Mol Biosyst [JOURNAL]
Sun
200 papers
Network-based modelling and percolation analysis of conformational dynamics and activation in the CDK2 and CDK4 proteins: dynamic and energetic polarization of the kinase lobes may determine divergence of the regulatory mechanisms.
Verkhivker GM
Mol Biosyst · 2017 Oct · PMID 28926061 · Publisher ↗
The overarching goal of delineating molecular principles underlying differentiation of the activation mechanisms in cyclin-dependent kinases (CDKs) is important for understanding regulatory divergences among closely rela...
The overarching goal of delineating molecular principles underlying differentiation of the activation mechanisms in cyclin-dependent kinases (CDKs) is important for understanding regulatory divergences among closely related kinases which can be exploited in drug discovery of targeted and allosteric inhibitors. To systematically characterize dynamic, energetic and network signatures of the activation mechanisms, we combined atomistic simulations and elastic network modeling with the analysis of the residue interaction networks and rigidity decomposition of the CDK2-cyclin A and CDK4-cyclin D1/D3 complexes. The results of this study show that divergences in the activation mechanisms of CDK2 and CDK4 may be determined by differences in stabilization and allosteric cooperativity of the regulatory regions. We show that differential stabilization of the kinase lobes in the CDK4-cyclin D complexes caused by the elevated mobility of the N-lobe residues can weaken allosteric interactions between regulatory regions and compromise cooperativity of the inter-lobe motions that is required to trigger activating transitions. Network modelling and percolation analysis were used to emulate thermal unfolding and perform decomposition of rigid and flexible regions in the CDK2 and CDK4 complexes. These simulations showed that the percolation phase transition in the CDK2-cyclin A complexes is highly cooperative and driven by allosteric coupling between functional regions from both kinase lobes. In contrast, the imbalances in the distribution of rigid and flexible regions for the CDK4-cyclin D complexes, which are manifested by the intrinsic instability of the N-lobe, may weaken allosteric interactions and preclude productive activation. The results of this integrative computational study offer a simple and robust network-based model that explains regulatory divergences between CDK2 and CDK4 kinases.
A novel method for identifying potential disease-related miRNAs via a disease-miRNA-target heterogeneous network.
Ding L, Wang M, Sun D … +1 more , Li A
Mol Biosyst · 2017 Oct · PMID 28920619 · Publisher ↗
MicroRNAs (miRNAs), as a kind of important small endogenous single-stranded non-coding RNA, play critical roles in a large number of human diseases. However, the currently known experimental verifications of the disease-...
MicroRNAs (miRNAs), as a kind of important small endogenous single-stranded non-coding RNA, play critical roles in a large number of human diseases. However, the currently known experimental verifications of the disease-miRNA associations are still rare and experimental identification is time-consuming and labor-intensive. Accordingly, identifying potential disease-related miRNAs to help people understand the pathogenesis of complex diseases has become a hot topic. In this study, we take advantage of known disease-miRNA associations combined with a large number of experimentally validated miRNA-target associations, and further develop a novel disease-miRNA-target heterogeneous network for identifying disease-related miRNAs. The leave-one-out cross validation experiment and several statistical measures demonstrate that our method can effectively identify potential disease-related miRNAs. Furthermore, the good predictive performance of 15 common diseases and the manually confirmed analyses of the top 30 candidates of hepatocellular carcinoma, ovarian neoplasms and breast neoplasms further provide convincing evidence of the practical ability of our method. The source code implemented by our method is freely available at: .
HIV/HAART-associated oxidative stress is detectable by metabonomics.
Williams AA, Sitole LJ, Meyer D
Mol Biosyst · 2017 Oct · PMID 28920117 · Publisher ↗
Chronic human immunodeficiency virus (HIV) infection, separately and in combination with highly active antiretroviral therapy (HAART) is closely associated with oxidative stress (OS). Most studies demonstrating redox imb...
Chronic human immunodeficiency virus (HIV) infection, separately and in combination with highly active antiretroviral therapy (HAART) is closely associated with oxidative stress (OS). Most studies demonstrating redox imbalances in HIV-infected individuals have done so using conventional biochemical methodologies. The limited simultaneous detection of multiple OS markers within one sample is a major drawback of these methodologies and can be addressed through the use of metabonomics. HIV-metabonomic studies utilizing biofluids from HAART cohorts as the investigative source, are on the increase. Data from many of these studies identified metabolic markers indicative of HIV-induced OS, usually as an outcome of an untargeted metabonomics study. Untargeted studies cast a wide net for any and all detectable metabolites in complex mixtures. Given the prevalence of OS during HIV infection and antiviral treatment, it is perhaps not surprising that indicators of this malady would become evident during metabolite identification. At times, targeted studies for specific (non-OS) metabolites would also yield OS markers as an outcome. This review examines the findings of these studies by first providing the necessary background information on OS and the main ways in which free radicals/reactive oxygen species (ROS) produced during OS, cause biomolecular damage. This is followed by information on the biomarkers which come about as a result of free radical damage and the techniques used for assaying these stress indicators. The established links between elevated ROS and lowered antioxidants during HIV infection and the subsequent use of HAART is then presented followed by a review of the OS markers detected in HIV metabonomic studies to date. We identify gaps in HIV/HAART-associated OS research and finally suggest how these research gaps can be addressed through metabonomic analysis, specifically targeting the multiple markers of HIV-induced OS.
Real-time activity assays of β-lactamases in living bacterial cells: application to the inhibition of antibiotic-resistant E. coli strains.
Ge Y, Zhou YJ, Yang KW … +3 more , Zhang YL, Xiang Y, Zhang YJ
Mol Biosyst · 2017 Oct · PMID 28906528 · Publisher ↗
The emergence of antibiotic resistance caused by β-lactamases, including serine β-lactamases (SβLs) and metallo-β-lactamases (MβLs), is a global public health threat. L1, a B3 subclass MβL, hydrolyzes almost all of known...
The emergence of antibiotic resistance caused by β-lactamases, including serine β-lactamases (SβLs) and metallo-β-lactamases (MβLs), is a global public health threat. L1, a B3 subclass MβL, hydrolyzes almost all of known β-lactam antibiotics. We report a simple and straightforward UV-Vis approach for real-time activity assays of β-lactamases inside living bacterial cells, and this method has been exemplified by choosing antibiotics, L1 enzyme, Escherichia coli expressing L1 (L1 E. coli), Escherichia coli expressing extended-spectrum β-lactamases (ESBL-E. coli), clinical bacterial strains, and reported MβL and SβL inhibitors. The cell-based studies demonstrated that cefazolin was hydrolyzed by L1 E. coli and clinical strains, and confirmed the hydrolysis to be inhibited by two known L1 inhibitors EDTA and azolylthioacetamide (ATAA), with an IC value of 1.6 and 18.9 μM, respectively. Also, it has been confirmed that the breakdown of cefazolin caused by ESBL-E. coli was inhibited by clavulanic acid, the first SβL inhibitor approved by FDA. The data gained through this approach are closely related to the biological function of the target enzyme in its physiological environment. The UV-Vis method proposed here can be applied to target-based whole-cell screening to search for potent β-lactamase inhibitors, and to assays of reactions in complex biological systems, for instance in medical assays.
Enantioselective recognition of an isomeric ligand by a biomolecule: mechanistic insights into static and dynamic enantiomeric behavior and structural flexibility.
Peng W, Ding F
Mol Biosyst · 2017 Oct · PMID 28884187 · Publisher ↗
Chirality is a ubiquitous basic attribute of nature, which inseparably relates to the life activity of living organisms. However, enantiomeric differences have still failed to arouse enough attention during the biologica...
Chirality is a ubiquitous basic attribute of nature, which inseparably relates to the life activity of living organisms. However, enantiomeric differences have still failed to arouse enough attention during the biological evaluation and practical application of chiral substances, and this poses a large threat to human health. In the current study, we explore the enantioselective biorecognition of a chiral compound by an asymmetric biomolecule, and then decipher the molecular basis of such a biological phenomenon on the static and, in particular, the dynamic scale. In light of the wet experiments, in silico docking results revealed that the orientation of the latter part of the optical isomer structures in the recognition domain can be greatly affected by the chiral carbon center in a model ligand molecule, and this event may induce large disparities between the static chiral bioreaction modes and noncovalent interactions (especially hydrogen bonding). Dynamic stereoselective biorecognition assays indicated that the conformational stability of the protein-(S)-diclofop system is clearly greater than the protein-(R)-diclofop adduct; and moreover, the conformational alterations of the diclofop enantiomers in the dynamic process will directly influence the conformational flexibility of the key residues found in the biorecognition region. These points enable the changing trends of biopolymer structural flexibility and free energy to exhibit significant distinctions when proteins sterically recognize the (R)-/(S)-stereoisomers. The outcomes of the energy decomposition further showed that the van der Waals' energy has roughly the same contribution to the chiral recognition biosystems, whereas the contribution of electrostatic energy to the protein-(R)-diclofop complex is notably smaller than to the protein-(S)-diclofop bioconjugate. This proves that differences in the noncovalent bonds would have a serious impact on the stereoselective biorecognition between a biomacromolecule and chiral ligand. The present scenario is expected to attract more interest from both researchers and administrative agencies, since in a chiral environment, enantioselectivity exists in all of the biochemical processes of a chiral chemical, and this might finally elicit the disparate biological activities of (R)-/(S)-enantiomers.
Correction: An integrated anti-arrhythmic target network of compound Chinese medicine Wenxin Keli revealed by combined machine learning and molecular pathway analysis.
Wang T, Lu M, Du Q … +7 more , Yao X, Zhang P, Chen X, Xie W, Li Z, Ma Y, Zhu Y
Mol Biosyst · 2017 Sep · PMID 28884186 · Publisher ↗
Correction for 'An integrated anti-arrhythmic target network of a Chinese medicine compound, Wenxin Keli, revealed by combined machine learning and molecular pathway analysis' by Taiyi Wang et al., Mol. BioSyst., 2017, 1...
Correction for 'An integrated anti-arrhythmic target network of a Chinese medicine compound, Wenxin Keli, revealed by combined machine learning and molecular pathway analysis' by Taiyi Wang et al., Mol. BioSyst., 2017, 13, 1018-1030.
Computational study on the origin of the cancer immunotherapeutic potential of B and T cell epitope peptides.
Li H, Schaduangrat N, Simeon S … +1 more , Nantasenamat C
Mol Biosyst · 2017 Oct · PMID 28880325 · Publisher ↗
Immune therapy is generally seen as the future of cancer treatment. The discovery of tumor-associated antigens and cytotoxic T lymphocyte epitope peptides spurned intensive research into effective peptide-based cancer va...
Immune therapy is generally seen as the future of cancer treatment. The discovery of tumor-associated antigens and cytotoxic T lymphocyte epitope peptides spurned intensive research into effective peptide-based cancer vaccines. One of the major obstacles hindering the development of peptide-based cancer vaccines is the lack of humoral response induction. As of now, very limited work has been performed to identify epitope peptides capable of inducing both cellular and humoral anticancer responses. In addition, no research has been carried out to analyze the structure and properties of peptides responsible for such immunological activities. This study utilizes a machine learning method together with interpretable descriptors in an attempt to identify parameters determining the immunotherapeutic activity of cancer epitope peptides.
Mass spectrometry based identification of galectin-3 interacting proteins potentially involved in lung melanoma metastasis.
Dange MC, Bhonsle HS, Godbole RK … +4 more , More SK, Bane SM, Kulkarni MJ, Kalraiya RD
Mol Biosyst · 2017 Oct · PMID 28875213 · Publisher ↗
Adhesive interactions between molecules on tumor cells and those on target organs play a key role in organ specific metastasis. Poly-N-acetyl-lactosamine (polyLacNAc) substituted N-oligosaccharides on melanoma cell surfa...
Adhesive interactions between molecules on tumor cells and those on target organs play a key role in organ specific metastasis. Poly-N-acetyl-lactosamine (polyLacNAc) substituted N-oligosaccharides on melanoma cell surface glycoproteins promote lung specific metastasis via galectin-3 by facilitating their arrest and extravasation. This study reports the identification and characterization of galectin-3 interacting proteins using a combination of galectin-3 sepharose affinity and leucoagglutinating phytohemagglutinin (L-PHA) columns. A total of 83 proteins were identified as galectin-3 interacting glycoproteins, of which 35 were constituents of the L-PHA bound fraction, suggesting that these proteins carry polyLacNAc substituted β1,6 branched N-glycans. The identities of some of these proteins, like LAMP-1, LAMP-3, basigin, embigin, and α5 and β1 Integrin, have been confirmed by western blotting, and functional relevance with respect to metastatic properties has been established.
MicroRNAs regulate the main events in rice drought stress response by manipulating the water supply to shoots.
Fard EM, Bakhshi B, Farsi M … +5 more , Kakhki AM, Nikpay N, Ebrahimi MA, Mardi M, Salekdeh GH
Mol Biosyst · 2017 Oct · PMID 28872648 · Publisher ↗
MicroRNAs (miRNAs) are small endogenous regulatory RNAs that are involved in a variety of biological processes related to proliferation, development, and response to biotic and abiotic stresses. miRNA profiles of rice (O...
MicroRNAs (miRNAs) are small endogenous regulatory RNAs that are involved in a variety of biological processes related to proliferation, development, and response to biotic and abiotic stresses. miRNA profiles of rice (Oryza sativa L. cv. IR64.) leaves in a partial root zone drying (PRD) system were analysed using a high-throughput sequencing approach to identify miRNAs associated with drought signalling. The treatments performed in this study were as follows: well-watered ("wet" roots, WW), wherein both halves of the pot were watered daily; drought ("dry" roots, DD), wherein water was withheld from both halves of the pot; and well-watered/drought ("wet" and "dry" roots, WD), wherein one half of each pot was watered daily, the same as in WW, and water was withheld from the other part, the same as in DD. High-throughput sequencing enabled us to detect novel miRNAs and study the differential expression of known miRNAs. A total of 209 novel miRNAs were detected in this study. Differential miRNA profiling of the DD, WD and WW conditions showed differential expression of 159 miRNAs, among which 83, 44 and 32 miRNAs showed differential expression under both DD and WD conditions. The detection of putative targets of the differentially expressed miRNAs and investigation of their functions showed that most of these genes encode transcription factors involved in growth and development, leaf morphology, regulation of hormonal homeostasis, and stress response. The most important differences between the DD and WD conditions involved regulation of the levels of hormones such as auxin, cytokinin, abscisic acid, and jasmonic acid and also regulation of phosphor homeostasis. Overall, differentially expressed miRNAs under WD conditions were found to differ from those under DD conditions, with such differences playing a role in adaptation and inducing the normal condition. The mechanisms involved in regulating hormonal homeostasis and involved in energy production and consumption were found to be the most important regulatory pathways distinguishing the DD and WD conditions.
Investigation of a common gene expression signature in gastrointestinal cancers using systems biology approaches.
Baghaei K, Hosseinkhan N, Asadzadeh Aghdaei H … +1 more , Zali MR
Mol Biosyst · 2017 Oct · PMID 28868547 · Publisher ↗
According to GLOBOCAN 2012, the incidence and the mortality rate of colorectal, stomach and liver cancers are the highest among the total gastrointestinal (GI) cancers. Here we aimed to find the common genes and pathways...
According to GLOBOCAN 2012, the incidence and the mortality rate of colorectal, stomach and liver cancers are the highest among the total gastrointestinal (GI) cancers. Here we aimed to find the common genes and pathways that are simultaneously deregulated in these three malignancies using systems biology approaches. Here we conducted a differential expression analysis on high-quality gene expression datasets of gastric cancer (GC), colorectal cancer (CRC) and hepatocellular carcinoma (HCC). To address the inter gene correlations that were neglected in differential expression studies, we also applied differential co-expression analysis on the understudied datasets. The common significant differentially expressed genes (DEGs) among the three cancers were used for further regulatory and PPI network construction. In parallel the regulatory roles of miRNAs and lncRNAs in the common DEGs were investigated. 23 common DEGs were detected between GC, CRC and HCC. Two cases of potential feed forward loops were identified in the constructed TF-target regulatory network, indicating the probable cross-talk between biological pathways. The result of a vulnerability test on the common PPI network resulted in the finding of three candidates, the simultaneous targeting of which will disintegrate the main parts of the network. The results of the differential co-expression study led to the identification of respectively 7 and 1 common differentially co-expressed pairs of genes between GC and CRC and between CRC and HCC. The results of the differential expression study introduced new common players in CRC, GC and HCC and provided better insights into the molecular characteristics of these GI malignancies. Moreover, we concluded that differential co-expression studies are an essential complement for differential expression studies that just take single differentially expressed genes into account.
A systems biology approach to identify microRNAs contributing to cisplatin resistance in human ovarian cancer cells.
Liu W, Wang S, Zhou S … +4 more , Yang F, Jiang W, Zhang Q, Wang L
Mol Biosyst · 2017 Oct · PMID 28861582 · Publisher ↗
Cisplatin (CDDP)-based chemotherapy is a standard first-line therapy for ovarian cancer. However, drug resistance remains a major obstacle to its efficacy. Recently, increasing evidence suggested that the aberrant expres...
Cisplatin (CDDP)-based chemotherapy is a standard first-line therapy for ovarian cancer. However, drug resistance remains a major obstacle to its efficacy. Recently, increasing evidence suggested that the aberrant expression of microRNAs (miRNAs) may contribute to drug resistance. Here, we proposed a systems biology analysis strategy to identify the novel miRNAs potentially involved in CDDP resistance in human ovarian cancer cells. Firstly, we identified the candidate miRNAs associated with CDDP resistance using NCI-60 data. Next, the differentially expressed genes (DEGs) in the CDDP-resistant ovarian cancer cell line OVCAR-8R were obtained. After mapping the DEGs to a human protein-protein interaction network, a CDDP resistance-related sub-network for ovarian cancer was constructed, and subsequently the functional gene modules were identified. Then, based on the experimentally validated miRNA regulations to target genes, 4 candidate miRNAs (miR-24-3p, miR-192-5p, miR-139-5p and miR-155-5p) were identified to potentially contribute to ovarian cancer cell chemoresistance to CDDP through mediating OVCAR-8R cell CDDP resistance-related gene modules, which participated in functions that were closely related to "apoptosis", "cell cycle" and "adhesion". In addition, we predicted the therapeutic drugs that might reduce or reverse CDDP resistance by targeting these 4 identified miRNAs. This study revealed the underlying mechanism of CDDP resistance, and provided novel potential drug targets and therapeutics for CDDP-resistant ovarian cancer patients.
mRNA-miRNA bipartite network reconstruction to predict prognostic module biomarkers in colorectal cancer stage differentiation.
Motieghader H, Kouhsar M, Najafi A … +2 more , Sadeghi B, Masoudi-Nejad A
Mol Biosyst · 2017 Sep · PMID 28861579 · Publisher ↗
Biomarker detection is one of the most important and challenging problems in cancer studies. Recently, non-coding RNA based biomarkers such as miRNA expression levels have been used for early diagnosis of many cancer typ...
Biomarker detection is one of the most important and challenging problems in cancer studies. Recently, non-coding RNA based biomarkers such as miRNA expression levels have been used for early diagnosis of many cancer types. In this study, a systems biology approach was used to detect novel miRNA based biomarkers for CRC diagnosis in early stages. The mRNA expression data from three CRC stages (Low-grade Intraepithelial Neoplasia (LIN), High-grade Intraepithelial Neoplasia (HIN) and Adenocarcinoma) were used to reconstruct co-expression networks. The networks were clustered to extract co-expression modules and detected low preserved modules among CRC stages. Then, the experimentally validated mRNA-miRNA interaction data were applied to reconstruct three mRNA-miRNA bipartite networks. Twenty miRNAs with the highest degree (hub miRNAs) were selected in each bipartite network to reconstruct three bipartite subnetworks for further analysis. The analysis of these hub miRNAs in the bipartite subnetworks revealed 30 distinct important miRNAs as prognostic markers in CRC stages. There are two novel CRC related miRNAs (hsa-miR-190a-3p and hsa-miR-1277-5p) in these 30 hub miRNAs that have not been previously reported in CRC. Furthermore, a drug-gene interaction network was reconstructed to detect potential candidate drugs for CRC treatment. Our analysis shows that the hub miRNAs in the mRNA-miRNA bipartite network are very essential in CRC progression and should be investigated precisely in future studies. In addition, there are many important target genes in the results that may be critical in CRC progression and can be analyzed as therapeutic targets in future research.
An immunoinformatics approach to promiscuous peptide design for the Plasmodium falciparum erythrocyte membrane protein-1.
Khan N, Kumar R, Chauhan S … +1 more , Farooq U
Mol Biosyst · 2017 Sep · PMID 28856362 · Publisher ↗
Plasmodium falciparum erythrocyte membrane protein-1 (Pfemp-1), a variant adhesion molecule, can act as a key component of immunity against malaria. In the current selection of malaria vaccines, no efficient vaccines are...
Plasmodium falciparum erythrocyte membrane protein-1 (Pfemp-1), a variant adhesion molecule, can act as a key component of immunity against malaria. In the current selection of malaria vaccines, no efficient vaccines are available that can be employed for its proper treatment. Unfortunately, resistance to post-infection treatments is increasing and therefore there is a pressing need to develop an efficient vaccine. Peptide-based vaccines can be effective tools against malaria but HLA restriction is a major hindrance which can be conquered by using promiscuous peptides. In this work, we employed a combined in silico and experimental approach to identify promiscuous peptides for the treatment of malaria. At first, using the immunoinformatics approach, promiscuous peptides were predicted from two conserved domains, CIDR-1 and DBL-3γ, of the Pfemp-1 antigen. These peptides were selected on the basis of their predicted binding affinity with different HLA class-I & class-II alleles. A total of 13 peptides were selected based on their predicted IFN-γ and IL-4 induction ability as well as their hydrophobicity. Out of these 13, the peptide C6 was synthesised and experimentally evaluated for further rationalization, HLA-peptide complex modelling and binding interaction analysis. Interestingly, the peptide C6 (SFIHIYLYRNIRIQL) showed an encouraging immunological response and T-cell proliferation in the immunological assay. This valuable content can aid the better design of more potent and selective vaccine candidates against infectious diseases.
Effects of flexibility and electrostatic interactions on the coupled binding-folding mechanisms of Chz.core and H2A.z-H2B.
Shang X, Chu W, Chu X … +3 more , Liu C, Xu L, Wang J
Mol Biosyst · 2017 Sep · PMID 28832695 · Publisher ↗
The intrinsically disordered protein (IDP) Chz.core, which is the interaction core of Chz1, shows binding preference to histone variant H2A.z. Although there are several studies on the binding process of Chz.core, the de...
The intrinsically disordered protein (IDP) Chz.core, which is the interaction core of Chz1, shows binding preference to histone variant H2A.z. Although there are several studies on the binding process of Chz.core, the detailed coupled binding-folding processes are still elusive. In this study, we explored the coupled binding-folding mechanism and the effect of flexibility by continuously monitoring the flexibility degree of Chz.core. We applied an all-atom structure-based model (SBM), which takes advantage of providing both backbone and sidechain information about the conformational changes of Chz.core during binding. We presented a somewhat different "fly-casting" picture that the long IDP can undergo a tertiary stretching and bending with larger capture radii than ordered proteins. Our results suggest that the higher flexibility of Chz.core contributes to the shorter times for capturing events, leading to higher recognition efficiencies. In addition, compared to the ordered proteins, the high flexibility of the intrinsically disordered protein enables Chz.core to have a lower binding barrier and a faster association rate, which are favorable for the binding process to its partner H2A.z-H2B.
Rational design of an orthogonal noncovalent interaction system at the MUPP1 PDZ11 complex interface with CaMKIIα-derived peptides in human fertilization.
Zhang YL, Han ZF
Mol Biosyst · 2017 Sep · PMID 28832060 · Publisher ↗
The recognition and association between the Ca/calmodulin-activated protein kinase II-α (CaMKIIα) and the multi-PDZ domain protein 1 (MUPP1) plays an important role in the sperm acrosome reaction and human fertilization....
The recognition and association between the Ca/calmodulin-activated protein kinase II-α (CaMKIIα) and the multi-PDZ domain protein 1 (MUPP1) plays an important role in the sperm acrosome reaction and human fertilization. Previously, we have demonstrated that the MUPP1 PDZ11 domain is the primary binding partner of the CaMKIIα C-terminal tail, which can be targeted by a rationally designed sia peptide with nanomolar affinity. Here, we further introduced an orthogonal noncovalent interaction (ONI) system between a native hydrogen bond and a designed halogen bond across the complex interface of the PDZ11 domain with the sia [Asn-1Phe] peptide mutant, where the halogen bond was formed by substituting the o-hydrogen atom of the benzene ring of the peptide Phe-1 residue with a halogen atom (F, Cl, Br or I). Molecular dynamics simulations and high-level theoretical calculations suggested that bromine (Br) is a good compromise between the halogen-bonding strength and steric hindrance effect due to introduction of a bulkier halogen atom into the tightly packed complex interface. Fluorescence spectroscopy assays revealed that the resulting o-Br-substituted peptide (K = 18 nM) exhibited an ∼7.6-fold affinity increase relative to its native counterpart (K = 137 nM). In contrast, the p-Br-substituted peptide, a negative control that is unable to establish the ONI according to structure-based analysis, has decreased affinity (K = 210 nM) upon halogenation.
RNA-sequencing dissects the transcriptome of polyploid cancer cells that are resistant to combined treatments of cisplatin with paclitaxel and docetaxel.
Wang Q, Lu F, Lan R
Mol Biosyst · 2017 Sep · PMID 28825433 · Publisher ↗
Overcoming chemoresistance will prevent cancer relapse and contribute to clinical chemotherapy. In order to explore the underlying mechanism of chemoresistance, we firstly incubated cancer cells with a combination of cis...
Overcoming chemoresistance will prevent cancer relapse and contribute to clinical chemotherapy. In order to explore the underlying mechanism of chemoresistance, we firstly incubated cancer cells with a combination of cisplatin + paclitaxel (C + P) or cisplatin + paclitaxel + docetaxel (C + P + D) to mimic the treatment of cancer therapy in the laboratory. We found that polyploidy is a recurring strategy that cells adopt in response to cisplatin-based treatments. RNA-sequencing was performed to identify differentially expressed genes (DEGs) that may contribute to drug resistance. 4830 and 5518 DEGs were discovered in C + P and C + P + D resistant cells, respectively, and 4384 (73.40%) genes were shared. Possible drug resistance genes like Atg14, Abcb1b, Tbx2, Slc2a9, Slc10a3 and Slc22a18 were up-regulated while Foxm1, Bcl2, Brca1, Chek1, Hiatl1 and Abcb9 were down regulated. Genes involved in the pathways of p53 signaling, lysosomes and apoptosis were up-regulated, and in contrast, genes in the cell cycle, DNA replication, and mismatch repair pathways were down-regulated. Moreover, representative proteins relative to DEGs were examined to validate the results of RNA-seq and RT-PCR. Taken together, these results will contribute to revealing the mechanism of chemoresistance and discovering potential prognostic factors for cancer medication.
Discovering potential driver genes through an integrated model of somatic mutation profiles and gene functional information.
Xi J, Wang M, Li A
Mol Biosyst · 2017 Sep · PMID 28825429 · Publisher ↗
The accumulating availability of next-generation sequencing data offers an opportunity to pinpoint driver genes that are causally implicated in oncogenesis through computational models. Despite previous efforts made rega...
The accumulating availability of next-generation sequencing data offers an opportunity to pinpoint driver genes that are causally implicated in oncogenesis through computational models. Despite previous efforts made regarding this challenging problem, there is still room for improvement in the driver gene identification accuracy. In this paper, we propose a novel integrated approach called IntDriver for prioritizing driver genes. Based on a matrix factorization framework, IntDriver can effectively incorporate functional information from both the interaction network and Gene Ontology similarity, and detect driver genes mutated in different sets of patients at the same time. When evaluated through known benchmarking driver genes, the top ranked genes of our result show highly significant enrichment for the known genes. Meanwhile, IntDriver also detects some known driver genes that are not found by the other competing approaches. When measured by precision, recall and F1 score, the performances of our approach are comparable or increased in comparison to the competing approaches.
CXCR7 attenuates the TGF-β-induced endothelial-to-mesenchymal transition and pulmonary fibrosis.
Guan S, Zhou J
Mol Biosyst · 2017 Sep · PMID 28820530 · Publisher ↗
Lung fibrosis is a progressive and often fatal lung disease characterized by fibroblast proliferation and excessive deposition of extracellular matrix in the lungs. The chemokine receptor CXCR7 has been shown to control...
Lung fibrosis is a progressive and often fatal lung disease characterized by fibroblast proliferation and excessive deposition of extracellular matrix in the lungs. The chemokine receptor CXCR7 has been shown to control cell adhesion, migration and proliferation by regulating the epithelial-to-mesenchymal transition (EMT), but the role of CXCR7 in regulating the endothelial-to-mesenchymal transition (EndMT) and lung fibrosis remains largely unclear. In this study, we investigated the interrelation of CXCR7 and TGF-β, a crucial player in lung fibrogenesis. We report herein that CXCR7 expression is significantly increased in animal models of TGF-β1-induced pulmonary fibrosis and in TGF-β1-treated endothelial cells. TGF-β1 up-regulates CXCR7 expression in a Smad2/3-dependent manner in endothelial cells. The overexpression of CXCR7 effectively attenuates TGF-β1-induced EndMT in lung endothelial cells, whereas CXCR7 knockdown in endothelial cells further promotes TGF-β1-induced EndMT. Mechanically, CXCR7 attenuates EndMT by inhibiting the Jag1-Notch pathway. CXCR7 overexpression in mice also results in a significant enhancement in endothelial markers and a decrease in mesenchymal markers, indicating a decreased susceptibility to TGF-β1-induced lung fibrosis and deposition of extracellular matrix and collagen. These data suggest that CXCR7 upregulation induced by TGF-β is a feedback mechanism to regulate TGF-β-induced EndMT and pulmonary fibrosis.
A cross-platform metabolomics workflow for volume-restricted tissue samples: application to an animal model for polycystic kidney disease.
Sánchez-López E, Happé H, Steenvoorden E … +4 more , Crego AL, Marina ML, Peters DJM, Mayboroda OA
Mol Biosyst · 2017 Sep · PMID 28820206 · Publisher ↗
Metabolic profiling provides an unbiased view of the physiological status of an organism as a "function" of the metabolic composition of a measured sample. Here, we propose a simple LC-MS based workflow for metabolic pro...
Metabolic profiling provides an unbiased view of the physiological status of an organism as a "function" of the metabolic composition of a measured sample. Here, we propose a simple LC-MS based workflow for metabolic profiling of volume-restricted samples, namely individual 20 μm-thick histological sections of a mouse kidney. The main idea of this workflow is to re-use the material after an RPLC-MS run, namely using the volume remaining in the vial after injection, and then introducing a phase changing step to enable HILIC-MS analysis. To test the applicability of the workflow and its ability to extract valuable biological information, we applied it to an animal model of polycystic kidney disease (PKD).
Comprehensive analysis of long noncoding RNA-mRNA co-expression patterns in thyroid cancer.
Du Y, Xia W, Zhang J … +3 more , Wan D, Yang Z, Li X
Mol Biosyst · 2017 Sep · PMID 28817151 · Publisher ↗
Novel molecular-targeted treatments show great prospects for radioiodine-refractory and surgically inoperable thyroid carcinomas. While aberrations in protein-coding genes are a focus in molecular thyroid cancer medicine...
Novel molecular-targeted treatments show great prospects for radioiodine-refractory and surgically inoperable thyroid carcinomas. While aberrations in protein-coding genes are a focus in molecular thyroid cancer medicine, the impact of oncogenes on the expression of long noncoding RNAs (lncRNAs) has been largely uncharacterized. We aimed to identify the expression patterns of lncRNAs and mRNAs in high-throughput molecular profiles of 18 papillary thyroid cancer (PTC) patients. We identified 452 mRNAs and 240 unannotated lncRNAs that were differentially expressed in PTC. Significantly enriched GO terms and pathways were identified, many of which were linked to cancer. By integrating the predicted lncRNA target genes with differentially expressed mRNAs, we identified 20 candidate lncRNAs in 45 PTC patients. Five lncRNAs (CTD-3193O13.11, RP5-1024C24.1, AC007255.8, HOXD-AS1, and RP11-402L6.1) were verified to be differentially expressed in PTC and to exhibit specific topological characteristics in the lncRNA-mRNA co-expression network. LncRNA CTD-3193O13.11 was determined to comprise a node of co-regulation with the other lncRNAs in PTC tumorigenesis. LncRNA RP5-1024C24.1, AC007255.8, and HOXD-AS1 expression was significantly related to clinical stage, lncRNA RP11-402L6.1 expression was associated with lymph node metastasis, lncRNA CTD-3193O13.11 expression was proportional to tumor size, and lncRNA AC007255.8 expression was proportional to patient age. Therefore, our study provides a genome-wide screening and analysis of lncRNA expression in PTC, which brings novel insights into the roles of lncRNAs in PTC progression.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe