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Targeted delivery of anti-inflammatory therapy to rheumatoid tissue by fusion proteins containing an IL-4-linked synovial targeting peptide
Get PDFWe provide first-time evidence that the synovial endothelium-targeting peptide (SyETP) CKSTHDRLC successfully delivers conjugated IL-4 to human rheumatoid synovium transplanted into SCID mice. SyETP, previously isolated by in vivo phage display and shown to preferentially localize to synovial xenografts, was linked by recombinant technology to hIL-4 via an MMP-cleavable sequence. Both IL-4 and the MMP-cleavable sequence were shown to be functional. IL-4-SyETP augmented production of IL-1ra by synoviocytes stimulated with IL-1[beta] in a dose-dependent manner. In vivo imaging confirmed increased retention of SyETP-linked-IL-4 in synovial grafts which was enhanced by increasing number of copies (one to three) in the constructs. Strikingly, SyETP delivered bioactive IL-4 in vivo as demonstrated by increased pSTAT6 in synovial grafts. Thus, this study provides proof of concept for peptide-tissue-specific targeted immunotherapy in rheumatoid arthritis. This technology is potentially applicable to other biological therapies providing enhanced potency to inflammatory sites and reducing systemic toxicity
Identification and Evolution of Transcription Factors in Stramenopiles
Get PDFBackground. 
Many transcriptional regulatory proteins have been identified and classified into several families on the basis of sequence similarity (Fukami, 2003), these families usually regulate important biological processes, such as development and responses to external stimuli. Transcription factors (TFs) regulate spatial and temporal gene expression by binding to DNA and either activating or repressing the action of RNA polymerases (Latchman, 2004); in addition to TFs, other Transcriptional regulators (TRs) participate in transcriptional modulation by e.g., chromatin remodeling. With the availability of genome sequences for several organisms and computational strategies for gene functional annotation, the entire set of Transcription factors (TFs) and Transcription regulators (TRs) can be identified, described, and compared between species and lineages. The diversity among Stramenopiles is striking; they range from large multicellular seaweeds to tiny unicellular species, they are present in freshwater, marine and terrestrial habitats and embrace many ecologically important algal (e.g. diatoms, brown algae, chrysophytes), and heterotrophic (e.g., Oomycetes) groups.

Methods. 
In order to find TF and TR genes in the deduced proteomes of Stramenopile we followed the approach developed in Perez et al. 2010. Briefly, it exploits the presence of protein domains and their combinations, in the form of boolean rules, that are specific for different families of TFs and TRs. Such rules are represented as a bipartite graph in which a set of nodes represent gene families and the other set of nodes, protein domains. Edges are drawn between nodes of different types indicating whether a protein domain is required in the gene family or it is forbidden.

Results. 
We applied an enlarged set of rules to the deduced proteomes of 8 different Stramenopiles, identifying more than 400 different regulatory genes in each species belonging to up to 59 different gene families.

Conclusions. 
The identification of this class of regulatory genes will constitute and important resource that could be exploited in gene functional characterization and evolutionary analyses. All TFs and TRs families found will be publicly released via a web database.

References.
Pérez-Rodríguez P, Riaño-Pachón DM, Corrêa LG, Rensing SA, Kersten B, Mueller-Roeber B. 2010. Nucleic Acids Res. 38(Database issue):D822-
Gas phase enthalpies of formation, isomerization, and disproportionation of mono- through tetra-substituted tetrahedranes: A G4MP2/G4 theoretical study
Get PDFGas phase (298.15 K, 1 atm) enthalpies of formation (Δ~f~H°~(g)~), enthalpies of disproportionation to two corresponding acetylene molecules (Δ~rxn~H°~(g),Td→acet~), and enthalpies of isomerization from a tetrahedrane geometry to a 1,3-cyclobutadiene structure (Δ~isom~H°~(g),Td→CBD~) were calculated for the mono- through tetra-substituted hydro, fluoro, chloro, bromo, methyl, ethynyl, and cyano carbon tetrahedrane derivatives at the G4MP2 and G4 levels of theory. All derivatives have endothermic Δ~f~H°~(g)~ indicative of the cage strain in these systems. In all cases, Δ~rxn~H°~(g),Td→acet~ and Δ~isom~H°~(g),Td→CBD~ are predicted to be substantially exothermic. High quality linear regression fits within a homologous series were obtained between the number of substituents and the G4MP2/G4 estimated Δ~f~H°~(g)~. Via calculations on lower homolog members, this strategy was employed to allow extrapolated G4 and/or G4MP2 Δ~f~H°~(g)~ (as well as some Δ~rxn~H°~(g),Td→acet~ and Δ~isom~H°~(g),Td→CBD~) to be obtained for the mono- through tetra-substituted t-butyl, trifluoromethyl, and trimethylsilyl carbon tetrahedrane derivatives
ChemTextMiner: An open source tool kit for mining medical literature abstracts
Get PDFText mining involves recognizing patterns from a wealth of information hidden latent in unstructured text and deducing explicit relationships among data entities by using data mining tools. Text mining of Biomedical literature is essential for building biological network connecting genes, proteins, drugs, therapeutic categories, side effects etc. related to diseases of interest. We present an approach for textmining biomedical literature mostly in terms of not so obvious hidden relationships and build biological network applied for the textmining of important human diseases like MTB, Malaria, Alzheimer and Diabetes. The methods, tools and data used for building biological networks using a distributed computing environment previously used for ChemXtreme[1] and ChemStar[2] applications are also described
Large scale expansion of mobile elements in specific hotspot regions of the German outbreak _Escherichia coli_ O104:H4
Get PDFThe outbreak strain of _E. coli_ O104:H4 has been sequenced by several groups and made available publicly for CrowdSourcing purposes. Genome comparisons of the complete finished sequence of TY2482 (BGI), have been made with the draft assemblies of c22711 (PacBio) and an historical outbreak strain from 2001 (U. Münster & Life Technologies). A plasmid, pTY2, carrying the _agg_ operon specifying the genes for aggregative adherence fimbriae reveals a frameshift in a gene, _aggB_, that may result in altered binding _in vivo_ compared to the unframeshifted state. Comparisons additionally reveal the presence of genomic islands specific to the outbreak strain relative to other sequenced _E. coli_ strains. These regions, and islands shared with the closest previously sequenced relative _E. coli_ 55989 have been analyzed for insertion sequences and transposable elements. Several islands found in the above strains that are not present in other sequenced _E. coli_ are found to harbor a large-scale expansion of mobile elements that are by and large confined to these hotspot or permissive areas of the chromosome. The implication is that these regions are in genomic flux and may represent specific areas of future concern due to the possibility of mobilisation of the associated genomic features likely responsible for the pathogenic features and antibiotic resistance seen in these strains
Potential Use of Folate-polyethylene glycol (PEG)-Appended Dendrimer (G3) Conjugate with alpha-Cyclodextrin as DNA Carriers to Tumor Cells
Get PDFWe previously reported that polyamidoamine STARBURST dendrimer (generation 3, G3) (dendrimer) conjugate with alpha-cyclodextrin (alpha-CyD) having an average degree of substitution of 2.4 of alpha-CyD (alpha-CDE) provided remarkable aspects as novel carriers for DNA and siRNA. To develop novel alpha-CDE derivatives with tumor cell specificity, we prepared folate-appended alpha-CDEs (Fol-alpha-CDEs) and folate-polyethylene glycol (PEG)-appended alpha-CDEs (Fol-PalphaCs) with the various degrees of substitution of folate (DSF), and evaluated in vitro and in vivo gene transfer activity, cytotoxicity, cellular association and physicochemical properties. In vitro gene transfer activity of Fol-alpha-CDEs (G3, DSF 2, 5 or 7) was lower than that of α-CDE (G3) in KB cells, folate receptor (FR)-overexpressing cancer cells. Of the three Fol-PalphaCs (G3, DSF 2, 5 or 7), Fol-PalphaC (G3, DSF 5) had the highest gene transfer activity in KB cells. The activity of Fol-PalphaC (G3, DSF 5) was significantly higher than that of alpha-CDE (G3) in KB cells, but not in A549 cells, FR-negative cells. Negligible cytotoxicity of the pDNA complex with Fol-PalphaC (G3, DSF 5) was observed in KB cells or A549 cells up to a charge ratio of 100/1 (carrier/pDNA). The cellular association of the pDNA complex with Fol-PalphaC (G3, DSF 5) could be mediated by FR on KB cells, resulting in its efficient cellular uptake. Fol-PalphaC (G3, DSF 5) had higher binding affinity with folate binding protein (FBP) than alpha-CDE (G3), although the physicochemical properties of pDNA complex with Fol-PalphaC (G3, DSF 5) were almost comparable to that with alpha-CDE (G3), although the onset charge ratio and the compaction ability of Fol-PalphaC (G3, DSF 5) were slightly different. Fol-PalphaC (G3, DSF 5) tended to show higher gene transfer activity than alpha-CDE (G3) 12 h after intratumoral administration in mice. These results suggest that Fol-PalphaC (G3, DSF 5), not Fol-alpha-CDEs, could be potentially used as a FR-overexpressing cancer cell-selective DNA carrier
In-silico analysis and identification of novel lead molecule for human IGFBP-4 involved in cardiovascular diseases
No full textCardiovascular disease is the major cause of disability and premature death throughout the world and contributes substantially to the escalating costs of health care. Insulin like growth factor binding protein 4 (IGFBP-4) mainly belongs to the family of IGFB protein. Over expression of IGFBP-4 leads to cardiovascular diseases namely stroke, acute myocardial infarction and heart failure. IGFBP-4 serves as an effective drug target against cardiovascular disease. Hence, ligand based virtual screening was persuaded in the present study to propose potential inhibitors of IGFBP-4. Two inhibitors (mainly from literature search) were selected to initiate high throughput virtual screening from small molecule databases namely, NCI, ChemBank, ChemPDB, AKos GmbH, Asinex Ltd and KEGG ligand. The structures listed through database search were docked with IGFBP-4 using virtual screening workflow of Maestro v9.2. Three leads that showed better binding affinity and good correlation with two published inhibitors were proposed as potential IGFBP-4 inhibitors. The three proposed leads showed good pharmacological properties in comparison to the two existing inhibitors. The analyses supported efficiency of three leads for next generation drug designing for cardiovascular diseases
The Starving Cell: Metabolic Syndrome as an Adaptive Process
Get PDFMetabolic syndrome (MetS) is commonly presumed to stem from obesity, with both propelled by energy surfeit: positive balance of calories consumed to energy expended. A complementary thesis is proposed: that episodes of cell energy deficit (not expressly calorie deficit) drive MetS – the “Starving Cell.” 
Risk factors for MetS include hypoxemia from sleep apnea, severe calorie debt, mitochondrial dysfunction, oxidative stress; and sleep restriction, illness, surgery, trauma, cold. Each fosters inadequate cell energy, hampering production or boosting demand. MetS factors support energy: glucose, triglycerides, abdominal/visceral fat – and blood pressure, sustaining perfusion. Additional energy-supportive adaptations co-occur in MetS: e.g. increased free fatty acids and deposition of metabolically active ectopic fat. Indeed, increased appetite/calories and reduced activity – features of the energy surfeit model – also arise as adaptations to cell energy deprivation. Among persons who are overweight, the risk for MetS remains determined by energy deprivation contributors. 
The Thrifty Gene hypothesis, and MetS promotion by fetal energy deprivation, prefigure the Starving Cell thesis. However, evidence is vastly more comprehensive in connecting cell energy deprivations to MetS elements: generalizing the sources of energy deficit that dispose to MetS; the populations vulnerable to their impact; and the forms of adaptation implemented to protect energy. This clarifies why MetS factors cohere; and why other energy-supportive adaptations attend them. It explains bidirectional MetS associations; and why MetS factors appear “paradoxically” protective in some populations. It generates predictions, and suggests approaches to MetS mitigation that complement and modify existing approaches, and may augment their efficacy
Food Physical Chemistry and Biophysical Chemistry
Get PDFFood Physical Chemistry is considered to be a branch of Food Chemistry^1,2^ concerned with the study of both physical and chemical interactions in foods in terms of physical and chemical principles applied to food systems, as well as the applications of physical/chemical techniques and instrumentation for the study of foods^3,4,5,6^. This field encompasses the "physiochemical principles of the reactions and conversions that occur during the manufacture, handling, and storage of foods"^7^. Two rapidly growing, related areas are Food Biotechnology and Food Biophysical Chemistry. 

A comparative study on the production of ethanol from lignocellulosic biomass by chemical and biological method
Get PDFEthanol derived from non-edible biomass is renewable and a clean source of energy. It is independent of the food industry and it is economically feasible. The first generation biofuel or bioethanol is still not a very convenient source of energy as it prominently depends on the availability of grains. The main objective of this work is to develop an industrious efficient process to produce ethanol from lignocellulosic biomasses like wood and leaf in a lab scale. Two processes were compared. The first process involved an alkaline pre-treatment of the powdered biomass followed by dilute acid hydrolysis. The second process involved an alkaline treatment followed by direct hydrolysis of the biomass by use of a fungal species obtained from rotting wood. Following hydrolysis, fermentation was performed using _Saccharomyces cerevisiae_ and ethanol produced was measured. The process methodologies performed here are liable to be scaled up easily. The final study determines factors such as temperature, strength of the reagents and retention time to maximize ethanol production