Molecular Terms Research Articles

Assessing the Public and Philanthropic Financial Contribution to the Development of New Drugs: A Bibliographic Analysis

Background: There is wide debate on the cost of some pharmaceutical products and the impact this has on access to medicine. Little publicized knowledge on the public and philanthropic contribution to research and development costs exists so far. The objective of work reported here was to collect information on public contributions to research funding and thus contribute to the discussion on return on public investment. Methods: A multi-level search process was developed to search for public and philanthropic research funding based on 3 main steps: (1) identification of all generic and molecular names and terms, (2) systematic search for pre-marketing pathway information and related research funding, (3) systematic search for corresponding research funding amounts. Three Paediatric Orphan Drugs (Spinraza®, Brineura®, Crysvita®), which were approved by the European Medicines Agency (EMA) in 2017, were chosen to pilot the methods. Results: We estimated that public/philanthropic contributions to funding of product-related research ranged between approximately € 20 million (Spinraza®) and € 31 million (Brineura®). However, this is a very conservative estimate since pharmaceutical development calls upon basic research, which does not mention product-specific terms. For instance, for research into SMA as a whole, public and philanthropic research funding contributions totalling € 165 million were identified. Conclusions: Researching public and philanthropic R & D funding proved to be difficult and time consuming. Further piloting including the refinement and standardisation of the search strategy is underway.

Mathematical Modeling of Sucrose Hydrolysis with Product and Substrate Inhibition

In this work, the enzymatic hydrolysis reaction of sucrose through invertase under unsteady-state conditions has been investigated. The aim is to evaluate the inhibition phenomena influence on the reaction rate and, then, on the concentration and temperature profiles by simulating the process in a tubular reactor, varying the enzyme concentration and the reactant mixture velocity. The transport phenomena considered during the enzymatic hydrolysis process have been described by means of unsteady-state momentum, mass and energy balance equations, taking into account molecular and convective transport and generation terms. Interpretation and discussion of the results obtained by FEM resolution of PDEs involved allow to understand the relevance of the operating parameters.

Proteasome inhibition creates a chromatin landscape favorable to RNA Pol II processivity

Proteasome inhibition creates a chromatin landscape favorable to RNA Pol II processivity

<p><strong>A new <em>Disperis</em> (Orchidoideae; Orchidaceae) for the flora of the Mascarenes</strong></p>

Disperis was established by Swartz (1800: 218), and there is little doubt that the genus is monophyletic in morphological and molecular (Waterman et al. 2009) terms. Kurzweil & Manning (2005) proposed two subgenera, subgenus Dryorkis (Thouars) Kurzweil & Manning (2005: 172), comprising the species in the tropics and subtropics of Africa, Madagascar and Asia, and subgenus Disperis with mostly the South African taxa. Disperis currently includes 80 species distributed in sub-Saharan Africa, Madagascar and the adjacent islands of the Indian Ocean (la Croix et al. 2002, Manning & Kurzweil 2005, Govaerts, 2019) and one widespread species in tropical Asia (Kurzweil & Manning 2005). The highest diversity is found in the humid tropics of Africa, the Cape Floristic Region and Madagascar, with little species overlap between these regions (Kuzrweil & Manning, 2005). So far, four species have been confirmed for the Mascarenes (la Croix et al. 2002). However, the presence of Disperis similis Schlechter (1924: 111) is doubtful because no picture or herbarium specimen documenting its presence on the Mascarenes is available. All four species also occur on Madagascar. Here, we report the presence of a fifth species of this genus for the Mascarenes.

Emodin regulates microRNA expressions of ileum in sepsis mice model

Objective To investigate the regulation of emodin on microRNA expressions in mouse model with sepsis by GeneChip microRNA array. Methods Forty two c57 mice were randomly (random number) divided into 3 groups: sham operation group (sham group, n=14),sepsis group(n=14) and emodin group (n=14). The sepsis model of the mouse was subjected to cecal ligation and puncture (CLP). Mice in emodin group received intraperitoneal injection of emodin (40 mg/kg) half an hour before operation and every 12 hours after CLP. All mice were sacrificed 48 h after surgery and part of the ileum were removed for intestine tissue stained with hematoxylin eosin. The levels of tumor necrosis factor-α(TNF-α), interleukin-6 (IL-6) and intestinal fatty acid binding protein (I-FABP) in peripheral blood were measured by enzyme-linked immunosorbent assay (ELISA). Total RNA of ileum tissues was extracted from the sepsis group and emodin group, and then subjected to miRNA microarray. The results of microarray were further verified by quantitative real-time PCR (qRT-PCR). Target genes of differentially expressed miRNAs were predicted and subjected to gene ontology (GO) and KEGG pathway enrichment analysis. Data of multi-groups were analyzed by one way variance (ANOVA) and inter-group comparisons were made by SNK-q tests. Mann-Whitney U test was used when homogeneity of variance were not met. The value of P<0.05 was considered statistically significant. Results Compared to the sepsis group, the levels of serum TNF-α, IL-6 and I-FABP in the emodin group were decreased significantly. MiRNA microarray showed that 23 miRNAs were differentially expressed in the emodin group as compared to the sepsis group, among which 17 miRNAs were up-regulated and 6 miRNAs were down-regulated. qRT-PCR results were consistent with miRNA array data. Target genes of 10 selected miRNAs were predicted and subjected to bioinformatic analysis. A total of 3 410 target genes were significantly enriched in 2 072 GO biological process terms, 246 GO cellular component items and 277 GO molecular function terms. Moreover, KEGG pathway analysis showed that these differential miRNAs were involved in the regulation of PI3K-Akt signaling pathway, MAPK signaling pathway, and TNF signaling pathway. Conclusions Emodin can regulate the expression of multiple microRNAs, and play an important role in protecting the intestinal mucosal barrier via a variety of targets and pathways. Key words: Emodin; Sepsis; Intestinal mucosa; MicroRNA; Expression profiles; Bioinformatics

Splicing System in Automata Theory : A Review

The study of formal language theory rapidly evolves after Tom Head introduce his research on formal language theory in 1987. Splicing system involves the process of cutting and pasting on DNA molecules with the presence of restriction enzymes and ligase, respectively. A mathematical model of the splicing system has been developed by using the concept of formal language theory, which is a branch of theoretical computer science and applied discrete mathematics, and also informational macromolecules. Over the year, theoretical results in splicing systems have contributed to new research in formal language theory focused on modelling of biochemical processes. In this paper, the relation between formal language theory and some related molecular biological terms are explored. In addition, new ideas in the framework of biomolecular science, for example, the design of automated enzymatic processes are then discussed. Then, a mutual relation that exist in these field is then explained. The regular language can be implemented in the splicing system to show the DFA structure in the splicing system.

Transcriptome signatures reveal candidate key genes in the whole blood of patients with lumbar disc prolapse.

The present study aimed to investigate differentially expressed genes (DEGs) in whole blood (WB) obtained from patients with lumbar disc prolapse (LDP) and healthy volunteers. A total of 8 patients with LDP and 8 healthy volunteers were recruited. An Agilent SurePrint G3 human gene expression microarray 8×60 K was used to perform the microarray analyses. R was employed to identify DEGs, which were then subjected to bioinformatics analysis, including a Gene Ontology (GO) analysis, Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis and protein-protein interaction (PPI) network analysis. DEGs in the degenerative annulus fibrosis (AF) and nucleus pulposus (NP) compared with non-degenerative tissues were also identified based on microarray data and the intersections of the three were assessed. Furthermore, reverse transcription-quantitative (RT-q)PCR was performed to confirm the aberrant expression levels of selected DEGs in the WB of all subjects. A total of 161 DEGs between LDP patients and the healthy controls were identified (128 upregulated and 33 downregulated). These DEGs were enriched in 293 biological process, 36 cellular component and 21 molecular function GO terms, as well as in 24 KEGG pathways. The PPI network contained 4 submodules, and Toll-like receptor 4 had the highest degree centrality. A total of 22 DEGs were common to the three groups of DEGs. The RT-qPCR assay confirmed that the expression levels of cytochrome P450 family 27 subfamily A member 1, superoxide dismutase 2, protein disulfide isomerase family A member 4, FKBP prolyl isomerase 11 and ectonucleotide pyrophosphatase/phosphodiesterase 4 were significantly different between the patient group and the volunteer group. In conclusion, several genes were identified as potential biomarkers in WB that should be further explored in future studies to determine their potential application in the clinical treatment and diagnosis of LDP, and the present bioinformatics analysis revealed several GO terms, KEGG pathways and submodules of the PPI network that may be involved in LDP, although the exact mechanisms remain elusive.

Genomic Analyses Identify Novel Molecular Signatures Specific for the Caenorhabditis and other Nematode Taxa Providing Novel Means for Genetic and Biochemical Studies.

The phylum Nematoda encompasses numerous free-living as well as parasitic members, including the widely used animal model Caenorhabditis elegans, with significant impact on human health, agriculture, and environment. In view of the importance of nematodes, it is of much interest to identify novel molecular characteristics that are distinctive features of this phylum, or specific taxonomic groups/clades within it, thereby providing innovative means for diagnostics as well as genetic and biochemical studies. Using genome sequences for 52 available nematodes, a robust phylogenetic tree was constructed based on concatenated sequences of 17 conserved proteins. The branching of species in this tree provides important insights into the evolutionary relationships among the studied nematode species. In parallel, detailed comparative analyses on protein sequences from nematodes (Caenorhabditis) species reported here have identified 52 novel molecular signatures (or synapomorphies) consisting of conserved signature indels (CSIs) in different proteins, which are uniquely shared by the homologs from either all genome-sequenced Caenorhabditis species or a number of higher taxonomic clades of nematodes encompassing this genus. Of these molecular signatures, 39 CSIs in proteins involved in diverse functions are uniquely present in all Caenorhabditis species providing reliable means for distinguishing this group of nematodes in molecular terms. The remainder of the CSIs are specific for a number of higher clades of nematodes and offer important insights into the evolutionary relationships among these species. The structural locations of some of the nematodes-specific CSIs were also mapped in the structural models of the corresponding proteins. All of the studied CSIs are localized within the surface-exposed loops of the proteins suggesting that they may potentially be involved in mediating novel protein–protein or protein–ligand interactions, which are specific for these groups of nematodes. The identified CSIs, due to their exclusivity for the indicated groups, provide reliable means for the identification of species within these nematodes groups in molecular terms. Further, due to the predicted roles of these CSIs in cellular functions, they provide important tools for genetic and biochemical studies in Caenorhabditis and other nematodes.

Exploiting Cryo-EM Structural Information and All-Atom Simulations To Decrypt the Molecular Mechanism of Splicing Modulators.

Splicing modulators (SMs) pladienolides, herboxidienes, and spliceostatins exert their antitumor activity by altering the ability of SF3B1 and PHF5A proteins, components of SF3b splicing factor, to recognize distinct intron branching point sequences, thus finely calibrating constitutive/alternative/aberrant splicing of pre-mRNA. Here, by exploiting structural information obtained from cryo-EM data, and by performing multiple μs-long all-atom simulations of SF3b in apo form and in complex with selected SMs, we disclose how these latter seep into the narrow slit at the SF3B1/PHF5A protein interface. This locks the intrinsic open/closed conformational transitions of SFB1's solenoidal structure into the open state. As a result, SMs prevent the formation of a closed/intron-loaded conformation of the SF3B1 protein by decreasing the internal SF3B1 cross-correlation and reducing SF3B1's functional plasticity. We further compellingly support the proposition that SMs' action exceeds a purely competitive inhibition. Indeed, our simulations also demonstrate that the introduction of recurrent drug resistance/sensitizing mutations in SF3B1 or PHF5A, besides affecting the binding affinity of SMs, likewise influence the functional dynamics of SF3B1. This knowledge clarifies the molecular terms of SF3b modulation by small-molecules, fostering the rational-based discovery of drugs tackling distinct cancer types resulting from dysregulated splicing. This work also supports the coming of age usage of cryo-EM structural data in forthcoming drug-discovery studies.

Liver proteome analysis of grass carp (Ctenopharyngodon idellus) following treatment with enrofloxacin.

Enrofloxacin is widely used for the prevention and control of bacterial diseases in aquaculture. The liver is crucial for enrofloxacin metabolism, but enrofloxacin can induce liver damage. Herein, we explored proteomic changes in the liver of grass carp (Ctenopharyngodon idellus) following treatment with enrofloxacin using isobaric tag for relative and absolute quantitation (iTRAQ) technology. All experiments included two biological replicates and blank controls. Among the 3082 proteins identified, 103 were differentially abundant, comprising 49 up- and 54 downregulated proteins. Gene Ontology (GO) annotation identified macromolecular complex (63.60%), intracellular non-membrane-bound organelle (51.50%), and non-membrane-bound organelle (51.50%) as the most enriched cellular component terms. Structural molecule activity (26.80%), structural constituent of ribosome (17.90%), and calcium ion binding (16.10%) were the top three molecular function terms. Organic substance biosynthetic process (37.80%), biosynthetic process (37.80%), and protein metabolic process (37.80%) were the top three biological process terms. The Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis found 17 enriched KEGG pathways, with protein digestion and absorption, extracellular matrix (ECM)-receptor interactions, and ribosome and focal adhesion the most significant (p < 0.001). Analysis of the most enriched pathways revealed that chymotrypsin-like precursor, pancreatic elastase precursor, Na+/K+ transporting ATPase, collagen, and dermatopontin were upregulated, while ribosomal proteins, alpha-actinin, and myosin light chain were downregulated. These findings suggest that enrofloxacin affects liver function and has a risk of inducing an inflammatory response in extrahepatic organs.

In silico study of α-γ phase transformation in hexahydro-1,3,5-trinitro-1,3,5-triazine

Molecular dynamics (MD) simulations are performed using the Smith and Bharadwaj (SB) molecular potential to study the response of α-RDX to hydrostatic compression up to 4 GPa between 300 K and 450 K. We observe a phase transformation to the high-pressure γ polymorph around 2.5 GPa for temperatures greater than or equal to 350 K. The α-γ phase transformation is captured through an abrupt decrease in the ‘b’ lattice parameter and volume while the ‘c’ lattice parameter shows an abrupt increase. The molecular conformation is shown to evolve from AAE to AAE-AAI during the phase transition, consistent with experimental observations. Abrupt changes are also observed in molecular and non-bonded energy terms of the SB potential. The phase at the end of hydrostatic loading is verified to be γ-RDX. The simulations demonstrate that SB potential can be effective in further elucidating the deformation mechanisms in RDX compressed beyond the phase transition pressure. We hypothesize that the difference in angle energy between the two phases plays an important role in the occurrence of α-γ phase transformation in RDX using the SB potential.

Diagnosis: From classification to prediction

Over the last two decades diagnostic labels have increasingly been sub-divided based on molecular and genetic ‘signatures’. But this emphasis on disease sub-types defined in molecular terms, elides the central role of population-based predictive technologies in determining these new diagnoses. While molecular diagnostic sub-types might flow from the laboratory, the clinical validity of every putative diagnostic category must ultimately be tested against its predictive powers. In effect, the former logic of prognosis following diagnosis is reversed. This paper explores the emergence of this new method of diagnostic practice over the last half century.

An apical hypoxic niche sets the pace of shoot meristem activity.

Complex multicellular organisms evolved on Earth in an oxygen-rich atmosphere1; their tissues, including stem-cell niches, require continuous oxygen provision for efficient energy metabolism2. Notably, the maintenance of the pluripotent state of animal stem cells requires hypoxic conditions, whereas higher oxygen tension promotes cell differentiation3. Here we demonstrate, using a combination of genetic reporters and in vivo oxygen measurements, that plant shoot meristems develop embedded in a low-oxygen niche, and that hypoxic conditions are required to regulate the production of new leaves. We show that hypoxia localized to the shoot meristem inhibits the proteolysis of an N-degron-pathway4,5 substrate known as LITTLEZIPPER2 (ZPR2)-which evolved to control the activity of the class-III homeodomain-leucine zipper transcription factors6-8-and thereby regulates the activity of shoot meristems. Our results reveal oxygen as a diffusible signal that is involved in the control of stem-cell activity in plants grown under aerobic conditions, which suggests that the spatially distinct distribution of oxygen affects plant development. In molecular terms, this signal is translated into transcriptional regulation by the N-degron pathway, thereby linking the control of metabolic activity to the regulation of development in plants.

Signature microRNAs and long noncoding RNAs in laryngeal cancer recurrence identified using a competing endogenous RNA network.

The aim of the present study was to identify novel microRNA (miRNA) or long noncoding RNA (lncRNA) signatures of laryngeal cancer recurrence and to investigate the regulatory mechanisms associated with this malignancy. Datasets of recurrent and nonrecurrent laryngeal cancer samples were downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus database (GSE27020 and GSE25727) to examine differentially expressed miRNAs (DE-miRs), lncRNAs (DE-lncRs) and mRNAs (DEGs). miRNA-mRNA and lncRNA-miRNA networks were constructed by investigating the associations among these RNAs in various databases. Subsequently, the interactions identified were combined into a competing endogenous RNA (ceRNA) regulatory network. Feature genes in the miRNA-mRNA network were identified via topological analysis and a recursive feature elimination algorithm. A support vector machine (SVM) classifier was established using the betweenness centrality values in the miRNA-mRNA network, consisting of 32 optimal feature-coding genes. The classification effect was tested using two validation datasets. Furthermore, coding genes in the ceRNA network were examined via pathway enrichment analyses. In total, 21 DE-lncRs, 507 DEGs and 55 DE-miRs were selected. The SVM classifier exhibited an accuracy of 94.05% (79/84) for sample classification prediction in the TCGA dataset, and 92.66 and 91.07% in the two validation datasets. The ceRNA regulatory network comprised 203 nodes, corresponding to mRNAs, miRNAs and lncRNAs, and 346 lines, corresponding to the interactions among RNAs. In particular, the interactions with the highest scores were HLA complex group 4 (HCG4)-miR-33b, HOX transcript antisense RNA (HOTAIR)-miR-1-MAGE family member A2 (MAGEA2), EMX2 opposite strand/antisense RNA (EMX2OS)-miR-124-calcitonin related polypeptide α (CALCA) and EMX2OS-miR-124-γ-aminobutyric acid type A receptor γ2 subunit (GABRG2). Gene enrichment analysis of the genes in the ceRNA network identified that 11 pathway terms and 16 molecular function terms were significantly enriched. The SVM classifier based on 32 feature coding genes exhibited high accuracy in the classification of laryngeal cancer samples. miR-1, miR-33b, miR-124, HOTAIR, HCG4 and EMX2OS may be novel biomarkers of recurrent laryngeal cancer, and HCG4-miR-33b, HOTAIR-miR-1-MAGEA2 and EMX2OS-miR-124-CALCA/GABRG2 may be associated with the molecular mechanisms regulating recurrent laryngeal cancer.

RNA-Sequencing and Bioinformatics Analysis of Long Noncoding RNAs and mRNAs in the Prefrontal Cortex of Mice Following Repeated Social Defeat Stress.

Background Repeated or continuous chronic psychological stress may induce diverse neuropsychiatric disorders; however, the underlying mechanisms remain unclear. In this study, we explored the expression profiles of long noncoding RNAs (lncRNAs) and mRNAs, along with their biological function and regulatory network, in mice after repeated social defeat (RSD) stress to explore their potential involvement in the development of anxiety-like behaviors. Main Methods RNA-sequencing was used to screen all differentially expressed (DE) lncRNAs and mRNAs between the RSD and control groups. Quantitative real-time polymerase chain reaction (qRT-PCR) was used for confirmation of the RNA-sequencing results. The function of DE lncRNAs was predicted by Gene Ontology (GO) enrichment and pathway analyses of target mRNAs. In addition, the functional regulatory network of the target mRNAs was constructed to reveal potential relationships between lncRNAs and their target genes with bioinformatics approaches. Key Findings In mice experiencing RSD, 373 and 454 lncRNAs, along with 1142 and 654, mRNAs were significantly upregulated and downregulated, respectively. The detailed regulatory network included 126 eligible lncRNA-mRNA pairs. Among them, 14 genes such as Arhgef1, Chchd2, Fam107a, Dlg1, Nova2, Dpf1, and Shank3 involved in neurite growth, neural development, and synaptic plasticity were direct targets of the DE lncRNAs. qRT-PCR of four of the DE lncRNAs and mRNAs confirmed the reliability of RNA-sequencing. GO clustering analyses showed that the top enriched biological process, cellular component, and molecular function terms were synaptic transmission, neuron spine, and glutamate receptor binding, respectively. Further, the top three significant enriched pathways were synaptic adhesion-like molecule (SALM) protein interactions at the synapses, trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, as well as glutamate binding, activation of AMPA receptors, and synaptic plasticity. Significance Hundreds of lncRNAs and mRNAs are dysregulated after RSD, and many of these lncRNAs might participate in the development of anxiety-like behaviors via multiple complex mechanisms such as target regulation. Available informatics evidence highlighted the likely role of synapse dysfunction and abnormal synaptic neurotransmission in these behaviors. Thus, our findings provide potential candidate biomarkers or intervention targets for chronic psychological stress-induced neuropsychiatric disorders.

Salt-sensitive transcriptome of isolated kidney distal tubule cells.

In the distal kidney tubule, the steroid hormone aldosterone regulates sodium reabsorption via the epithelial sodium channel (ENaC). Most studies seeking to identify ENaC-regulating aldosterone-induced proteins have used transcriptional profiling of cultured cells. To identify salt-sensitive transcripts in an in vivo model, we used low-NaCl or high-NaCl diet to stimulate or suppress endogenous aldosterone, in combination with magnetic- and fluorescence-activated cell sorting to isolate distal tubule cells from mouse kidney for transcriptional profiling. Of the differentially expressed transcripts, 162 were more abundant in distal tubule cells isolated from mice fed low-NaCl diet, and 161 were more abundant in distal tubule cells isolated from mice fed high-NaCl diet. Enrichment analysis of Gene Ontology biological process terms identified multiple statistically overrepresented pathways among the differentially expressed transcripts that were more abundant in distal tubule cells isolated from mice fed low-NaCl diet, including ion transmembrane transport, regulation of growth, and negative regulation of apoptosis. Analysis of Gene Ontology molecular function terms identified differentially expressed transcription factors, transmembrane transporters, kinases, and G protein-coupled receptors. Finally, comparison with a recently published study of gene expression changes in distal tubule cells in response to administration of aldosterone identified 18 differentially expressed genes in common between the two experiments. When expression of these genes was measured in cortical collecting ducts microdissected from mice fed low-NaCl or high-NaCl diet, eight were differentially expressed. These genes are likely to be regulated directly by aldosterone and may provide insight into aldosterone signaling to ENaC in the distal tubule.

Dissecting molecular mechanisms underlying salt tolerance in rice: a comparative transcriptional profiling of the contrasting genotypes

BackgroundSalinity expansion in arable land is a threat to crop plants. Rice is the staple food crop across several countries worldwide; however, its salt sensitive nature severely affects its growth under excessive salinity. FL478 is a salt tolerant indica recombinant inbred line, which can be a good source of salt tolerance at the seedling stage in rice. To learn about the genetic basis of its tolerance to salinity, we compared transcriptome profiles of FL478 and its sensitive parent (IR29) using RNA-seq technique.ResultsA total of 1714 and 2670 genes were found differentially expressed (DEGs) under salt stress compared to normal conditions in FL478 and IR29, respectively. Gene ontology analysis revealed the enrichment of transcripts involved in salinity response, regulation of gene expression, and transport in both genotypes. Comparative transcriptome analysis revealed that 1063 DEGs were co-expressed, while 338/252 and 572/908 DEGs were exclusively up/down-regulated in FL478 and IR29, respectively. Further, some biological processes (e.g. iron ion transport, response to abiotic stimulus, and oxidative stress) and molecular function terms (e.g. zinc ion binding and cation transmembrane transporter activity) were specifically enriched in FL478 up-regulated transcripts. Based on the metabolic pathways analysis, genes encoding transport and major intrinsic proteins transporter superfamily comprising aquaporin subfamilies and genes involved in MAPK signaling and signaling receptor kinases were specifically enriched in FL478. A total of 1135 and 1894 alternative splicing events were identified in transcripts of FL478 and IR29, respectively. Transcripts encoding two potassium transporters and two major facilitator family transporters were specifically up-regulated in FL478 under salt stress but not in the salt sensitive genotype. Remarkably, 11 DEGs were conversely regulated in the studied genotypes; for example, OsZIFL, OsNAAT, OsGDSL, and OsELIP genes were up-regulated in FL478, while they were down-regulated in IR29.ConclusionsThe achieved results suggest that FL478 employs more efficient mechanisms (especially in signal transduction of salt stress, influx and transport of k+, ionic and osmotic homeostasis, as well as ROS inhibition) to respond to the salt stress compared to its susceptible parent.

The Role of MicroRNAs in the Osseointegration Process

Regulation of cellular function is key to bone formation at endosseous implant surfaces. Osseointegration was "discovered" prior to the discovery of genetic regulation of osteoinduction or characterization of mesenchymal stem cells. Understanding osseointegration in cellular and molecular terms has benefited from genome-wide characterization of this healing process at endosseous implants in vivo. These in vivo studies also demonstrate a role for osteoprogenitor cells and cells involved in immune regulation and osteoclastogenesis. The identification of noncoding RNAs, including microRNAs, as key factors controlling cell function has highlighted the role of microRNAs in cell differentiation control. This review summarizes emerging in vitro and in vivo investigations emphasizing the role of microRNAs in the osseointegration process. Many microRNAs influence key osteoinductive pathways controlling Osterix, runt-related transcription factor 2 (RUNX2), and bone morphogenetic protein (BMP)/SMAD function. Others influence the monocyte/macrophage lineage. While significant progress has been made in elucidating the mechanisms associated with the regulation of surface modulation of osteoblast differentiation by microRNAs, knowledge gaps are evident in the identification and characterization of microRNAs linked to osseointegration. Given existing knowledge regarding the varied expression of microRNAs and their role in inflammation, it is important to understand how microRNA expression may influence the process of bone accrual at implant surfaces during osseointegration.

RNA-seq based elucidation of mechanism underlying Ganoderma atrum polysaccharide induced immune activation of murine myeloid-derived dendritic cells

Abstract Our previous study has demonstrated that Ganoderma atrum polysaccharide (PSG-1) could induce activation and maturation of dendritic cells (DCs). Hereby, this study aimed to further elucidate the underlying mechanism of PSG-1 induced immune activation based on RNA-seq. The results of RNA-seq analysis showed 2231 differentially expressed genes between PSG-1 and control group. 28 biological processes terms, 20 molecular functions terms, and 10 cellular components terms were identified by GO analysis. PI3K/Akt and NF-κB pathways were belong to 20 most significantly affected signaling pathways analyzed by KEGG. p-Akt and p-IκBα levels in DCs were raised by PSG-1, and PSG-1-induced expression of MHC-II, CD80 and CD86 and production of IL-6 and TNF-α were decreased by the inhibitors of PI3K/Akt and NF-κB pathways. These results indicated that immune response and immune function were regulated in PSG-1 stimulated DCs based on RNA-seq, in which PI3K/Akt and NF-κB pathways played a vital role.

Drug–DNA interaction, a joint DFT-D3/MD study on safranal as an anticancer and DNA nanostructure model

In this research, using a combination of quantum mechanics and molecular dynamic (MD) simulations, the interaction of safranal (2,6,6-trimethylcyclohexa-1,3-dien-1-carboxaldehyde) as an anti-cancer drug and Dickerson B-DNA was studied. MD simulations were executed for 35 ns in water. Binding energy analysis in three definite parts of the B-DNA and comparison between different contributions of the binding energy shows that the van der Waals energy part of the interaction is impressive among the standard molecular mechanic energy terms. On the basis of Gibbs energies, it is confirmed that the most important interactions in the safranal complex are related to the A–T and C–G rich regions, which is in agreement with the experimental data. Quantum theory of atoms in molecules and natural bond orbital analyses were applied. A diminution in the electronic chemical potential of the safranal–DNA complex in comparison with the isolated DNA, 0.026 and 0.022 au for the S1 region and 0.012 and 0.017 au for the S2 region, was obtained in the gas phase and water, respectively, which increases the complex stability. An enhancement in the electrophilicity character, during the complexation process, shows the electron charge flux between the safranal and DNA, especially in water. The strengths of the CH⋯O bonds at the center of safranal–DNA interaction were also evaluated. A mean value of 0.06 au for the electron density of the bond critical point of the H⋯O in the complex confirms the H-bond formation during the complexation.