Signaling Elements Research Articles

Calcium nutrition nanoagent rescues tomatoes from mosaic virus disease by accelerating calcium transport and activating antiviral immunity.

As an essential structural, metabolic and signaling element, calcium shows low remobilization from old to young tissues in plants, restricting the nutrient-use efficiency and control efficacy against mosaic virus disease. Nanotechnology has been applied to prevent/minimize nutrient losses and improve the accessibility of poorly-available nutrients. Herein, the current study applied a star polycation (SPc) to prepare a calcium nutrition nanoagent. The SPc could assemble with calcium glycinate through hydrogen bond and Van der Waals force, forming stable spherical particles with nanoscale size (17.72 nm). Transcriptomic results revealed that the calcium glycinate/SPc complex could activate the expression of many transport-related genes and disease resistance genes in tomatoes, suggesting the enhanced transport and antiviral immunity of SPc-loaded calcium glycinate. Reasonably, the calcium transport was accelerated by 3.17 times into tomato leaves with the help of SPc, and the protective effect of calcium glycinate was remarkably improved to 77.40% and 67.31% toward tomato mosaic virus with the help of SPc after the third and fifth applications. Furthermore, SPc-loaded calcium glycinate could be applied to increase the leaf photosynthetic rate and control the unusual fast growth of tomatoes. The current study is the first success to apply nano-delivery system for enhanced calcium transport and antiviral immunity, which is beneficial for increasing nutrient-use efficiency and shows good prospects for field application.

The origin and evolution of salicylic acid signaling and biosynthesis in plants

Salicylic acid (SA) plays a pivotal role in plant response to biotic and abiotic stress. Several core SA signaling regulators and key proteins in SA biosynthesis have been well characterized. However, much remains unknown about the origin, evolution, and early diversification of core elements in plant SA signaling and biosynthesis. In this study, we identified 10 core protein families in SA signaling and biosynthesis across green plant lineages. We found that the key SA signaling receptors, the nonexpresser of pathogenesis-related (NPR) proteins, originated in the most recent common ancestor (MRCA) of land plants and formed divergent groups in the ancestor of seed plants. However, key transcription factors for SA signaling, TGACG motif-binding proteins (TGAs), originated in the MRCA of streptophytes, arguing for the stepwise evolution of core SA signaling in plants. Different from the assembly of the core SA signaling pathway in the ancestor of seed plants, SA exists extensively in green plants, including chlorophytes and streptophyte algae. However, the full isochorismate synthase (ICS)-based SA synthesis pathway was first assembled in the MRCA of land plants. We further revealed that the ancient abnormal inflorescence meristem 1 (AIM1)-based β-oxidation pathway is crucial for the biosynthesis of SA in chlorophyte algae, and this biosynthesis pathway may have facilitated the adaptation of early-diverging green algae to the high-light-intensity environment on land. Taken together, our findings provide significant insights into the early evolution and diversification of plant SA signaling and biosynthesis pathways, highlighting a crucial role of SA in stress tolerance during plant terrestrialization.

QIST: One-dimensional quantum integer wavelet S-transform

We present the first quantum version of the one-dimensional integer wavelet S-Transform (QIST). This version is based on a new Quantum Block Representation by Basis States (QBRBS) and the design of a quantum rounding operator. The QBRBS format facilitates storing and manipulating pairs of signal elements, decreasing the use of additional qubits and gates. Also, the quantum rounding operator exploits the features of the S-Transform to avoid nonlinearities. Complete quantum circuits for addition, subtraction, and halving operations were developed. The complexity analysis showed a polynomial quantum complexity, O(n), and a time complexity of O(1). The experiments performed on MATLAB and Qiskit verify the theoretical results coinciding with the results of the classical version. Finally, the new quantum transform’s feasibility and accuracy enable new quantum developments in information hiding, compression, and IoT applications.

Impact of Phospholipase C Gamma 2 Alzheimer's Disease Variants on Microglial Biology and Disease Pathogenesis

AbstractBackgroundAlzheimer’s disease (AD) and other neurodegenerative diseases are typified by a robust microglial‐mediated immune response. Phospholipase C gamma 2 (PLCG2), whose variants confer altered risk for AD, is a critical signaling element for various immune receptors and is a key regulatory hub gene for immune signaling. A functional hypermorphic P522R variant (rs72824905) of PLCG2 has been identified to be protective against AD (OR= 0.68, p=5.83‐10). Significantly, we identified a novel SNP (rs617749044) associated with elevated AD risk (OR=1.164; p=0.047) encoding the PLCG2 M28L variant.MethodTo investigate the impact of PLCG2 AD risk variants on microglial biology and disease pathogenesis, we have generated mice bearing either the M28L risk or the P522R protective PLCG2 variant, all crossed onto the 5XFAD amyloidogenic murine model of AD.ResultHere, we provide comprehensive analysis of PLCG2 action in mouse models of AD. We demonstrate that PLCG2 variants regulate protein‐protein interaction, alter microglial phenotypes in 5XFAD mice, regulate cytokine levels, drive distinct transcriptional phenotypes of microglia, and affect plaque pathology. Our data demonstrate that the M28L variant results in accelerated and exacerbated disease‐related pathology, and conversely, the P522R variant appeared to attenuate disease severity and progression.ConclusionTogether, our finding provides evidence that PLCG2 play an important role in AD pathophysiology, indicating PLCG2 as a potential new therapeutic target for AD.

Functional role of PLD1 signalosome in Tauopathies

AbstractBackgroundPhospholipase D (PLD), a lipolytic enzyme for membrane phospholipids, exists in two isoforms of mammalian phosphatidyl choline (PC) specific PLD, inducible PC‐PLD1 and constitutive PC‐PLD2. Elevated PLD activity is well documented in clinical studies involving Alzheimer’s disease (AD). Our lab was the first to show elevated PLD1 facilitates synaptic dysfunction and underlying memory deficits driven by amyloidogenic insults by Aß/tau. We observed preservation of memory in response to PLD1 specific small molecule inhibitor in transgenic mouse models and documented preservation of dendritic spines as a underlying basis. In this study, we explored a role for PLD1 in Frontotemporal Dementia in an attempt to explore its pathological role in this tauopathy‐driven dementia.MethodWe studied altered expression/activity of key F‐actin signaling elements common to PLD1 signalosome in synaptosomal fractions of human post‐mortem FTD brain regions. Synaptic deficits associated with elevated PLD1 expression in human FTD samples was studied by Fluorescence Analysis of Single Synapse Long Term Potentiation (FASS‐LTP). Using immunofluorescence, we studied the association of PLD1 with tau, presynaptic and post‐synaptic receptors, and neuroinflammation markers.ResultElevated PLD1 expression in synaptosomal fractions of post‐mortem FTD brain tissues was corroborated by synaptic deficits and association of PLD1 with postsynaptic density protein (PSD95). FASS‐LTP assay indicated relatively lower long‐term potentiation in synaptosomal fractions of FTD brains as compared to the control brains implying synaptic deficits in FTD subjects.ConclusionIn the light of these observations, we conclude elevated PLD1 expression is associated with toxicity of tau causing memory deficits in FTD patients. This PLD1‐tau interaction alters PLD signaling partners such as mTOR (mammalian target of rapamycin), cofilin and phosphocofilin. This would implicate the actin‐dependent remodeling of synapse to be a key step in the role of PLD1 signalosome in FTD. Delineating the effects of PLD1 signalosome in tauopathies such as FTD will hugely be beneficial in tau‐targeting therapeutics for a multipronged approach in the treatment of neurodegenerative disorders.

An evolutionarily conserved N-terminal leucine is essential for MX1 GTPase antiviral activity against different families of RNA viruses

Myxovirus resistance protein 1 (MX1) and MX2 are homologous, dynamin-like large GTPases, induced upon interferon exposure. Human MX1 (HsMX1) is known to inhibit many viruses, including influenza A virus, by likely acting at various steps of their life cycles. Despite decades of studies, the mechanism(s) of action with which MX1 proteins manage to inhibit target viruses is not fully understood. MX1 proteins are mechano-enzymes and share a similar organization to dynamin, with a GTPase domain and a carboxy-terminal stalk domain, connected by a bundle signaling element. These three elements are known to be essential for antiviral activity. HsMX1 has two unstructured regions, the L4 loop, also essential for antiviral activity, and a short amino (N)-terminal region, which greatly varies between MX1 proteins of different species. The role of this N-terminal domain in antiviral activity is not known. Herein, using mutagenesis, imaging, and biochemical approaches, we demonstrate that the N-terminal domain of HsMX1 is essential for antiviral activity against influenza A virus, Vesicular Stomatitis Virus, and La Crosse virus. Furthermore, we pinpoint a highly conserved leucine within this region, which is absolutely crucial for human, mouse, and bat MX1 protein antiviral activity. Importantly, mutation of this leucine does not compromise GTPase activity or oligomerization capabilities but does modify MX1 protein subcellular localization. The discovery of this essential and highly conserved residue defines this region as key for antiviral activity and may reveal insights as to the mechanism(s) of action of MX1 proteins.

Pre-Folded G-Quadruplex as a Tunable Reporter to Facilitate CRISPR/Cas12a-Based Visual Nucleic Acid Diagnosis.

Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas12a-based detection strategies with a fluorophore quencher-labeled ssDNA reporter or gold nanoparticle ssDNA reporter have been widely used in point-of-care (POC) molecular diagnostics. However, the potential of these CRISPR/Cas12a strategies for POC molecular diagnostics is often compromised due to the complex labeling, high cost, and low signal-to-noise ratio. Herein, we show a pre-folded G-quadruplex (G4) structure with tunable tolerance to CRISPR/Cas12a trans-cleavage and explore its mechanism. Two G4 structures (i.e., Tel22-10 and G16C) sensitive or tolerant to CRISPR/Cas12a trans-cleavage are designed and used as signal elements to fabricate a label-free visible fluorescent strategy or "signal-on" colorimetric strategy, respectively. These two strategies facilitate an ultrasensitive visual nucleic acid determination of Group B Streptococci with a naked-eye limit of detection of 1 aM. The feasibility of the developed G4-assisted CRISPR/Cas12a strategies for real-world applications is demonstrated in clinical vaginal/anal specimens and further verified by a commercial qPCR assay. This work suggests that the proposed G4 structures with tunable tolerance can act as promising signal reporters in the CRISPR/Cas12a system to enable ultrasensitive visible nucleic acid detection.

Alteration of the IFN-Pathway by Human Papillomavirus Proteins: Antiviral Immune Response Evasion Mechanism.

A persistent infection with the so-called high-risk Human Papillomaviruses (hr-HPVs) plays a fundamental role in the development of different neoplasms. The expression of the HPV proteins throughout the different steps of the viral life cycle produce a disruption of several cellular processes, including immune response, which can lead to cell transformation. The interferon-mediated response plays an important role in eliminating HPV-infected and -transformed cells. The ability of HPV to disrupt the proper function of the interferon response is based on a series of molecular mechanisms coordinated by HPV proteins intended to prevent clearance of infection, ultimately producing an immunotolerant environment that facilitates the establishment of persistence and cancer. In this review, we focus on the molecular actions performed by HPV E1, E2, E5, E6 and E7 proteins on IFN signaling elements and their contribution to the establishment of infection, viral persistence and the progression to cancer.

Cocaine and Its Abstinence Condition Modulate Striatal and Hippocampal Wnt Signaling in a Male Rat Model of Drug Self-Administration.

Recent years have provided more and more evidence confirming the important role of Wnt/β-catenin signaling in the pathophysiology of mental illnesses, including cocaine use disorder. High relapse rates, which is a hallmark of drug addiction, prompt the study of changes in Wnt signaling elements (Wnt5a, Wnt7b, and Ctnnb1) in the motivational aspects of cocaine use and early drug-free period (3 days after the last exposure to cocaine). For this purpose, an animal model of intravenous cocaine self-administration and two types of drug-free period (extinction training and abstinence in the home cage) were used. The studies showed that chronic cocaine self-administration mainly disturbs the expression of Wnt5a and Ctnnb1 (the gene encoding β-catenin) in the examined brain structures (striatum and hippocampus), and the examined types of early abstinence are characterized by a different pattern of changes in the expression of these genes. At the same time, in cocaine self-administrated animals, there were no changes in the level of Wnt5a and β-catenin proteins at the tested time points. Moreover, exposure to cocaine induces a significant reduction in the striatal and hippocampal expression of miR-374 and miR-544, which can regulate Wnt5a levels post-transcriptionally. In summary, previous observations from experimenter-administered cocaine have not been fully validated in the cocaine self-administration model. Yoked cocaine administration appears to disrupt Wnt signaling more than cocaine self-administration. The condition of the cocaine-free period, the routes of drug administration, and the motivational aspect of drug administration play an important role in the type of drug-induced molecular changes observed. Furthermore, in-depth research involving additional brain regions is needed to determine the exact role of Wnt signaling in short-term and long-lasting plasticity as well as in the motivational aspects of cocaine use, and thus to assess its potential as a target for new drug therapy for cocaine use disorder.

Abstract 13155: Apelin and Apela for Therapy of Myocardial Fibrosis and Heart Failure

The apelin/apela – apelin receptor system regulates a variety of physiological cardiovascular functions including vascular tone, cardiac contractility, angiogenesis, and energy metabolism. However, the cell type specific effects of apelin/apela in the cardiovascular system are not well understood. The aim of this study was to investigate the potential role of apelin and apela in regulating development of myocardial fibrosis and to identify the signaling mechanisms underlying the anti-fibrotic effects. To investigate the role of apelin and apela in vivo , 2-month-old C57BL/6N male mice were injected with AAV9.LacZ, AAV9.Apelin or AAV9.Apela and subjected to thoracic aortic constriction (TAC) for 6 weeks. Echocardiography analysis at the end of the study showed that overexpression of either apelin or apela attenuated TAC-induced left ventricular (LV) dysfunction and increase in LV mass. Analysis of cardiac tissue showed downregulation of collagen I and fibrosis related periostin mRNA expression levels and reduced accumulation of interstitial fibrosis in the left ventricles of mice overexpressing apelin or apela. Studies in human cardiac fibroblasts in vitro showed that apelin and apela attenuate TGFβ1-induced collagen expression and secretion. Analyses of LV tissue and human fibroblast samples indicated that apelin and apela regulate the stress-induced activation of MAPK pathways. Chemical inhibitors and genetic modification of specific signaling elements identified p38 MAPK as a central signaling pathway mediating the inhibitory effect of apelin and apela on TGFβ1 signaling and TGFβ1-induced collagen production. In summary, we show that apelin and apela attenuate hemodynamic pressure overload -induced LV dysfunction and myocardial fibrosis and identify a novel signaling mechanism regulating the response. Our data suggests that activation of apelinergic signaling could offer a novel therapeutic approach to prevent the development of cardiac fibrosis and heart failure.

Interactive contribution of hyperinsulinemia, hyperglycemia, and mammalian target of rapamycin signaling to valvular interstitial cell differentiation and matrix remodeling.

Diabetes and its major key determinants insulin resistance and hyperglycemia are known risk factors for calcific aortic valve disease (CAVD). The processes leading to molecular and structural alterations of the aortic valve are yet not fully understood. In previous studies, we could show that valvular interstitial cells (VIC) display canonical elements of classical insulin signaling and develop insulin resistance upon hyperinsulinemia and hyperglycemia accompanied by impaired glucose metabolism. Analyses of cultured VIC and aortic valve tissue revealed extracellular matrix remodeling and degenerative processes. Since PI3K signaling through mammalian target of rapamycin (mTOR) is involved in fibrotic processes of the heart, we aim at further functional investigation of this particular Akt-downstream signaling pathway in the context of diabetes-induced CAVD. Primary cultures of VIC were treated with hyperinsulinemia and hyperglycemia. Phosphorylation of mTOR(Ser2448) was determined by Western blot analysis after acute insulin stimulus. Inhibition of mTOR phosphorylation was performed by rapamycin. Phosphorylation of mTOR complex 1 (MTORC1) downstream substrates 4E-BP1(Thr37/46) and P70S6K(Thr389), and MTORC2 downstream substrate Akt(Ser473) as well as the PDK1-dependent phosphorylation of Akt(Thr308) was investigated. Markers for extracellular matrix remodeling, cell differentiation and degenerative changes were analyzed by Western blot analysis, semi-quantitative real-time PCR and colorimetric assays. Hyperinsulinemia and hyperglycemia lead to alterations of VIC activation, differentiation and matrix remodeling as well as to an abrogation of mTOR phosphorylation. Inhibition of mTOR signaling by rapamycin leads to a general downregulation of matrix molecules, but to an upregulation of α-smooth muscle actin expression and alkaline phosphatase activity. Comparison of expression patterns upon diabetic conditions and rapamycin treatment reveal a possible regulation of particular matrix components and key degeneration markers by MTORC1 downstream signaling. The present findings broaden the understanding of mitogenic signaling pathways in VIC triggered by hyperinsulinemia and hyperglycemia, supporting the quest for developing strategies of prevention and tailored treatment of CAVD in diabetic patients.

Preparation and properties of boron affinity molecularly imprinted mesoporous polymers based on Mn-doped ZnS quantum dots.

Sialic acid (SA), known as N-acetyl neuraminic acid, is a natural 9-carbomonosaccharide derivative. SA has been widely applied in the early diagnosis of diseases as therapeutic target. However, the abundance of SA is very low in biological samples, which is usually interfered by the similar molecules coexisting at high abundance. Combining the advantages of high selectivity and specificity of molecularly imprinted technology, high specific surface area of mesoporous materials and excellent optical properties of quantum dots, we chose Mn-doped ZnS quantum dots as signal elements, and sialic acid as the template molecule. KH-4-MAPB with recognition ability to SA was synthesized by one-step hydrothermal method using thiolene click reaction as functional monomer. Based on the principle of boron affinity, molecularly imprinted polymers with highly ordered mesoporous structure were prepared, and the structure and fluorescence properties of fluorescent molecularly imprinted polymers were studied. FT-IR, XRD, TEM and nitrogen adsorption-desorption experiments were used to characterize the structure and morphology of the molecularly imprinted polymers. The results showed that the prepared molecularly imprinted polymers had highly ordered mesoporous structure and a large number of imprinted holes, which ensured the specific selectivity of the molecularly imprinted polymers. The fluorescence properties of MIMPs were characterized and analyzed by fluorescence spectra, equilibrium adsorption kinetics experiments were conducted and imprinting properties were recorded under different pH. The above experimental results showed that the fluorescence quenching was successfully achieved when the template molecule SA was captured by the molecularly imprinted polymer. When the concentration of SA was 1.25-100 × 10-2g/L, the fluorescence quenching degree of MIMPs showed a fine linear relationship with SA. The correlation coefficient was 0.9946, and the detection equation was F0/F-1 = 0.0215 [CSA] + 0.0241. MIMPs had a high recognition ability for SA, and the imprinting factor was 2.44. As a fluorescent sensor for SA, the response time of MIMPs was 20min. When the buffer solution pH was 7, the imprinting factor was the largest. Under the best conditions, MIMPs revealed good selectivity and specificity for the fluorescence recognition of SA. MIMPS were also applied to the analysis of SA in real human serum samples with satisfactory results.

Reusable molecularly imprinted electrochemiluminescence assay for kanamycin based on ordered mesoporous carbon loaded with indium oxide nanoparticles and carbon quantum dots.

Ahighly sensitive kanamycin electrochemiluminescence (ECL) switch sensor was constructed. A signal element consisting of ordered mesoporous carbon loaded with indium oxide nanoparticles/carbon quantum dots (OMC/In2O3/C-dots) was assembled on the surface of a gold electrode. Then, a molecularly imprinted polymer (MIP) was prepared on the modified electrode surface using kanamycin as the template molecule and o-aminophenol as the functional monomer. After kanamycin elution, the prepared sensor retained specific kanamycin recognition sites. OMC/In2O3 effectively amplified the ECL signal of the C-dots, thereby enhancing the detection sensitivity, whereas kanamycin quenched the signal. Therefore, the imprinted sites acted as a switch, providing a new method for detecting kanamycin. Under the optimal experimental conditions, the concentration of kanamycin was proportional to the degree of ECL quenching within a linear range of 5-4500 × 10-12mol L-1 at 0.8V (vs. Ag/AgCl electrode electrode), and the detection limit was 5.8 × 10-13mol L-1. Whenapplied to the detection of kanamycin in actual samples, such as chicken, duck, pork, and milk, the recovery for spiked samples was in the range92.7-110%.

Элементная база МИС СВЧ для многоканального многочастотного радиотермометра

Modern medical microwave diagnostic equipment requires the use of solutions related to the compactness of the developed devices and high performance. It is possible to achieve the set conditions with the use of a modern semiconductor component base based on A3B5 compounds. The paper presents the designs of the main control elements of the microwave signal as part of the microwave radiothermometer monolithic Al-GaN/GaN/SiC HEMT SPDT transistor switch and MIC LNA developed on the basis of the pHEMT heterostructure of gallium arsenide.

Phosphorylation, compartmentalization, and cardiac function.

Protein phosphorylation is a fundamental element of cell signaling. First discovered as a biochemical switch in glycogen metabolism, we now know that this posttranslational modification permeates all aspects of cellular behavior. In humans, over 540 protein kinases attach phosphate to acceptor amino acids, whereas around 160 phosphoprotein phosphatases remove phosphate to terminate signaling. Aberrant phosphorylation underlies disease, and kinase inhibitor drugs are increasingly used clinically as targeted therapies. Specificity in protein phosphorylation is achieved in part because kinases and phosphatases are spatially organized inside cells. A prototypic example is compartmentalization of the cyclic adenosine 3',5'-monophosphate (cAMP)-dependent protein kinase A through association with A-kinase anchoring proteins. This configuration creates autonomous signaling islands where the anchored kinase is constrained in proximity to activators, effectors, and selected substates. This article primarily focuses on A kinase anchoring protein (AKAP) signaling in the heart with an emphasis on anchoring proteins that spatiotemporally coordinate excitation-contraction coupling and hypertrophic responses.

Construction of integrated and portable fluorescence sensor and the application for visual detection in situ

The development of portable and low-cost fluorescence sensors is significant for on-site detection. Herein, a novel fluorescence sensor integrating power source, light source, filter, sample cell and smartphone was constructed. The model of fluorescence sensor was designed by using Autodesk Computer Aided Design (CAD) software, and printed with 3D printing technology, followed by assembling with various components. With advantages of convenient carrying, good stability, wide applicability and low cost, the fluorescence sensor showed great adaptability for on-site visual detection. Nitrite was chosen as the model of analyte, and ratiometric fluorescent probe (B/R-CDs) was employed as the identification and signal element for detecting nitrite. With the increase of nitrite concentration, the fluorescence intensity of B/R-CDs at 460 nm decreased, while that at 615 nm kept stable. Therefore, the fluorescence color of B/R-CDs changed from blue to red. By using the portable sensor to collect RGB value of fluorescence color, the R/B channel values showed a linear relationship with nitrite concentration in 2.5–600 µM, with detection limit of 0.8 µM. Then the fluorescence sensor was used to detect nitrite in preserved meat and pickles, and recovery rate was among 94.0%−105%. The detection results were consistent with those of fluorescence method and spectrophotometry. This work provides a novel detection device for on-site analysis, and also offers an effective approach for developing miniature fluorescence sensors.

599. TOLL-LIKE RECEPTORS AND ESOPHAGEAL CANCER. DIAGNOSIS, PROGNOSIS AND THERAPY

Abstract Esophageal cancer is the sixth leading cause of cancer related morbidity worldwide. It has to predominant subtypes, esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC). Despite all the advances in surgical therapy and adjuvant therapies, prognosis of esophageal cancer remains poor. EAC develops through Barrett’s esophagus (BE) and columnar dysplasia, preceded by gastro-esophageal reflux disease (GERD). Incidence of ESCC is increased with tobacco smoking and alcohol abuse. Toll-like receptors (TLRs) can act as prognostic factors and potential therapeutic targets of esophageal cancer. TLRs, an important family of pattern recognition receptors, allow immune cells to recognize pathogens, triggering inflammation. TLRs-signaling pathway activates signaling elements, regulating inflammatory response, possibly correlating to carcinogenesis. In normal esophagus, TLRs play an important role in innate immunity, recognizing molecular patterns on microorganisms and inflammatory responses produced by tissue damage. It is known that TLR3, TLR4, TLR5 and TLR are increasingly expressed from GERD to AC, with TLR4 known for being a mediator of proliferation in AC, while TRL1 and TLR4 overexpression in AC is related to poor prognosis and metastatic potential. Additionally, TLR3, TLR4 and TLR9 expression in stromal cells of ESCC has been associated with lymphatic metastasis, while TLR7 and TLR9 increased expression has also been addressed to advanced disease. Herein, we aim to present all available data regarding the relations of TLRs and EC. It seems that TLRs expression can indicate esophageal metaplasia, dysplasia, and cancer. Toll-like receptors can act as significant and valuable indications in diagnosis, prognosis and potentially can be used as therapeutic target of esophageal cancer.

Environmental estrogens inhibit insulin-like growth factor (IGF) receptor mRNA expression, IGF binding, and IGF signaling ex vivo in rainbow trout (Oncorhynchus mykiss)

In this study, we used juvenile rainbow trout to examine the direct effects of selected environmental estrogens (EE), specifically, 17 β-estradiol (E2), β-sitosterol (βS), and 4-n-nonylphenol (NP), on target tissue sensitivity to insulin-like growth factor (IGF) as assessed by expression of IGF receptor type 1 (IGFR1) mRNAs and IGF-1 binding capacity, as well as on the cell signaling pathways through which EE exert their effects. E2 and NP inhibited IGFR1A and IGFR1B mRNA expression in a time- and concentration-related manner in gill and muscle; however, βS had no effect on expression of IGFR1 mRNAs in either tissue. NP reduced 125I-IGF binding in gill and E2 and NP reduced 125I-IGF in white muscle; βS had no effect on 125I-IGF binding in either gill or white muscle. Treatment of gill filaments with either E2 or NP rapidly deactivated (via reduced proportion of phosphorylation) JAK2, STAT5, Akt, and ERK; βS had no effect on the activation state of any cell signaling elements tested. The effects of EE on IGFR mRNA expression in gill were estrogen receptor (ER) dependent as the inhibitory effects were rescued by the ER antagonist, ICI 182,780. All EE tested blocked growth hormone (GH)-stimulated IGFR mRNA expression in gill filaments. GH-stimulated activation of JAK2, STAT5, Akt, and ERK were blocked by E2, βS, and NP. Lastly, E2 and NP stimulated suppressor of cytokine signaling 2 (SOCS-2) mRNA expression, an effect that also was ER dependent. These results indicate that EE directly reduce the sensitivity of peripheral tissues to IGF by reducing mRNA and functional expression of IGFRs. Such inhibitory actions of EE are mediated, at least in part, by ER-dependent mechanisms that deactivate JAK, STAT, Akt, and ERK and enhance expression of SOCS-2. These findings together with our previous results show that EE retard growth of post-embryonic rainbow trout through widespread direct effects on the GH-IGF system, specifically, by reducing tissue sensitivity to GH, inhibiting IGF production, reducing tissue sensitivity to IGF, and by deactivating post-receptor IGF cell signaling pathways.

The antidepressant effects and serum metabonomics of bifid triple viable capsule in a rat model of chronic unpredictable mild stress.

BackgroundProbiotics have shown potential antidepressant effects. This study evaluated the effect and probable mechanisms of bifid triple viable capsules (BTVCs) on a rat model of chronic unpredictable mild stress (CUMS).Materials and methodsRats were randomly divided into Normal, CUMS model, fluoxetine hydrochloride (FLX), BTVCs, and FLX+BTVCs groups. Depressive-like behaviours, pathological changes in the hippocampus, changes in serum metabolites and potential biomarkers, and metabolic pathways were detected via behavioural tests, haematoxylin-eosin staining, nissl staining, non-targetted metabolomics, and ingenuity pathway analysis (IPA).ResultsThe rats displayed depressive-like behaviours after CUMS exposure, but BTVCs ameliorated the depressive-like behaviours. In addition, the pathological results showed that the hippocampal tissue was damaged in rats after CUMS exposure and that the damage was effectively alleviated by treatment with BTVCs. A total of 20 potential biomarkers were identified. Treatment with BTVCs regulated D-phenylalanine, methoxyeugenol, (±)-myristoylcarnitine, 18:3 (6Z, 9Z, 12Z) /P-18:1 (11Z), propionyl-L-carnitine, and arachidonic acid (AA) concentrations, all compounds that are involved with biosynthesis of unsaturated fatty acids, glycerophospholipid metabolism, linoleic acid metabolism and AA metabolism. The IPA demonstrated that endothelin-1 signalling and cyclic adenosine monophosphate response element binding protein (CREB) signalling in neurons may be involved in the development of depression.ConclusionOur findings suggest that BTVCs can alleviate depressive-like behaviours, restore damage to the hippocampus in CUMS rats and regulate serum metabolism, which may be related to endothelin-1 signalling or CREB signalling in neurons.

Ultra-sensitive electrochemiluminescence biosensor for abrin detection based on dual-labeled phage display affibodies and polystyrene nanospheres

Abrin is a plant cytotoxin that poses a high threat to public safety and therefore requires highly sensitive and efficient detection methods. Affibodymolecules are artificial affinity proteins that have been widely studied in bioimaging and medical treatment but rarely used in bioassays. In this work, an electrochemiluminescence (ECL) biosensor for abrin was established with biotin and Ru(bpy)32+ dual-labeled phage display affibodies as molecular recognition and signal element. On this basis, dual-labeled polystyrene nanospheres (nano-PSs) were chosen to link with phages and further achieve ultra-sensitive detection. This assay has a triple signal amplification. First, capsid proteins of M13 phages have connected numerous signal molecules. Second, the nano-PSs bound to the surface of the phages also contained quite a few signal molecules. Third, with the theoretically infinitely repeatable “biotin - streptavidin (SA) - biotin” composite unit as the “mortise and tenon structure”, the dual-labeled nano-PSs further formed highly stacked nano-aggregates, ultimately achieving significant signal amplification. Besides, the detection platform of this assay is a portable electrochemiluminescence sensor based on the screen-printed electrode, which is small and easy to operate. Limit of detection (LOD) for abrin of the ECL biosensor was 9.3 fg/mL and the linear detection range was observed from 10 fg/mL to 100 pg/mL. This new biosensing system has also demonstrated good reproducibility, specificity, practicability and has great potential for highly sensitive detection of contaminants, toxins and biomarkers in environmental monitoring and clinical application.