Direct-acting antivirals failed to reduce the incidence of hepatocellular carcinoma occurrence in hepatitis C virus associated cirrhosis: A real-world study.

BACKGROUND: Direct-acting antivirals (DAAs) revolutionized the treatment of chronic hepatitis C virus (HCV)-associated disease achieving high rates of sustained virological response (SVR). However, whether DAAs can reduce the occurrence of hepatocellular carcinoma (HCC) in patients with HCV-associated cirrhosis who are at high risk have not been concluded. AIM: To investigate the effect of DAAs on the occurrence of HCC in patients with HCV-associated cirrhosis after achieving SVR. METHODS: Of 427 inpatients with HCV-associated cirrhosis were enrolled in Tianjin Second People's Hospital from January 2014 to April 2020. 118 patients weren't received antiviral treatment with any reasons named non-antiviral treatment group, and 236 patients obtained from the 309 DAAs treatment patients according to the propensity score matching named DAAs treatment group. Demographic information and laboratory data were collected from baseline and the following up. Kaplan-Meier curve and Log-Rank test were used to compare the incidence and cumulative incidence of HCC between the two groups. Cox proportional risk regression was used to re-evaluate the risk factors for HCC. RESULTS: HCC incidence was 4.68/100PY (95%CI, 3.09-6.81) in the DAAs treatment group, while it was 3.00/100PY (95%CI, 1.50-5.37) in the non-antiviral treatment group, and the relative risk was 1.82 (95%CI, 0.93-3.53, P > 0.05). The incidence of HCC at 12, 24, 36 and 48 months was 3.39%, 6.36%, 8.47% and 10.17% in the DAAs treatment group, and it was 0%, 0%, 3.39% and 9.32% in the non-antiviral treatment group, respectively. Age > 58 [hazard ratio (HR) = 1.089; 95%CI, 1.033-1.147; P = 0.002] and liver stiffness measurement > 27.85 kPa (HR = 1.043; 95%CI, 1.022-1.065; P = 0.000) were risk factors for HCC in all patients (n = 427), and DAAs treatment didn't show protective efficacy. CONCLUSION: DAAs treatment seems failed to reduce the incidence of HCC occurrence in HCV-associated cirrhosis in 48 months, and even increased the incidence of HCC in 36 months.

Essential Oils from Spices Inhibit Cholinesterase Activity and Improve Behavioral Disorder in AlCl3 Induced Dementia.

The chemical compositions of essential oils (EOs) prepared from six spices including cinnamon, amomum tsao-ko, cardamom, amomum, black pepper and white pepper were analyzed by gas chromatography-mass spectrometry (GC/MS), which led to identify almost 200 volatile compounds. All EOs of spices showed cholinesterase inhibitory activity. Among them, pepper EO showed most potent acetylcholinesterase (AChE) inhibitory activity with IC50 values of 8.54 µg/mL (black pepper EO) and 5.02 µg/mL (white pepper EO). Molecular docking and in vitro validation suggested that 3-carene, α-pinene and ß-pinene with IC50 value of 1.73, 2.66, and 14.75 µg/mL, respectively, might be active constituents of spices oil in inhibiting AChE. Furthermore, amomum tsao-ko EO and amomum EO can improve behavioral disorder in dementia zebrafish induced by aluminum trichloride (AlCl3 ).

Correlation of the retinopathy degree with the change of ocular surface and corneal nerve in patients with type 2 diabetes mellitus.

AIM: To investigate the change of ocular surface and corneal nerve and their correlation in patients suffering from type 2 diabetes mellitus under different degrees of retinopathy. METHODS: Totally 129 type 2 diabetes mellitus patients (257 eyes) were included. They were divided into three groups: no diabetic retinopathy (NDR) group (33 cases, 66 eyes), non-proliferative diabetic retinopathy (NPDR) group (32 cases, 64 eyes), and proliferative diabetic retinopathy (PDR) group (34 cases, 67 eyes). Healthy normal individuals were enrolled as controls (30 cases, 60 eyes). Ocular Surface Disease Index (OSDI) questionnaire was completed by all subjects, and dry eye analyzer was applied to examine tear meniscus height (TMH), first tear break-up time (FTBUT), average tear break-up time (ATBUT), tear film lipid layer thickness classification, and meibomian gland loss (MGL) score. Corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL), and corneal nerve fiber tortuosity (CNFT) were examined by in vivo confocal microscopy (IVCM). The differences and correlation among these parameters were analyzed. RESULTS: Total OSDI score, TMH, FTBUT, ATBUT, tear film lipid layer thickness, MGL score, CNFD, CNBD, CNFL, and CNFT were statistically different among the four groups (P<0.05). In NDR group, CNFL was positively correlated with TMH (r=0.493, both P<0.01) and ATBUT (r=0.437, P<0.05). CNFL in NPDR group was positively correlated with TMH (r=0.642, P<0.01) and ATBUT (r=0.6, P<0.01). CNFL in PDR group was positively correlated with TMH (r=0.364, P<0.05) and ATBUT (r=0.589, P<0.01), with low negative correlation with MGL score (r=-0.331, P<0.05). CONCLUSION: With the progression of diabetic retinopathy, TMH, BUT, lipid layer thickness, CNFL, CNFD, and CNBD gradually decreased, while total OSDI score, MGL score, and CNFT increased. CNFL is correlated with TMH and ATBUT in diabetic patients.

Prediction of the Drug-Drug Interaction Types with the Unified Embedding Features from Drug Similarity Networks.

Drug combination therapies are a promising strategy to overcome drug resistance and improve the efficacy of monotherapy in cancer, and it has been shown to lead to a decrease in dose-related toxicities. Except the synergistic reaction between drugs, some antagonistic drug-drug interactions (DDIs) exist, which is the main cause of adverse drug events. Precisely predicting the type of DDI is important for both drug development and more effective drug combination therapy applications. Recently, numerous text mining- and machine learning-based methods have been developed for predicting DDIs. All these methods implicitly utilize the feature of drugs from diverse drug-related properties. However, how to integrate these features more efficiently and improve the accuracy of classification is still a challenge. In this paper, we proposed a novel method (called NMDADNN) to predict the DDI types by integrating five drug-related heterogeneous information sources to extract the unified drug mapping features. NMDADNN first constructs the similarity networks by using the Jaccard coefficient and then implements random walk with restart algorithm and positive pointwise mutual information for extracting the topological similarities. After that, five network-based similarities are unified by using a multimodel deep autoencoder. Finally, NMDADNN implements the deep neural network (DNN) on the unified drug feature to infer the types of DDIs. In comparison with other recent state-of-the-art DNN-based methods, NMDADNN achieves the best results in terms of accuracy, area under the precision-recall curve, area under the ROC curve, F1 score, precision and recall. In addition, many of the promising types of drug-drug pairs predicted by NMDADNN are also confirmed by using the interactions checker tool. These results demonstrate the effectiveness of our NMDADNN method, indicating that NMDADNN has the great potential for predicting DDI types.

[Effects of butylphthalide on H2S/CBS pathway in hippocampal and amygdala and learning and memory ability in chronic alcoholism rats].

Objective: To investigate the effects of butylphthalide (NBP) on learning and memory related ability, hydrogen sulfide (H2S) content in hippocampus and amygdala, cystathionine-ß-synthase (CBS) expression and mitochondrial ATPase activity in rats with chronic alcoholism. Methods: Ninety SD male rats were randomly divided into three groups: normal control group (NC), model group (M) and butylphthalide remedy group (BR). Except for the control group, the water solution containing 6% (v/v) alcohol was used as the sole source of drinking water in the other two groups. After 14 days of feeding, the butylphthalide remedy group was injected with NBP intraperitoneally at the dose of 5 mg/kg once a day for 14 consecutive days, and the remaining two groups were injected with the same dose of normal saline. The control group subsequently used the Morris water maze method to observe and record the animals after entering the water. The time required for the underwater platform, their strategies and their swimming trajectories could analyze and infer the animal's ability to learn and remember. H2S concentration, CBS expression and mitochondrial ATPase activity in hippocampus and amygdale were dectected. Results: Compared with NC group, the latency period and swimming distance of M group were increased, the content of H2S and the mean optical density of CBS in hippocampus and amygdala were increased, and the activity of mitochondrial ATPase in hippocampus and amygdala was decreased significantly (P＜0. 01) . Compared with the M group, the latency period and swimming distance of learning and memory performance of BR group were decreased, the content of H2S and the mean optical density of CBS in hippocampus and amygdala were decreased, and the activity of mitochondrial ATPase in hippocampus and amygdala was increased significantly (P＜0. 01) . Conclusion: NBP can alleviate the effect of ethanol on learning and memory in rats, which may be related to the effect of NBP on the concentration of H2S and the expression of CBS in the amygdala of hippocampus and the increase of ATPase activity.

Significantly enhanced conversion efficiency of high-order harmonic generation by introducing chirped laser pulses into scheme of spatially inhomogeneous field.

An effective scheme to enhance the yield of high-order harmonic generation originated from spatially inhomogeneous field through the interaction between few-cycle chirped laser pulses and a nano-tip structure is demonstrated. The conversion efficiency of harmonics from chirped laser pulses was significantly improved by nearly three more orders of magnitude than that of chirp-free pulses, and the cutoff energy of the corresponding harmonics was dramatically enhanced. By superimposing a series of properly selected orders of harmonics, isolated attosecond pulses of high intensity can be obtained. Furthermore, we compared the effects of different types of chirps on harmonics.

Optimization of expression of orange carotenoid protein in Escherichia coli.

Naturally-occurring orange carotenoid protein (OCP) is synthesized in cyanobacteria and red algae for photoprotection. Holo-OCP can be produced with three plasmids in E. coli, which needs two inducers (arabinose and isopropyl ß-D-thiogalactoside) to initiate two processes: one for generation of carotenoid and the other for generation of apo-OCP, so takes about two days. Afterwards, a two-plasmid method using two plasmids in E. coli is established, in which E. coli cells are induced only by isopropyl ß-D-thiogalactoside, so can yield different holo-OCPs from several cyanobacteria within three days. In this work, we optimized the two-plasmid method as follows: (1) re-organization of the two plasmids, letting carotenoid-generating gene, crtW, be arranged together with apo-OCP-generating gene, ocp, in a single plasmid, which causes that both carotenoid and apo-protein were properly produced, (2) modification of several amino acids at the N-terminus of apo-OCP, in this way increasing the yield and purity of holo-OCP. After these optimizations, we can generate much more amount of holo-OCP within shorter time of only 16 h, and pure holo-OCP be conveniently prepared after routine purification. Comparing with the reported data, the general yield of holo-OCP is increased by ∼10-fold under similar conditions. The high quality of the prepared holo-OCPs is verified by fluorescence quenching of the phycobilisomes.

Chromophorylation (in Escherichia coli) of allophycocyanin B subunits from far-red light acclimated Chroococcidiopsis thermalis sp. PCC7203.

Cyanobacterial phycobilisomes funnel the harvested light energy to the reaction centers via two terminal emitters, allophycocyanin B and the core-membrane linker. ApcD is the α-subunit of allophycocyanin B responsible for its red-shifted absorbance (λmax 665 nm). Far-red photo-acclimated cyanobacteria contain certain allophycocyanins that show even further red-shifted absorbances (λmax > 700 nm). We studied the chromophorylation of the three far-red induced ApcD subunits ApcD2, ApcD3 and ApcD4 from Chroococcidiopsis thermalis sp. PCC7203 during the expression in E. coli. The complex behavior emphasizes that a variety of factors contribute to the spectral red-shift. Only ApcD2 bound phycocyanobilin covalently at the canonical position C81, while ApcD3 and ApcD4 gave only traces of stable products. The product of ApcD2 was, however, heterogeneous. The major fraction had a broad absorption around 560 nm and double-peaked fluorescence at 615 and 670 nm. A minor fraction was similar to the product of conventional ApcD, with maximal absorbance around 610 nm and fluorescence around 640 nm. The heterogeneity was lost in C65 and C132 variants; in these variants only the conventional product was formed. With ApcD4, a red-shifted product carrying non-covalently bound phycocyanobilin could be detected in the supernatant after cell lysis. While this chromophore was lost during purification, it could be stabilized by co-assembly with a far-red light-induced ß-subunit, ApcB3.

Chemical Composition and Acetylcholinesterase Inhibitory Activity of Essential Oils from Piper Species.

The essential oils (EOs) derived from aromatic plants such as Piper species are considered to play a role in alleviating neuronal ailments that are associated with inhibition of acetylcholinesterase (AChE). The chemical compositions of 23 EOs prepared from 16 Piper spp. were analyzed by both gas chromatography with a flame ionization detector (GC-FID) and gas chromatography-mass spectrometry (GC-MS). A total of 76 compounds were identified in the EOs from the leaves and stems of 19 samples, while 30 compounds were detected in the EOs from the fruits of four samples. Sesquiterpenes and phenylpropanoids were found to be rich in these EOs, of which asaricin, caryophyllene, caryophyllene oxide, isospathulenol, (+)-spathulenol, and ß-bisabolene are the major constituents. The EOs from the leaves and stems of Piper austrosinense, P. puberulum, P. flaviflorum, P. betle, and P. hispidimervium showed strong AChE inhibitory activity with IC50 values in the range of 1.51 to 13.9 mg/mL. A thin-layer chromatography (TLC) bioautography assay was employed to identify active compound(s) in the most active EO from P. hispidimervium. The active compound was isolated and identified as asaricin, which gave an IC50 value of 0.44 ± 0.02 mg/mL against AChE, comparable to galantamine with an IC50 0.15 ± 0.01 mg/mL.

Far-red light photoacclimation: Chromophorylation of FR induced α- and ß-subunits of allophycocyanin from Chroococcidiopsis thermalis sp. PCC7203.

Cyanobacterial light-harvesting complexes, phycobilisomes, can undergo extensive remodeling under varying light conditions. Acclimation to far-red light involves not only generation of red-shifted chlorophylls in the photosystems, but also induction of additional copies of core biliproteins that have been related to red-shifted components of the phycobilisome (Gan et al., Life 5, 4, 2015). We are studying the molecular basis for these acclimations in Chroococcidiopsis thermalis sp. PCC7203. Five far-red induced allophycocyanin subunits (ApcA2, ApcA3, ApcB2, ApcB3 and ApcF2) were expressed in Escherichia coli, together with S-type chromophore-protein lyases and in situ generated chromophore, phycocyanobilin. Only one subunit, ApcF2, shows an unusual red-shift (λAmax~675nm, λFmax~698nm): it binds the chromophore non-covalently, thereby preserving its full conjugation length. This mechanism operates also in two Cys-variants of the induced subunits of bulky APC. All other wild-type subunits bind phycocyanobilin covalently to the conventional Cys-81 under catalysis of the lyase, CpcS1. Although three of them also show binding to additional cysteines, all absorb and fluoresce similar to conventional APC subunits (λAmax~610nm, λFmax~640nm). Another origin of red-shifted complexes was identified, however, when different wild-type α- and ß-subunits of the far-red induced bulky APC were combined in a combinatorial fashion. Strongly red-shifted complexes (λFmax≤722nm) were formed when the α-subunit, PCB-ApcA2, and the ß-subunit, PCB-ApcB2, were generated together in E. coli. This extreme aggregation-induced red-shift of ~90nm of covalently bound chromophores is reminiscent, but much larger, than the ~30nm observed with conventional APC.

[Development of a model for the diagnosis and risk classification on anthrax through artificial neural network].

OBJECTIVE: Based on data through clinical and epidemiological studies, a model regarding the diagnosis and risk classification on anthrax was developed by artificial neural network (ANN). The model could integrally diagnose anthrax cases, judge the risk tendency in time, and increase the ability of recognizing the anthrax accidents. METHODS: Clinical, laboratory and epidemiological data from anthrax cases was collected and analyzed. The important factors which could greatly influence the results on diagnosis and judgment was chosen and used as the neural units. Through the use of artificial neural network analytic method (back propagation, BP), an intelligent model on the diagnosis and risk classification was developed. RESULTS: Results from the multivariate analysis revealed that: 11 factors including incubation period, chest radiographic and microscopic findings, characteristics on professions etc. were associated with the judgment on the diagnosis and intensity of the epidemics. Through 500 times training on the neural network, the performance error decreased from 6.669 59 to 5.051 19 x 10(-11). The model was then validated. With 100% average correct rate, the predictive value was good. CONCLUSION: It was feasible to use the disease information to develop a diagnosis and risk classification model on anthrax by artificial neural network. With 100% average correct rate, the established model was valuable in practice.