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At least 973 records · Page 54Linked to original sources
PubMed2003

Robust neural integration from retinal transplants in mice deficient in GFAP and vimentin.

With recent progress in neuroscience and stem-cell research, neural transplantation has emerged as a promising therapy for treating CNS diseases. The success of transplantation has been limited, however, by the restricted ability of neural implants to survive and establish neuronal connections with the host. Little is known about the mechanisms responsible for this failure. Neural implantation triggers reactive gliosis, a process accompanied by upregulation of intermediate filaments in astrocytes and formation of astroglial scar tissue. Here we show that the retinas of adult mice deficient in glial fibrillary acidic protein and vimentin, and consequently lacking intermediate filaments in reactive astrocytes and Müller cells, provide a permissive environment for grafted neurons to migrate and extend neurites. The transplanted cells integrated robustly into the host retina with distinct neuronal identity and appropriate neuronal projections. Our results indicate an essential role for reactive astroglial cells in preventing neural graft integration after transplantation.

Animals↗
PubMed2002

Model for a robust neural integrator.

Integrator circuits in the brain show persistent firing that reflects the sum of previous excitatory and inhibitory inputs from external sources. Integrator circuits have been implicated in parametric working memory, decision making and motor control. Previous work has shown that stable integrator function can be achieved by an excitatory recurrent neural circuit, provided synaptic strengths are tuned with extreme precision (better than 1% accuracy). Here we show that integrator circuits can function without fine tuning if the neuronal units have bistable properties. Two specific mechanisms of bistability are analyzed, one based on local recurrent excitation, and the other on the voltage-dependence of the NMDA (N-methyl-D-aspartate) channel. Neither circuit requires fine tuning to perform robust integration, and the latter actually exploits the variability of neuronal conductances.

Computer Simulation↗
PubMed2025

Robust and accurate Bayesian inference of genome-wide genealogies for hundreds of genomes.

The Ancestral Recombination Graph (ARG), which describes the genealogical history of a sample of genomes, is a vital tool in population genomics and biomedical research. Recent advancements have substantially increased ARG reconstruction scalability, but they rely on approximations that can reduce accuracy, especially under model misspecification. Moreover, they reconstruct only a single ARG topology and cannot quantify the considerable uncertainty associated with ARG inferences. Here, to address these challenges, we introduce SINGER (sampling and inferring of genealogies with recombination), a method that accelerates ARG sampling from the posterior distribution by two orders of magnitude, enabling accurate inference and uncertainty quantification for hundreds of whole-genome sequences. Through extensive simulations, we demonstrate SINGER's enhanced accuracy and robustness to model misspecification compared to existing methods. We demonstrate the utility of SINGER by applying it to individuals of British and African descent within the 1000 Genomes Project, identifying signals of population differentiation, archaic introgression and strong support for ancient polymorphism in the human leukocyte antigen region shared across primates.

Humans↗
PubMed2000

A robust test for assortative mating.

Testing for random mating in human populations is difficult due to confounding factors such as ethnic preference and population stratification. With HLA, the high level of polymorphism is an additional problem since it is rare for couples to share the same haplotype. Focus on an ethnically homogeneous population, where levels of polymorphism at HLA loci are more limited, may provide the best situation in which to detect non-random mating. However, such populations are often genetic isolates where there may be inbreeding to an extent that is difficult to quantify and account for. We have developed a test for random mating at a multiallelic locus that is robust to stratification and inbreeding. This test relies on the availability of genotypic information from the parents of both spouses. The focus of the test is on families where there is allele sharing between the parents of both spouses, so that potential spouses could share an allele. Denoting the shared allele at the locus of interest by A, then under the assumption of random mating, heterozygous parents AX should transmit allele A equally as frequently as allele X to their offspring. When there is positive (negative) assortative mating, A will be transmitted more (less) often than X. The power of the test has been computed in a number of situations. Data on high resolution HLA haplotypes from the Hutterite population were reinvestigated by the proposed test. The test detects significant negative assortative mating when the parental origin of the shared haplotype is taken into account.

Alleles↗
PubMed2006

Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology.

We have generated a novel transgenic mouse model on a C57BL/6J genetic background that coexpresses KM670/671NL mutated amyloid precursor protein and L166P mutated presenilin 1 under the control of a neuron-specific Thy1 promoter element (APPPS1 mice). Cerebral amyloidosis starts at 6-8 weeks and the ratio of human amyloid (A)beta42 to Abeta40 is 1.5 and 5 in pre-depositing and amyloid-depositing mice, respectively. Consistent with this ratio, extensive congophilic parenchymal amyloid but minimal amyloid angiopathy is observed. Amyloid-associated pathologies include dystrophic synaptic boutons, hyperphosphorylated tau-positive neuritic structures and robust gliosis, with neocortical microglia number increasing threefold from 1 to 8 months of age. Global neocortical neuron loss is not apparent up to 8 months of age, but local neuron loss in the dentate gyrus is observed. Because of the early onset of amyloid lesions, the defined genetic background of the model and the facile breeding characteristics, APPPS1 mice are well suited for studying therapeutic strategies and the pathomechanism of amyloidosis by cross-breeding to other genetically engineered mouse models.

Amyloid beta-Peptides↗
PubMed2002

Robust and prolonged gene expression from injectable polymeric implants.

We introduce an injectable system for the formation of a biodegradable DNA-containing implant that releases DNA over a 2-month period to provide a robust and prolonged gene expression at the site. Sustained delivery of the appropriate plasmid DNA resulted in sustained expression of luciferase, the persistent appearance of secreted alkaline phosphatase in the serum and small blood vessel formation in the vicinity of the implant from the delivery of the development endothelial locus-1 gene. Local expression of development endothelial locus-1 protein promotes the development of blood vessels to meet the metabolic demands of new tissue and is a paradigm for the delivery of other growth factors that act locally to aid tissue regeneration. This delivery system involves simple preparation procedures and can be injected directly into the site, hence should be a useful approach to plasmid-based gene transfer for vaccination and tissue engineering.

Absorbable Implants↗
PubMed2004

Robust functional gene validation by adenoviral vectors: one-step Escherichia coli-derived recombinant adenoviral genome construction.

We describe here a clonal approach for efficient and robust construction of recombinant adenoviral genomes that holds certain advantages over existing approaches. Transgenes of interest are cloned into a small, conditionally replicating plasmid containing the left end of a recombinant adenoviral genome, encompassing pIX coding regions. Transformation of this plasmid into recombination-competent Escherichia coli bearing a plasmid containing the right end of a recombinant adenoviral genome, commencing from pIX coding regions, yields a stable co-integrated plasmid encoding a full adenoviral genome, by virtue of shared homology in pIX coding regions contained in both plasmids. The recombination process yielding the full adenoviral plasmid requires only one step, and always results in the formation of only the desired recombinant adenoviral genome. Thus, no screening is required to identify the correct plasmid encoding the desired recombinant adenoviral genome. In addition, the plasmid encoding the right-hand side of the adenoviral genome is itself incapable of producing contaminating adenovirus. We have successfully employed this approach to generate over 200 recombinant adenoviruses, obtaining only the desired recombinant adenoviral species each time. The process is amenable to medium-to-high-throughput parallel construction of adenoviral genomes, and as such should aid efforts aimed towards high-throughput functional annotation of therapeutic gene targets, which aim to leverage the benefits of adenoviruses as gene delivery and expression vectors.

Adenoviridae↗
PubMed2000

Validation and robustness testing of a HPLC method for the determination of avermectins and moxidectin in animal liver samples using an alumina column clean-up.

A multi-residue method has been developed for the quantitative determination of moxidectin, abamectin, doramectin and ivermectin in liver samples, with capability for qualitative identification of the presence of eprinomectin. Liver samples are extracted with isooctane, followed by clean-up on alumina-N solid phase extraction (SPE) cartridges. Extracts are derivatised and determined by high-performance liquid chromatography (HPLC) with fluorescence detection. The method was validated using bovine liver fortified at levels of 4 and 20 micrograms kg-1 with the drugs. The mean recovery from bovine liver ranged between 90 and 96%. The intra and inter-assay variations showed RSD typically of < 5% and < 10%, respectively. The procedure was applied also to ovine and porcine liver, giving similar results. A robustness study, carried out on the alumina clean-up step, indicated that the step is relatively insensitive to method changes. However, significant differences overall were found for the type of alumina and/or commercial SPE cartridge used. The limit of quantitation of the method is 2 micrograms kg-1 (ppb).

Aluminum↗
PubMed2003

Ship-in-a-bottle synthesis of 2,4,6-triphenylthiapyrylium cations encapsulated in zeolites Y and beta: a novel robust photocatalyst.

The 2,4,6-triphenylthiapyrylium ion has been obtained imprisoned inside the supercages of the tridirectional, large pore zeolites Y and beta via ship-in-a-bottle synthesis from chalcone and acetophenone in the presence of hydrogen sulfide. The resulting solids are efficient and robust photocatalysts that are able to degrade phenol and aniline in water with a higher efficiency than the P-25 TiO(2) standard. Preliminary tests have shown that these encapsulated dye materials are also efficient photocatalysts for the oxidative degradation of malodorous sulfur-containing molecules.

Journal Article↗
PubMed2004

Robust hydrogen-bonded self-assemblies from biimidazole complexes. Synthesis and structural characterization of [M(biimidazole)2(OH2)2]2+ (M = Co2+, Ni2+) complexes and carboxylate modules.

A robust heteromeric hydrogen-bonded synthon [R2(2) (9)-Id] is exploited to drive the modular self-assembly of four coordination complexes [M(H2biim)2(OH2)2]2+ (M = Co2+, Ni2+) and carboxylate counterions. This strategy allowed us to build molecular architectures of 0-, 1-, and 2-dimensions. A hydrogen-bonded 2D-network with cavities has been designed, which maintains its striking integrity after reversible water desorption-resorption processes.

Carboxylic Acids↗
PubMed2004

A robust, porous, cationic silver(i) 3,5-diphenyl-1,2,4-triazolate framework with a uninodal 4(9).6(6) net.

The reactions of silver(i) salts with 3,5-diphenyl-1,2,4-triazole result in three-dimensional, porous, cationic metal-organic frameworks based on novel 6-connected, trigonal-prismatic, pentanuclear silver-triazolate clusters, interconnected by linear N-Ag-N linkers; this robust water- and organic-insoluble structure exhibits both nonpolar-solvent adsorption and anion-exchange properties.

Journal Article↗
PubMed2004

Curve-fitting overlapped bands: quantification and improvement of curve-fitting robustness in the presence of errors in the model and in the data.

Estimation of the band parameters of overlapped bands often relies on curve-fitting. It has been demonstrated that curve-fitting provides the maximum likelihood estimation of band parameters under a series of assumptions. One of these assumptions is that the curve-fitting model is correct and any error in the data is random. Under real conditions, we have to acknowledge the unavoidable presence of errors in the model and systematic errors in the data. Here, we derive an expression for the estimation of how these errors affect the quality of the parameters obtained from curve-fitting. In addition, we derive theoretical expressions to quantify the extent to which different methods can improve the curve-fitting robustness to these errors. The methods considered are: (i) deterministic and (ii) probabilistic constraints in the band parameters, (iii) curve-fitting band-narrowed data, and (iv) building a more accurate model. The theoretical expressions obtained are tested in the curve-fitting of a synthetic noisy spectrum with either baseline or band shape errors, and in the curve-fitting of the experimental infrared amide I band of the membrane protein bacteriorhodopsin.

Animals↗
PubMed2004

Design of a robust Ru(salen) complex: aziridination with improved turnover number using N-arylsulfonyl azides as precursors.

A new robust fluorinated (OC)Ru(salen) complex was designed on the basis of an X-ray structure of its parent complex to show improved turnover numbers (up to 878) and enantioselectivities (up to 99%) in aziridination reactions using p-toluenesulfonyl (Ts) or p-nitrobenzenesulfonyl (Ns) azide as the nitrene precursor; the latter is synthetically advantageous since the Ns group is N-protecting and can be removed under mild conditions.

Journal Article↗
PubMed2004

Flavin radicals, conformational sampling and robust design principles in interprotein electron transfer: the trimethylamine dehydrogenase-electron-transferring flavoprotein complex.

TMADH (trimethylamine dehydrogenase) is a complex iron-sulphur flavoprotein that forms a soluble electron-transfer complex with ETF (electron-transferring flavoprotein). The mechanism of electron transfer between TMADH and ETF has been studied using stopped-flow kinetic and mutagenesis methods, and more recently by X-ray crystallography. Potentiometric methods have also been used to identify key residues involved in the stabilization of the flavin radical semiquinone species in ETF. These studies have demonstrated a key role for 'conformational sampling' in the electron-transfer complex, facilitated by two-site contact of ETF with TMADH. Exploration of three-dimensional space in the complex allows the FAD of ETF to find conformations compatible with enhanced electronic coupling with the 4Fe-4S centre of TMADH. This mechanism of electron transfer provides for a more robust and accessible design principle for interprotein electron transfer compared with simpler models that invoke the collision of redox partners followed by electron transfer. The structure of the TMADH-ETF complex confirms the role of key residues in electron transfer and molecular assembly, originally suggested from detailed kinetic studies in wild-type and mutant complexes, and from molecular modelling.

Animals↗
PubMed1999

A simple, robust, validated and highly predictive index for the determination of risk-directed therapy in acute myeloid leukaemia derived from the MRC AML 10 trial. United Kingdom Medical Research Council's Adult and Childhood Leukaemia Working Parties.

Data on 1711 patients, aged up to 55 years, in the MRC AML 10 trial were used to create a prognostic index for use in risk-directed therapy decision making for younger patients with acute myeloid leukaemia (AML). Two parameters, response after course 1 and cytogenetics, were strongly predictive of outcome. For patients with complete remission, partial remission and resistant disease, 5-year survival from the start of course 2 was 53%, 44% and 22% and relapse rates were 46%, 48% and 69% respectively, and for patients with favourable, intermediate and adverse karyotypic abnormalities, survival was 72%, 43% and 17% and relapse rates were 34%, 51% and 75% respectively (all P < 0.0001). Patients with FAB type M3 but no cytogenetic t(15;17) also had a low relapse rate (29%). These three factors were combined to give three risk groups: good (favourable karyotype or M3, irrespective of response status or presence of additional abnormalities), standard (neither good nor poor), poor (adverse karyotype or resistant disease, and no good-risk features). Survival for these three groups was 70%, 48% and 15% respectively and relapse rates were 33%. 50% and 78% (both P < 0.0001). The index is simple (based on just three parameters), robust (derived from 1711 patients), highly discriminatory (55% survival difference between good and poor risk) and validated, so can be applied in the clinical setting to assist with therapeutic decisions as in the current AML 12 trial.

Acute Disease↗