Molecular Mechanism Of Interaction Research Articles

Deciphering the molecular mechanisms of BPTF interactions with nucleosomes via molecular simulations.

Transcription factors play a pivotal role in regulating DNA accessibility and gene transcription. They often have regions for recognizing and binding to post translational modifications on the long, disordered tail regions of the histone octamers found in nucleosomes. Historically these transcription factors have often been studied in vitro with short peptide sequences that mimic the histone tail, which may preclude a complete understanding of the mechanisms and potential conformational changes these proteins are subject to in vivo, where the full nucleosome is present. Here, we have used classical molecular dynamics simulations to study the transcription factor BPTF's PHD finger with and without a bromodomain alone in solution, bound to a short H3 tail peptide fragment, and bound to a full-length histone H3 in a nucleosome core particle. In addition to enhancing the accessibility of DNA for transcription, the PHD finger and bromodomain adopted different conformations in each context, which appears to be driven by electrostatic forces present in the nucleosome but absent otherwise. Together, our results suggest that transcription factor binding in the context of the full-length nucleosome is regulated by multiple factors, including interactions with nucleosomal DNA and histone proteins, which are unaccounted for in the standard histone code hypothesis.

Calcium-dependent membrane interactions of tumor-targeting peptide pHLIP.

Cancerous tissues undergo extensive changes to their cellular environments that differentiate them from healthy tissues. These changes include changes in extracellular pH and Ca2+ concentrations, and the exposure of phosphatidylserine (PS) to the extracellular environment, which can modulate the interaction of peptides and proteins with the plasma membrane. Deciphering the molecular mechanisms of such interactions is critical for advancing the knowledge-based design of cancer-targeting molecular tools, such as pHLIP (pH-Low Insertion Peptide). Here, we explore the effects of PS, Ca2+, and peptide protonation state on the interactions of pHLIP with lipid membranes. Cellular studies demonstrate that exposed PS on the plasma membrane promotes pHLIP targeting. The magnitude of this effect is dependent on extracellular Ca2+ concentration, indicating that divalent cations play an important role in pHLIP targeting in vivo. The targeting mechanism is further explored with a combination of fluorescence and circular dichroism experiments in model membranes and microsecond-timescale all-atom molecular dynamics simulations. Our results demonstrate that Ca2+ is engaged in coupling peptide-lipid interactions in the unprotonated transmembrane conformation of pHLIP. The simulations reveal that while the pH-induced insertion leads to a strong depletion of PS around pHLIP, the Ca2+-induced insertion has the opposite effect. Thus, extracellular levels of Ca2+ are crucial to link cellular changes in membrane lipid composition with the selective targeting and insertion of pHLIP. The characterized Ca2+-dependent coupling between pHLIP sidechains and PS provides atomistic insights into the general mechanism for lipid-coupled regulation of protein-membrane insertion by divalent cations.

The interaction between first-episode drug-naïve schizophrenia and age based on gray matter volume and its molecular analysis: a multimodal magnetic resonance imaging study.

Schizophrenia is a neurodevelopmental disorder characterized by progressive and widespread gray matter (GM) atrophy. Studies have shown that normal brain development has an impact on schizophrenia-induced GM alterations. However, the neuropathology and underlying molecular mechanisms of interaction between age and schizophrenia are unclear. This study enrolled 66/84 first-episode drug-naïve patients with early-onset/adult-onset schizophrenia ((EOS)/(AOS)) and matched normal controls (NC) (46 adolescents/73 adults), undergoing T1-weighted high-resolution magnetic resonance imaging. Gray matter volume (GMV) in four groups was detected using 2-way analyses of variance with diagnosis and age as factors. Then, factors-related volume maps and neurotransmitter maps were spatially correlated using JuSpace to determine the relationship to molecular structure. Compared to AOS, EOS and adult NC had larger GMV in right middle frontal gyrus. Compared to adolescent NC, EOS and adult NC had smaller GMV in right lingual gyrus, right fusiform gyrus, and right cerebellum_6. Disease-induced GMV reductions were mainly distributed in frontal, parietal, thalamus, visual, motor cortex, and medial temporal lobe structures. Age-induced GMV alterations were mainly distributed in visual and motor cortex. The changed GMV induced by schizophrenia, age, and their interaction was related to dopaminergic and serotonergic receptors. Age is also related to glutamate receptors, and schizophrenia is also associated with GABAaergic and noradrenergic receptors. Our results revealed the multimodal neural mechanism of interaction between disease and age. We emphasized age-related GM abnormalities of ventral stream of visual perceptual pathways and high-level cognitive brain in EOS, which may be affected by imbalance of excitatory and inhibitory neurotransmitters.

Comparative Transcriptomic Analysis Reveals Variable Responses to the Brown Planthopper Nilaparvata lugens in Different Rice Cultivars

Rice is an indispensable crop in East and Southeast Asia, and the study of its biological characteristics has important value. We observed that different cultivars of rice have different levels of resistance to the brown planthopper (BPH), Nilaparvata lugens. In this study, transcriptome sequencing was used to analyze the differentially expressed genes (DEGs) of three rice varieties caused by BPH damage combined with physical stimulation and controls. We performed weighted correlation network analysis (WGCNA) and found a module positively related to physical stimulation. KEGG analysis showed that this module is strongly related to the ribosome pathway. Through comparative analysis with controls, we found the differential genes of each cultivar after BPH damage; through trend analysis, we found the differential genes shared by the three varieties after BPH damage. The KEGG/GO enrichment analysis of these genes found that they are mainly functionally concentrated in signal transduction, redox reactions, etc. The results of this research will be helpful to study the molecular mechanism of the BPH-rice interaction, identify resistance genes, and facilitate further studies on molecular resistance breeding and pest control.

Exploring the Potential Molecular Mechanisms of Interactions between a Probiotic Consortium and Its Coral Host.

Beneficial microorganisms for corals (BMCs) have been demonstrated to be effective probiotics to alleviate bleaching and mitigate coral mortality in vivo. The selection of putative BMCs is traditionally performed manually, using an array of biochemical and molecular tests for putative BMC traits. We present a comprehensive genetic survey of BMC traits using a genome-based framework for the identification of alternative mechanisms that can be used for future in silico selection of BMC strains. We identify exclusive BMC traits associated with specific strains and propose new BMC mechanisms, such as the synthesis of glycine betaine and ectoines. Our roadmap facilitates the selection of BMC strains while increasing the array of genetic targets that can be included in the selection of putative BMC strains to be tested as coral probiotics. IMPORTANCE Probiotics are currently the main hope as a potential medicine for corals, organisms that are considered the marine "canaries of the coal mine" and that are threatened with extinction. Our experiments have proved the concept that probiotics mitigate coral bleaching and can also prevent coral mortality. Here, we present a comprehensive genetic survey of probiotic traits using a genome-based framework. The main outcomes are a roadmap that facilitates the selection of coral probiotic strains while increasing the array of mechanisms that can be included in the selection of coral probiotics.

Nitrogen supply affects ion homeostasis by modifying root Casparian strip formation through the miR528-LAC3 module in maize

Although nitrogen (N) is known to affect mineral element homeostasis in plants, the molecular mechanisms of interactions between N and other nutrients remain largely unclear. We report here that N supply affects ion homeostasis in maize. Berberine hemisulfate staining and a propidium iodide penetration assay showed that N luxury significantly delayed Casparian strip (CS) formation in maize roots. We further demonstrated that N-mediated CS formation in maize was independent of RBOHF-activated H2O2 production. N luxury induced the expression of ZmmiR528 in whole roots and root tips. Knockdown and loss-of-function of ZmmiR528 promoted CS formation under both N-luxury and N-deficient conditions. Both ZmMIR528a and ZmMIR528b contribute to early CS formation under different N conditions. RNA-seq and real-time RT-PCR analysis demonstrated that ZmLAC3, but not ZmLAC5, responded to N treatments. Consistent with results obtained with ZmmiR528 TM transgenic maize and mir528a/b loss-of-function mutants, transgenic maize overexpressing ZmLAC3 displayed early CS formation under different N conditions. Under field conditions, K, Ca, Mn, Cu, Mg, and Zn concentrations were greater in the ear leaf of ZmLAC3-overexpressing transgenic maize than in the wild type. These results indicate that ZmmiR528 affects CS formation in maize by regulating the expression of ZmLAC3, and modification of CS formation has the potential to improve maize quality.

Assembled Bisphenol A with cyclic oligosaccharide as the controlled release complex to reduce risky effects.

Herein, in order to improve the bioavailability of a non-biodegradable pollutant, inclusion complexation procedures had been used to develop better formulations of this pollutant, Bisphenol A (BPA). In our research, an inclusion complex (IC) of β-cyclodextrin (β-CD) with BPA was formed to investigate the effect of β-CD on the water solubility, anti-oxidant, anti-bacterial activity, toxicity, and thermal stability of BPA. UV-Vis and other spectrometric methods such as NMR, FTIR, and XRD indicated the molecular mechanism of interactions between β-CD and BPA, which was further hypothesized using molecular modeling to confirm preliminary results. Studies of TGA and DSC demonstrated that encapsulation boosted the thermal stability of BPA. This research also makes predictions about BPA's release behavior when CT-DNA is present. In vitro testing of the IC's antibacterial activities showed that it outperformed pure BPA. The in silico study was found to have a considerable decrease in toxicity level for IC compared to pure BPA. Therefore, β-CD-encapsulated BPA can lessen toxicity by raising antioxidant levels. Additionally, as its antibacterial activity increases, it may be employed therapeutically. Thus, this discovery of creating BPA formulations with controlled release and/or protective properties allows for a more logical application of BPA by reducing its hazardous effects through boosting its efficacy.

Development of fluorophore labeled or biotinylated anticancer small molecule NSC243928

Small molecule NSC243928 binds with LY6K, a potential target for the treatment of triple-negative breast cancer, and induces cancer cell death with an unclear mechanism. We have developed chemical tools to identify the molecular mechanisms of NSC243928-LY6K interaction. Herein, we report on the development and synthesis of biotinylated and fluorophore-tethered derivatives of NSC243928 guided by docking studies and molecular dynamics. Surface plasmon resonance assay indicates that these derivatives retained a direct binding with LY6K protein. Confocal analysis revealed that nitrobenzoxadiazole (NBD) fluorophore tagged NSC243928 is retained in LY6K expressing cancer cells. These novel modified compounds will be employed in future in vitro and in vivo studies to understand the molecular mechanisms of NSC243928 mediated cancer cell death. These studies will pave the path for developing novel targeted therapeutics and understanding any potential side-effects of these treatments for hard-to-treat cancers such as triple-negative breast cancer or other cancers with high expression of LY6K.

Molecular mechanisms of adaptive evolution in wild animals and plants.

Wild animals and plants have developed a variety of adaptive traits driven by adaptive evolution, an important strategy for species survival and persistence. Uncovering the molecular mechanisms of adaptive evolution is the key to understanding species diversification, phenotypic convergence, and inter-species interaction. As the genome sequences of more and more non-model organisms are becoming available, the focus of studies on molecular mechanisms of adaptive evolution has shifted from the candidate gene method to genetic mapping based on genome-wide scanning. In this study, we reviewed the latest research advances in wild animals and plants, focusing on adaptive traits, convergent evolution, and coevolution. Firstly, we focused on the adaptive evolution of morphological, behavioral, and physiological traits. Secondly, we reviewed the phenotypic convergences of life history traits and responding to environmental pressures, and the underlying molecular convergence mechanisms. Thirdly, we summarized the advances of coevolution, including the four main types: mutualism, parasitism, predation and competition. Overall, these latest advances greatly increase our understanding of the underlying molecular mechanisms for diverse adaptive traits and species interaction, demonstrating that the development of evolutionary biology has been greatly accelerated by multi-omics technologies. Finally, we highlighted the emerging trends and future prospects around the above three aspects of adaptive evolution.

The Bi-Functional Paxilline Enriched in Skin Secretion of Tree Frogs (Hyla japonica) Targets the KCNK18 and BKCa Channels.

The skin secretion of tree frogs contains a vast array of bioactive chemicals for repelling predators, but their structural and functional diversity is not fully understood. Paxilline (PAX), a compound synthesized by Penicillium paxilli, has been known as a specific antagonist of large conductance Ca2+-activated K+ Channels (BKCa). Here, we report the presence of PAX in the secretions of tree frogs (Hyla japonica) and that this compound has a novel function of inhibiting the potassium channel subfamily K member 18 (KCNK18) channels of their predators. The PAX-induced KCNK18 inhibition is sufficient to evoke Ca2+ influx in charybdotoxin-insensitive DRG neurons of rats. By forming π-π stacking interactions, four phenylalanines located in the central pore of KCNK18 stabilize PAX to block the ion permeation. For PAX-mediated toxicity, our results from animal assays suggest that the inhibition of KCNK18 likely acts synergistically with that of BKCa to elicit tingling and buzzing sensations in predators or competitors. These results not only show the molecular mechanism of PAX-KCNK18 interaction, but also provide insights into the defensive effects of the enriched PAX.

Thermodynamic Mechanism of Physical Stability of Amorphous Pharmaceutical Formulations

Hygroscopicity is an important factor affecting the physical stability of amorphous solid dispersions (ASDs) during long-term storage. In this work, the effects of temperature, relative humidity (RH), and polymeric excipients on the phase behavior of amorphous irbesartan (IRB) and oxaprozin (OXA) were systematically investigated. The ASDs were prepared by the solvent evaporation method. The water sorption in formulations was measured under the conditions of 25 °C, 60% RH, 25 °C, 90% RH, and 40 °C, 75% RH. The results showed that the hygroscopicity of formulations containing polyvinylpyrrolidone (PVP) was stronger than that containing poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA 46) and the hygroscopicity increased with increasing temperature and RH. With increasing content of active pharmaceutical ingredients (APIs), the recrystallization phenomenon is significant at the same RH. PVP can better inhibit IRB recrystallization than PVPVA 46. In contrast, PVPVA 46 can better maintain the amorphous form of OXA than PVP. The thermodynamic phase diagrams of amorphous API/polymer formulations at 60% RH and anhydrous conditions were predicted using perturbed chain statistical associated fluid theory (PC-SAFT) and the Gordon–Taylor equation. Furthermore, the electrostatic potential (ESP) and binding energies between APIs and polymers were calculated with density functional theory (DFT), which explained the molecular interaction mechanism of ASDs. This work is expected to guide the screening of excipients and API loadings for designing ASDs and the selection of storage conditions.

Deciphering the interaction mechanism of natural actives against larval proteins of Aedes aegypti to identify potential larvicides: a computational biology analysis

Aedes aegypti is the target for repellents to curb incidences of vector-borne diseases. Stopping breeding of this mosquito species at its larval stages helps in controlling spread of insect-borne diseases. Therefore, the present study focused on deciphering the mechanism of interaction of selected natural actives against larval proteins of A. aegypti to identify potential natural alternative larvicides. 65 larval proteins were identified from literature, whose structures were modelled and validated using RaptorX and ProCheck. 11 natural actives were selected for predicting their ligand properties and toxicities via Toxicity Estimation Software Tool and ProTox-II. Molecular docking studies were carried out using POAP followed by 100 ns molecular dynamic simulation studies for top three best docked complexes to better understand the robustness of docking, complex stabilities and molecular mechanisms of interactions. Toxicity predictions revealed that 6 molecules belonged to toxicity class 4, and five to toxicity class 5, implying that they were all safe to use. Complexes goniothalamin-translation elongation factor (−10 kcal/mol), andrographolide-acetyl-CoA C-myristoyltransferase (−9.2 kcal/mol) and capillin-translation elongation factor (−8.4 kcal/mol) showed best binding energies. When simulated, capillin-translation elongation factor showed most stability, while the remaining two also evidenced robust docking. Evolutionary studies for top two larval proteins disclosed 100 other insect species in which these proteins can be targeted using various larvicides. Protein-protein interaction network analysis revealed several protein pathways that might be affected due to aforesaid naturals. Therefore, this study provides computational insights into the molecular interaction of naturals against larval proteins, acting as potential natural larvicides. Communicated by Ramaswamy H. Sarma

Prediction of the retention factor in cetyltrimethylammonium bromide modified micellar electrokinetic chromatography using a machine learning approach

Capillary electrophoresis (CE) is an analytical technique widely applied in clinical, industrial, and scientific laboratories. Discussion of scientists' and specialists' concerns regarding the superiority of CE and more frequently used high-performance liquid chromatography (HPLC) is well known. With several advantages like a short analysis time, high efficiency, and low reagents consumption (mostly organic solvent), CE is considered a “green” alternative to HPLC. The relationship between retention and molecule structure has paid attention practically from the very beginning of separation methods. It can be established using a quantitative structure retention relationship (QSRR) method. The main goal of our investigation is to fill the gap related to QSRR analyses for the cetrimonium bromide (CTAB) micellar electrokinetic chromatography (MEKC) system using a heterogeneous set of 89 model molecules. The genetic algorithm (GA) supported the selection of theoretical descriptors that quantitatively describe target solutes. Comparison of linear and non-linear algorithms has been performed. Finally, QSRR models using partial least squares regression (PLS) and support vector regression (SVR) have been developed, and their performances were evaluated. The obtained results clearly indicate that machine learning (ML) models can be used as supportive tools in predicting retention in the CTAB-MEKC system. Among investigated models, the best performance showed GA-PLS. This finding has been proved by leave-one-out cross-validation and external validation procedures. Notably, the established models also give a view into the molecular mechanism of interaction between molecules and CTAB-formed micelles. Our investigations confirmed that descriptors related to the lipophilicity of molecules are the most significant factors in these types of interactions.

Assessing Polysaccharides/Aloe Vera-Based Hydrogels for Tumor Spheroid Formation.

In vitro tumor spheroids have proven to be useful 3D tumor culture models for drug testing, and determining the molecular mechanism of tumor progression and cellular interactions. Therefore, there is a continuous search for their industrial scalability and routine preparation. Considering that hydrogels are promising systems that can favor the formation of tumor spheroids, our study aimed to investigate and develop less expensive and easy-to-use amorphous and crosslinked hydrogels, based on natural compounds such as sodium alginate (NaAlg), aloe vera (AV) gel powder, and chitosan (CS) for tumor spheroid formation. The ability of the developed hydrogels to be a potential spheroid-forming system was evaluated using MDA-MB-231 and U87MG cancer cells. Spheroid abilities were influenced by pH, viscosity, and crosslinking of the hydrogel. Addition of either AV or chitosan to sodium alginate increased the viscosity at pH 5, resulting in amorphous hydrogels with a strong gel texture, as shown by rheologic analysis. Only the chitosan-based gel allowed formation of spheroids at pH 5. Among the variants of AV-based amorphous hydrogels tested, only hydrogels at pH 12 and with low viscosity promoted the formation of spheroids. The crosslinked NaAlg/AV, NaAlg/AV/glucose, and NaAlg/CS hydrogel variants favored more efficient spheroid formation. Additional studies would be needed to use AV in other physical forms and other formulations of hydrogels, as the current study is an initiation, in evaluating the potential use of AV gel in tumor spheroid formation systems.

Combined Immune Checkpoint Blockade Enhances Antiviral Immunity against Bovine Leukemia Virus.

Bovine leukemia virus (BLV) is a retrovirus that causes enzootic bovine leukosis (EBL) in cattle and is widespread in many countries, including Japan. Recent studies have revealed that the expression of immunoinhibitory molecules, such as programmed death-1 (PD-1) and PD-ligand 1, plays a critical role in immunosuppression and disease progression during BLV infection. In addition, a preliminary study has suggested that another immunoinhibitory molecule, T-cell immunoglobulin domain and mucin domain-3 (TIM-3), is involved in immunosuppression during BLV infection. Therefore, this study was designed to further elucidate the immunoinhibitory role of immune checkpoint molecules in BLV infection. TIM-3 expression was upregulated on peripheral CD4+ and CD8+ T cells in BLV-infected cattle. Interestingly, in EBL cattle, CD4+ and CD8+ T cells infiltrating lymphomas expressed TIM-3. TIM-3 and PD-1 were upregulated and coexpressed in peripheral CD4+ and CD8+ T cells from BLV-infected cattle. Blockade by anti-bovine TIM-3 monoclonal antibody increased CD69 expression on T cells and gamma interferon (IFN-γ) production from peripheral blood mononuclear cells from BLV-infected cattle. A syncytium formation assay also demonstrated the antiviral effects of TIM-3 blockade against BLV infection. The combined inhibition of TIM-3 and PD-1 pathways significantly enhanced IFN-γ production and antiviral efficacy compared to inhibition alone. In conclusion, the combined blockade of TIM-3 and PD-1 pathways shows strong immune activation and antiviral effects and has potential as a novel therapeutic method for BLV infection. IMPORTANCE Enzootic bovine leukosis caused by bovine leukemia virus (BLV) is an important viral disease in cattle, causing severe economic losses to the cattle industry worldwide. The molecular mechanisms of BLV-host interactions are complex. Previously, it was found that immune checkpoint molecules, such as PD-1, suppress BLV-specific Th1 responses as the disease progresses. To date, most studies have focused only on how PD-1 facilitates escape from host immunity in BLV-infected cattle and the antiviral effects of the PD-1 blockade. In contrast, how T-cell immunoglobulin domain and mucin domain-3 (TIM-3), another immune checkpoint molecule, regulates anti-BLV immune responses is rarely reported. It is also unclear why PD-1 inhibition alone was insufficient to exert anti-BLV effects in previous clinical studies. In this study, the expression profile of TIM-3 in T cells derived from BLV-infected cattle suggested that TIM-3 upregulation is a cause of immunosuppression in infected cattle. Based on these results, anti-TIM-3 antibody was used to experimentally evaluate its function in influencing immunity against BLV. Results indicated that TIM-3 upregulation induced by BLV infection suppressed T-cell activation and antiviral cytokine production. Some T cells coexpressed PD-1 and TIM-3, indicating that simultaneous inhibition of PD-1 and TIM-3 with their respective antibodies synergistically restored antiviral immunity. This study could open new avenues for treating bovine chronic infections.

Probing the interaction between coal particle and collector using atomic force microscope and density functional theory calculation

Revealing the interaction mechanism between coal and collector is essential for coal flotation. However, direct determination of the interaction force between coal and collector has rarely been reported. In this work, an atomic force microscope (AFM) was used to directly measure the interaction between collectors, i.e., n-dodecane, nonyl benzene and sub-bituminous coal (SC), bituminous coal (BC) and anthracite coal (BC) with different metamorphic degrees, and density functional theory calculation (DFT) was used to simulate the interaction mechanism of coal and collectors at the molecular level. The results indicate that the interaction force between coal and collector improves with the increase of coal metamorphic degrees for the same type of collector. Extended DLVO fitting reveals that the hydrophobic interaction decays exponentially. Consistent with the AFM force measurement results, the adsorption energy between the coal and the collector calculated by DFT all show that the interaction between n-dodecane and the three types of coals is weaker than that of nonyl benzene. This work provides quantitative information on the molecular interaction mechanism underlying the adsorption of collectors on the coal of varying surface chemistry at the nanoscale, with valuable implications for developing influential collectors for coal preparation and many other engineering processes.

Identification and characterization of the conformation and size of amyloid-β (42) oligomers targeting the receptor LilrB2.

Experimental observations revealed that the amyloid-β 42 oligomer (AβO) can directly bind to the LilrB2 D1D2(LDD) receptor with nanomolar-affinity, leading to changes in synaptic plasticity and cognitive deficits. However, the dependence of neurotoxicity on the morphology, size, and aggregation stage (SP1, SP2) of AβO, as well as the specific molecular mechanism of AβO-LDD interaction, remain uncertain. To address these uncertainties, we investigated the interaction between the LDD neuroreceptor and AβO with different Aβ42 species (nontoxic species, toxic species, and protofibril) and sizes. Our results showed that the LDD selectively binds AβO species rather than the Aβ42 monomer, accommodating various Aβ42 dimers and trimers as well as SP2 AβO, in a specific pose in the pocket of the LDD receptor (region I). Additionally, protofibrils with exposed β1/β2 regions can also bind to region I of the LDD receptor, as observed experimentally (Cao, et al., Nat. Chem., 2018, 10, 1213; and Aim et al., Nat. Commun., 2021, 12, 3451). More extensively, we identified two additional regions of the LDD receptor, regions II and III, suitable for binding to larger AβO species at the SP1 with different molecular weights and conformations, accounting for the stronger binding strength obtained experimentally. We suggest that the two regions are more competitive than region I in causing toxicity by AβO binding. The detailed and systematic characterization for the complexes generated between the LDD receptor and various AβO species, including the protofibril, offers deep insight into the dependence of neurotoxicity on the AβO size and conformation at the molecular level, and provides novel and specific targets for drug design of Alzheimer's disease.

Disease-associated oligodendrocyte signatures in neurodegenerative disease: the known and unknown.

Disease-associated oligodendrocyte signatures in neurodegenerative disease: the known and unknown.

The microRNA pathway activation in insect cell model upon Autographa californica multiple nucleopolyhedrovirus infection

Background: The immune system of insects exerts fundamentally different antiviral mechanisms than mammals. MicroRNAs (miRNAs) play vital roles in developing insect antiviral immunity. MiRNAs expression profiles of insects changed significantly during baculovirus infection. Methods: Differential expression profiles of miRNAs in Spodoptera frugiperda were monitored by next-generation sequencing (NGS) and RT-qPCR during Autographa californica multiple nucleopolyhedrovirus (AcMNPV) infection. The transcription levels of genes were detected by RT-qPCR. The 50% tissue culture infective dose (TCID50) endpoint dilution assay was used to determine the proliferation of progeny virus. Results: NGS revealed that 49 miRNAs were differentially expressed in Sf9 cells, and 10 of them were significantly up- or down-regulated. Though RT-qPCR analysis, we observed the similar trends for the expression patterns of significantly differentially expressed miRNAs from NGS. Moreover, the transcription levels of core genes, Exportin5, Dicer1, and Argonaute1, in miRNA biogenesis pathways were significantly increased after AcMNPV infection. For five selected miRNAs, miR-34-5p could regulate the proliferation of baculovirus progeny virus and energy metabolism. Conclusion: The miRNAs biogenesis pathway in Sf9 cells plays an important role and may be stimulated to resist AcMNPV infection. This work provides evidence for the molecular mechanism of baculovirus-insect interaction and offers novel ideas and directions for green pest control technology.

Role of Interaction between Zinc and Amyloid Beta in Pathogenesis of Alzheimer's Disease.

Progression of Alzheimer's disease is accompanied by the appearance of extracellular deposits in the brain tissues of patients with characteristic supramolecular morphology (amyloid plaques) the main components of which are β-amyloid isoforms (Aβ) and biometal ions (zinc, copper, iron). For nearly 40 years and up to the present time, the vast majority of experimental data indicate critical role of formation and accumulation of amyloid plaques (cerebral amyloidogenesis) in pathogenesis of Alzheimer's disease, however, nature of the molecular agents that initiate cerebral amyloidogenesis, as well as causes of aggregation of the native Aβ molecules in vivo remained unknown for a long time. This review discusses the current level of fundamental knowledge about the molecular mechanisms of interactions of zinc ions with a number of Aβ isoforms present in amyloid plaques of the patients with Alzheimer's disease, and also shows how this knowledge made it possible to identify driving forces of the cerebral amyloidogenesis in Alzheimer's disease and made it possible to determine fundamentally new biomarkers and drug targets as part of development of innovative strategy for diagnosis and treatment of Alzheimer's disease.