Allantoinase (ALLase; EC 3.5.2.5) possesses a binuclear metal center in which two metal ions are bridged by a posttranslationally carbamylated lysine. ALLase acts as a key enzyme for the biogenesis ...and degradation of ureides by catalyzing the conversion of allantoin into allantoate. Biochemically, ALLase belongs to the cyclic amidohydrolase family, which also includes dihydropyrimidinase, dihydroorotase, hydantoinase (HYDase), and imidase. Previously, the crystal structure of ALLase from
K-12 (EcALLase-K12) was reported; however, the two active site loops crucial for substrate binding were not determined. This situation would limit further docking and protein engineering experiments. Here, we solved the crystal structure of
BL21 ALLase (EcALLase-BL21) at a resolution of 2.07 Å (PDB ID 8HFD) to obtain more information for structural analyses. The structure has a classic TIM barrel fold. As compared with the previous work, the two missed active site loops in EcALLase-K12 were clearly determined in our structure of EcALLase-BL21. EcALLase-BL21 shared active site similarity with HYDase, an important biocatalyst for industrial production of semisynthetic penicillin and cephalosporins. Based on this structural comparison, we discussed the functional role of the two active site loops in EcALLase-BL21 to better understand the substrate/inhibitor binding mechanism for further biotechnological and pharmaceutical applications.
A high basal level of autophagic flux in bladder cancer (BC) cells prevents cell death and weakens chemotherapy efficacy. However, how autophagy influences cancer‐associated immunosuppression in BC ...remains undetermined. In this study, we observed a negative correlation between the autophagy‐related markers LC3‐II and programmed death ligand‐1 (PD‐L1) in BC cells. The autophagy inhibitors chloroquine (CQ) and bafilomycin A1 (Baf‐A1) increased PD‐L1 expression in BC cells through the ERK–JNK–c‐Jun signal‐transduction pathway. Moreover, the treatment of BC cells with CQ and Baf‐A1 inhibited hsa‐microRNA‐34a (miR‐34a) expression and miR‐34a overexpression in BC cells prevented the autophagy blockade–induced PD‐L1 expression; a negative correlation between miR‐34a and PD‐L1 expression was observed during treatment with autophagy inhibitors. Furthermore, miR‐34a overexpression induced the cytotoxic activity of natural killer cells against BC cells. Our results provide evidence that autophagy blockade and its regulatory pathway affect cancer‐associated immunosuppression through PD‐L1 elevation. Thus, the coadministration of autophagy inhibitors and a PD‐L1 immune checkpoint blockade provides a potential therapeutic approach for treating BC.
Graphical
Our model illustrates the pharmacological inhibition of autophagy could induce PD‐L1 expression in BC cells through the ERK–JNK–c‐Jun signaling transduction pathway and miR‐34a downregulation, revealing the effect of genetic and epigenetic regulation of autophagy on PD‐L1. In consequence, BC cells expressing PD‐L1 suppress NK cell cytotoxic activity.
A GaN metal-insulator-semiconductor-high electron mobility transistor (HEMT) using hybrid ferroelectric charge trap gate stack (FEG-HEMT) is demonstrated for normally-OFF operation. The ferroelectric ...(FE) polarization increases the number of trapped charges in the HfON charge trapping layer, leading to high positive threshold voltage (V th ) shift for the normally-OFF device. Besides, under the positive bias temperature instability (PBTI) test, the internal electric field induced by FE polarization causes smoother slope of the conduction band in FE gate stack, resulting in better V th stability. With the proposed hybrid FE charge trap gate stack, the device exhibits a high V th of +2.71 V at I Dh = 1μA/mm, a high maximum current density of 820 mA/mm and low on-resistance (R ON ) of 11.1 Ω · mm. The FE device also shows good V th -temperature stability compared to the non-FE device results. Besides, a high current device with 40 A is also fabricated in this letter to demonstrate the feasibility of the proposed FEG-HEMT device for high power device application.
The goal of this study was to evaluate the obliteration rate of intracranial dural arteriovenous fistulas (DAVFs) in patients treated with stereotactic radiosurgery (SRS), and to compare obliteration ...rates between cavernous sinus (CS) and noncavernous sinus (NCS) DAVFs, and between DAVFs with and without cortical venous drainage (CVD).
A systematic literature review was performed using PubMed. The CS DAVFs and the NCS DAVFs were categorized using the Barrow and Borden classification systems, respectively. The DAVFs were also categorized by location and by the presence of CVD. Statistical analyses of pooled data were conducted to assess complete obliteration rates in CS and NCS DAVFs, and in DAVFs with and without CVD.
Nineteen studies were included, comprising 729 patients harboring 743 DAVFs treated with SRS. The mean obliteration rate was 63% (95% CI 52.4%-73.6%). Complete obliteration for CS and NCS DAVFs was achieved in 73% and 58% of patients, respectively. No significant difference in obliteration rates between CS and NCS DAVFs was found (OR 1.72, 95% CI 0.66-4.46; p=0.27). Complete obliteration in DAVFs with and without CVD was observed in 56% and 75% of patients, respectively. A significantly higher obliteration rate was observed in DAVFs without CVD compared with DAVFs with CVD (OR 2.37, 95% CI 1.07-5.28; p=0.03).
Treatment with SRS offers favorable rates of DAVF obliteration with low complication rates. Patients harboring DAVFs that are refractory or not amenable to endovascular or surgical therapy may be safely and effectively treated using SRS.
Background
Periodontal disease is a chronic inflammatory disease. Given its high prevalence, especially in aging population, the detailed mechanisms about pathogenesis of periodontal disease are ...important issues for study. Neutrophil firstly infiltrates to periodontal disease‐associated pathogen loci and amplifies the inflammatory response for host defense. However, excessive neutrophil‐secreted neutrophil elastase (NE) damages the affected gingival. In lung and esophageal epithelium, NE had been proved to upregulate several growth factors including placenta growth factor (PGF). PGF is an angiogenic factor with proinflammatory properties, which mediates the progression of inflammatory disease. Therefore, we hypothesize excessive NE upregulates PGF and participates in the pathogenesis and progression of periodontal disease.
Methods
In gingival epithelial cells (GEC), growth factors array demonstrated NE‐increased growth factors and further be corroborated by Western blot assay and ELISA. The GEC inflammation was evaluated by ELISA. In mice, the immunohistochemistry results demonstrated ligature implantation‐induced neutrophil infiltration and growth factor upregulation. By multiplex assay, the ligature‐induced proinflammatory cytokines level in gingival crevicular fluid (GCF) were evaluated. Finally, alveolar bone absorption was analyzed by micro‐CT images and H & E staining.
Results
NE upregulated PGF expression and secretion in GEC. PGF promoted GEC to secret IL‐1β, IL‐6, and TNF‐α in GCF In periodontal disease animal model, ligature implantation triggered NE infiltration and PGF expression. Blockade of PGF attenuated the ligature implantation‐induced IL‐1β, IL‐6, TNF‐α and MIP‐2 secretion and ameliorated the alveolar bone loss in mice.
Conclusion
In conclusion, the NE‐induced PGF triggers gingival epithelium inflammation and promotes the pathogenesis and progression of periodontal disease.
The purpose of this study is to assess the preclinical therapeutic efficacy of magnetic resonance imaging (MRI)-monitored focused ultrasound (FUS)-induced blood-brain barrier (BBB) disruption to ...enhance Temozolomide (TMZ) delivery for improving Glioblastoma Multiforme (GBM) treatment. MRI-monitored FUS with microbubbles was used to transcranially disrupt the BBB in brains of Fisher rats implanted with 9L glioma cells. FUS-BBB opening was spectrophotometrically determined by leakage of dyes into the brain, and TMZ was quantitated in cerebrospinal fluid (CSF) and plasma by LC-MS\MS. The effects of treatment on tumor progression (by MRI), animal survival and brain tissue histology were investigated. Results demonstrated that FUS-BBB opening increased the local accumulation of dyes in brain parenchyma by 3.8-/2.1-fold in normal/tumor tissues. Compared to TMZ alone, combined FUS treatment increased the TMZ CSF/plasma ratio from 22.7% to 38.6%, reduced the 7-day tumor progression ratio from 24.03 to 5.06, and extended the median survival from 20 to 23 days. In conclusion, this study provided preclinical evidence that FUS BBB-opening increased the local concentration of TMZ to improve the control of tumor progression and animal survival, suggesting its clinical potential for improving current brain tumor treatment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
Background
Chronic hepatitis B virus (HBV) infection is a great health burden with geographical variations.
Aims
To explore genetic variants associated with chronic HBV infection.
Methods
The ...study included 15 352 participants seropositive for HBV core antibodies in Taiwan Biobank. Among them, 2591 (16.9%) seropositive for HBV surface antigen (HBsAg) were defined as having chronic HBV infection. All participants were examined for whole‐genome genotyping by Axiom‐Taiwan Biobank Array. The human leucocyte antigen (HLA) imputation was performed after identification of the variants within the region. Logistic regressions were used to estimate odds ratios (ORs) with 95% confidence intervals. Correlations of different HLA allele frequencies with HBsAg seroprevalence were evaluated across worldwide populations by Pearson correlation coefficients. Epitope prediction was performed for HLA alleles using NetMHCIIpan method.
Results
Located within a cluster of 450 single nucleotide polymorphisms in HLA class II, rs7770370 (P = 2.73 × 10−35) was significantly associated with HBV chronicity (Pcorrected < 8.6 × 10−8). Imputation analyses showed that HLA‐DPA1*02:02 and HLA‐DPB1*05:01 were associated with chronic HBV, with adjusted ORs of 1.43 (1.09‐1.89) and 1.61 (1.29‐2.01). These allele frequencies were positively correlated with global HBsAg seroprevalence, with R of 0.75 and 0.62 respectively (P < 0.05). HLA‐DRB1*13:02, HLA‐DQA1* 01:02 and HLA‐DQB1*06:09 associated with HBV chronicity negatively, with adjusted ORs of 0.31 (0.17‐0.58), 0.70 (0.56‐0.87) and 0.33 (0.18‐0.63). These HLA alleles had various binding affinities to the predicted epitopes derived from HBV nucleocapsid protein.
Conclusions
HLA class II variants are relevant for chronicity after HBV acquisition.
Computer-assisted surgical navigation has been used in total knee arthroplasty (TKA) procedures for years trying to the accuracy of prosthesis placement. We conducted this prospective randomized ...clinical trial to compare the accuracy of the radiographic parameters of the prosthesis, total blood loss (TBL), and related complications, between a new pinless navigation system (Stryker OrthoMap Express Knee Navigation) and conventional method in patients undergoing minimally invasive (MIS) TKA procedures.
A consecutive series of 100 patients underwent unilateral primary TKA were randomly assigned into two groups: navigation group and convention group. The radiographic parameters of the knee implant and the alignment of lower limb were measured at 3 months after surgery. TBL was calculated according to Nadler's method. The duplex ultrasonography of both lower limbs was performed in all patients to detect the presence of deep-vein thrombosis (DVT).
Totally, 94 patients have completed the radiographic measures. Only the coronal femoral component angle in the navigation group (89.12° ± 1.83°) had significant differences from that in the convention group (90.09° ± 2.18°) (p = 0.022). There were no differences in the rate of outliers. The mean TBL in the navigation group was 841 ± 267 mL, which was similar to that in the convention group at 860 ± 266 mL (p = 0.721). Postoperative DVT risk did not differ between the two groups (2% vs. 0%, p = 0.315).
This pinless navigation TKA showed a comparable acceptable alignment compared with conventional MIS-TKA. There were no differences regarding postoperative TBL between the two groups.
Carbon capture is a critical issue due to worsening global warming. Mixed matrix membranes incorporating 2D fillers have been attractive since they exhibit superior separation performance. In this ...study, the synthesis of ALDH was adjusted by sodium dodecyl sulfate (SDS) intercalation and 3-aminopropyltrimethoxysilane (APTMS) surface functionalization. Owing to this modification, the ALDH was delaminated in Pebax solutions, leading to a green process for fabricating 2D ALDH nanosheets incorporated in mixed matrix membranes. Due to the increased filler-polymer interfacial area produced by the ALDH nanosheets, CO2 passed through the membrane more quickly, which endowed the membrane with efficient CO2 separation performance. The optimal performance was obtained by adding 50 % PEGDME and 4 % ALDH to Pebax-1657, and the CO2 permeability and CO2/N2 selectivity were 460 barrer and 63, respectively. No toxic solvent was used in the process, providing an environmentally friendly method for fabricating 2D ALDH MMMs for efficient CO2 capture.
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•Delaminated LDH was prepared using a green process.•SDS intercalation and APTMS functionalization of ALDH are conducive to the delamination.•PEGDME facilitates the delamination of ALDH.•Effect of delamination on gas separation performance.•ALDH-based MMMs exhibit outstanding CO2/N2 separation performance.
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