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A new modular indole synthesis. Construction of the highly strained CDEF parent tetracycle of nodulisporic acids A and B.

[reaction: see text] Construction of the highly strained CDEF parent tetracycle, a structural motif found only in the potent ectoparasiticidal agents (+)-nodulisporic acids A and B and related congeners, has been achieved via a new modular indole synthesis, exploiting a sequential Stille cross-coupling/Buchwald-Hartwig union/cyclization tactic. The new indole synthesis holds the promise of rapid assembly of diverse, highly substituted indoles possessing uncommon substitution patterns.

Cyclization↗

Modular asymmetric synthesis of 1,2-diols by single-pot allene diboration/hydroboration/cross-coupling.

Chiral allyl vinyl boronates are generated by catalytic enantioselective diboration of prochiral allenes. They may then be reacted, in situ, with a hydroborating reagent to form a novel triboron intermediate. The least hindered and most reactive C-B bond then participates in cross-coupling wherein the coupling is brought about by the same catalyst as that which catalyzed the diboration reaction. The remaining C-B bonds are then oxidized in the reaction workup, thereby allowing for the modular synthesis of chiral diols in a concise single-pot fashion.

Alkadienes↗

A set of modular plant transformation vectors allowing flexible insertion of up to six expression units.

We have constructed a binary vector for Agrobacterium-mediated plant transformation, which has a multiple cloning site consisting of 13 hexanucleotide restriction sites, 6 octanucleotide restriction sites and 5 homing endonuclease sites. The homing endonuclease sites have the advantages to be extremely rare in natural sequences and to allow unidirectional cloning. We have also constructed a set of auxiliary vectors allowing the assembly of expression cassettes flanked by homing endonuclease sites. The expression cassettes assembled in these auxiliary vectors can be transferred into the binary vector with virtually no risk of cutting the vector within previously introduced sequences. This vector set is ideally suited for the construction of plant transformation vectors containing multiple expression cassettes and/or other elements such as matrix attachment regions. With this modular vector system, six different expression units were constructed in as many auxiliary vectors and assembled together in one plant transformation vector. The transgenic nature of Arabidopsis thaliana plants, transformed with this plant transformation vector, was assessed and the expression of each of the six genes was demonstrated.

Arabidopsis↗

Measuring quality of life in early HIV disease: the modular approach.

RATIONALE: to examine the reliability and validity of the General Health Self-assessment, a modular questionnaire for self-assessment of quality of life (QoL) in human immunodeficiency virus (HIV) clinical trials and to describe the baseline QoL of participants in a large HIV clinical trial. DESIGN: the domains assessed include health perceptions, physical, psychological and role/social functioning, health care utilization and symptom distress. METHOD: 1,694 subjects with early HIV infection enrolled in the AIDS Clinical Trials Group Protocol 175 completed the scale at baseline. RESULTS: the domains demonstrated reliability, construct and discriminant validity. A worse QoL was associated with recent hospitalization and symptomatic status. Prior antiretroviral therapy was associated with higher health perceptions and well-being. The presence of symptom distress was related to lower QoL on the other scales. There was no relationship between QoL scales and the baseline CD4 count. Women showed a lower QoL than men on all scales, while ethnicity was related to differences in health perceptions and physical and psychological functioning. CONCLUSIONS: the General Health Self-assessment shows excellent potential as a measure of QoL for HIV-infected patients in clinical trials. Further research is necessary to determine the responsiveness of the scale to clinical and immunological changes in HIV-infected individuals.

Adolescent↗

Application of modular control analysis to inhibition of the adenine nucleotide translocator by palmitoyl-CoA.

Modular kinetic analysis was used to characterize inhibition of adenine nucleotide translocation by palmitoyl-CoA in isolated rat-liver mitochondria. To this purpose, oxidative phosphorylation has been divided into two modules with the fraction of matrix ATP as linking intermediate. The adenine nucleotide translocator is the matrix ATP-consuming module and the remainder of oxidative phosphorylation (ATP synthesis, respiratory chain and transport of phosphates and respiratory substrate) is the matrix ATP-producing module. We found that palmitoyl-CoA inhibits ATP-consuming module (ANT) and has no effect on ATP-producing module. There were no significant differences between kinetic curves obtained with oligomycin and myxothiazol, inhibitors that have opposite effect on membrane potential, suggesting that the use of the fraction of matrix ATP as the only intermediate is a good approximation. A new method has been used to determine the fraction of ATP in the mitochondrial matrix.

Adenine Nucleotides↗

The targets of 2,2',5,5'-tetrachlorobiphenyl in the respiratory chain of rat liver mitochondria revealed by modular kinetic analysis.

The response of the respiratory subsystem of oxidative phosphorylation to the environmental pollutant, 2,2',5,5'-tetrachlorobiphenyl (2,2',5,5'-TCB) was investigated by modular kinetic approach. The effects of 20 microM 2,2',5,5'-TCB on the activity of the respiratory chain modules in rat liver mitochondria oxidizing succinate (+ rotenone) in state 3 were assessed. The toxin inhibited the rate of respiration by 23%. Analysis around cytochrome c revealed that 2,2',5,5'-TCB inhibited both cytochrome c-oxidizing and reducing modules. The toxin inhibited also CoQ-oxidizing module, however it did not affect the kinetics of CoQ-reducing module. Taken together, these data indicated that 2,2',5,5'-TCB inhibited cytochrome bc1 but had no effect on succinate dehydrogenase.

Animals↗

Concept for modular extracorporeal liver support for the treatment of acute hepatic failure.

Acute liver failure has a poor prognosis. The introduction of liver transplantation as a therapeutic option reduced mortality to 20-40%.With the growing disparity between the number of organ donations and the number of patients waiting for liver transplantation, efforts have been made to optimize the allocation of organs and to design extracorporeal methods to support the failing liver. The modular extracorporeal liver support is a concept for the treatment of hepatic failure. The CellModule is a multicompartment bioreactor for extracorporeal liver support therapy. The construction provides efficient integrated oxygenator functions and decentralized mass transfer is effected by a woven array of capillary systems. The bioreactor promotes primary human liver cells to spontaneous neo-formation of liver sinusoidal structures in vitro. Small capillary subunits, in which interwoven membrane links represent the liver lobuli, are simultaneously perfused. The used cell mass of 400-600 g enabled the clinical application of a liver lobe equivalent hybrid organ. The DetoxModule enables albumin-dialysis for removal of albumin-bound toxins; a DialysisModule for continuous veno-venous hemofiltration can be added to the system, in the case of hepato-renal failure.

Humans↗

The modular organization of multifunctional peptide synthetases.

Gramicidin S synthetase 2 from B. brevis was affinity labeled at its valine thiolation center with the thiol reagent N-[3H]ethylmaleimide. From a tryptic digest of the enzyme-inhibitor complex a radioactive fragment was isolated in pure form by two reversed-phase HPLC steps. It was identified by liquid-phase N-terminal sequencing in combination with electrospray mass spectrometry (ESI-MS) as a hexadecapeptide containing the thiolation motif LGG(H/D)S(L/I). By ESI-MS it was demonstrated that a 4'-phosphopantetheine cofactor was attached to this fragment at its reactive serine. These results are consistent with the "Multiple Carrier Model" of nonribosomal peptide biosynthesis. Site-specific mutagenesis has been performed in thiolation, elongation, and epimerization motifs of some of the modules of surfactin synthetase from B. subtilis to clarify the function of prominent conserved amino acid residues in the intermediate steps of peptide biosynthesis. The modular structure of multifunctional peptide synthetases is discussed.

Amino Acid Isomerases↗

Boronic acid based modular fluorescent sensors for glucose.

Modular photoinduced electron transfer (PET) sensors bearing two phenylboronic acid groups, one or two fluorophores: pyrene(a), phenanthrene(b), anthracene(c), 1-naphthalene(d), 2-naphthalene(e) and alkylene linkers, from trimethylene(3) to octamethylene(8), have been evaluated. Systems with a single pyrene fluorophore 34a, 35a and 36a bind the strongest with D-glucose (36a also binds well with D-melibiose). Whilst 37a and 38a bind the strongest with D-galactose. Changing the fluorophore, also, influences the binding, 36a, 36b and 36c are D-glucose selective, whilst 36d and 36e are D-galactose selective. Systems with two fluorophores 36a-a and 36a-b show an overall decrease in binding efficiency. Energy transfer in 36a-b results in enhanced sensitivity and selectivity towards D-glucose.

Biosensing Techniques↗

Dihydropyridines in MCRs. Tandem processes leading to modular tetrahydroquinoline systems with up to 6 diversity elements.

An efficient, modular method for the synthesis of highly substituted tetrahydroquinoline systems is described. The Lewis acid catalyzed interaction of dihydropyridines with glyoxalate and anilines affords the heterocyclic parent systems in good yields. Tandem one-pot processes allow the incorporation of additional components: a preliminary nucleophilic attack on pyridinium salts generates the reactive dihydropyridine in situ, and subsequent electrophilic reactions on the secondary amine complete the assembly of the final targets, which have up to 6 diversity points.

Aldehydes↗

Simple technique to ensure coaxial guidewire positioning for placement of iliac limb of modular aortic endograft.

Endovascular abdominal aortic aneurysm repair using a modular bifurcated stent-graft requires the initial placement of the main component in the infrarenal aorta, followed by insertion of additional iliac stent-graft(s) to exclude aneurysm and to securely affix the device. Placement of the contralateral iliac component within the main bifurcated device is critical in this endovascular procedure, as malpositioning of the contralateral iliac limb can require conversion to open aneurysm repair. A simple adjunctive technique utilizing a rotational maneuver of a pigtail catheter is described. This maneuver reliably confirms the proper placement of the contralateral iliac stent-graft within the main bifurcated device.

Aorta, Abdominal↗

Psychophysiological responses to imagined infidelity: the specific innate modular view of jealousy reconsidered.

Three studies measured psychophysiological reactivity (heart rate, blood pressure, and electrodermal activity) while participants imagined a mate's infidelity. The specific innate modular theory of gender differences in jealousy hypothesizes that men are upset by sexual infidelity and women are upset by emotional infidelity, because of having faced different adaptive challenges (cuckoldry and loss of a mate's resources, respectively). This view was not supported. In men, sexual-infidelity imagery elicited greater reactivity than emotional-infidelity imagery. But, sexual imagery elicited greater reactivity even when infidelity was not involved, suggesting that the differential reactivity may not specifically index greater jealousy. In two studies with reasonable power, women did not respond more strongly to emotional infidelity. Moreover, women with committed sexual relationship experience showed reactivity patterns similar to those of men. Hypothetical infidelity self-reports were unrelated to reactivity.

Adult↗

Recognizing words and pictures in sentence contexts: a test of lexical modularity.

Words or pictures completed sentence fragments to form coherent or incoherent sentences. Subjects made lexical decisions about words and object decisions about pictures. Modality was blocked in Experiment 1 and mixed in Experiment 2. In both experiments there were similar effects of context for words and pictures, contrary to the hypothesis that lexical priming produces the sentence context effect. Mixed conditions produced longer response latencies than blocked conditions but did not interact with the context effect. The finding of no interaction between the effect of context and the mixed-blocked manipulation, supports a version of lexical modularity in which context effects arise as a function of post-access integration processing.

Adult↗

Brain and cognitive evolution: forms of modularity and functions of mind.

Genetic and neurobiological research is reviewed as related to controversy over the extent to which neocortical organization and associated cognitive functions are genetically constrained or emerge through patterns of developmental experience. An evolutionary framework that accommodates genetic constraint and experiential modification of brain organization and cognitive function is then proposed. The authors argue that 4 forms of modularity and 3 forms of neural and cognitive plasticity define the relation between genetic constraint and the influence of developmental experience. For humans, the result is the ontogenetic emergence of functional modules in the domains of folk psychology, folk biology, and folk physics. The authors present a taxonomy of these modules and review associated research relating to brain and cognitive plasticity in these domains.

Animals↗

Voltage-sensitive dyes reveal a modular organization in monkey striate cortex.

Voltage-sensitive dyes allow neuronal activity to be studied by non-invasive optical techniques. They provide an attractive means of investigating striate cortex, where important response properties are organized in two dimensions. In the present study, patterns of ocular dominance and orientation selectivity were obtained repeatedly from the same patch of cortex using the dye merocyanine oxazolone, together with current image-processing techniques. The patterns observed agree with most established features of monkey striate cortex and suggest a new unit of cortical organization; one that is modular in structure and which appears to link the organization of orientation selectivity with that of ocular dominance.

Animals↗

NMR of modular proteins.

NMR studies of domains, dissected from large modular proteins, are described. Particular emphasis is placed on modules from the extracellular proteins fibrillin-1 and fibronectin.

Amino Acid Sequence↗

The Oxford modular cataract image analysis system.

A modular system of acquisition and analysis of Scheimpflug, retro-illumination and fluorescence images of the in vivo human crystalline lens is described. Image analysis is directed towards the following goals: Scheimpflug slit-images are analysed for: (1) The optical density of nuclear cataract present; (2) The dimensions of the lens and the lenticular zones; (3) The curvatures of the lens and lenticular zones. Retro-illumination images are analysed for: (1) The percentage area which is occupied by cataract; (2) A combined measure (weighted integral) describing both the amount of cataract present and its optical density. Lenticular auto-fluorescence images are analysed for the mean density (fluorescence) of the lens as a whole. A pilot study of the repeatability of the methods is presented.

Cataract↗

The proteomes of neurotransmitter receptor complexes form modular networks with distributed functionality underlying plasticity and behaviour.

Neuronal synapses play fundamental roles in information processing, behaviour and disease. Neurotransmitter receptor complexes, such as the mammalian N-methyl-D-aspartate receptor complex (NRC/MASC) comprising 186 proteins, are major components of the synapse proteome. Here we investigate the organisation and function of NRC/MASC using a systems biology approach. Systematic annotation showed that the complex contained proteins implicated in a wide range of cognitive processes, synaptic plasticity and psychiatric diseases. Protein domains were evolutionarily conserved from yeast, but enriched with signalling domains associated with the emergence of multicellularity. Mapping of protein-protein interactions to create a network representation of the complex revealed that simple principles underlie the functional organisation of both proteins and their clusters, with modularity reflecting functional specialisation. The known functional roles of NRC/MASC proteins suggest the complex co-ordinates signalling to diverse effector pathways underlying neuronal plasticity. Importantly, using quantitative data from synaptic plasticity experiments, our model correctly predicts robustness to mutations and drug interference. These studies of synapse proteome organisation suggest that molecular networks with simple design principles underpin synaptic signalling properties with important roles in physiology, behaviour and disease.

Animals↗