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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2017

Crosslink: A Fast, Scriptable Genetic Mapper For Outcrossing Species

SummaryCrosslink is genetic mapping software for outcrossing species designed to run efficiently on large datasets by combining the best from existing tools with novel approaches. Tests show it runs much faster than several comparable programs whilst retaining a similar accuracy.\n\nAvailability and implementationAvailable under the GNU General Public License version 2 from https://github.com/eastmallingresearch/crosslink\n\nContactrobert.vickerstaff@emr.ac.uk\n\nSupplementary informationSupplementary data are available at Bioinformatics online and from https://github.com/eastmallingresearch/crosslink/releases/tag/v0.5.

genetics↗

bioRxiv2017

MicroRNA-451a regulates colorectal cancer radiosensitivity

Colorectal cancer (CRC) is a leading cause of cancer-related death. The responses of CRC to standard of care adjuvant therapies such as radiation or chemotherapy are poorly understood. MicroRNAs (miRs) are small non-coding RNAs that affect gene expression programs in cells by downregulating specific mRNAs. In this study, we discovered a set of microRNAs upregulated rapidly in response to a single 2 Gy dose fraction of {gamma}-radiation in a mouse colorectal carcinoma xenograft model. The most upregulated candidate in our signature, miR-451a inhibits tumor cell proliferation and attenuated surviving fraction in longer-term cultures. Conversely, inhibition of miR-451a increased proliferation, tumorsphere formation and surviving fraction of tumor cells. Using a bioinformatics approach, we identified four genes-CAB39, EMSY, MEX3C and EREG as targets of miR-451a. Transfection of miR-451a decreased both mRNA and protein levels of these targets. Importantly, we found miR-451a expression was decreased with tumor stage in a small subset of CRC patients. Finally, analysis of a TCGA colorectal cancer dataset reveals that the CAB39 and EMSY are upregulated at the protein level in a significant number of CRC patients and correlates with poorer overall survival. Taken together, our data indicates miR-451a influences the radiation sensitivity of colorectal carcinomas.

cancer biology↗

bioRxiv2017

Synthesis Of Extracellular Stable Gold Nanoparticles By Cupriavidus metallidurans CH34 Cells

The biogenic synthesis of metallic nanoparticles is of increasing interest. In this report, synthesis of gold nanoparticles by the model heavy metal-resistant strain Cupriavidus metallidurans CH34 and Escherichia coli strain MG1655 was studied. For the synthesis of AuNPs, bacterial cells and secretomes were incubated with Au(III) ions, revealing that only CH34 cells can produce dispersions of AuNPs. Comparative bioinformatic analysis of proteomes from both strains showed potential CH34 proteins that may be electron donors during reduction of extracellular Au(III) ions and for the biosynthesis of gold nuggets in nature. Powder X-ray diffraction demonstrated that biogenic AuNPs are composed of face-centered cubic gold with a crystallinity biased towards {111} planes. Transmission electron microscopy images showed that AuNPs morphology was dominated by triangular and decahedral nanostructures. EDX and FT-IR spectra showed the presence of sulfur and vibrations associated to the biogenic AuNPs. Based on these results, and analyses of previous genomic and proteomic data, a mechanism for extracellular gold reduction and synthesis of AuNPs by strain CH34 is proposed. Average AuNPs diameter was obtained by nanoparticle tracking analysis, dynamic light scattering and analysis of electron microscopy images. DLS studies showed that biogenic AuNPs colloids are stable after exposure to ultrasound, high ionic strength and extreme pH conditions, and revealed the presence of basic groups associated to the AuNPs surface. Electrophoretic and dynamic light scattering indicated that biogenic dispersions of AuNPs are stabilized by a steric mechanism. The AuNPs produced by C. metallidurans CH34 are not cytotoxic towards bacterial cells, in contrast to biogenic AgNPs. These stable non-toxic biogenic AuNPs have potential clinical applications including development of topic delivery formulations and optical biosensors.

biochemistry↗

bioRxiv2017

RetroPath2.0: A retrosynthesis workflow for metabolic engineers

Synthetic biology applied to industrial biotechnology is transforming the way we produce chemicals. However, despite advances in the scale and scope of metabolic engineering, the bioproduction process still remains costly. In order to expand the chemical repertoire for the production of next generation compounds, a major engineering biology effort is required in the development of novel design tools that target chemical diversity through rapid and predictable protocols. Addressing that goal involves retrosynthesis approaches that explore the chemical biosynthetic space. However, the complexity associated with the large combinatorial retrosynthesis design space has often been recognized as the main challenge hindering the approach. Here, we provide RetroPath2.0, an automated open source workflow for retrosynthesis based on generalized reaction rules that perform the retrosynthesis search from chassis to target through an efficient and well-controlled protocol. Its easiness of use and the versatility of its applications make of this tool a valuable addition into the biological engineer bench desk. We show through several examples the application of the workflow to biotechnological relevant problems, including the identification of alternative biosynthetic routes through enzyme promiscuity; or the development of biosensors. We demonstrate in that way the ability of the workflow to streamline retrosynthesis pathway design and its major role in reshaping the design, build, test and learn pipeline by driving the process toward the objective of optimizing bioproduction. The RetroPath2.0 workflow is built using tools developed by the bioinformatics and cheminformatics community, because it is open source we anticipate community contributions will likely expand further the features of the workflow.\n\nHighlightsO_LIState-of-the-art Computer-Aided Design retrosynthesis solutions lack open source and ease of use\nC_LIO_LIWe propose RetroPath2.0 a modular and open-source workflow to perform retrosynthesis\nC_LIO_LIRetroPath2.0 computes reaction network between Source and Sink sets of compounds\nC_LIO_LIRetroPath2.0 is distributed as a KNIME workflow for desktop computers\nC_LIO_LIRetroPath2.0 is ready-for-use and distributed with reaction rules\nC_LI\n\nFundingThis work was supported by the French National Research Agency [ANR-15-CE1-0008], the Biotechnology and Biological Sciences Research Council, Centre for synthetic biology of fine and speciality chemicals [BB/M017702/1]; Synthetic Biology Applications for Protective Materials [EP/N025504/1], and GIP Genopole.

systems biology↗

bioRxiv2017

Contextual Tumor Suppressor Function Of T Cell Death-Associated Gene 8 (TDAG8) In Hematological Malignancies

Key points1. TDAG8 (GPR65) gene expression is down-regulated in hematological malignancies.\n\n2. Restoration of TDAG8 gene expression in blood cancer cells suppresses tumor growth and metastasis.\n\nAbstractExtracellular acidosis is a condition found within the tumor microenvironment due to inadequate blood perfusion, hypoxia, and altered tumor cell metabolism. Acidosis has pleiotropic effects on malignant progression; therefore it is essential to understand how acidosis exerts its diverse effects. In this study a bioinformatics analysis revealed the expression of the proton sensing G-protein-coupled receptor TDAG8 is significantly reduced in human blood cancers in comparison to normal blood cells. To understand how TDAG8 functions in hematological malignancies, TDAG8 expression was restored in U937 acute myeloid leukemia cells and other blood cancer cells. It was discovered that severe acidosis, pH 6.4, inhibited U937 cell proliferation while mild acidosis, pH 6.9, stimulated cell proliferation. However, restoring TDAG8 gene expression modulated the U937 cell response to mild extracellular acidosis and physiological pH by reducing cell proliferation. Tumor xenograft experiments further revealed that restoring TDAG8 expression in U937 and Ramos cancer cells reduced tumor growth. It was also shown U937 cells with restored TDAG8 expression attached less to Matrigel, migrated slower toward a chemoattractant, and metastasized less in severe combined immunodeficient mice. These effects correlated with a reduction in c-myc oncogene expression. The mechanistic investigation indicated that G13/RhoA signaling arbitrated the TDAG8-mediated c-myc oncogene repression in response to acidosis. Overall, this study provides compelling data to support the concept that TDAG8 functions as a contextual tumor suppressor in hematological malignancies and sensitizes blood cancer cells to acidotic stress.

cancer biology↗

bioRxiv2017

Deciphering Molecular Cascades In A Novel Acclimatization Strategy For Rapid Ascent To High Altitude

The repercussions of hypobaric hypoxia are dependent upon two factors-time and intensity of exposure. The effects of intensity i.e. variation of altitude are yet unknown although it is a significant factor in terms of acclimatization protocols. In this study we present the effects of acute (24 h) exposure to high (10,000 ft), very high (15,000 ft) and extreme altitude (25,000 ft) zones on lung and plasma using semi-quantitative redox specific transcripts and quantitative proteo-bioinformatics workflow in conjunction with redox stress assays. Our findings indicate that very high altitude exposure elicits systemic redox homeostatic processes due to failure of lung redox homeostasis without causing mortality. We also document a rapid acclimatization protocol causing a shift from 0 to 100% survival at 25,000 ft in male SD rats upon rapid induction. Finally we posit the various processes involved and the plasma proteins that can be used to ascertain the acclimatization status of an individual.

systems biology↗

bioRxiv2017

A plausible explanation for in silico reporting of erroneous MET gene expression in tumor-educated platelets (TEP) intended for "liquid biopsy" of non-small cell lung carcinoma still refutes the TEP-study

Final amendment noteThis paper had proposed a plausible way for detecting large quantities of MET, which the authors have clarified was not done :the possible explanation proposed for this erroneous MET gene expression does bypass the filtering step we perform in the data processing pipeline, i.e. selection of intron-spanning reads, as can be read in the main text\" comments in http://www.biorxiv.org/content/early/2017/07/02/146134, where a continuing critique of the TEP study continues. Please consider this pre-print closed.\n\nOriginal abstractThe reported over-expression of MET genes in non-small cell lung carcinoma (NSCLC) from an analysis of the RNA-seq data from tumor-educated platelets (TEP), intended to supplement existing liquid biopsy techniques [1], has been refuted recently (http://biorxiv.org/content/early/2017/06/05/146134, not peer-reviewed). The MET proto-oncogene (Accid:NG 008996.1, RefSeqGene LRG 662 on chromosome 7, METwithintrons) encodes 21 exons resulting in a 6710 bps MET gene (Accid: NM 001127500.2, METonlyexons). METwithintrons has multiple matches in the RNA-seq derived reads of lung cancer samples (for example: SRR1982756.11853382). Unfortunately, these are non-specific sequences in the intronic regions, matching to multiple genes on different chromosomes with 100% identity (KIF6 on chr6, COL6A6 on chr3, MYO16 on chr13, etc. for SRR1982756.11853382). In contrast, METonlyexons has few matches in the reads, if at all [2]. However, even RNA-seq from healthy donors have similar matches for METwithintrons so the computation behind the over-expression statistic remains obscure, even if METwithintrons was used as the search gene. In summary, this work re-iterates the lack of reproducibility in the bioinformatic analysis that establishes TEP as a possible source for \"liquid biopsy\".

genomics↗

bioRxiv2017

A Rational Drug Combination Design Proves to Inhibit Epithelial-Mesenchymal Transition in a Three-Dimensional Microenvironment

Epithelial-Mesenchymal Transition (EMT) is a major player of tumor invasiveness whose inhibition is challenged by redundancy of multiple inducing factors. We applied a systems-pharmacology approach by integrating network-based analyses with multiple bioinformatic resources to design a drug combination regimen reversing EMT phenotype in aggressive cancers. We observed that histone deacetylases were critical targets to tune expression of multiple epithelial versus mesenchymal genes. Moreover, SRC and IKBK were the principal intracellular kinases regulating multiple signaling pathways. To validate the anti-EMT efficacy of the target combinations, we inhibited the pinpointed proteins with already prescribed drugs and observed that whereas low dose mono-therapy failed to limit cell dispersion from collagen spheroids in a microfluidic device as a metric of EMT, the combination fully inhibited dissociation and invasion of cancer cells toward co-cultured endothelial cells. Given the approval status and safety profiles of the suggested drugs, the proposed combination set can be considered in clinical trials.

systems biology↗

bioRxiv2017

A set of Columbia-0-specific single nucleotide polymorphism markers for the genetic analysis of natural variation in Arabidopsis thaliana

Genetic markers are important tools for the study of natural and induced genetic variation. Due to the strong increase in the number of genome sequences, an overview of the genomic diversity of many natural strains from individual species could be gained. This allows for the design of markers for flexible use and cost-efficient small scale genetic studies requiring minimal laboratory and bioinformatics effort. Here, we describe 140 single nucleotide polymorphism (SNP) markers with genome-wide distribution that discriminate between the genotype of the common Arabidopsis thaliana reference accession Columbia-0 (Col-0) and the majority of Arabidopsis thaliana accessions that have been sequenced to date. We designed, generated and validated the markers using the kompetitive allele-specific PCR (KASP) technology and made all 140SNPvCol marker assays publicly available through a service provider. Through the integration of available genomic SNP allele information of 1,135 accessions, we found that 120 of these 140 markers could detect non-reference alleles in 647 accessions and more than 100 markers showed non-reference alleles in 1,094 accessions. We further show that the marker set can be used for the verification or identification of accessions of unknown identity. As the KASP methodology is very flexible, an optimal marker subset can be easily selected among the available 140SNPvCol markers presented here to analyze genetic combinations of Col-0 with any other accession.

genetics↗

bioRxiv2017

A dementia-associated risk variant near TMEM106B alters chromatin architecture and gene expression

Neurodegenerative diseases pose an extraordinary threat to the worlds aging population, yet no disease-modifying therapies are available. While genome-wide association studies (GWAS) have identified hundreds of novel risk loci for neurodegeneration, the mechanisms by which these loci influence disease risk are largely unknown. Indeed, of the many thousands of SNP-trait associations identified by GWAS over the past ~10 years, very few are understood mechanistically. Here, we investigate the association of common genetic variants at the 7p21 locus with risk for the neurodegenerative disease frontotemporal lobar degeneration. We show that variants associated with disease risk correlate with increased brain expression of the 7p21 gene TMEM106B, and no other genes. Furthermore, incremental increases in TMEM106B levels result in incremental increases in lysosomal phenotypes and cell toxicity. We then combine fine-mapping, bioinformatics, and bench-based approaches to functionally characterize all candidate causal variants at this locus. This approach identified a noncoding variant, rs1990620, which differentially recruits CTCF, influencing CTCF-mediated long-range chromatin looping interactions between multiple cis-regulatory elements, including the TMEM106B promoter. Our findings thus provide an in-depth analysis of the 7p21 locus linked by GWAS to frontotemporal lobar degeneration, nominating a causal variant and a causal mechanism for allele-specific expression and disease association at this locus. Finally, we show that genetic variants associated with risk for neurodegenerative diseases beyond frontotemporal lobar degeneration are enriched in brain CTCF-binding sites genome-wide, implicating CTCF-mediated gene regulation in risk for neurodegeneration more generally.

genetics↗

bioRxiv2017

A Bayesian Framework for Multiple Trait Colocalization from Summary Association Statistics

MotivationMost genetic variants implicated in complex diseases by genome-wide association studies (GWAS) are non-coding, making it challenging to understand the causative genes involved in disease. Integrating external information such as quantitative trait locus (QTL) mapping of molecular traits (e.g., expression, methylation) is a powerful approach to identify the subset of GWAS signals explained by regulatory effects. In particular, expression QTLs (eQTLs) help pinpoint the responsible gene among the GWAS regions that harbor many genes, while methylation QTLs (mQTLs) help identify the epigenetic mechanisms that impact gene expression which in turn affect disease risk. In this work we propose multiple-trait-coloc (moloc), a Bayesian statistical framework that integrates GWAS summary data with multiple molecular QTL data to identify regulatory effects at GWAS risk loci.\n\nResultsWe applied moloc to schizophrenia (SCZ) and eQTL/mQTL data derived from human brain tissue and identified 52 candidate genes that influence SCZ through methylation. Our method can be applied to any GWAS and relevant functional data to help prioritize disease associated genes.\n\nAvailabilitymoloc is available for download as an R package (https://github.com/clagiamba/moloc). We also developed a web site to visualize the biological findings (icahn.mssm.edu/moloc). The browser allows searches by gene, methylation probe, and scenario of interest.\n\nContactclaudia.giambartolomei@gmail.com\n\nSupplementary informationSupplementary data are available at Bioinformatics online.

genomics↗

bioRxiv2017

Proteomic Architecture of Human Coronary and Aortic Atherosclerosis

The inability to detect premature atherosclerosis significantly hinders implementation of personalized therapy to prevent coronary heart disease. A comprehensive understanding of arterial protein networks and how they change in early atherosclerosis could identify new biomarkers for disease detection and improved therapeutic targets. Here we describe the human arterial proteome and the proteomic features strongly associated with early atherosclerosis based on mass-spectrometry analysis of coronary artery and aortic specimens from 100 autopsied young adults (200 arterial specimens). Convex analysis of mixtures, differential dependent network modeling and bioinformatic analyses defined the composition, network re-wiring and likely regulatory features of the protein networks associated with early atherosclerosis. Among other things the results reveal major differences in mitochondrial protein mass between the coronary artery and distal aorta in both normal and atherosclerotic samples - highlighting the importance of anatomic specificity and dynamic network structures in in the study of arterial proteomics. The publicly available data resource and the description of the analysis pipeline establish a new foundation for understanding the proteomic architecture of atherosclerosis and provide a template for similar investigations of other chronic diseases characterized by multi-cellular tissue phenotypes.\n\nHighlightsO_LILC MS/MS analysis performed on 200 human aortic or coronary artery samples\nC_LIO_LINumerous proteins, networks, and regulatory pathways associated with early atherosclerosis\nC_LIO_LIMitochondrial proteins mass and selected metabolic regulatory pathways vary dramatically by disease status and anatomic location\nC_LIO_LIPublically available data resource and analytic pipeline are provided or described in detail\nC_LI

molecular biology↗

bioRxiv2017

Tracking Subclonal Mutation Frequencies Throughout Lymphomagenesis Identifies Cancer Drivers in Mouse Models of Lymphoma.

Determining whether recurrent but rare cancer mutations are bona fide driver mutations remains a bottleneck in cancer research. Here we present the most comprehensive analysis of retrovirus driven lymphomagenesis produced to date, sequencing 700,000 mutations from >500 malignancies collected at time points throughout tumor development. This enabled identification of positively selected events, and the first demonstration of negative selection of mutations that may be deleterious to tumor development indicating novel avenues for therapy. Customized sequencing and bioinformatics methodologies were developed to quantify subclonal mutations in both premalignant and malignant tissue, greatly expanding the statistical power for identifying driver mutations and yielding a high-resolution, genome wide map of the selective forces surrounding cancer gene loci. Screening two BCL2 transgenic models confirms known drivers of human B-cell non-Hodgkin lymphoma, and implicates novel candidates including modifiers of immunosurveillance such as co-stimulatory molecules and MHC loci. Correlating mutations with genotypic and phenotypic features also gives robust identification of known cancer genes independently of local variance in mutation density. An online resource http://mulv.lms.mrc.ac.uk allows customized queries of the entire dataset.

cancer biology↗

bioRxiv2017

MCE domain proteins: conserved inner membrane lipid-binding proteins required for outer membrane homeostasis

Bacterial proteins with MCE domains were first described as being important for Mammalian Cell Entry. More recent evidence suggests they are components of lipid ABC transporters. In Escherichia coli, the single-domain protein MlaD is known to be part of an inner membrane transporter that is important for maintenance of outer membrane lipid asymmetry. Here we describe two multi MCE domain-containing proteins in Escherichia coli, PqiB and YebT, the latter of which is an orthologue of MAM-7 that was previously reported to be an outer membrane protein. We show that all three MCE domain-containing proteins localise to the inner membrane. Bioinformatic analyses revealed that MCE domains are widely distributed across bacterial phyla but multi MCE domain-containing proteins evolved in Proteobacteria from single-domain proteins. Mutants defective in mlaD, pqiAB and yebST were shown to have distinct but partially overlapping phenotypes, but the primary functions of PqiB and YebT differ from MlaD. Complementing our previous findings that all three proteins bind phospholipids, results presented here indicate that multi-domain proteins evolved in Proteobacteria for specific functions in maintaining cell envelope homeostasis.

microbiology↗

bioRxiv2017

RXFP1 expression is regulated by miR-144-3p in Fibroblasts from Patients with Idiopathic Pulmonary Fibrosis

Relaxin has been considered as a potential therapy for patients with pulmonary fibrosis. We have previously shown, however, that a potential limitation of relaxin-based therapy for Idiopathic Pulmonary Fibrosis (IPF) is the loss of expression of the relaxin receptor Relaxin/Insulin Like Receptor 1 (RXFP1) expression in fibroblasts. The molecular mechanism for RXFP1 down-regulation in IPF patients remains unclear. To determine whether microRNAs play a role in RXFP1 gene expression, we employed a bioinformatics approach to identify microRNAs (miRs) that are predicted to target RXFP1. By in silico analysis, we identified a putative target site in the RXFP1 mRNA for the miR-144 family. We found that miR-144-3p was upregulated in IPF fibroblasts compared to donor lung fibroblast controls. Forced miR-144-3p mimic expression reduced RXFP1 mRNA and protein levels and increased expression of the myofibroblast marker alpha-smooth muscle actin (-SMA) in donor lung fibroblasts. IPF lung fibroblasts transfected with a miR-144-3p inhibitor increased RXFP1 expression and reduced -SMA expression. A lentiviral luciferase reporter vector carrying the WT 3UTR of RXFP1 was repressed more in lung fibroblasts whereas vector carrying a mutated miR-144-3p binding site exhibited less sensitivity to endogenous miR-144-3p expression, suggesting that RXFP1 is a direct target of miR-144-3p. Thus, miR-144-3p is highly expressed in IPF fibroblasts and acts as a negative regulator of RXFP1 protein expression.

biochemistry↗

bioRxiv2017

SLFL Genes Participate in the Ubiquitination and Degradation of S-RNase in Self-Compatible Chinese Peach

The gametophytic self-incompatibility (SI) mediated by S-RNase of Rosaceae, Solanaceae and Plantaginaceae, is controlled by two tightly linked genes located at highly polymorphic S-locus: the S-RNase for pistil specificity and the F-box gene (SFB/SLF) for pollen specificity, respectively. The F-box gene of peach (Prunus persica) is S haplotype-specific F-box (SFB). In this study, we selected 37 representative varieties according to the evolution route of peach and identified their S genotypes. We cloned pollen determinant genes mutant PperSFB1m, PperSFB2m, PperSFB4m and normal PperSFB2, and style determinant genes S1-RNase, S2-RNase, S2m-RNase and S4-RNase. Mutant PperSFBs were translated terminated prematurely because of fragment insertion. Yeast two-hybrid showed that mutant PperSFBs and normal PperSFB2 interacted with all S-RNases. Normal PperSFB2 was divided into four parts: box, box-V1, V1-V2 and HVa-HVb. Protein interaction analyses showed that the box portion did not interact with S-RNases, both of the box-V1 and V1-V2 had interactions with S-RNases, while the hypervariable region of PperSFB2 HVa-HVb only interacted with S2-RNase. Bioinformatics analysis of peach genome revealed that there were other F-box genes located at S-locus, and of which three F-box genes were specifically expressed in pollen, namely PperSLFL1, PperSLFL2 and PperSLFL3, respectively. Phylogenetic analysis showed that PperSFBs and PperSLFLs were classified into two different clades. Yeast two-hybrid analysis revealed that as with PperSFBs, the three F-box proteins interacted with PperSSK1. Yeast two-hybrid and BiFC showed that PperSLFLs interacted with S-RNases with no allelic specificity. In vitro ubiquitination assay showed that PperSLFLs could tag ubiquitin molecules to PperS-RNases. In all, the above results suggest that three PperSLFLs are the appropriate candidates for the general inhibitor, which would inactivate the S-RNases in pollen tubes, and the role of three PperSLFL proteins is redundant, as S-RNase repressors involved in the self-incompatibility of peach.

molecular biology↗

bioRxiv2017

Methyl donor deficient diets cause distinct alterations in lipid metabolism but are poorly representative of human NAFLD

Non-alcoholic fatty liver disease (NAFLD) is a global health issue. Dietary methyl donor restriction is used to induce a NAFLD/non-alcoholic steatohepatitis (NASH) phenotype in rodents, however the extent to which this model reflects human NAFLD remains incompletely understood. To address this, we undertook hepatic transcriptional profiling of methyl donor restricted rodents and compared these to published human NAFLD datasets.\n\nAdult C57BL/6J mice were maintained on control, choline deficient (CDD) or methionine/choline deficient (MCDD) diets for four weeks; the effects on methyl donor and lipid biology were investigated by bioinformatic analysis of hepatic gene expression profiles followed by a cross-species comparison with human expression data of all stages of NAFLD.\n\nCompared to controls, expression of the very low density lipoprotein (VLDL) packaging carboxylesterases (Ces1d, Ces1f, Ces3b) and the NAFLD risk allele Pnpla3 were suppressed in MCDD; with Pnpla3 and the liver predominant Ces isoform, Ces3b, also suppressed in CDD. With respect to 1-carbon metabolism, down-regulation of Chka, Chkb, Pcty1a, Gnmt and Ahcy with concurrent upregulation of Mat2a suggests a drive to maintain S-adenosylmethionine levels. There was minimal similarity between global gene expression patterns in either dietary intervention and any stage of human NAFLD, however some common transcriptomic changes in inflammatory, fibrotic and proliferative mediators were identified in MCDD, NASH and HCC.\n\nIn conclusion, this study suggests suppression of VLDL assembly machinery may contribute to hepatic lipid accumulation in these models, but that CDD and MCDD rodent diets are minimally representative of human NAFLD at the transcriptional level.\n\nSummary statementWe used transcriptional profiling of methyl donor restricted rodents to examine effects on methyl donor and lipid biology. We report novel mechanisms for lipid accumulation in this model and describe significant disparity between both dietary interventions and human disease.

molecular biology↗

bioRxiv2017

Exploration of Western Himalayan region for identification of gold nanoparticles synthesizing bacteria

The development of eco-friendly methods for the synthesis of nanomaterial shape and size is an important area of research in the field of nanotechnology. In present study an indigenous bacterial strain GPI-1 has been isolated from a local gold mine Khaltunala. It was characterized morphological, biochemically and also by using 16S rrna gene technology and was identified as Bacillus flexus GPI-1, the phylogeny of this bacterial strain was determined using various bioinformatics tools viz BLASTn and MEGA 5.0. To achieve maximum invitro gold nanoparticles synthesis various parameters such as pH, incubation temperature, incubation time period and wavelength were optimized as 6.8, 37{degrees}C, 36 hrs, 560 nm respectively. Stable and cubical gold nanoparticles (GNPs) formation with 40-45 nm dimensions were synthesized successfully under invitro conditions upon exposure of gold chloride trihydrates (HAuCl4) solution to the supernatant of Bacillus flexus strain GPI-1. These gold nanoparticles have been characterized by Transmission electron microscope, Fourier transform infrared spectroscopy (FTIR). Thus in the present study successful biosynthesis method of stable and cubical gold nanoparticles in the size range of 12-30 nm using this efficient Bacillus flexus GPI-1 strain. Thus in the present study leading to development of an easy bioprocess for synthesis of GNPs of desired size and shape, has been reported and this green route of biosynthesis of GNPs is a simple, economically viable and an eco-friendly process. The use of gold nanoparticles in biomedical research like X-ray computed tomography and magnetic resonance imaging, cancer research, drug delivery applications.

microbiology↗