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Introduction: Inflammation plays a crucial role in the pathophysiology of cardiometabolic disease. Some experimental data and clinical trials suggest that PPAR-α activation and fibrate therapy suppress inflammation in humans, potentially promoting anti-atherogenic actions. Human experimental endotoxemia provides a controlled model for the study of atherogenic inflammatory responses and their modulation in vivo . We hypothesized that fenofibrate would suppress the inflammatory responses to endotoxin (LPS) in healthy humans. Methods: In the Fenofibrate and Omega-3 Fatty Acid Modulation of Endotoxemia study, 36 healthy volunteers (mean age 26 ± 7 years; mean BMI 24 ± 3 kg/m 2 ; 56% male; 72% Caucasian, 19% African, 8% Asian ancestry) were randomized to fenofibrate 145 mg or placebo daily. After 8 weeks of treatment, subjects underwent a low-dose LPS challenge (0.6 ng/kg intravenous bolus). Anthropometric, clinical, and blood measures were collected at baseline, pre-LPS, and serially for 24 hours after LPS exposure. Results: Compared to placebo, fenofibrate reduced total cholesterol (170 ± 35 to 137 ± 31 mg/dL, p=0.009) and tended to decrease triglycerides (78 ± 40 to 57 ± 23 mg/dL, p=0.611) prior to LPS. LPS induced a modest clinical response with increased temperature, heart rate, and blood pressure ( p p p p =0.08 for both). Conclusions: PPAR-α modulation with fenofibrate did not attenuate clinical or inflammatory responses during low-grade human endotoxemia. These data suggest the anti-inflammatory properties of fenofibrate at clinically-relevant dosing are limited.

The phenylpropanoid pathway is responsible for the biosynthesis of a variety of products that include lignin, flavonoids and hydroxycinnamic acid conjugates. Many intermediates and end products of this pathway play important role in plants as phytoalexins, antiherbivory compounds, antioxidants, ultra-violet (UV) protectants, pigments and aroma compounds. Lignin has far reaching impacts on agriculture, industry and the environment, making phenylpropanoid metabolism a globally important part of plant biochemistry. The mechanical support provided by lignin prevents lodging, a problem in many agronomically important plants, it also provides a hydrophobic surface, essential for longitudinal water transport, and provides a barrier against pathogens. Finally the many functions of lignin and related products in resistance to biotic and abiotic stresses make the phenylpropanoid pathway vital to the health and survival of plants. Besides its critical role in normal plant health and development, high lignin levels are problematic in the agro-industrial exploitation of various plant species. Lignin is considered an undesirable component in paper manufacture, and has a negative impact on forage crop digestibility. Leucaena leucocephala is one of the most versatile, fast growing commercially important trees for paper and pulp industry in India, contributing 1/4th of the total raw material. Lignin composition, quantity and distribution are known to affect the agro-industrial utilization of plant biomass. High quantity and low Syringyl (S) to Guaiacyl (G) lignin ratio plays a detrimental role in economy and ecology of paper production. Every unit increase in S/G ratio decreases the cost of paper production by two and half times. Moreover chemical processing of pulp for lignin removal releases chlorinated organic compounds in effluent, which are hazardous and a serious threat to the environment. Hence, there is currently intense interest in modifying the content and/or composition of the cell wall structural polymer (lignin) as a means of improving the efficiency of the paper pulping process for forest trees. To engineer plants with agronomically useful lignin related traits, we need to devise strategies that can flexibly and predictably yield reductions in lignin content and/or changes in lignin monomer composition. Our studies have concentrated on attempts to alter the levels of enzymes involved in early as well as late phenylpropanoid pathway, mainly by downregulation or upregulation of the phenylpropanoid pathway genes in transgenic L. leucocephala and tobacco plants. Besides, we are also working on some R2R3 type MYB transcription factors supposed to play important role in lignin biosynthesis and some other genes which are not directly involved in phenylpropanoid pathway, but are important for carrying out polymerization of monolignols (peroxidases) and defense mechanism of plants (β glucosidase: family 1 Glycosyl hydrolase). Major phenylpropanoid pathway genes (C4H, 4-CL, CCoAOMT, CCR, Cald5H and CAD) were isolated using PCR based approach. Their 5’ and 3’ UTR determined by rapid amplification of cDNA race (RACE). We could isolate multiple isoforms of most of the genes in this way well supported by Southern hybridization experiment. All the genes were expressed in E. coli and/or yeast with/without the signal sequence. The over-expressed proteins were purified using suitable methods and were used for raising polyclonal antibodies against them. The most un-conserved region of each gene was cloned in antisense orientation in suitable binary vector and L. leucocephala and tobacco explants were transformed using the antisense construct to down-regulate the targeted gene. In order to increase the S/G ratio of lignin monomers sense construct of the target gene was used. We have also done RNAi based downregulation of Cinnamate 4-Hydroxylase (C4H), a key enzyme of phenylpropanoid pathway and a member of cytochrome P450 family in tobacco. Spatio-temporal expression of each gene was studied in L. leucocephala in different tissues at different periods of their growth. Kinetics study of some of the enzymes has been carried out in our lab. We are also trying to establish the structure function correlation of some enzymes. We have also isolated promoters of some phenylpropanoid pathway genes and have identified R2-R3 type MYB binding domain(s) in them. Two MYB genes have been isolated from L. leucocephala and heterologously expressed in Escherichia coli. Their DNA binding efficiency and role in regulating phenylpropanoid pathway remain to be seen. All the isolated genes shared 70-80% homology with the already reported sequences from other species at nucleotide level and more than 80% identity at amino acid level. Different isoforms of different genes had varying degree of identity between them ranging from 80% to more than 95%. We could easily locate the ribosome binding site in the 5’ UTR and the polyadenylation signal in the 3’ UTR in all the genes. Proteins were expressed in both prokaryotic and eukaryotic system. Some of the genes were difficult to express in BL21 (DE3), primarily because of the translational incompatibility of some of the codons in E. coli and may be partly because of the signal sequence present in most of the proteins. All the genes were found to be actively expressing in lignifying tissues and roots in comparison to leaves albeit a time dependent regular expression pattern could not be drawn in case of every gene. We used three methods of genetic transformation for transferring our gene constructs to L. leucocephala embryo viz: Agrobacterium mediatd, gene gun mediated and gene gun followed by cocultivation with Agrobacterium. The transformation and regeneration efficiency varied with each protocol. The transgenic plants invariably showed stunted vigour and slow growth irrespective of the nature of the gene downregulated or upregulated. Initial screening of the transformants was done on MS medium containing appropriate antibiotic and later confirmation was done using PCR with hptII/nptII, gus specific and CaMV35S promoter specific primers. At least one tobacco plant downregulated for C4H showed rudimentary root system and curled leaves with brown tip. Transformed Leucaena and tobacco plants had reduced lignin content with varying degree in case of every downregulated gene. Histochemical staining of transverse root and stem tissue sections showed reduced lignification as evidenced by immunocytolocalization patterns of the candidate protein under study. Promoters of few lignin biosynthetic pathway genes having R2R3 type MYB-binding signal sequences (AC elements) have been cloned. Two R2R3 type MYB transcription factors from L. leucocephala that have been expressed and purified from E. coli will be used for gel retardation studies with the promoter sequences. Also in vitro synthesized oligonucleotides having the highly conserved MYB-binding motifs will be designed to determine the most probable binding sites of the two MYB proteins. Sense construct for the two MYB genes have been transformed in tobacco and antisense construct have been transformed in Leucaena plants to study the after effects of gene manipulation. In short, we have isolated and characterized several genes belonging to phenylpropanoid pathway and have expressed them in different systems. Transgenics for down-regulation or upregulation of those genes have shown very interesting results.

B-tree and R-tree are two basic index structures; many different variants of them are proposed after them. Different variants are used in specific application for the performance optimization. In this paper different variants of B-tree and Rtree are discussed and compared. Index structures are different in terms of structure, query support, data type support and application. Index structure’s structures are discussed first. Btree and its variants are discussed and them R-tree and its variants are discussed. Some structures example is also shown for the more clear idea. Then comparison is made between all structure with respect to complexity, query type support, data type support and application.

We report high gain, high sensitivity 1064-1550 nm avalanche photodiodes (APDs) that are capable of single photon counting in the linear mode below the breakdown voltage and at room temperature. Epitaxial Technologies has developed AIInAs/GaInAs APDs with multiplication gains as high as 347,000, sensitivities of -69 to -77 dBm and photon detection efficiencies as high as 27%. The single photon counting APDs are free of afterpulse artifacts even for pulse widths in the nanosecond range. They can detect single photons at up to 139 MHz and have the capability for gigahertz repetition rate. Based on innovative and proprietary APD production technologies, the APDs have excess noise factors as low as 2 with the high gain. To our knowledge, these are the highest multiplication gains simultaneous with low excess noise factors and high sensitivities reported so far for long wavelength APDs.

Brown tumor is a giant cell lesion associated with hypepararthyroidism. It is a non-neoplastc condition and represents terminal stage of the remodeling process in hyperparathyroid state. This severe parathyroid bone disease is a rare clinical presentation of primary hyperparathyroidism which is due most often to a parathyroid adenoma, secreting parathormone(PTH). Elevated PTH levels cause bone resorption, the formation of polyostotic lesions and a reduction in bone mineral density, predisposing to pathological fractures. Here we report the case of young female having primary hyperthyroidism due to parathyroid adenoma with osteolytic cysic lesions at distal femur, distal end clavicle, iliac bone. She was treated with surgical excision of parathyroid with curettage, autogenous bone grafting, internal fixation with plate after confirming the biopsy report and biochemical, histopathological investigations. At the follow up time patient had no symptoms with full range of motions at knee with excellent fracture healing.

The ability of the chloroplast signal recognition particle (cpSRP) to post-translationally target light harvesting complex proteins (LHCs) to the thylakoid membrane relies on a chloroplast-specific subunit, cpSRP43. cpSRP43 is a multidomain protein that forms a heterodimer with the conserved GTPase, cpSRP54, and subsequently interacts with LHCP substrates to form a soluble targeting complex in the chloroplast stroma. Single-molecule Forster Resonance Energy Transfer (smFRET) and molecular dynamics simulations was employed to determine how the inter-domain structural dynamics of cpSRP43 is affected by binding to cpSRP54 to help address how the formation of the cpSRP heterodimer enables LHCPs to bind and adopt an insertion-competent transit complex. Our results reveal significant inter-domain dynamics (i.e. flexibility) in cpSRP43 across the whole protein with 3 major conformations being identified. Upon binding to cpSRP54, there is a reduction in the flexibility of cpSRP43 in certain regions of the protein. Using isothermal titration calorimetry, we found that the affinity of the L18 recognition site of LHCP to cpSRP43 increased when cpSRP43 was complexed with a cpSRP54 peptide, which corresponds to the cpSRP43 binding site on cpSRP54. These results support the model that cpSRP54 promotes transit complex formation by regulating the inter-domain structural dynamics of cpSRP43.

Passive dry-powder inhalers (DPIs) have been developed as an alternative to pressurised metered-dose inhalers (pMDIs) to improve aerosol delivery on inhalation and eliminate the need for propellants. However, new DPI formulations of generic drugs must be rigorously compared with conventional pMDI therapy. This randomised, double-blind, double-dummy, placebo-controlled, seven-way crossover study evaluated bronchoprotection from methacholine challenge in order to compare a novel salbutamol DPI (Clickhaler) with a reference salbutamol pMDI (Ventolin). Adult asthma patients with airway hyperresponsiveness to methacholine (provocative concentration of methacholine causing a 20% fall in the forced expiratory volume in one second (PC20)

Parallel analysis of RNA ends (PARE) is a technique utilizing high-throughput sequencing to profile uncapped, mRNA cleavage or decay products on a genome-wide basis. Tools currently available to validate miRNA targets using PARE data employ only annotated genes, whereas important targets may be found in unannotated genomic regions. To handle such cases and to scale to the growing availability of PARE data and genomes, we developed a new tool, 'sPARTA' (small RNA-PARE target analyzer) that utilizes a built-in, plant-focused target prediction module (aka 'miRferno'). sPARTA not only exhibits an unprecedented gain in speed but also it shows greater predictive power by validating more targets, compared to a popular alternative. In addition, the novel 'seed-free' mode, optimized to find targets irrespective of complementarity in the seed-region, identifies novel intergenic targets. To fully capitalize on the novelty and strengths of sPARTA, we developed a web resource, 'comPARE', for plant miRNA target analysis; this facilitates the systematic identification and analysis of miRNA-target interactions across multiple species, integrated with visualization tools. This collation of high-throughput small RNA and PARE datasets from different genomes further facilitates re-evaluation of existing miRNA annotations, resulting in a 'cleaner' set of microRNAs.

With its host of outstanding material properties, single-crystal diamond is an attractive material for nanomechanical systems. Here, the mechanical resonance characteristics of freestanding, single-crystal diamond nanobeams fabricated by an angled-etching methodology are reported. Resonance frequencies displayed evidence of significant compressive stress in doubly clamped diamond nanobeams, while cantilever resonance modes followed the expected inverse-length-squared trend. Q-factors on the order of 104 were recorded in high vacuum. Results presented here represent initial groundwork for future diamond-based nanomechanical systems which may be applied in both classical and quantum applications.

As of late, automated methods for generation and tuning of neuronal models have been gaining popularity (e.g. [1]). Several such techniques, including brute-force parameter search space exploration (e.g.[2]) or particle swarm optimization (e.g.[3]), have been successfully applied in this area; however, evolutionary/genetic algorithms seem to be the tool of choice for an increasing number of computational neuroscientists (e.g.[4,5]). Multi-objective evolutionary algorithms (MOEA) lend themselves especially well to this application, as they are capable of generating or tuning neuronal models by optimizing multiple, often conflicting, objectives at the same time (e.g.[6,7]). The one weakness of MOEA-based construction of neuronal models, however, is the fact that it solely relies on the convergence efficiency of the chosen algorithm, and it largely ignores the plethora of available biological knowledge (other than what is utilized in the initial stages of model building in terms of the overall design of the model structure and the definition of fitness functions) that could be used to make the process itself more efficient. In this work, we propose to remedy this situation by hybridizing multi-objective evolutionary algorithms with a fuzzy logic-based controller in order to supply the MOEA with expert knowledge that can improve the algorithm's effectiveness. Fuzzy logic (FL) is a form of multiple-valued logic, which can emulate and incorporate human-like intelligence into a system controlling a process within a closed loop [8]. Fuzzy IF-THEN rules can be used to determine the best possible adjustment to the process based on its current output. Here, the process is the evolutionary algorithm, and the models generated by it are subjected to a set of fuzzy rules to determine the best adjustments, if any, to increase the likelihood of generating models that meet the predefined criteria. The application of fuzzy logic allows for utilization of linguistic rules that are easy to articulate and understand by humans (e.g. "IF spiking frequency is too low, THEN increase axon sodium conductance"), but at the same time can be directly applied to the neuronal models generated by the MOEA via the process of fuzzification (i.e. translation of crisp numerical values into linguistic concepts) and defuzzification, after the pertinent rules have been triggered. Importantly, as the loop continues to execute, more rules can be extracted from the evolutionary algorithm itself by simply identifying the changes across the generations that produced improvement, and mapping that information onto the fuzzy logic domain.

MANETs are Vulnerable to malicious attackers because of their open medium and wide distribution of malicious attackers. Intrusion Detection System detects and reports the malicious activity in ad hoc networks. IDSs usually act as the second layer in MANETs. A detection system called Enhanced Adaptive Acknowledgement (EAACK) specially designed for MANETs. By the accepting MRA scheme, EAACK is capable of finding malicious nodes contempt the existence of the false misbehavior report and against other popular mechanisms in different scenario through simulation. Malicious attackers to falsely report nodes as malicious can produce the false misbehavior report. EAACK is an acknowledgment-based encroachment detection system. When measured over 40% malicious nodes the routing overhead for EAACK (DSA) is 0.58% and Packet delivery ratio is 0.92% for the same. This attack can be deadly to the entire network when the attackers break down sufficient nodes and thus cause a network division. Hybrid Enhanced Adaptive Acknowledgement (HEAACK) which is proposed system adds cryptography mechanism such as RSA and Triple DES giving a secure network and thus the rate of data manipulation and network overhead decreases.

Primers and RACE sequences for BALR-6. Table S2. Antibodies used for bone marrow transplant flow cytometry analysis, and population gating schematics. Tables S3. Antibodies used for CD34 enrichment of human bone marrow flow cytometry analysis, and population gating schematics. (PDF 125 kb)

Serum amyloid a (SAA) is an acute-phase protein that modulates HDL function and predicts cardiovascular disease. The determinants of the inflammatory SAA response are uncertain. Experimental human endotoxemia is a model to study inflammatory modulation of atherogenic pathways in vivo. SAA levels