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Acid protease is widely used in industries such as food processing and feed additives. In the study, low frequency magnetic field (LF-MF) as an aid enhances acid protease production by Aspergillus niger (A. niger). The study assessed mycelial biomass, the enzymic activity of the acidic protease and underlying mechanism. At low intensities, alternating magnetic field (AMF) is more effective than static magnetic fields (SMF). Under optimal magnetic field conditions, acid protease activity and biomass increased by 91.44% and 16.31%, as compared with the control, respectively. Maximum 19.87% increase in enzyme activity after magnetic field treatment of crude enzyme solution in control group. Transcriptomics analyses showed that low frequency alternating magnetic field (LF-AMF) treatment significantly upregulated genes related to hydrolases and cell growth. Our results showed that low-frequency magnetic fields can enhance the acid protease production ability of A. niger, and the effect of AMF is better at low intensities. The results revealed that the effect of magnetic field on the metabolic mechanism of A. niger and provided a reference for magnetic field-assisted fermentation of A. niger. [ABSTRACT FROM AUTHOR]

Background: Existing pharmacogenetic algorithms cannot fully explain warfarin dose variability in all patients. CYP2C9*13 is an important allelic variant in the Han Chinese population. However, adjustment of warfarin dosing in CYP2C9*13 variant carriers remains unclear. To the best of our knowledge, this study is the first to assess the effects of adjusting warfarin dosages in Han Chinese patients harbouring CYP2C9*13 variants. Methods: In total, 971 warfarin-treated Han Chinese patients with atrial fibrillation were enrolled in this study. Clinical data were collected, and CYP2C9*2, *3, *13 and VKORC1-1639 G > A variants were genotyped. We quantitatively analysed the effect of CYP2C9*13 on warfarin maintenance dose and provided multiplicative adjustments for CYP2C9*13 using validated pharmacogenetic algorithms. Results: Approximately 0.6% of the Han Chinese population carried CYP2C9*13 variant, and the genotype frequency was between those of CYP2C9*2 and CYP2C9*3. The warfarin maintenance doses were significantly reduced in CYP2C9*13 carriers. When CYP2C9*13 variants were not considered, the pharmacogenetic algorithms overestimated warfarin maintenance doses by 1.03–1.16 mg/d on average. The actual warfarin dose in CYP2C9*13 variant carriers was approximately 40% lower than the algorithm-predicted dose. Adjusting the warfarin-dosing algorithm according to the CYP2C9*13 allele could reduce the dose prediction error. Conclusion: Our study showed that the algorithm-predicted doses should be lowered for CYP2C9*13 carriers. Inclusion of the CYP2C9*13 variant in the warfarin-dosing algorithm tends to predict the warfarin maintenance dose more accurately and improves the efficacy and safety of warfarin administration in Han Chinese patients. [ABSTRACT FROM AUTHOR]

A novel Alteromonas phage JH01, with the host strain identified to be Alteromonas marina SW-47(T), was isolated from the Qingdao coast during the summer of 2017. Transmission electron microscopy analysis showed that phage JH01 can be categorized into the Siphoviridae family, with an icosahedral head of 62 ± 5 nm and a long contractile tail of 254 ± 10 nm. The bioinformatic analysis shows that this phage consists of a linear, double-stranded 46,500 bp DNA molecule with a GC content of 44.39%, and 58 ORFs with no tRNA genes. The ORFs are classified into four groups, including phage packaging, phage structure, DNA replication and regulation, and hypothetical protein. The phylogenetic tree, constructed using neighbor-joining analysis, shows that phage JH01 has altitudinal homology with some Vibrio and Pseudoalteromonas phage B8b. Comparative analysis reveals the high similarity between phage JH01 and phage B8b. Additionally, our study of phage JH01 provides useful information for further research on the interaction between Alteromonas phages and their hosts. [ABSTRACT FROM AUTHOR]

Purpose: To determine the expression patterns of imprinted genes and their methylation status in aborted cloned porcine fetuses and placentas. Methods: RNA and DNA were prepared from fetuses and placentas that were produced by SCNT and controls from artificial insemination. The expression of 18 imprinted genes was determined by quantitative real-time PCR (q-PCR). Bisulfite sequencing PCR (BSP) was conducted to determine the methylation status of PRE- 1 short interspersed repetitive element (SINE), satellite DNA and H19 differentially methylated region 3 (DMR3). Results: The weight, imprinted gene expression and genome-wide DNA methylation patterns were compared between the mid-gestation aborted and normal control samples. The results showed hypermethylation of PRE- 1 and satellite sequences, the aberrant expression of imprinted genes, and the hypomethylation of H19 DMR3 occurred in mid-gestation aborted fetuses and placentas. Conclusions: Cloned pigs generated by somatic cell nuclear transfer (SCNT) showed a greater ratio of early abortion during mid-gestation than did normal controls because of the incomplete epigenetic reprogramming of the donor cells. Altered expression of imprinted genes and the hypermethylation profile of the repetitive regions ( PRE- 1 and satellite DNA) may be associated with defective development and early abortion of cloned pigs, emphasizing the importance of epigenetics during pregnancy and implications thereof for patient-specific embryonic stem cells for human therapeutic cloning and improvement of human assisted reproduction. [ABSTRACT FROM AUTHOR]

Introduction: With the levodopa threshold effect for dyskinesia observed, threshold dosage of levodopa was identified in the general Parkinson's disease (PD) population. While early-onset PD (EOPD) and late-onset PD (LOPD) differ in the pathogenesis and clinical manifestations, threshold dosage of levodopa for individualized treatment remains unestablished. The objective of this study was to propose threshold dosage of levodopa in EOPD and LOPD patients, respectively. Methods: Data on demographic and clinical and treatment measures were collected in 539 PD patients. Patients were divided into different onset groups using 50 as the cut-off age. We used univariable and multivariable analysis to screen for risk factors for dyskinesia. Receiver operating characteristic curve was used to determine the levodopa threshold dosages for dyskinesia. Results: The prevalence of dyskinesia was 47.7% (53/111) in the EOPD group and 24.1% (103/428) in the LOPD group. Risk factors identified for dyskinesia include high levodopa daily dose and levodopa responsiveness for EOPD patients and high levodopa daily dose, long levodopa treatment duration, low body weight, use of entacapone, and high Hoehn–Yahr stage in off state for LOPD patients. The daily levodopa threshold dosages were 400 mg or 5.9 mg/kg for EOPD and 450 mg or 7.2 mg/kg for LOPD. Conclusion: EOPD patients had lower levodopa threshold dosage comparing with LOPD patients. Treatment of EOPD requires stricter levodopa dose control to delay the onset of dyskinesia. [ABSTRACT FROM AUTHOR]

Purpose: Cancer cells alter regular metabolic pathways in order to sustain rapid proliferation. One example of metabolic remodeling in cancerous tissue is the upregulation of pyruvate kinase isoenzyme M2 (PKM2), which is involved in aerobic glycolysis. Indeed, PKM2 has previously been identified as a tumor biomarker and as a potential target for cancer therapy. Here, the role of PKM2 in the anticancer efficacy of 5-fluorouracil (5-FU) was evaluated in colorectal cancer (CRC).Methods: HCT116, SW480 and HT-29 cells were used by transfection with lentiviral vectors expressing short hairpin RNA (shRNA) against PKM2. In response to 5-FU treatment, cellular proliferation was examined, the levels of ATP/ADP ratio were monitored, the intracellular accumulation of 5-FU was measured, and intracellular levels of phosphoenolpyruvate (PEP), pyruvate and lactate were evaluated by using liquid chromatography-mass spectrometry (LC-MS). A CRC subcutaneous tumor model was performed to investigate the effect of PKM2 inhibition on 5-FU efficacy in vivo.Results: Suppression of PKM2 resulted in changes in glucose metabolism, leading to decreased synthesis of adenosine triphosphate (ATP). Reduced levels of ATP/ADP ratio resulted in the intracellular accumulation of 5-FU, consequently enhancing the therapeutic efficacy of this drug in several CRC cell lines. Furthermore, the enhanced efficacy of 5-FU by simultaneous inhibition of PKM2 was demonstrated in an in vivo HCT116 CRC model.Conclusion: We show that the combination treatment showed superior anticancer efficacy as compared to 5-FU alone. These findings suggest that targeting PKM2 can increase the efficacy of chemotherapy, potentially providing a new approach for improving the outcome of chemotherapy in patients with CRC. [ABSTRACT FROM AUTHOR]

A previous report suggested that the expression of ten-eleven translocation (TET) proteins is abnormal in certain cancers. Quercetin has been demonstrated as anti-cancer role in cancer development. In order to explore the inhibitory effect and mechanism of quercetin on uveal melanoma cells, the expression of TET proteins was analyzed in the present study. Our results suggest that the expression of TET1 was increased following treatment with quercetin in OCM-1, SK-MEL-1, and B16 cells. In addition, quercetin treatment induced apoptosis and inhibited migration and invasion. To further investigate the association of the expression of TET1 with cell growth, apoptosis, migration, and invasion, cell lines in which TET1 was knocked-down or overexpressed were constructed. The results showed that the increased expression of TET1-induced apoptosis, increased 5-hydroxymethylcytosine (5 hmC). and inhibited invasion. Our bioinformatics studies indicated that TET1 is a target gene of microRNA-17 (miR-17) Our results showed that inhibition of the expression of miR-17 resulted in increased TET1 expression in OCM-1 cells. Furthermore, our results indicated that quercetin treatment increased TET1 expression and inhibited melanoma growth in nude mice. Taken together, our results suggest that quercetin can regulate cell proliferation and apoptosis through TET1 via miR-17 in melanoma cells. [ABSTRACT FROM AUTHOR]

Due to many drawbacks of the commonly used standard method (Nessler reagent spectrophotometry with sampling using sulfuric acid solution) for ammonia determination in workplace air, the method for airborne ammonia determination needs to be improved urgently. In this study, the determination methods of ammonia by ion chromatography and sampling with four different types of solid sorbent tubes were evaluated. The chromatographic conditions including eluent, calibration curve, precision, and accuracy were systematically investigated. For sampling of airborne ammonia, the tubes containing coconut shell charcoal and silica gel presented poor performances. The performances of the tubes filled with H2SO4-treated silica gel and carbon bead were significantly better than the above two types of tubes. The recovery of ammonia sampling with the H2SO4-treated silica gel tube was the highest. Sampling with the H2SO4-treated silica gel tube and detection by ion chromatography were more suitable for airborne ammonia determination in workplaces. [ABSTRACT FROM AUTHOR]

Background: Anti-PD-1 antibodies plus lenvatinib therapeutic regimens have demonstrated a relatively high antitumor response in many solid cancers; however, the efficacy and safety of anti-PD-1 antibodies plus lenvatinib in patients with advanced gallbladder cancer (GBC) has not been reported. Methods: Advanced GBC patients who received anti-PD-1 antibodies plus lenvatinib were retrospectively screened. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), PD-L1 expression and safety were evaluated to identify efficacy biomarkers. Results: A total of 31 GBC patients were included in this study. After a median follow-up of 8 months and 23 deaths were observed. The median PFS was 5.0 months (95% CI: 4.1–8.0 months), and the median OS was 11.3 months (95% CI: 7.5–20.9 months). Overall, the ORR was 32.3%, the DCR was 83.9%, and the CBR was 41.9%. Moreover, after treatment, 3 patients received conventional surgery, in which 1 patient achieved a pathological complete response. All patients (100%) experienced adverse events (AEs), and 58.1% of the patients experienced grade 3 AEs. The most commonly observed grade 3 AEs included fatigue (5/31, 16.1%), decreased appetite (5/31, 16.1%), hypertension (4/31, 12.9%) and bilirubin elevation (4/31, 12.9%). Subgroup analysis revealed that positive PD-L1 expression maybe associate with a longer PFS. Conclusion: Anti-PD-1 antibodies plus lenvatinib represent an effective and tolerable therapy for patients with advanced gallbladder cancer. [ABSTRACT FROM AUTHOR]

It has been reported that the expression of CD44 variant 9 could be utilized as a predictive marker for the recurrence in early gastric cancer (EGC) after endoscopic submucosal dissection (ESD). And circFNDC3B was proved to increase the migration and invasion of gastric cancer (GC) cells. In this study, we recruited 96 EGC patients after ESD treatment and grouped them into High circFNDC3B expression group (High expression group) and Low circFNDC3B expression group (Low expression group). Accordingly, we found that the recurrence-free rate in the High expression group was lower than that in the Low expression group. In the High expression group, the relative expression of miR-942 and miR-510 was both suppressed while the relative expression of CDH1 mRNA and CD44 mRNA/protein was increased compared with those in the Low expression group. CircFNDC3B was found to target miR-942 and miR-510 and suppress their expressions respectively. Moreover, miR-942 was found to target CD44 mRNA while miR-510 was found to target CDH1 mRNA. The overexpression of circFNDC3B led to the down-regulation of miR-942 and miR-510, which accordingly resulted in the up-regulation of CD44 and CDH1 in MKN28 cells. Moreover, we found H. pylori infection could promote the expression of circFNDC3B, which also resulted in up-regulated CD44 and CDH1 mRNA level in rTip-α cultivated MKN28 cells. In summary, our study demonstrated that a higher level of circFNDC3B could lead to the increased expression of CD44 and CDH1 via modulating the signaling pathways of miR-942/CD44 and miR-510/CDH1 in EGC patients. And the up-regulation of CD44 and CDH1 would accordingly result in a higher recurrence rate of EGC patients treated by ESD. [ABSTRACT FROM AUTHOR]

Environmental pollution by organic pollutants is a serious concern which may be solved by photocatalytic degradation of pollutants, yet the efficiency of actual photocatalytic materials is limited. For instance, conventional MoS2 nanosheets tend to agglomerate, which hinders the access of pollutants to active sites. To overcome this challenge, we hypothesized that assembling MoS2 nanosheets on a mineral support would improve access to active sites. We synthesized a catalyst made of 3–4 atomic layers of MoS2 nanosheets deposited on tourmaline using a microwave hydrothermal method. Results show that tourmaline occurs as a polyhedron single crystal that supports the epitaxial growth of 2H-MoS2 layers on tourmaline (77 3 ¯ ) facets, while an intrinsic rolling up behavior of MoS2 layer from [002] to [106] on the mineral surface accounts for the curly morphology. The pangolin-like MoS2/tourmaline composite degrades rhodamine B much better than the pure MoS2 nanosheets assembled microspheres. This is explained by the reduced thickness of MoS2 nanosheets according to the density functional theory. Overall, our findings represent a new tactic for the cost-effective batch preparation of two-dimensional materials with high catalytic performance. [ABSTRACT FROM AUTHOR]

Aberrant epigenetic modification, including N6-methylation of adenosine (m6A), has been frequently reported in embryos derived from parthenogenetic activation (PA). However, the role of Igf2bp1 expression pattern in m6A modification and the mechanism through which Igf2bp1 function is regulated in PA embryos remains elusive. Therefore, in this study, using si-Igf2bp1 and betaine (N,N,N-trimethylglycine, a major methyl donor), we investigated the effect of Igf2bp1 expression in m6A modification on the development of PA embryos. The results indicated that the down-regulation of Igf2bp1 reduced the cleavage and blastula rates of PA embryos. Moreover, m6A expression level was markedly down-regulated following microinjection with si-Igf2bp1. However, the treatment with betaine could significantly restore the m6A level. Further bioinformatics analysis revealed Igf2bp1 as the putative target of microRNA 670 (miR-670). Thus, to confirm this finding, mimics and inhibitor of miR-670 were microinjected into PA embryos. The results demonstrated that miR-670 inhibitor augmented the expression of Igf2bp1 and rescued cleavage and blastula rates. In addition, the miR-670 inhibitor promoted the m6A expression level. TUNEL assay revealed a loss of expression of Igf2bp1 induced cell apoptosis in PA embryos. Taken together, these results demonstrated that miR-670-3p functions as the regulator of Igf2bp1 expression and plays a crucial role in PA development through m6A modification. [ABSTRACT FROM AUTHOR]

Levodopa is widely used to treat Parkinson's disease (PD), and its long-term therapy may induce dyskinesia in a dose-dependent manner. However, the threshold dose with a relatively low risk for dyskinesia has not been determined. Demographic, clinical profiles and detailed information of dopaminergic drugs were recorded for 403 PD patients in treatment with levodopa. Variables were compared between dyskinesia and non-dyskinesia groups. Logistic regression analysis was used to assess the association between levodopa dose-related variables and dyskinesia. Receiver operating characteristic curve and decision tree classification model were used to investigate the cut-off value of levodopa dose to best separate the dyskinesia group from the non-dyskinesia group. Patients with dyskinesia tended to have a lower weight and age at onset, higher percentage of female and wearing-off, longer duration of disease and levodopa treatment, higher H-Y stage and MDS-UPDRS Part III score, and higher levodopa dose and levodopa equivalent dose than those without dyskinesia. After adjusted for demographical and clinical variables, levodopa dose-related factors (daily dose, cumulative dose, and weight-adjusted dose) were still associated with dyskinesia. Both the receiver operating characteristic and decision tree classification analysis indicated that patients who have taken levodopa dose ≤ 400 mg per day may be associated with a reduced risk for dyskinesia. In conclusion, we evaluated the thresholds of levodopa treatment with a relatively low risk for dyskinesia. These data should be considered for prevention and management of dyskinesia in patients with PD. [ABSTRACT FROM AUTHOR]

Programmed cell death 1 (PD-1) monoclonal antibodies have been approved by regulatory agencies for the treatment of various types of cancer, and the mechanism involves the restoration of T cell functions. We report herein the X-ray crystal structure of a fully human monoclonal antibody mAb059c fragment antigen-binding (Fab) in complex with the PD-1 extracellular domain (ECD) at a resolution of 1.70 Å. Structural analysis indicates 1) an epitope, comprising fragments from the C'D, BC and FG loops of PD-1, contributes to mAb059c interaction, 2) an unique conformation of the C'D loop and a different orientation of R86 enabling the capture of PD-1 by the antibody complementarity determining region (CDR) and the formation of one salt-bridge contact – ASP101(HCDR3):ARG86(PD-1), and 3) the contact of FG with light chain (LC) CDR3 is maintained by a second salt-bridge and two backbone hydrogen bonds. Interface analysis reveals that N-glycosylation sites 49, 74 and 116 on PD-1 do not contact mAb059c; while N58 in the BC loop is recognized by mAb059c heavy chain CDR1 and CDR2. Mutation of N58 attenuated mAb059c binding to PD-1. These findings and the novel anti-PD-1 antibody will facilitate better understanding of the mechanisms of the molecular recognition of PD-1 receptor by anti-PD-1 mAb and, thereby, enable the development of new therapeutics with an expanded spectrum of efficacy for unmet medical needs. [ABSTRACT FROM AUTHOR]

The influences of the temperature and the BDNPA/BDNPF (A3) content on the mechanical properties of and the binding energies between hexanitrohexaazaisowurtzitane (HNIW) and cellulose acetate butyrate (CAB)/A3 were studied via molecular dynamics simulations. The morphology of HNIW in acetone was simulated using an attachment energy (AE) model to elucidate the HNIW surfaces that are present under real-world conditions. The simulation results were consistent with the experimentally derived ones, and they indicated that the exposed HNIW surfaces were (0 0 1), (1 1 0), and (1 1 −1). The mechanical properties of CAB with different amounts of A3 were calculated at different temperatures, and the results showed that the amount of A3 was a stronger influence than the temperature on the mechanical properties. The binding energies between CAB/A3 and the exposed HNIW surfaces were calculated. Based on the binding energy and the area of each exposed surface, the weighted-average binding energy was calculated and then used instead of the total binding energy to evaluate the effect of the temperature and the A3 content on the binding energy. The average binding energy was found to be highest when the temperature was 313 K and the mass fraction of A3 was 0.15. [ABSTRACT FROM AUTHOR]

Background and Aims: This study aimed to evaluate the antifibrotic effects of NF-E2-Related Factor 2 (Nrf2) on intestinal fibrosis. Intestinal fibrosis is a common complication of Crohn's disease; however, its mechanism of intestinal fibrosis is largely unclear.Methods: BALB/c mice received 2,4,6-trinitrobenzene sulfonic acid weekly via intrarectal injections to induce chronic fibrotic colitis. They also diet containing received 1% (w/w) tert-butylhydroquinone (tBHQ), which is an agonist of Nrf2. Human intestinal fibroblasts (CCD-18Co cells) were pretreated with tBHQ or si-Nrf2 followed by stimulation with transforming growth factor-β1 (TGF-β1), which transformed the cells into myofibroblasts. The main fibrosis markers such as α-smooth muscle actin, collagen I, tissue inhibitor of metalloproteinase-1, and TGF-β1/SMADs signaling pathway were detected by quantitative real-time RT-PCR, immunohistochemical analysis, and Western blot analysis. Levels of cellular reactive oxygen species (ROS) were detected by dichlorodihydrofluorescein diacetate.Results: tBHQ suppressed the intestinal fibrosis through the TGF-β1/SMADs signaling pathway in TNBS-induced colitis and CCD-18Co cells. Moreover, Nrf2 knockdown enhanced the TGF-β1-induced differentiation of CCD-18Co cells. ROS significantly increased in TGF-β1-stimulated CCD-18Co cells. Pretreatment with H2O2, the primary component of ROS, was demonstrated to block the effect of tBHQ on reducing the expression of TGF-β1. Moreover, scavenging ROS by N-acetyl cysteine could inhibit the increasing expression of TGF-β1 promoted by Nrf2 knockdown.Conclusions: The results suggested that Nrf2 suppressed intestinal fibrosis by inhibiting ROS/TGF-β1/SMADs pathway in vivo and in vitro. [ABSTRACT FROM AUTHOR]

Molecular dynamic (MD) simulations were applied to investigate the binding energies and mechanical properties of 1,1-diamino-2,2-dinitroethene (FOX-7) based polymer bonded explosives (PBXs) with ethylenevinylacetate copolymer (EVA), fluorine (F2641), hydroxyl-terminated polybutadiene (HTPB), and styrene butadiene styrene block copolymer (SBS). The binding energies between FOX-7 and the four polymer binders are different, of which the descending order is FOX-7/HTPB ≈ FOX-7/SBS > FOX-7/EVA > FOX-7/F2641. Furthermore, the (002) surface of FOX-7 has the strongest interaction with the four polymers. The mechanical properties (elastic moduli and Poisson’s ratio) of pure FOX-7 and FOX-7 based PBXs were obtained. The results show that the descending order of the ability of polymer binders to improve plasticity of PBXs is SBS > F2641 > EVA > HTPB. The formability of FOX-7 based PBXs is better than that of pure FOX-7, as the order of FOX-7/SBS > FOX-7/EVA > FOX-7/F2641 > FOX-7/HTPB > FOX-7 shows. Poisson’s ratio of SBS is the highest. The calculated detonation performances for pure FOX-7 and FOX-7 based PBXs show that the detonation properties of explosives slightly decreases when the mass ratio of binder is about 5%. All the theoretical detonation velocities of FOX-7 based PBXs are higher than 8500 m/s. [ABSTRACT FROM AUTHOR]