Comprehensive Analysis of m7G-Related Genes and Chronic Hepatitis B: Diagnostic Markers, Immune Microenvironment Regulation, Disease Progression.

Chronic hepatitis B (CHB) is a major public health problem in the world. It is the main cause of liver cirrhosis and liver cancer. Although many important roles of RNA modification in stem cells or tumor diseases have been identified, the role of N7-methylguanosine (m7G) modification in the process of chronic HBV infection has not been clearly defined. Therefore, we conducted a systematic analysis on the process of chronic HBV infection. We found that a total of 18 m7G-related genes were altered in chronic HBV infection, and then we screened out CHB potential diagnostic biomarkers using machine learning and random forest methods. RT-qPCR was performed on the samples of healthy people and CHB, which further verified the possibility of being a diagnostic marker. Then, we typed CHB patients based on these 18 genes. We found that the immune microenvironment of different subtypes was different. Among them, patients with subtype-Ⅰ had severe immune response, that is, relatively serious immune cell infiltration, rich immune pathways, relatively many HLA genes, and immune checkpoints. Finally, we conducted an in-depth discussion on our m7G-related genes, and found that m7G gene related to immune cell infiltration may be involved in the disease progression of CHB patients, which was also confirmed in the GSE84044 dataset. In conclusion, m7G-related genes can not only serve as diagnostic markers of CHB, but also participate in the regulation of immune microenvironment and play an important role in the progression of CHB.

The necroptosis related gene LGALS3 can be used as a biomarker for the adverse progression from chronic HBV infection to HCC.

The number of patients with hepatocellular carcinoma (HCC) caused by hepatitis B virus (HBV) infection remains large, despite the remarkable effectiveness of antiviral drugs and vaccines for HBV in preventing and treating HBV infection. Necroptosis is closely related to the occurrence of inflammation, clearance of viral infection, and tumor progression. Presently, little is known about the changes in necroptosis-related genes in the progression from chronic HBV infection (CHI) to HBV-related hepatic fibrosis (HBV-HF) and HBV-related hepatocellular carcinoma (HBV-HCC). In this study, Cox regression analysis was performed using GSE14520 chip data and a necroptosis-related genes survival prognosis score (NRGPS) was established for HBV-HCC patients. NRGPS was constructed using three model genes (G6PD, PINK1 and LGALS3), and verified by data sequencing in the TCGA database. The HBV-HCC cell model was established by transfection of pAAV/HBV1.2C2, constructed by homologous recombination, into HUH7 and HEPG2 cells. The expression levels of G6PD, PINK1, and LGALS3 were detected using RT-qPCR. We further analyzed the expression of the model genes in GSE83148, GSE84044, and GSE14520 and found that LGALS3 was consistently highly expressed in CHI, high fibrosis score and high NRGPS. In addition, immune microenvironment analysis showed that LGALS3 was not only associated with the infiltration of regulatory T cells in the immune microenvironment but also with expression of CCL20 and CCR6. The expression levels of model genes, FOXP3 and CCR6, were analyzed using RT-qPCR in peripheral blood mononuclear cells of 31 hepatitis B surface antibody positive patients, 30 CHI, 21 HBV-HF, and 20 HBV-HCC. In further cell-model experiments, we analyzed the expression of CCL20 by RT-qPCR and the changes in cell proliferation and migration by CCK8 and transwell assays, respectively, in HBV-HCC cell models after LGALS3 knockdown. The findings of this study suggest that LGALS3 could be a biomarker for adverse progression following chronic HBV infection and may also be involved in the regulation of the immune microenvironment, making it a potential therapeutic target.

Atypical nontraumatic chylothorax in a monoclonal IgM elevated nodal marginal zone lymphoma: A case report and review of the literature.

Nodal Marginal Zone Lymphoma(NMZL) is an indolent lymphoma with a very low clinical incidence and is sometimes difficult to differentiate diagnostically from Lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM). NMZL with elevated monoclonal immunoglobulin M (IgM) is even rarer. Nontraumatic chylothorax can be seen in aggressive lymphoma, which often happens with chest tightness and dyspnea as the primary clinical manifestation. We reported the first case of monoclonal IgM elevated NMZL complicated by atypical nontraumatic chylothorax. A 64-year-old male patient was first admitted to the Department of Respiratory Medicine with symptoms of chest tightness and shortness of breath. He was given several times thoracentesis to drain pleural effusion to improve pulmonary compression symptoms. The patient had a combination of elevated monoclonal IgM and atypical lymph node biopsy pathology. After two times lymph node biopsies and genetic testing, the patient was finally diagnosed with NMZL. Within a short time, he was admitted to the Department of Hematology due to the reappearance of massive pleural effusion, which indicated chylothorax. The patient repeatedly presented with left-sided pleural effusion, and the color went from red to yellow, and finally white. Only about half of the chylothorax cases present with typical clinical manifestations. We report this case intending to draw the attention of clinicians to hematologic malignancies with atypical nontraumatic chylothorax.

Development and validation of a necroptosis-related gene prognostic score to predict prognosis and efficiency of immunotherapy in gastric cancer.

Necroptosis is a novel type of regulated cell death that is intimately associated with a variety of tumors. However, how necroptosis affects the identification of gastric cancer (GC) remains unclear. Here we seek to find new potential necroptosis-related biomarkers to predict GC prognosis and immunotherapy effect. We used Cox analysis to obtain shared prognostic markers related to necroptosis from five datasets (TCGA and four GEO datasets). Then, a necroptosis-related gene prognostic score (NRGPS) system was constructed using LASSO Cox regression, NRGPS consisting of three necroptosis-related mRNAs (AXL, RAI14, and NOX4) was identified, 31 pairs of GC and adjacent normal tissues from the Second Hospital of Harbin Medical University were collected and Real-Time Quantitative PCR (RT-qPCR) was used to detect the relative expression levels of the three necroptosis-related mRNAs, and external validation was performed on four GEO datasets (GSE84437, GSE26901, GSE62254 and GSE15459). In this study, Overall survival (OS) in the high-NRGPS group was significantly lower than in the low-NRGPS group. Cox regression analyses showed that NRGPS was an independent prognostic variable. Tumor-mutation-burden (TMB), tumor microenvironment (TME), microsatellite instability (MSI), and Tumor Immune Dysfunction and Exclusion (TIDE) scoring were used as predictors of the immunotherapy response. A cancer-friendly immune microenvironment, a high TIDE score, a low TMB, and a low MSI were all characteristics of the high-NRGPS group, and they all consistently showed that the issues seen there are related to immune escape in GC. The combination of three candidate genes may be an effective method for diagnostic assessment of GC prognosis and immunotherapy efficacy.

No-wait two-stage flowshop problem with multi-task flexibility of the first machine.

For the creation of intelligent management systems in hospitals, efficient resource arrangement is essential. Motivated by a real-world scenario in hospitals, we introduce the no-wait two-stage flowshop scheduling problem with the first-stage machine having multi-task flexibility. In this problem, each job has two operations which are processed in order on a two-stage flowshop without preemption and time delay between or on machines. The multi-task flexibility allows the first-stage machine to process the second-stage operations. The goal is to minimize the maximum completion time of all jobs. To the best of our knowledge, this is a pioneering work on this problem. We discover several novel structural properties, based on which we present a linear-time combinatorial algorithm with an approximation ratio 13 8 . This problem and its variants can find many other meaningful applications in modern manufacturing systems, such as the robot cell scheduling with computer numerical control machines or printed circuit boards. The idea behind our algorithm may inspire more practical algorithms.

Prevalence and Causes of Visual Impairment in Adults in Binhu District, Wuxi, China.

BACKGROUND Previously reported data has guided the treatment and prevention of blindness. This study aimed to evaluate the current prevalence and causes of visual impairment among adults who were 50 years old and older in the Binhu District of Wuxi City, China. MATERIAL AND METHODS A randomized sample of stratified clusters was used to analyze individuals from 30 basic sampling units in Wuxi Binhu District. Visual impairment was defined according to World Health Organization (WHO) standards. RESULTS A total of 6725 people who were at least 50 years old participated in this study. According to WHO standards, bilateral low vision and blindness prevalence were both higher in women than in men (low vision: 6.5% vs. 5.2%; and blindness: 1.4% vs. 0.8%; P=0.022 and P=0.039, respectively). The incidence of bilateral visual impairment increased significantly with age (P<0.001 and P<0.001, respectively). Further studies showed that the main causes of bilateral low vision were cataract, high myopic macular degeneration (MMD), and age-related macular degeneration (AMD). The main causes of bilateral blindness were cataract, MMD, and eye loss/atrophy, while the main causes of monocular low vision were cataract, MD, and AMD. The main causes of monocular blindness were cataract, eye loss/atrophy, and AMD. CONCLUSIONS The prevalence of low vision and blindness remains high in the Binhu District of Wuxi City in China, especially among older women. In our study, cataracts were the leading cause of visual impairment. Our study highlights that some efforts should be initiated to prevent and treat blindness and low vision. Additional causes of visual impairment were MMD, AMD, and eye loss/atrophy.

Red and Processed Meat Consumption Increases Risk for Non-Hodgkin Lymphoma: A PRISMA-Compliant Meta-Analysis of Observational Studies.

The association between consumption of red and processed meat and non-Hodgkin lymphoma (NHL) remains unclear. We performed a meta-analysis of the published observational studies to explore this relationship.We searched databases in MEDLINE and EMBASE to identify observational studies which evaluated the association between consumption of red and processed meat and risk of NHL. Quality of included studies was evaluated using Newcastle-Ottawa Quality Assessment Scale (NOS). Random-effects models were used to calculate summary relative risk (SRR) and the corresponding 95% confidence interval (CI).We identified a total of 16 case-control and 4 prospective cohort studies, including 15,189 subjects with NHL. The SRR of NHL comparing the highest and lowest categories were 1.32 (95% CI: 1.12-1.55) for red meat and 1.17 (95% CI: 1.07-1.29) for processed meat intake. Stratified analysis indicated that a statistically significant risk association between consumption of red and processed meat and NHL risk was observed in case-control studies, but not in cohort studies. The SRR was 1.11 (95% CI: 1.04-1.18) for per 100 g/day increment in red meat intake and 1.28 (95% CI: 1.08-1.53) for per 50 g/day increment in processed meat intake. There was evidence of a nonlinear association for intake of processed meat, but not for intake of red meat.Findings from our meta-analysis indicate that consumption of red and processed meat may be related to NHL risk. More prospective epidemiological studies that control for important confounders and focus on the NHL risk related with different levels of meat consumption are required to clarify this association.

Porcine reproductive and respiratory syndrome virus 3C protease cleaves the mitochondrial antiviral signalling complex to antagonize IFN-ß expression.

Porcine reproductive and respiratory syndrome, a highly infectious disease caused by porcine reproductive and respiratory syndrome virus (PRRSV), has developed various strategies to evade the host innate immune response, including the suppression of type I IFN activation. The mitochondrial antiviral signalling protein (MAVS) is an important bridging adaptor of retinoic acid-inducible gene I/melanoma differentiation-associated protein 5 signalling pathways. Here, we demonstrated that the 3C-like protease (3CLSP) of PRRSV prevented the induction of IFN-ß by cleaving MAVS in a proteasome- and caspase-independent manner. Moreover, this cleavage ability was dependent on the protease activity of 3CLSP. Mutations specifically disrupting the cysteine protease activity of 3CLSP eliminated MAVS cleavage and the inhibition of IFN induction. Subsequently, we determined that 3CLSP cleaved MAVS at Glu268. Remarkably, a MAVS point mutation at Glu268 rendered MAVS resistant to 3CLSP cleavage. These results reveal a novel PRRSV mechanism to escape host immunity by directly cleaving MAVS.

Complete genome sequence of a novel deletion porcine reproductive and respiratory syndrome virus strain.

Porcine reproductive and respiratory syndrome virus HZ-31 strain is different from any other previously sequenced porcine reproductive and respiratory syndrome virus strains. It contains a 59-amino acid (aa) discontinuous deletion in aa 467 to 474, aa 498 to 519, and aa 533 to 561 of nsp2. Here, we report the complete genome sequence of this novel Chinese virulent PRRSV variant.

A versatile and robust vesicle based on a photocleavable surfactant for two-photon-tuned release.

A small amphiphile that contains a coumarin unit and alkynyl groups, as a two-photon-cleavable segment and polymerizable groups, respectively, was designed and synthesized. The amphiphile showed a critical aggregation concentration of about 4.6×10(-5) M and formed a vesicle-type assembly. The formed vesicles were stabilized by in situ "click" polymerization without altering their morphology. Hydrophobic and hydrophilic guests can be encapsulated within the vesicle membrane and inside the aqueous core of the vesicle, respectively. The loaded guests can be released from the vesicle by using UV or near-IR stimuli, through splitting up the amphiphilic structure of the amphiphile. Distinguished dose-controlled photorelease of the polymeric vesicle is achieved with the maintenance of vesicular integrity, which makes the guest release dependent on the amount of cleavage of the amphiphilic structure during irradiation. This study provides a potential strategy for the development of versatile and stable drug-delivery systems that offer sustained and photo-triggered release.

Stabilized vesicles consisting of small amphiphiles for stepwise photorelease via UV light.

A small amphiphile consisting of hydrophilic tetraethylene glycol monoacrylate and hydrophobic alkyl chain which were connected by an o-nitrobenzyl unit, a photolabile group, was designed and synthesized. The critical aggregate concentration of the synthesized amphiphile was determined to be about 3 × 10(-5) M by the fluorescence probe technique. Nanosized vesicles were prepared and stabilized by in-situ radical polymerization without altering the morphology. The polymeric vesicle was highly stable which retained vesicular shape under dilution or UV irradiation. Hydrophobic guests can be encapsulated within the vesicle membrane and released out of the vesicle by UV stimulus through splitting the amphiphilic structure of the amphiphile. Distinguished dose-controlled photorelease of the polymeric vesicle is achieved due to the maintenance of the vesicular shape integrity which makes the guest release depend on the cleavage amount of amphiphilic structure during UV irradiation. This study provides a promising strategy to develop stable drug delivery systems for sustained and phototriggered release.

Enhancement of the function of rat serotonin and norepinephrine neurons by sustained vagus nerve stimulation.

BACKGROUND: Vagus nerve stimulation (VNS) is a recent intervention for treatment-resistant depression. Electrophysiological recordings in the rat brain showed that VNS increases the firing rate of norepinephrine (NE) neurons after 1 day of stimulation and that of serotonin (5-HT) neurons after 14 days. This study was conducted to further characterize these effects. METHODS: We implanted rats with a VNS electrode and stimulator. We used the selective noradrenergic toxin DSP-4 to lesion NE neurons of the locus coeruleus. We recorded dorsal raphe 5-HT neurons under chloral hydrate anesthesia. We recorded hippocampus CA(3) pyramidal neurons using 5-barreled iontophoretic pipettes. RESULTS: Analysis of a previously published data set revealed that VNS increased not only the spontaneous firing rates of NE neurons, but also the percentage of neurons firing in bursts. The enhancement of the 5-HT neuron firing rate by VNS was abolished by lesioning NE neurons. We found that VNS increased the degree of activation of postsynaptic alpha(1)-adrenoceptors on 5-HT neurons, probably through an increased release of endogenous NE. The tonic activation of postsynaptic 5-HT(1A) receptors in the hippocampus was enhanced after 14 days of VNS, as with other antidepressant treatments. LIMITATIONS: Our study limitations include the fact that we turned off the stimulator during the electrophysiological recordings, which likely decreased the vagal tone to the brain. Also, we obtained the data while the animals were under anesthesia, therefore studies need to be carried out in unanesthetized rats to ascertain whether the anesthetic agent influenced the changes observed between control rats and those treated with VNS. CONCLUSION: Vagus nerve stimulation initially increases the firing activity and pattern of NE neurons and subsequently those of 5-HT neurons, presumably as a cascade effect via alpha(1)-postsynaptic adrenoceptors. To date, VNS appears to be a unique antidepressant treatment increasing 5-HT transmission and enhancing the firing activity of NE neurons. These effects could contribute to the effectiveness of VNS in treatment-resistant depression.

Optimization of vagus nerve stimulation parameters using the firing activity of serotonin neurons in the rat dorsal raphe.

Vagus nerve stimulation (VNS) is a recently approved adjunctive intervention for treatment-resistant depression. This therapy enhances the firing rate of rat norepinephrine neurons after 1 h and that of serotonin (5-HT) neurons only after 14 days. Various stimulation parameters were thus tested on their capacity to enhance 5-HT neuronal firing because of the delayed action of VNS on the 5-HT system and its important role in the antidepressant response. Rats were implanted with a stimulator and treated for 14 days, each group of rats having only one stimulation parameter modified from the standard ones (0.25 mA, 20 Hz, 500 micros, 30 s ON/5 min OFF). Electrophysiological recordings showed that the usual parameters utilized in depressed patients, with the exception of current intensity, produced an optimal activation of 5-HT neurons. Excessive enhancement of the charge delivered to the nerve can lead to a loss of VNS effect on 5-HT neuronal firing.

[Determination of net electric field in dielectric barrier discharge in N2 by relative spectrum line intensity].

The process of N2 discharge in direct current electric field is simulated by Monte Carlo method. The electron drift velocity as a function of E/N is given, which is in good agreement with experimental result. The variations of the number density of electronic excitation states of N2 (A3 sigma(u)+ and a 1pi(g)) with the reduced field E/N are simulated. A method is proposed to determine the net reduced electric field in dielectric barrier discharge by monitoring the relative intensity of spectrum line 145 nm and spectrum line 201 nm.

Enhancement of serotoninergic function - a sometimes insufficient cause of antidepressant action.

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