Major depressive disorder and irritable bowel syndrome risk: A Mendelian randomization study.

BACKGROUND: Previous studies have revealed a connection between major depressive disorder (MDD) and irritable bowel syndrome (IBS), but it remains obscure if the two diseases are related causally. Mendelian randomization was utilized in this investigation to ascertain whether MDD contributed to the emergence of IBS. METHODS: To examine possible connections between MDD and IBS, we used two-sample Mendelian randomization (MR) utilizing summary data from genome-wide association studies (GWAS). The Psychiatric Genomics Consortium (PGC) provided information on genetic associations with MDD (cases: 135,458; controls: 344,901). The Medical Research Council Integrative Epidemiology Unit (MRC-IEU) provided information on genetic associations with IBS (cases:10,939; controls:451,994). Inverse Variance Weighted (main analyses), MR-Egger regression, Weighted mode, and Weighted Median were the four MR methods used in this investigation. In addition, we also performed multiplicity and heterogeneity analyses to eliminate possible biases. RESULTS: In the standard Inverse Variance Weighting (IVW) method, an increased risk of IBS was linked to a genetic susceptibility to MDD (OR: 1.01; 95% CI: 1.006 to 1.014, p = 1.02E-07). In addition, neither significant heterogeneity (IVW Q = 24.80, p = 0.73) nor horizontal pleiotropy (MR Egger p = 0.17; MRPRESSO p = 0.54) were detected in this MR analysis. The bidirectional analysis, however, did not show a genetic link between IBD and MDD (p steiger <0.01). CONCLUSION: A direct causal relationship between MDD and IBS was revealed by Mendelian randomization study, which contributes to the effective clinical management of both diseases.

NMDAR antagonists suppress tumor progression by regulating tumor-associated macrophages.

Neurotransmitter receptors are increasingly recognized to play important roles in anti-tumor immunity. The expression of the ion channel N-methyl-D-aspartate receptor (NMDAR) on macrophages was reported, but the role of NMDAR on macrophages in the tumor microenvironment (TME) remains unknown. Here, we show that the activation of NMDAR triggered calcium influx and reactive oxygen species production, which fueled immunosuppressive activities in tumor-associated macrophages (TAMs) in the hepatocellular sarcoma and fibrosarcoma tumor settings. NMDAR antagonists, MK-801, memantine, and magnesium, effectively suppressed these processes in TAMs. Single-cell RNA sequencing analysis revealed that blocking NMDAR functionally and metabolically altered TAM phenotypes, such that they could better promote T cell- and Natural killer (NK) cell-mediated anti-tumor immunity. Treatment with NMDAR antagonists in combination with anti-PD-1 antibody led to the elimination of the majority of established preclinical liver tumors. Thus, our study uncovered an unknown role for NMDAR in regulating macrophages in the TME of hepatocellular sarcoma and provided a rationale for targeting NMDAR for tumor immunotherapy.

Effects of Press Needling combined with general anesthesia on postoperative analgesia in thoracoscopic pulmonary resection for lung cancer: A randomized, single-blind, controlled trial.

OBJECTIVES: To investigate the effects of press needle therapy on postoperative analgesia and other relevant complications in patients undergoing thoracoscopic pulmonary resection. DESIGN: randomized, single-blind, controlled trial SETTING: Teaching hospitals affiliated with universities. INTERVENTIONS: Eighty-six patients were randomized into: the Acu group (press-needle group) and the control group MAIN OUTCOME MEASURES: Pain levels 24, 48, and three months after surgery were measured using the numeric rating scale (NRS). Perioperative hemodynamics, total and effective pressing numbers of patient-controlled intravenous analgesia (PCIA), and incidence of postoperative pulmonary complications were recorded. Peripheral blood samples were collected to measure the levels of inflammatory mediators RESULTS: Acu group had significantly lower NRS scores at 24 and 48 h after operation (NRS scores on movement at 24 h after surgery: Acu vs. Control, 3 (2,3) vs. 3 (3,5), Z = -3.393, P < 0.01 and NRS scores on movement at 48 h after surgery: 2 (1,3) vs. 3 (2,5), Z = -3.641, P < 0.01), lower number of PCIA attempts and effective rates (mean total pressing numbers: 4(2,8) vs. 6(3,19), Z = -1.994, P = 0.046 and mean effective pressing numbers: 3(2,8) vs. 6(3,16), Z = -2.116, P = 0.034). The Acu group had significantly reduced IL-1 (14.52 ± 3.84 vs. 16.36 ± 3.30, mean difference (MD): - 1.85, 95% confidence interval (CI): - 3.46, - 0.23, P = 0.026), HIF-1α (10.15 ± 1.71 vs. 10.96 ± 1.73, MD: -0.81, 95% CI: -1.59, -0.04, P = 0.040) and the incidence of pulmonary complications after surgery. CONCLUSION: Press needles are a non-invasive and feasible adjunctive intervention for postoperative analgesic management in patients undergoing thoracoscopic pulmonary resection.

Circ-C16orf62 Regulates Oxidized low-density Lipoprotein-induced Apoptosis, Inflammation, Oxidative Stress and Cholesterol Accumulation of Macrophages via Mediating RAB22A Expression by Targeting miR-377.

Atherosclerosis (AS) is one of the most common and important vascular diseases. It is believed that the abnormal expression of circular RNAs (circRNAs) plays an important role in AS. Hence, we investigate the function and mechanism of circ-C16orf62 in AS development.In this study, oxidized low-density lipoprotein (ox-LDL)-treated human macrophages (THP-1) were used as pathological conditions of AS in vitro. The expression of circ-C16orf62, miR-377 and Ras-related protein (RAB22A) mRNA was detected by real-time quantitative polymerase chain reaction (RT-qPCR) or western blot. Cell viability or cell apoptosis was assessed by cell counting kit-8 (CCK-8) assay or flow cytometry assay. The releases of proinflammatory factors were investigated using enzyme-linked immunosorbent assay (ELISA). The production of malondialdehyde (MDA) and superoxide dismutase (SOD) was examined to assess oxidative stress. Total cholesterol (T-CHO) level was detected, and cholesterol efflux level was tested using a liquid scintillation counter. The putative relationship between miR-377 and circ-C16orf62 or RAB22A was verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay.circ-C16orf62 expression was elevated in AS serum samples and ox-LDL-treated THP-1 cells. Apoptosis, inflammation, oxidative stress and cholesterol accumulation induced by ox-LDL were suppressed by circ-C16orf62 knockdown. Circ-C16orf62 could bind to miR-377 and thus increased the expression level of RAB22A. Rescued experiments showed that circ-C16orf62 knockdown alleviated ox-LDL-induced THP-1 cell injuries by increasing miR-377 expression, and miR-377 overexpression lessened ox-LDL-induced THP-1 cell injuries by degrading RAB22A level.In conclusion, circ-C16orf62 played a crucial role in the regulation of apoptosis, inflammation, oxidative stress and cholesterol accumulation in ox-LDL-treated human macrophages via mediating the miR-377/RAB22A axis, hinting that circ-C16orf62 might be involved in AS progression.

The role of glutamate receptors in the regulation of the tumor microenvironment.

Glutamate, as one of the most important carbon sources in the TCA cycle, is central in metabolic processes that will subsequently influence tumor progression. Several factors can affect the expression of glutamate receptors, playing either a tumor-promoting or tumor-suppressor role in cancer. Thus, the activation of glutamate receptors by the ligand could play a role in tumor development as ample studies have demonstrated the expression of glutamate receptors in a broad range of tumor cells. Glutamate and its receptors are involved in the regulation of different immune cells' development and function, as suggested by the receptor expression in immune cells. The activation of glutamate receptors can enhance the effectiveness of the effector's T cells, or decrease the cytokine production in immunosuppressive myeloid-derived suppressor cells, increasing the antitumor immune response. These receptors are essential for the interaction between tumor and immune cells within the tumor microenvironment (TME) and the regulation of antitumor immune responses. Although the role of glutamate in the TCA cycle has been well studied, few studies have deeply investigated the role of glutamate receptors in the regulation of cancer and immune cells within the TME. Here, by a systematic review of the available data, we will critically assess the physiopathological relevance of glutamate receptors in the regulation of cancer and immune cells in the TME and provide some unifying hypotheses for futures research on the role of glutamate receptors in the immune modulation of the tumor.

Fabrication of nitrogen-doped graphene nanosheets anchored with carbon nanotubes for the degradation of tetracycline in saline water.

The treatment of wastewater with high salinity is still a challenge because of the quenching effect of various anions on radical processes. The nonradical process may be a more promising pathway. Herein, a 3D structured nitrogen-doped graphene nanosheet anchored with carbon nanotubes (N-GS-CNTs) was prepared by direct pyrolysis of K3Fe(CN)6. The as-prepared catalyst can effectively activate peroxymonosulfate (PMS) for mineralization of tetracycline (TC) over a wide pH range (from 3 to 11) and even in high saline water (500 mM Cl-, HCO3-, etc.). The degradation mechanism was elucidated by both experimental characterizations and DFT calculations. The high catalytic efficiency was attributed to accelerated electron transfer from donor (TC) to acceptor (PMS) in the presence of the catalyst, which acts as electron shuttle mediators to promote a nonradical process. At the same time, the catalyst also enhances the production of singlet oxygen (1O2), hence further increasing the degradation rate. This study not only provides a simple method for synthesizing N-GS-CNT catalysts but also provides new insights into the electron transfer pathway for the removal of organic pollutants under high salinity conditions.

The finite-difference time-domain (FDTD) guided preparation of Ag nanostructures on Ti substrate for sensitive SERS detection of small molecules.

Surface-enhanced Raman Scattering (SERS) has become a powerful analytical technique for highly sensitive detection of target molecules. Its performance, however, is heavily dependent on the substrates. Relatively low sensitivity for small molecules and poor reproducibility in quantitative analysis are often encountered in most of nanoparticle modified SERS substrate. The present work starts by theoretical investigation of the electromagnetic field enhancement by nanomaterials of coinage metals with different sizes. The finite-difference time-domain (FDTD) simulation results revealed that the Ag NPs with the size around 100 nm exhibit the strongest SERS effect and the 'Ag-Ag' gaps have shown higher electromagnetic field enhancement than that of the 'Ag-Ti' gap. Subsequently, a multilayered Ag nanoparticles SERS substrate (or other coinage metals) was prepared by a two-step electroless deposition of Ag on Ti substrate. This was achieved by in situ reduction of Ag precursor to subsequently form a Ag nanoflake (Ag NF) layer and a Ag nanoparticle (Ag NPs) layer on the Ti base (Ti/AgNFs/AgNPs). The as-prepared SERS substrate showed a substantially enhanced SERS effect for small molecule detection and detection limit as low as 1.0 × 10-17 M for picric acid (PA), 1.0 × 10-14 M for p-nitrotoluene (PNT) and 1.0 × 10-6 M for uric acid (UA) were obtained respectively. The facile method developed in this work should be widely applicable for in-situ preparation of other SERs substrates.

A facile electroless preparation of Cu, Sn and Sb oxides coated Ti electrode for electrocatalytic degradation of organic pollutants.

Electrocatalytic degradation of organic pollutants is an encouraging technology for wastewater treatment. To achieve practical application, electrode plate with cost effective fabrication, high catalytic efficiency and long service life is urgently required. This work prepared a CuO-SnO2-SbOX electrode on Ti substrate, which is achieved by ultrasonic assisted deposition of Cu layer, followed by electroless deposition of SnSb layer and finalized by calcination at 500 °C. The obtained electrode (Ti/CuO-SnO2-SbOX) exhibited high catalytic degradation activity and a high oxygen evolution potential (OEP) of 2.13 V, which is 0.4 V greater than that of the widely recognized Ti/SnO2-SbOX electrode. The oxygen evolution reaction (OER) models of active oxygen intermediate adsorption was optimized by density functional theory (DFT) calculations. The results revealed that (1) the ΔG of the OER rate-determining step was raised to 2.30 eV after Cu doping on 101 plane; (2) binding energies of the optimized surface with reactive oxygen species (ROS) were substantially decreased. Furthermore, the as-prepared electrode has a high yield of hydroxyl radical generation as evidenced by terephthalic acid detection. The potential for hydroxyl radical generation was measured to be 1.8 V at pH = 12 and 2.6 V at pH = 2.The catalytic degradation rate of methylene blue (MB) follows pseudo first order reaction kinetics, and the reaction constant K value reached 0.02964 -k/min-1, twice as much as that obtained from electrodeposition electrode (Ti/Cu/SnO2-SbOX). A degradation rate of 94.6% was achieved for MB in 100 min in the first run, and the value remained over 85% in the subsequent 10 runs. At the same conditions, the degradation rate of p-nitrophenol was over 90% in 100 min and complete mineralization was achieved in 4 h.

ASPP2 inhibits tumor growth by repressing the mevalonate pathway in hepatocellular carcinoma.

Cancer is, fundamentally, a disorder of cell growth and proliferation, which requires adequate supplies of energy and nutrients. In this study, we report that the haplo-insufficient tumor suppressor ASPP2, a p53 activator, negatively regulates the mevalonate pathway to mediate its inhibitory effect on tumor growth in hepatocellular carcinoma (HCC). Gene expression profile analysis revealed that the expression of key enzymes in the mevalonate pathway were increased when ASPP2 was downregulated. HCC cells gained higher cholesterol levels and enhanced tumor-initiating capability in response to the depletion of ASPP2. Simvastatin, a mevalonate pathway inhibitor, efficiently abrogated ASPP2 depletion-induced anchorage-independent cell proliferation, resistance to chemotherapy drugs in vitro, and tumor growth in xenografted nude mice. Mechanistically, ASPP2 interacts with SREBP-2 in the nucleus and restricts the transcriptional activity of SREBP-2 on its target genes, which include key enzymes involved in the mevalonate pathway. Moreover, clinical data revealed better prognosis in patients with high levels of ASPP2 and low levels of the mevalonate pathway enzyme HMGCR. Our findings provide functional and mechanistic insights into the critical role of ASPP2 in the regulation of the mevalonate pathway and the importance of this pathway in tumor initiation and tumor growth, which may provide a new therapeutic opportunity for HCC.

Obesity-Induced Methylation of Osteopontin Contributes to Adipogenic Differentiation of Adipose-Derived Mesenchymal Stem Cells.

Obesity is a major risk factor for many chronic diseases, including diabetes, fatty livers, and cancer. Expansion of the adipose mass has been shown to be related to adipogenic differentiation of adipose-derived mesenchymal stem cells (ASCs). However, the underlying mechanism of this effect has yet to be elucidated. We found that osteopontin (OPN) is downregulated in ASCs and adipose tissues of obese mice and overweight human beings because of methylation on its promoter, indicating that OPN may affect the development of obesity. Silencing of OPN in wild-type ASCs promotes adipogenic differentiation, while reexpression of OPN reduced adipogenic differentiation in OPN-/- ASCs. The role of extracellular OPN in ASC differentiation was further demonstrated by supplementation and neutralization of OPN. Additionally, OPN suppresses adipogenic differentiation in ASCs through the C/EBP pathways. Consistent with these in vitro results, by intravenous injection of OPN-expressing adenovirus to the mice, we found OPN can delay the development of obesity and improve insulin sensitivity. Therefore, our study demonstrates an important role of OPN in regulating the development of obesity, indicating OPN might be a novel target to attenuate obesity and its complications.

Impacts of the Dispersal Delay on the Stability of the Coexistence Equilibrium of a Two-Patch Predator-Prey Model with Random Predator Dispersal.

In this paper, we study a predator-prey system with random predator dispersal over two habitat patches. We show that in most cases the dispersal delay does not affect the stability and instability of the coexistence equilibrium. However, if the mean time that the predator spent in one patch is much shorter than the timescale of reproduction of the prey and is larger than the double mean time of capture of prey, the dispersal delay can induce stability switches such that an otherwise unstable coexistence equilibrium can be stabilized over a finite number of stability intervals.

The joint impacts of dispersal delay and dispersal patterns on the stability of predator-prey metacommunities.

A predator-prey metapopulation model over arbitrary number of patches is considered in this paper. The model assumes that only prey move (with a dispersal delay) between all connected patches. Two cases of dispersal patterns are considered. For the case the dispersal of prey is due to random effect only (independent of predator density), we show that either the dispersal delay is harmless in the sense that it does not affect the stability of the metacommunity, or the dispersal delay can induce stability switches with finite number of stability intervals. For the case the dispersal of prey is due to predator-avoidance (dependent on predator density), we show that the interplay of density-dependent dispersal and dispersal delay may also induce finite number of stability switches. This indicates that the combination of the density-dependent dispersal and dispersal delay can exhibit both stabilizing and destabilizing effects on the stability of the coexistence equilibrium. Our results show that the delay and the patterns of prey dispersal jointly affect the stability of predator-prey metacommunities and can induce multiple stability switches.

The long noncoding RNA XIST protects cardiomyocyte hypertrophy by targeting miR-330-3p.

Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are implicated in numerous kinds of cardiovascular diseases, and their vital role in regulating cardiac hypertrophy still needs to be explored. In this study, we demonstrated that lncRNA X-inactive specific transcript (XIST) was upregulated in hypertrophic cardiac of mice and phenylephrine (PE)-treated cardiomyocytes. Next, we observed that inhibition of XIST induced hypertrophic response of cardiomyocyte and overexpression of XIST attenuated cardiomyocyte hypertrophy induced by PE. Furthermore, through online predictive tools and functional experiments, we demonstrated that XIST and S100B were targets of miR-330-3p. XIST and miR-330-3p suppressed each other in a reciprocal way in cardiomyocytes. Additionally, XIST promoted S100B expression through harboring the complementary binding sites with miR-330-3p, eventually prevented cardiac hypertrophy. In conclusion, our findings revealed a novel molecular mechanism that XIST/miR-330-3p/S100B pathway modulates the progression of cardiomyocyte hypertrophy.

Novel Virophages Discovered in a Freshwater Lake in China.

Virophages are small double-stranded DNA viruses that are parasites of giant DNA viruses that infect unicellular eukaryotes. Here we identify a novel group of virophages, named Dishui Lake virophages (DSLVs) that were discovered in Dishui Lake (DSL): an artificial freshwater lake in Shanghai, China. Based on PCR and metagenomic analysis, the complete genome of DSLV1 was found to be circular and 28,788 base pairs in length, with a G+C content 43.2%, and 28 predicted open reading frames (ORFs). Fifteen of the DSLV1 ORFs have sequence similarity to known virophages. Two DSLV1 ORFs exhibited sequence similarity to that of prasinoviruses (Phycodnaviridae) and chloroviruses (Phycodnaviridae), respectively, suggesting horizontal gene transfer occurred between these large algal DNA viruses and DSLV1. 46 other virophages-related contigs were also obtained, including six homologous major capsid protein (MCP) gene. Phylogenetic analysis of these MCPs showed that DSLVs are closely related to OLV (Organic Lake virophage) and YSLVs (Yellowstone Lake virophages), especially to YSLV3, except for YSLV7. These results indicate that freshwater ecotopes are the hotbed for discovering novel virophages as well as understanding their diversity and properties.

Agarose gel purification of PCR products for denaturing gradient gel electrophoresis results in GC-clamp deletion.

The 16S ribosomal RNA (rRNA) gene of marine archaeal samples was amplified using a nested PCR approach, and the V3 region of 16S rRNA gene of crab gut microbiota (CGM) was amplified using the V3 universal primer pair with a guanine and cytosine (GC)-clamp. Unpurified PCR products (UPPs), products purified from reaction solution (PPFSs), and products purified from gel (PPFGs) of above two DNA samples were used for denaturing gradient gel electrophoresis (DGGE) analysis, respectively. In contrast to almost identical band patterns shared by both the UPP and PPFS, the PPFGs were barely observed on the DGGE gel for both the marine archaea and CGM samples. Both PPFS and PPFG of CGM V3 regions were subjected to cloning. A small amount of positive clones was obtained for PPFS, but no positive clones were observed for PPFG. The melt curve and direct sequencing analysis of PPFS and PPFG of E. coli V3 region indicated that the Tm value of PPFG (82.35 ± 0.19 °C) was less than that of PPFS (83.81 ± 0.11 °C), and the number of shorter GC-clamps was significant higher in PPFG than in PPFS. The ultraviolet exposure experiment indicated that the ultraviolet was not responsible for the deletion of the GC-clamps. We conclude that the gel purification method is not suitable for DGGE PCR products or even other GC-rich DNA samples.

Fine structure of Tibetan kefir grains and their yeast distribution, diversity, and shift.

Tibetan kefir grains (TKGs), a kind of natural starter for fermented milk in Tibet, China, host various microorganisms of lactic acid bacteria, yeasts, and occasionally acetic acid bacteria in a polysaccharide/protein matrix. In the present study, the fine structure of TKGs was studied to shed light on this unusual symbiosis with stereomicroscopy and thin sections. The results reveal that TKGs consist of numerous small grain units, which are characterized by a hollow globular structure with a diameter between 2.0 and 9.0 mm and a wall thickness of approximately 200 µm. A polyhedron-like net structure, formed mainly by the bacteria, was observed in the wall of the grain units, which has not been reported previously to our knowledge. Towards the inside of the grain unit, the polyhedron-like net structures became gradually larger in diameter and fewer in number. Such fine structures may play a crucial role in the stability of the grains. Subsequently, the distribution, diversity, and shift of yeasts in TKGs were investigated based on thin section, scanning electron microscopy, cloning and sequencing of D1/D2 of the 26S rRNA gene, real-time quantitative PCR, and in situ hybridization with specific fluorescence-labeled oligonucleotide probes. These show that (i) yeasts appear to localize on the outer surface of the grains and grow normally together to form colonies embedded in the bacterial community; (ii) the diversity of yeasts is relatively low on genus level with three dominant species--Saccharomyces cerevisiae, Kluyveromyces marxianus, and Yarrowia lipolytica; (iii) S. cerevisiae is the stable predominant yeast species, while the composition of Kluyveromyces and Yarrowia are subject to change over time. Our results indicate that TKGs are relatively stable in structure, and culture conditions to some extent shape the microbial community and interaction in kefir grains. These findings pave the way for further study of the specific symbiotic associations between S. cerevisiae and Lactobacillus bacteria in TKGs.

Infinitely many homoclinic solutions for second order nonlinear difference equations with p-Laplacian.

We employ Nehari manifold methods and critical point theory to study the existence of nontrivial homoclinic solutions of discrete p-Laplacian equations with a coercive weight function and superlinear nonlinearity. Without assuming the classical Ambrosetti-Rabinowitz condition and without any periodicity assumptions, we prove the existence and multiplicity results of the equations.

Efficient purification and concentration of viruses from a large body of high turbidity seawater.

Marine viruses are the most abundant entities in the ocean and play crucial roles in the marine ecological system. However, understanding of viral diversity on large scale depends on efficient and reliable viral purification and concentration techniques. Here, we report on developing an efficient method to purify and concentrate viruses from large body of high turbidity seawater. The developed method characterizes with high viral recovery efficiency, high concentration factor, high viral particle densities and high-throughput, and is reliable for viral concentration from high turbidity seawater. Recovered viral particles were used directly for subsequent analysis by epifluorescence microscopy, transmission electron microscopy and metagenomic sequencing. Three points are essential for this method:•The sampled seawater (>150 L) was initially divided into two parts, water fraction and settled matter fraction, after natural sedimentation.•Both viruses in the water fraction concentrated by tangential flow filtration (TFF) and viruses isolated from the settled matter fraction were considered as the whole viral community in high turbidity seawater.•The viral concentrates were re-concentrated by using centrifugal filter device in order to obtain high density of viral particles.