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At least 343 records · Page 19Linked to original sources

PubMed2005

Application of a KDPG-aldolase gene-dependent addiction system for enhanced production of cyanophycin in Ralstonia eutropha strain H16.

Two different recombinant plasmids both containing the cyanophycin synthetase gene (cphA) of Synechocystis sp. strain PCC6308 but differing concerning the resistance marker gene were tested for their suitability to produce high amounts of cyanophycin in recombinant strains of Ralstonia eutropha. Various cultivation experiments at the 30-L scale revealed very low cyanophycin contents of the cells ranging from 4.6% to 6.2% (w/w) of cellular dry weight (CDW) only, most probably because most cells had lost the corresponding plasmid during cultivation. To establish a cost effective and high efficient system for production of cyanophycin at larger scales using recombinant strains of R. eutropha, we applied two strategies: First, we integrated cphA into the dispensable chromosomal l-lactate dehydrogenase gene (ldh) of R. eutropha. Depending on the cultivation conditions used, relatively low cyanophycin contents between 2.2% and 7.7% (w/w) of CDW were reproducibly detected, which might be due to weak expression or low gene dosage in the single cphA copy strain of R. eutropha. In a second strategy we constructed a KDPG-aldolase gene (eda)-dependent addiction system, which combined features of a multi-copy plasmid with stabilized expression of cphA. Flasks experiments revealed that the cells accumulated extraordinarily high amounts of cyanophycin between 26.9% and 40.0% (w/w) of CDW even under cultivation conditions lacking cyanophycin precursor substrates or plasmid stabilizing antibiotics. Cyanophycin contents of up to 40.0% (w/w) of CDW were also obtained at a 30-L scale or a 500-L pilot-plant scale under such non-selective conditions. This demonstrates impressively that the stabilizing effect of the constructed eda-dependent addiction system can be used for production of enhanced amounts of cyanophycin at a larger scale in recombinant strains of R. eutropha.

Aldehyde-Lyases↗

PubMed2001

Potent antitumor activity and improved pharmacological profile of ST1481, a novel 7-substituted camptothecin.

Relevant drawbacks of the molecular structure and mechanism of the action of camptothecins are the instability of the E ring lactone and the reversibility of drug-target interaction. Such features are expected to limit the clinical efficacy of conventional camptothecins. In an attempt to overcome these limitations and to improve the pharmacological profile of camptothecins, a novel series of seven modified lipophilic analogues was synthesized based on the hypothesis that lipophilicity could promote a rapid cellular accumulation and stabilization of drug-target interaction. A novel analogue (ST1481) of the series, characterized by a potent antitopoisomerase and cytotoxic activity, was selected for preclinical development. A detailed preclinical study of ST1481 was performed in the H460 non-small cell lung tumor model using oral administration and various treatment schedules. Under all of the conditions, ST1481 exhibited an impressive efficacy in terms of tumor growth inhibition (tumor volume inhibition percentage > 99%), log(10) cell kill, rate of complete responses (including "cures"), and an improvement of the therapeutic index compared with topotecan (used as the reference drug). The cytotoxic potency was also reflected by the in vivo potency, because the drug activity was observed at doses as low as 0.25 mg/kg with the daily schedule. In contrast to topotecan, no cross-resistance to ST1481 was found in ovarian carcinoma cells overexpressing P-glycoprotein (A2780/DX). A similar trend in the improvement of activity was also observed in the same tumor model growing in vivo with a 100% rate of complete tumor regressions. A rapid intestinal absorption and good oral bioavailability were supported by in vivo distribution studies, because the peak values of drug accumulation were found from 1 to 2 h after administration. The relevant liver accumulation may account for a marked effect of ST1481 against liver metastases induced by the ovarian carcinoma IGROV-1. In conclusion, the results support the hypothesis that a potent lipophilic camptothecin with a proper substituent at the position 7 may have therapeutic advantages likely related to a rapid intracellular uptake and tissue distribution, stabilization of the drug-target complex, and good oral bioavailability. Overall, the results support the preclinical interest of ST1481 in terms of efficacy, potency, toxicity profile, and ability to overcome multidrug resistance.

Administration, Oral↗

PubMed1998

Sociometric classification methods in school peer groups: a comparative investigation.

The categorical consequences and psychometric properties of different sociometric classification methods were evaluated. Children aged 9 to 12 years (N = 254) completed three sociometric questionnaires and a peer assessment measure on two occasions 5 weeks apart. The sociometric data were analysed using 13 different methods. Analysis of kappa values indicated relatively poor agreement across methods on subject classification. Temporal stability of the classifications was also poor. Assessment of construct validity involved analysis of the peer assessment items, using MANOVA to test hypotheses based on ideas from social exchange theory. Cross-sex rating biases and difficulties with the neglected and controversial classifications are discussed as indicating a need for the application of theoretically based approaches which consider features of the peer group social system and a need for caution in selecting methods for clinical use.

Child↗

PubMed1988

New features of microtubule behaviour observed in vivo.

The microtubule cytoskeleton is thought to be intimately involved in generating and maintaining cell polarity and can generate many different morphological structures from a few structural elements. The mechanism by which these structures are generated has been partially elucidated from studies of microtubule polymerization both in vitro and in vivo. Microtubules in vitro exist in growing (polymerizing) and shrinking (depolymerizing) populations that interconvert infrequently. This behaviour, termed dynamic instability, permits microtubules in the cell rapidly to explore different arrangements and allows selective stabilization of specific morphologies. To investigate the regulation of these processes, we have implemented techniques for direct observation of fluorescently labelled microtubules and developed them to observe the dynamic behaviour of individual microtubules in single living cells. Sammak and Borisy recently used this technique to show that the dynamics of microtubules in fibroblasts is explained by dynamic instability. Although we also conclude here that dynamic instability explains much of microtubule behaviour in vivo, we find significant deviations from the properties of tubulin in vitro. These results suggest that local cytoplasmic factors strongly influence microtubule dynamics; such control has important implications for cellular morphogenesis.

Animals↗

PubMed1996

An Adaptive Structure Neural Networks with Application to EEG Automatic Seizure Detection.

This paper introduces a new algorithm for adaptively adjusting the structure of a multi-layer back-propagation network. The proposed algorithm belongs to the class of neuron generating strategies as opposed to the class of neuron pruning strategies. Initially a "small" multi-layer perceptron network is selected. The stabilized error is used as an index to determine whether the network needs to generate a new neuron or not. If after a period of learning the error is stabilized, but the error is larger than a desired value, then new neuron(s) is (are) generated. The new neurons are placed at locations that contribute most to the network error behavior through the fluctuation in their input weight vectors. Among the features of the new architecture are its improved performance and generalization capabilities compared to a standard fixed-structure back-propagation network. Application to an electroencephalogram (EEG) automatic epileptic seizure detection is presented to illustrate advantages and capabilities of the proposed algorithm. Using an actual data from five patients it is shown that the proposed approach correctly identifies all true seizures that are also identified by an expert physician. The new algorithm provides a reduction of 60-70% in the training epochs as compared to a back-propagation algorithm. Furthermore, it is shown that by utilizing a new training algorithm it is possible to reduce the false seizure detections to zero while resulting in a 5.1% error in identifying the true seizures. Copyright 1996 Elsevier Science Ltd

Journal Article↗

PubMed1999

Structure-physicochemical function relationships of soybean beta-conglycinin constituent subunits.

Beta-conglycinin, one of the dominant storage proteins of soybean, has a trimeric structure, being composed of three subunits alpha, alpha', and beta. The alpha and alpha' subunits contain the extension regions in addition to the core regions common to all subunits, which are N-glycosylated. Physicochemical functions of recombinant nonglycosylated individual subunits and deletion mutants (alpha(c) and alpha'(c)) lacking the extension regions of the alpha and alpha' subunits were examined at pH 7.6 and 3.7 at low (mu = 0.08) and high (mu = 0.5) ionic strengths. Although individual recombinant subunits exhibited different properties at all conditions, there were some consistencies. Surface hydrophobicities and thermal stabilities of the individual subunits were likely to be conferred by their core regions, and the carbohydrate moieties did not contribute to these properties at any conditions examined here. Solubility at mu = 0.08, heat-induced association, and emulsifying ability remarkably depended on the extension regions and the carbohydrate moieties in addition to the structural features of the core regions. These findings indicate that various end products could be produced by the selection of soybean varieties containing beta-conglycinin with different subunit compositions and suggest a direction for a principle of soybean breeding.

Antigens, Plant↗

PubMed2005

Probing the intermediates of halogen addition to alkynes: bridged halonium versus open halovinyl cation; a theoretical study.

[Reaction: see text]. Intermediates formed in halogen addition (X = Br, Cl, F) to alkynes (ethyne, propyne, 2-butyne, trifluoromethylethyne, trimethylsilylethyne, and 1-trimethylsilylpropyne) were studied computationally by MP2 at the MP2/6-311++G(3df,3pd) level and/or by DFT at the B3LYP/6-31+G(d) level. Structure optimization and frequency calculations were performed to identify the minima and to obtain their relative energies. PCM calculations (with H2O, CH2Cl2, and CCl4 as model solvents) were employed to examine solvation effects on the relative stabilities in the resulting bridged halonium, -halovinyl, or -halovinyl cations. GIAO-MP2 and GIAO-DFT calculations were employed to compute NMR chemical shifts (13C, 19F, and 29Si as appropriate). In selected cases, PCM-GIAO calculations were also performed to investigate the extent of solvent effects on the computed NMR shifts. The NPA-derived charges and the GIAO shifts were examined in comparative cases to shed light on structural features. In several cases, structure optimization starting with the -halovinyl cations resulted in -halovinyl cations (via formal hydride shift or trimethylsilyl shift). With the CF3 derivative (when X = F), a formal F shift results in polyfluoroallyl cation generation from fluorovinyl cation as starting geometry.

Alkynes↗

PubMed2006

Deposition of DNA rafts on cationic SAMs on silicon [100].

We demonstrate a guided self-assembly approach to the fabrication of DNA nanostructures on silicon substrates. DNA oligonucleotides self-assemble into "rafts" 8 x 37 x 2 nm in size. The rafts bind to cationic SAMs on silicon wafers. Electron-beam lithography of a thin poly(methyl methacrylate) (PMMA) resist layer was used to define trenches, and (3-aminopropyl)triethoxysilane (APTES), a cationic SAM precursor, was deposited from aqueous solution onto the exposed silicon dioxide at the trench bottoms. The remaining PMMA can be cleanly stripped off with dichloromethane, leaving APTES layers 0.7-1.2 nm in thickness and 110 nm in width. DNA rafts bind selectively to the resulting APTES stripes. The coverage of DNA rafts on adjacent areas of silicon dioxide is 20 times lower than on the APTES stripes. The topographic features of the rafts, measured by AFM, are identical to those of rafts deposited on wide-area SAMs. Binding to the APTES stripes appears to be very strong as indicated by "jamming" of the rafts at a saturation coverage of 42% and the stability to repeated AFM scanning in air.

Microscopy, Atomic Force↗

PubMed2026

Bacteriophages Control Epiphytic Pseudomonas syringae Populations in Highbush Blueberry Leaves.

The Pseudomonas syringae complex (Psc) is a group of globally distributed phytopathogens responsible for substantial agricultural losses. Although bacteriophage-based biocontrol has shown promise against Psc, no studies have examined phages targeting blueberry-tropic Psc lineages. Here, we isolated phages infecting Psc strains from diseased highbush blueberry (Vaccinium corymbosum), and evaluated their suitability for biocontrol using a multi-stage screening pipeline incorporating host-range analysis, comparative genomics, environmental stability testing, in vitro antibacterial efficacy assays and ex planta validation. Twelve of the isolated phages exhibited favourable host-range characteristics. Genomic analyses revealed substantial phylogenetic diversity among these candidates but simultaneously identified multiple clonal groups, reducing the collection to eight non-redundant phages spanning five distinct genera. Candidate phages generally retained infectivity under environmentally relevant conditions and exhibited heterogeneous but largely favourable stability profiles. Planktonic killing assays uncovered considerable variation in antibacterial efficacy, but phage performance appeared to be driven by infection compatibility and host-specific factors rather than properties intrinsic to individual phages. Notably, the jumbo phageCB10 emerged as a particularly promising candidate due to its strong antibacterial activity (median GRC = 0.943), favourable environmental stability and unique genomic features. Cocktails containing the most effective candidates produced substantial and longitudinally sustained reductions in epiphytic colonization of detached blueberry leaves by Psc, exceeding five orders of magnitude at peak efficacy and demonstrating robust activity in a biologically relevant ex planta system. Importantly, in vitro antibacterial efficacy was predictive of performance in our ex planta model (r = 0.67; p = 0.0003), supporting the utility of tiered screening approaches for candidate selection. Taken together, these findings establish a framework for the systematic identification and evaluation of phages targeting Psc, and support the development of phage-based interventions for managing plant diseases.

Pseudomonas syringae↗

PubMed1981

Transport models for secretory IgA and secretory IgM.

At least seven models have been proposed for the epithelial transport of IgA, and each model presents particular features which are not generally appreciated. Much of the confusion in this field has been caused by the many conflicting reports about the cellular origin of the secretory component (SC) and the mode in which it is expressed by secretory epithelial cells. The transport model proposed in 1973-74 on the basis of test-tube experiments and immunohistochemical studies has now gained considerable support from observations made on both normal and neoplastic living epithelial cells According to this model, the J ("joining') chain and SC represent "the lock and key' in the selective external translocation of both dimeric IgA and pentameric IgM through serous-type secretory epithelial cell. Incorporation of J chains into these two Ig isotypes during their production in gland-associated immunocytes induces a configurational fit (binding site) allowing them to combine by specific non-covalent interactions with SC in the plasma membrance of the epithelial cell. After being formed on the basolateral surface of the cell, the SC-IgA and SC-IgM complexes are transported in cytoplasmic vesicles to the gland lumen along with some free SC. Covalent stabilization of human secretory IgA during this process depends on unique possibilities for disulphide-exchange reactions and is not an inherent feature of the transport model.

Animals↗

PubMed2002

The use of stereotactic radiosurgery to treat intractable childhood partial epilepsy.

PURPOSE: Although conventional surgery is presently used to treat seizures of temporolimbic and neocortical origin, deep-seated lesions are often associated with morbidity. Stereotactic radiosurgery is a noninvasive procedure that effectively treats patients with vascular malformations and brain tumors, but its efficacy for epileptogenic foci is limited, especially in children. METHODS: Between 1995 and 1999, four candidates who had medically uncontrolled seizures and localized seizure foci were selected for stereotactic radiosurgery, with a mean age of 9.75 years at the time of surgery (range, 4-17 years). Seizure foci were identified on the basis of ictal and interictal video-EEG. Magnetic resonance (MR) images were obtained before and after surgery. Ictal single-photon emission computed tomography (SPECT) was performed by using stabilized hexamethyl-propyleneamine oxime (HMPAO; 300 microcuries/kg) with early injection after electrographic ictal onset. The clinical features of the patients are given. All radiosurgical procedures were performed with the gamma knife unit with the Leksell stereotactic frame, stereotactic MRI imaging, and the Gamma Plan workstation. Seizure outcome was scored according to Engel's classification. RESULTS: Two patients had hypothalamic hamartoma (HH), and two had neocortical epilepsy. At mean follow-up of 39.2 months (range, 26-69 months), two patients were seizure free, one with a HH and one with a suggestive developmental tumor in the insular cortex by MRI findings. The other patient with HH had 90% reduction of seizures. One patient with a widespread seizure focus that involved the motor strip was unimproved. The two patients with HH also exhibited markedly improved neurobehavioral status after surgery. There were no significant complications of radiosurgical therapy. CONCLUSIONS: Our findings suggest that gamma knife surgery is a potentially valuable treatment modality for children with medically intractable epilepsy due to a well-localized seizure focus that is difficult to excise by conventional techniques or for whom they are deemed unsuitable. More widespread application in childhood epilepsy should be investigated in larger series.

Adolescent↗

PubMed2006

The complete sequence and segregational stability analysis of a new cryptic plasmid pIGWZ12 from a clinical strain of Escherichia coli.

A new cryptic plasmid from a multi-resistant, multi-plasmid clinical strain of Escherichia coli has been isolated. The sequence of the 4072-base-pair pIGWZ12 (GenBank Accession No. DQ311641) was determined and analyzed. Two open-reading frames that code for proteins involved in plasmid mobilization and initiation of replication were identified. The putative origin of replication possesses all characteristic features of the theta mechanism for replicating plasmids. pIGWZ12 is stably maintained without selective pressure in bacterial cultures (for up to 80 generations), making it a good candidate for engineering a new cloning vector.

Amino Acid Sequence↗

PubMed2002

Solution structure of Pisum sativum defensin 1 by high resolution NMR: plant defensins, identical backbone with different mechanisms of action.

Pisum sativum defensin 1 (Psd1) is a 46 amino acid residue plant defensin isolated from seeds of pea. The three-dimensional structure in solution of Psd1 was determined by two-dimensional NMR data recorded at 600 MHz. Experimental restraints were used for structure calculation using CNS and torsion-angle molecular dynamics. The 20 lowest energy structures were selected and further subjected to minimization, giving a root-mean-square deviation of 0.78(+/- 0.22) A in the backbone and 1.91(+/-0.60) A for over all atoms of the molecule. The protein has a globular fold with a triple-stranded antiparalell beta-sheet and an alpha-helix (from residue Asn17 to Leu27). Psd1 presents the so called "cysteine stabilized alpha/beta motif" and presents identical three-dimensional topology in the backbone with other defensins and neurotoxins. Comparison of the electrostatic surface potential among proteins with high three-dimensional (selected using the softwares TOP and DALI) topology gave insights into the mode of action of Psd1. The surface topologies between proteins that present antifungal activity or sodium channel inhibiting activity are different. On the other hand the surface topology presents several common features with potassium channel inhibitors, suggesting that Psd1 presents this activity. Other common features with potassium channel inhibitors were found including the presence of a lysine residue essential for inhibitory activity. The identity of Psd1 in primary sequence is not enough to infer a mechanism of action, in contrast with the strategy proposed here.

Amino Acid Sequence↗

PubMed2005

Structural modification of phenylpropanoid-derived compounds and the effects on their participation in redox processes.

Oxidation and reduction processes are fundamental to many of the proposed mechanisms by which dietary phytochemicals are thought to exert protective effects against cardiovascular disease and some cancers. An understanding of the redox chemistry of these compounds is essential in assessing their potential to participate in these processes. Phenylpropanoid-derived compounds were selected and synthesised where required to represent many of the structural features found in this important group of compounds. Using electron paramagnetic resonance spectroscopy and computational chemistry a structure-redox activity relationship was obtained. Good correlation of computational and experimental results was observed for the mono-hydroxylated compounds. This demonstrated the value of computational chemistry in obtaining information about compounds, not readily available and the effect of electron delocalisation on parent radical stability. For compounds containing more than one hydroxyl, the relationship was found to be more complex. The importance of quinone formation in compounds containing more than one hydroxyl substituent was highlighted, as this was found to have a significant effect on stabilisation and therefore, their participation in redox processes.

Electron Spin Resonance Spectroscopy↗

PubMed2000

Secondary structure prediction and in vitro accessibility of mRNA as tools in the selection of target sites for ribozymes.

We have investigated the relative merits of two commonly used methods for target site selection for ribozymes: secondary structure prediction (MFold program) and in vitro accessibility assays. A total of eight methylated ribozymes with DNA arms were synthesized and analyzed in a transient co-transfection assay in HeLa cells. Residual expression levels ranging from 23 to 72% were obtained with anti-PSKH1 ribozymes compared to cells transfected with an irrelevant control ribozyme. Ribozyme efficacy depended on both ribozyme concentration and the steady state expression levels of the target mRNA. Allylated ribozymes against a subset of the target sites generally displayed poorer efficacy than their methylated counterparts. This effect appeared to be influenced by in vivo accessibility of the target site. Ribozymes designed on the basis of either selection method displayed a wide range of efficacies with no significant differences in the average activities of the two groups of ribozymes. While in vitro accessibility assays had limited predictive power, there was a significant correlation between certain features of the predicted secondary structure of the target sequence and the efficacy of the corresponding ribozyme. Specifically, ribozyme efficacy appeared to be positively correlated with the presence of short stem regions and helices of low stability within their target sequences. There were no correlations with predicted free energy or loop length.

Algorithms↗

PubMed2003

Live recombinant vectors for AIDS vaccine development.

Live recombinant vectors entered the AIDS vaccine field with the realization that live attenuated HIV vaccines posed too great a safety risk, and that subunit vaccines elicited antibodies which lacked the breadth or potency needed to induce sterilizing immunity. Vectored vaccines provided a means to bring the cellular arm of the immune system into play by mimicking natural viral infection. By delivering antigens within host cells, processing and presentation could occur for induction of cellular immune responses. This recombinant vector approach, either alone or combined with other strategies, has produced impressive results. Recombinants have been generated from DNA and RNA viruses and bacteria. With few exceptions, each vector poses some risk, yet each possesses unique features that make it attractive. In addition to safety, key considerations in vector selection have included previous success as a vaccine against the wild-type agent or other pathogens; ability to induce potent, persistent immune responses; ability to target mucosal inductive sites and antigen presenting cells; lack of integration into the host genome; presence of pre-existing immunity in people; ease of mucosal administration; cloning capacity; ease of engineering and production; and stability of the final product. Here we up-date the status of several live recombinant vectors that have shown good potential in pre-clinical studies. Some have progressed to human clinical trials, and others will shortly. The abundance of vectors, coupled with the complexity arising from use of combination regimens with other vaccine types and heterologous vectors, will necessitate selection of the most promising candidates for large-scale efficacy trials in people. The sooner comparative studies can be designed and implemented in which live recombinant vectors containing the same inserted genes are evaluated head-to-head, the closer we will be to an eventual vaccine.

AIDS Vaccines↗

PubMed1982

Epidemiology of esophageal cancer in China.

Chinese historical records of about 2,000 years ago noted several unique epidemiological features and possible risk factors of esophageal cancer in this country. This paper presents selected recent findings on the epidemiology of esophageal cancer in China with special attention directed to geographical distribution, risk factors, and preventive measures. Some of the major characteristics of this disease in China include: 1) an unusually high mortality, the highest in the world; 2) wide geographical differences in mortality; 3) an irregular concentric belt area of elevated mortality; 4) stability of rates over the years; 5) variations in rate by sex; 6) great ethnic differences in mortality; 7) gullet cancer in chickens comparable to the human disease; and 8) associations with high prevalence of epithelial dysplasia of the esophagus. It has been hypothesized that the prevalence of esophageal cancer in high-risk areas may be associated with fermented and moldy foodstuffs, nitrosamines, deficiencies of molybdenum, nutritional deficiencies, specific living habits, and poor oral hygiene. Accordingly, comprehensive studies are being conducted in Lin County and other areas with elevated risk of this diseases so that the possible function of fungi and nitrosamines in the carcinogenesis of esophageal cancer can be determined.

China↗

PubMed1982

Cloning yeast telomeres on linear plasmid vectors.

We have constructed a linear yeast plasmid by joining fragments from the termini of Tetrahymena ribosomal DNA to a yeast vector. Structural features of the terminus region of the Tetrahymena rDNA plasmid maintained in the yeast linear plasmid include a set of specifically placed single-strand interruptions within the cluster of hexanucleotide (C4A2) repeat units. An artificially constructed hairpin terminus was unable to stabilize a linear plasmid in yeast. The fact that yeast can recognize and use DNA ends from the distantly related organism Tetrahymena suggests that the structural features required for telomere replication and resolution have been highly conserved in evolution. The linear plasmid was used as a vector to clone chromosomal telomeres from yeast. One Tetrahymena end was removed by restriction digestion, and yeast fragments that could function as an end on a linear plasmid were selected. Restriction mapping and hybridization analysis demonstrated that these fragments were yeast telomeres, and suggested that all yeast chromosomes might have a common telomere sequence. Yeast telomeres appear to be similar in structure to the rDNA of Tetrahymena, in which specific nicks or gaps are present within a simple repeated sequence near the terminus of the DNA.

Animals↗