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At least 325 records · Page 18Linked to original sources
PubMed1998

A whole-genome radiation hybrid map of the dog genome.

A whole genome radiation hybrid (RH) map of the canine genome was constructed by typing 400 markers, including 218 genes and 182 microsatellites, on a panel of 126 radiation hybrid cell lines. Fifty-seven RH groups have been determined with lod scores greater than 6, and 180 framework landmarks were ordered with odds greater than 1000:1. Average spacing between adjacent markers is 23 cR5000, an estimated physical distance of 3.8 Mb. Fourteen groups have been assigned to 9 of the canine chromosomes, and a comparison of RH and genetic groups allowed the successful bridging of both types of data on one map composed of 31 RH and 13 syntenic RH groups. Comparison of canine, human, mouse, and pig maps underlined regions of conserved synteny. This integrated map, covering an estimated 80% of the dog genome, should prove a powerful tool for localizing and identifiying genes implicated in pathological and phenotypical traits.

Animals↗
PubMed2001

Curvature matching and strain relief in bucky-tori: usage of sp3-hybridization and nonhexagonal rings.

The relief of different types of curvature strain in bucky-tori of elemental carbon is considered in a general formal framework. This theory then is used to aid in the design of several structures, which are treated via molecular mechanics. Novel illustrations of the remnant strain are made, and some modest conclusions as to the nature of the structure of the experimentally observed bucky-tori are suggested.

Carbon↗
PubMed2004

A hybrid scheme for the resolution-of-the-identity approximation in second-order Møller-Plesset linear-r(12) perturbation theory.

In the framework of second-order Møller-Plesset linear-r(12) (MP2-R12) perturbation theory, a method is developed and implemented that uses an auxiliary basis set for the resolution-of-the-identity (RI) approximation for the three- and four-electron integrals. In contrast to previous work, the two-electron integrals that must be evaluated never involve more than one auxiliary basis function. The new method therefore scales linearly with the number of auxiliary basis functions and is much more efficient than the previous one, which scaled quadratically. A general formulation of MP2-R12 theory is presented for various ansatze, approximations, and orbitals (canonical or localized). The new method is assessed by computations of the valence-shell second-order Møller-Plesset correlation energy of a few small closed-shell systems. The preliminary calculations indicate that the difference between the new and previous methods is about one order of magnitude smaller than the errors that occur due to basis-set truncations and RI approximations and under the assumptions of generalized and extended Brillouin conditions.

Journal Article↗
PubMed2004

Fractal geometry is heritable in trees.

Understanding the genetic basis to landscape vegetation structure is an important step that will allow us to examine ecological and evolutionary processes at multiple spatial scales. Here for the first time we show that the fractal architecture of a dominant plant on the landscape exhibits high broad-sense heritability and thus has a genetic basis. The fractal architecture of trees is known to influence ecological communities associated with them. In a unidirectional cottonwood-hybridizing complex (Populus angustifolia x P. fremontii) pure and hybrid cottonwoods differed significantly in their fractal architecture, with phenotypic variance among backcross hybrids exceeding that of F1 hybrids and of pure narrowleaf cottonwoods by two-fold. This result provides a crucial link between genes and fractal scaling theory, and places the study of landscape ecology within an evolutionary framework.

Analysis of Variance↗
PubMed2026

Pervasive hybridization and introgression in Diervilleae (Caprifoliaceae).

Diervilleae (Caprifoliaceae) is a horticulturally important lineage with striking floral diversity and a long history of interspecific crossing, suggesting reticulate evolution. We integrated nuclear SNPs and whole plastome data to reconstruct a phylogenomic backbone for the tribe and to identify hybrids, cultivated accessions, and introgression among lineages. Nuclear and plastid phylogenies consistently recover Weigela and Diervilla as reciprocally monophyletic and resolve four major lineages within Weigela, providing a reproducible framework for revising sectional limits and species boundaries. Cultivated accessions form a well supported clade sister to W. florida and show predominantly W. florida ancestry while retaining contributions from multiple wild lineages, consistent with recurrent crossing, backcrossing, and selection. Analyses of wild populations reveal recurrent hybrids and enable plausible parental combinations to be inferred. Tests across the genome further indicate strong evidence for historical introgression across Diervilleae, with the strongest signals involving W. middendorffiana, W. maximowiczii, and Diervilla. Fossil evidence, divergence time estimation, and paleodistribution modelling together suggest range expansion during the Miocene and Pliocene followed by climate driven contraction, providing a spatiotemporal context for episodic contact, introgression, and the East Asia-North America disjunction.

Hybridization, Genetic↗
PubMed1993

High-frequency representation of a single VH gene in the expressed human B cell repertoire.

Idiotype (Id) 16/6 marks a variable (V) region structure that occurs frequently in the human immunoglobulin repertoire. The basis of the Id has been traced to a germline heavy chain gene segment, VH18/2 (VH26). To pursue the molecular basis for the frequency of Id 16/6, we have analyzed polymerase chain reaction-generated C mu, C gamma, and VH3 family V gene libraries derived from the circulating and tonsillar B cells of four normal individuals and from the B cells of two patients with active systemic lupus erythematosus (SLE). The frequency of VH18/2 in these libraries was compared with three control VH genes, VH56P1, VH21/28, and VHA57. Plaque lifts from C mu and C gamma VH cDNA libraries were screened with gene-specific oligonucleotide probes. The frequency of VH18/2 ranged from 4 to 10% of JH+ plaques (two of five times that of control VH genes). In four VH3 family-specific libraries derived from rearranged DNA, VH18/2 represented 19-33% of VH3+ plaques. Hybridizing VH18/2 plaques were 98-100% homologous to the germline VH gene; mutations when present were often in framework 3. Extensive variation was seen in the complementarity determining region 3 sequences of these rearranged V genes. The high frequency of VH18/2 expression in the B cell repertoire was confirmed by sequencing randomly picked JH+ plaques. In two patients with active SLE the frequency of use of VH18/2 was not greater than that observed in normal subjects. These results show that VH18/2 is overrepresented in the B cell repertoire of normal subjects and suggest that the immune repertoire may be dominated by relatively few V genes.

Amino Acid Sequence↗
PubMed2004

Kondo scaling in the optical response of YbIn1-xAgxCu4.

Theoretical work on Kondo systems predicts universality in the scaling of observable quantities with the Kondo temperature, T(K). Here we report infrared-frequency optical response measurements of the correlated system YbIn(1-x)AgxCu4. We observe that x-dependent variations in the frequency and strength of a low-energy excitation are related to the x-dependent Kondo temperature. Comparison of the inferred trends with existing theory and a model calculation provides a framework in which to view these experimental results as scaling phenomena arising from local-moment/conduction electron hybridization.

Journal Article↗
PubMed2026

MET-Aberrant non-small cell lung cancer: from kinase dependence to cell-surface targetability-mechanistic basis and biomarker framework for bispecific antibodies and antibody-drug conjugates.

MET-aberrant non-small cell lung cancer (NSCLC) is not a uniform therapeutic entity. Its biology, diagnostic pathways, and treatment sensitivity differ across MET exon 14 skipping alteration (METex14), MET amplification, and MET overexpression. This heterogeneity cannot be fully explained by conventional event-based classification and is reflected in the distinct clinical activity of MET tyrosine kinase inhibitors (MET-TKIs), bispecific antibodies (BsAbs), and antibody-drug conjugates (ADCs). With the emergence of antibody-based therapies, MET has evolved from a signaling driver to a cell-surface target for receptor modulation and payload delivery. We therefore propose a clinically anchored two-dimensional framework for interpreting therapeutic relevance in MET-aberrant NSCLC: kinase dependence and cell-surface targetability. Neither dimension should be regarded as a directly measurable binary variable. Kinase dependence is inferred from genomic and treatment-contextual proxies, most strongly METex14 and, more conditionally, high-level focal MET amplification. Cell-surface targetability is approximated by drug-specific IHC assessment of assay-defined c-MET protein expression; however, receptor internalization, intracellular trafficking, and payload delivery capacity remain incompletely measurable in routine clinical practice. Within this framework, MET-TKIs have the most evidence-supported established role in tumors with evidence of MET-driven kinase dependence. EGFR × MET BsAbs have demonstrated clinical activity in broad post-osimertinib EGFR-mutant NSCLC, while EGFR/MET co-dependence or MET-mediated bypass activation provides a mechanistic rationale for their use; MET-defined preferential benefit remains to be prospectively established. MET-directed antibody-drug conjugates (MET-ADCs) are supported in drug- and assay-defined populations with high c-MET protein overexpression, although the predictive relevance of delivery-related factors remains hypothesis-generating. Accordingly, MET testing should shift from single-event detection to platform-oriented stratification: next-generation sequencing (NGS) for driver alterations and resistance profiles, fluorescence in situ hybridization (FISH) for high-level focal amplification, and immunohistochemistry (IHC) for surface expression relevant to antibody-based therapies. This framework is intended to organize current biological and clinical evidence rather than to replace drug-specific companion diagnostics, regulatory indications, or prospectively validated treatment-selection algorithms. Precision treatment of MET-aberrant NSCLC is thus moving from event-based drug selection toward mechanism-based therapeutic matching. Future priorities include standardizing biomarkers, defining optimal target populations, and aligning biological subtypes, diagnostic strategies, and therapeutic platforms.

Antibody-drug conjugate↗
PubMed2003

Dynamic and coordinated expression profile of dbl-family guanine nucleotide exchange factors in the developing mouse brain.

Dbl-family guanine nucleotide exchange factors (Dbl-GEFs) act as activators of Rho-like small G proteins such as Rac1, Cdc42 and RhoA. Recently, some GEFs have been suggested to play important roles in the development of the nervous system. Here, we report a comprehensive expression profile analysis of 20 Dbl-GEFs that have yet to be well investigated. Northern analyses of murine mRNAs from brains of E13, E17, P7 and adult mice revealed expression of 18 out of 20 GEFs in some or all stages. In addition, we found that three human GEFs were highly expressed in the brain. Examination of the spatial expression patterns of five GEFs in embryos or neonatal brain by in situ hybridization revealed distinct patterns for each GEF. Our study reveals the dynamic and coordinated expression profiles of the Dbl-GEFs and provides a basic framework for understanding the function of GEFs in neural development.

Amino Acid Sequence↗
PubMed1988

Regional localization of the autosomal dominant polycystic kidney disease locus.

The localization of the autosomal dominant polycystic kidney disease locus (PKD1) within an array of anonymous polymorphic DNA sequences on chromosome 16 band p13 was determined by multipoint mapping. Nine polymorphic DNA markers, including two hypervariable sequences, were used to study 19 PKD1 and 21 reference families. PKD1 was found to lie proximal to the 3' and 5' hypervariable regions of alpha-globin and distal to the anonymous sequence CRI-0327. Somatic cell hybrid mapping places PKD1 within the region 16p13.11-16pter. The availability of an array of linked markers which bracket the PKD1 locus provides a framework for further attempts to identify the PKD1 gene and offers an improved method of presymptomatic diagnosis of the disease.

Animals↗
PubMed2006

Clinical performance of posterior metal-free polymer crowns with and without fiber reinforcement: one-year results of a randomised clinical trial.

OBJECTIVES: The aim of this study was to evaluate the clinical performance of posterior, metal-free polymer crowns with and without a glass-fiber framework, in comparison to metal-ceramic crowns. METHODS: After randomisation, 80 single crowns, manufactured from a newly designed polymer composite, were set in posterior teeth. Half of these received a glass-fiber framework, while half were prepared without any framework stabilisation. All polymer crowns were adhesively luted with resin cement. As the control group, 40 conventional metal-ceramic crowns were inserted with hybrid cement. Documentation included failures and other complications, as well as gingival/plaque status and aesthetic performance. RESULTS: During the 12-month observation period, eight polymer crowns and three metal-ceramic crowns showed clinically relevant complications. The most frequent complications were root canal treatments (n=4) and decementation (n=4) of the crowns. A total of two crowns (one polymer crown with fiber network and one crown of the control group) had to be replaced. After 12 months, polymer crowns with glass-fiber framework exhibited significantly higher plaque accumulation (p=0.005) and gingival index (p=0.04) than metal-ceramic crowns, while no significant differences could be demonstrated for polymer crowns without fiber reinforcement. Postoperative sensibility and aesthetic performance did not differ significantly between the groups. CONCLUSIONS: Within a 12-month observation period, posterior polymer crowns with and without glass-fiber framework demonstrated acceptable stability and aesthetic performance. Polymer crowns with fiber framework showed significant higher plaque accumulation and gingival index than metal-ceramic crowns.

Adult↗
PubMed1983

Chlorophyllide-substituted hemoglobin tetramers and hybrids: preparation, characterization, and energy transfer.

Three chlorophyllide-substituted human hemoglobin (Hb) complexes have been prepared: the tetrameric complex in which zinc pyrochlorophyllide alpha (ZnPChl alpha) is substituted for all four hemes and the two complementary hybrids in which ZnPChl alpha is substituted for heme in either the alpha- or beta-chains, while heme remains in the other chains. In each of these complexes, intramolecular Chl-Chl singlet energy transfer occurs. A variety of probes demonstrate that ZnPChl alpha-deoxyheme hybrids and the ZnPChl alpha-Hb complexes consistently exhibit properties associated with the well-known T-state tertiary and quaternary structure of deoxyHb itself. Using the known crystal structure of human deoxyHb, we have analyzed the steady-state fluorescence anisotropy of these complexes within the framework of the Förster energy-transfer theory. The result is the determination of the orientation of the Qy transition dipole moment of ZnPChl alpha. Nuclear magnetic resonance data for the hybrids offer insight into specific tertiary structural changes in the heme pocket surrounding the diamagnetic ZnPChl alpha, which accompany changes in the ligation state of the heme on the opposite chain.

Chlorophyll↗
PubMed1988

The spectrum of beta-thalassaemia mutations in Sicily.

To characterize beta-thalassaemia genes among the Sicilian population we have previously determined the DNA haplotypes in the beta-globin gene cluster of 99 beta-thal chromosomes. We found seven haplotypes, although 95 of 99 beta-thal chromosomes contained framework 1 and framework 3 beta genes. We have now determined the mutation in all 99 of these beta-thal genes by the use of oligonucleotide hybridization. PCR-amplification and direct genomic sequencing, and direct restriction analysis. Our results indicate that (1) the beta (0)-39 mutation is most frequent (35%); (2) beta(0)-39, IVS-1 nt 110 and IVS-1 nt 6 mutations account for 90% of beta-thal genes: (3) the IVS-1 nt 6 mutation is more frequent in thalassaemia intermedia (77%) than in Cooley's disease (34%): (4) the association between haplotypes and specific mutations is imperfect, but mutation spread has occurred within haplotypes containing the same beta-gene framework: (5) the beta(0)-39 and the IVS-1 nt 6 mutations, with a mutation spread to two major haplotypes, may be older than the IVS-1 nt 110 mutation: (6) these data make possible first-trimester prenatal diagnosis in many families (85%) in Sicily using only three pairs of oligonucleotides. In addition, a new mutation, a frameshift at codon 76 due to loss of a C residue, was found in a single beta-thal chromosome.

Child↗
PubMed1998

Cloning and chromosomal location of the murine keratinocyte lipid-binding protein gene.

The keratinocyte lipid-binding protein (KLBP) is a member of a large multigene family of intracellular fatty-acid-binding proteins. It is expressed in skin and tongue epithelia, adipose, lung and mammary tissue and has been found upregulated in several skin cell carcinomas and papillomas (Krieg et al., 1993). In order to study the regulation of KLBP expression, the murine gene has been cloned. Southern analysis using an exon 2 specific cDNA probe indicated the presence of multiple copies of the gene in the murine genome. Based on the highly conserved structure of the fatty-acid-binding protein genes, the third intron of the KLBP gene was PCR-amplified utilizing murine genomic DNA. Southern analysis with the intron 3 probe identified one unique gene in the murine genome. A full-length genomic clone of KLBP was obtained from a P1 library, and the structural gene was sequenced. Similar to the other FABP genes, the functional KLBP gene contains four exons separated by three introns and maintains the conservation of size and placement of each exon. A functional minimal promoter was demonstrated by transient transfections of 5' upstream KLBP-luciferase reporter constructs into line 308 keratinocyte cells as well as in primary adipocytes. RT-PCR on primary adipocyte RNA demonstrated expression of this KLBP gene by amplification of intron 3 from the primary transcript. Fluorescence in-situ hybridization identified the murine KLBP gene as the fourth FABP gene on chromosome 3, along with myelin P2, ALBP, and intestinal FABP. These studies provide a framework for analysis of KLBP expression in normal and pathophysiological conditions.

Adipocytes↗
PubMed1997

Framework YAC contig anchored into a 3.2-Mb high-resolution physical map in proximal 11q13.

Despite the presence on band q13 of chromosome 11 of a number of genes predisposing individuals to various human diseases, most of this genomic region remains loosely mapped. Moreover, there is a relative dearth of yeast artificial chromosome (YAC) contigs from genome-wide studies: YACs are irregularly distributed over this chromosomal region and have not been arranged into contigs. We have thus undertaken fine-scale mapping of a 3.2-Mb region flanked by ACTN3 and FGF3. Since this region has demonstrated a high degree of YAC instability, we have established a framework contig by anchoring YACs and cosmids into a high-resolution physical map based on fluorescence in situ hybridization and long-range restriction mapping. The 3.2-Mb area studied includes the boundaries of regions thought to contain genes predisposing individuals to osteoporosis-pseudoglioma syndrome and insulin-dependent diabetes mellitus, as well as genes driving amplification events in human carcinomas. Another feature of this genomic area is that it cross-hybridizes to nonsyntenic regions of the genome. In addition, it spans the region where syntenic conservation with mouse chromosome 19 ends, making clones that we have anchored there valuable tools in understanding genome evolution.

Animals↗
PubMed1986

HLA-JY328: mapping studies and expression of a polymorphic HLA class I gene.

The JY328 clone was identified in a human genomic library using cDNA corresponding to mRNA for HLA-B7 as a probe. The L/328 cell line was established by cotransformation of mouse Ltk- cells with the herpes thymidine kinase gene and clone JY328. On Northern blots, RNA from L/328 strongly hybridized to an HLA class I probe, and an antigen was recognized by an anti-HLA class I framework antibody on the cell surface. A DNA probe corresponding to a segment of intron 7 was developed by comparing the nucleotide sequence of clone JY328 with that of other HLA class I-type genes. Using the radiolabeled probe to screen Southern blots of DNA from families with siblings exhibiting intra-HLA recombinations, a restriction fragment length polymorphism was revealed--a 1.4 kb BstE II band not present in all individuals. A corresponding fragment was apparent in the base sequence of clone JY328. The occurrence of this band on Southern blots established that JY328 maps distinct from and centromeric to the HLA-C locus and near to the HLA-B locus. Antibody absorption studies and cytotoxicity tests indicated that the JY328 gene product was not an HLA-B antigen but that it did specifically absorb CW7-specific antibody. In sum, these results suggest a novel, polymorphic HLA class I gene which expresses a product serologically similar to HLA-Cw7 but which does not map within the corresponding locus.

Animals↗
PubMed2004

Mechanistic analysis of hydroarylation catalysts.

Recently, two organometallic systems ([Ir(micro-acac-O)(acac-O,O)(acac-C(3))](2) and (Tp)Ru(CO)(Ph)(NCCH(3))) have been discovered that catalyze hydroarylation of unactivated olefins. Herein, we use density functional theory (B3LYP) to study the factors underlying this class of catalysts. In addition, we calculate the key steps for Rh, Pd, Os, and Pt with similar ligand sets. We previously showed there to be two key steps in the process: (i) insertion of a phenyl into the pi bond of a coordinating olefin, and (ii) C-H activation/hydrogen transfer of an unactivated benzene. An important discovery in these studies is that the barriers for these two steps are inversely correlated, complicating optimization of the overall process. However, herein we elucidate the causes of this inverse correlation, laying the foundation for the rational design of improved catalysts. Both steps are directly influenced by the accessibility of the higher 2-electron oxidation state, M(n) --> M(n+2). Systems with an easily accessible M(n+2) state activate C-H bonds easily but suffer from high energy insertions due to significant back-bonding. Conversely, systems without an easily accessible M(n+2) state have no debilitating back-bonding which makes insertion steps facile, but cannot effectively activate the C-H bond (leading instead to polymerization). The relationship between accessibility of the M(n+2) state and the amount of back-bonding in the coordinating olefin can be visualized by inspecting the hybridization of the coordinating olefin. Furthermore, we find a linear relation between this hybridization and the barrier to insertion. On the basis of these concepts, we suggest some modifications of the sigma framework expected to improve the rates beyond this linear correlation.

Journal Article↗
PubMed2026

A versatile cGAMP reporter reveals principles of cGAS activation by DNA damage and chromosome instability.

cGAS is the primary innate immune DNA sensor. On binding DNA, cGAS generates cGAMP, ultimately driving inflammation. Although normally silenced on self-DNA, genotoxic stress can activate cGAS, proposed to be mediated by micronuclei, chromosome bridges and DNA:RNA hybrids. However, mechanistically, this is poorly understood due to a lack of sensitive and selective single-cell cGAS activation assays. Here we solve this with an improved cGAMP reporter for microscopy, flow cytometry and biochemical assays. Strikingly, we find that genotoxic stress-mediated cGAS activation is a rare event that is not driven by enrichment on micronuclei and occurs by mechanisms that vary in dependence on the genotoxic stress. Following chromosome mis-segregation, cGAS activation correlates with bridge association but, notably, ionizing radiation activates cGAS independently of bridges. Whereas simple DNA:RNA hybrids are inert, more complex structures such as R-loops activate cGAS. Our work revises the cGAS signalling framework and introduces a flexible tool to examine it.

Nucleotidyltransferases↗