, intestinal obstruction, surgical site infection, mesh infection, recurrence rate and hospital stay were similar among the two groups. Mean operative time of the flap closing procedure was higher than for patients with the free peritoneal flap left in-situ (p = 0.002). Comparisons of postoperative complications showed flap closure resulted in a higher incidence of seroma formation (p = 0.005). Conclusion: Providing a barrier-coated mesh is used during laparoscopic lower abdominal marginal hernia repair, it is safe to leave the free peritoneal flap in-situ and this approach may prevent the occurrence of seromas.

Exploring Central Vascular Anatomy With Axial Computed Tomography During Surgery for Sigmoid Colon and Rectal Cancer: New Insights Into the Anatomical Relationship Between the Inferior Mesenteric Artery and the Duodenum.

Background: In some individuals, the inferior mesenteric artery (IMA) originates from the aorta above the lower edge of the duodenum. This anatomical feature has rarely been reported but may be important in guiding central vascular ligation and lymph node dissection in colorectal surgery. This retrospective study aimed to explore the anatomical relationship between the IMA and the duodenum and evaluate its potential impact on the efficacy of D3 lymph node dissection. Methods: A total of 439 patients undergoing laparoscopic colorectal surgery at the Department of General Surgery, Qilu Hospital of Shandong University, were retrospectively enrolled. Clinical data from axial computed tomography (CT) scans were collected and analysed. Results: In 27.69% of patients, the IMA originated at or above the lower edge of the duodenum (median distance: -8 mm). These patients were characterised by a shorter superior mesenteric artery to aortic bifurcation distance, a superiorly located IMA origin, and a greater distance between the IMA and both the left colic artery and the inferior mesenteric vein. The number of harvested lymph nodes was not significantly associated with the distance between the IMA and the duodenum (P = 0.858). Conclusions: Preoperative axial CT scans can provide a great deal of information regarding central vascular anatomy in the context of sigmoid colon and rectal cancer surgery. Nearly one-third of patients have the IMA originating at or above the duodenum. Whether this anatomical feature affects D3 lymph node dissection warrants further investigation.

Effect of p18 on endothelial barrier function by mediating vascular endothelial Rab11a-VE-cadherin recycling.

Endothelial barrier integrity requires recycling of VE-cadherin to adherens junctions. Both p18 and Rab11a play significant roles in VE-cadherin recycling. However, the underlying mechanism and the role of p18 in activating Rab11a have yet to be elucidated. Performing in vitro and in vivo experiments, we showed that p18 protein bound to VE-cadherin before Rab11a through its VE-cadherin-binding domain (aa 1-39). Transendothelial resistance showed that overexpression of p18 promoted the circulation of VE-cadherin to adherens junctions and the recovery of the endothelial barrier. Silencing of p18 caused endothelial barrier dysfunction and prevented Rab11a-positive recycling endosome accumulation in the perinuclear recycling compartments. Furthermore, p18 knockdown in pulmonary microvessels markedly increased vascular leakage in mice challenged with lipopolysaccharide and cecal ligation puncture. This study showed that p18 regulated the pulmonary endothelial barrier function in vitro and in vivo by regulating the binding of Rab11a to VE-cadherin and the activation of Rab11a.