Resource recombinations in the firm: knowledge structures and the potential for schumpeterian innovation
Building on the resource-based view of the firm, this paper explores the notion of ‘resource recombinations’ within the firm. We suggest such recombinations can occur when competencies within the firm (which are interpreted as organized clusters of firm resources) either combine to synthesize novel competencies (synthesis-based recombinations) or experience a reconfiguration or relinking with other competencies (reconfiguration-based recombinations). Central to this paper is an examination of the antecedents necessary for such innovation to occur, and in particular the nature of knowledge in the firm. We argue that several characteristics of knowledge (tacitness, context specificity, dispersion) and its social organization (the way competencies come to be formed and institutionalized) will have important consequences on the likelihoods of resource recombinations. Our paper develops a model of resource recombination likelihoods and propositions. © 1998 John Wiley & Sons, Ltd.
Resource recombinations in the firm: knowledge structures and the potential for schumpeterian innovation
Building on the resource-based view of the firm, this paper explores the notion of ‘resource recombinations’ within the firm. We suggest such recombinations can occur when competencies within the firm (which are interpreted as organized clusters of firm resources) either combine to synthesize novel competencies (synthesis-based recombinations) or experience a reconfiguration or relinking with other competencies (reconfiguration-based recombinations). Central to this paper is an examination of the antecedents necessary for such innovation to occur, and in particular the nature of knowledge in the firm. We argue that several characteristics of knowledge (tacitness, context specificity, dispersion) and its social organization (the way competencies come to be formed and institutionalized) will have important consequences on the likelihoods of resource recombinations. Our paper develops a model of resource recombination likelihoods and propositions. © 1998 John Wiley & Sons, Ltd.
THE RELATION OF RECOMBINATION TO MUTATIONAL ADVANCE
The method of calculation is shown whereby a formula has been derived that states approximately the ratio of the rate of accumulation of advantageous mutant genes in a population that undergoes recombination to the rate in an otherwise nonrecombining one. A table is given showing the ratios thus found for different frequencies of advantageous mutations and different degrees of their advantage. I t is shown that this calculation does not apply for mutant genes that act advantageously only when in some special combinations with one or more other mutant ,genes, and that as far as these cases of special synergism are concerned recombining lines have no evolutionary advantage over non-recombining ones. Other limitations of the formula are pointed out and assessed. I t is explained that most factors that retard the rate of recombination--for example, linkage, rari ty of outbreeding, intercalation of sexual reproduction between more frequent cycles of asexual propagation, and partial isolation between subpopulat ions--must usually cause little long-term retardation of the speed of advance that is fostered by recombination. Moreover, even where long-term evolution has virtually ceased, recombination of mutant genes still confers upon a population the means of adopting short-term genetic "dodges", that adjust it to ecological and "physical" changes in its circumstances, much more rapidly than would be possible for a comparable asexual population. Under conditions where only stability of type is needed, a non-recombining population does not actually degenerate as a result of an excess of mutation over selection, after the usual equilibrium between these pressures is reached. However, a kind of irreversible ratchet mechanism exists in the non-recombining species (unlike the recombining ones) that prevents selection, even if intensified, from reducing the mutational loads below the lightest that were in existence when the intensified selection started, whereas, contrariwise, "drif t" and what might be called "selective noise" must allow occasional slips of the lightest loads in the direction of increased weight.
Gene recombination in postmitotic cells. Targeted expression of Cre recombinase provokes cardiac-restricted, site-specific rearrangement in adult ventricular muscle in vivo.
Mouse models of human disease can be generated by homologous recombination for germline loss-of-function mutations. However, embryonic-lethal phenotypes and systemic, indirect dysfunction can confound the use of knock-outs to elucidate adult pathophysiology. Site-specific recombination using Cre recombinase can circumvent these pitfalls, in principle, enabling temporal and spatial control of gene recombination. However, direct evidence is lacking for the feasibility of Cre-mediated recombination in postmitotic cells. Here, we exploited transgenic mouse technology plus adenoviral gene transfer to achieve Cre-mediated recombination in cardiac muscle. In vitro, Cre driven by cardiac-specific alpha-myosin heavy chain (alphaMyHC) sequences elicited recombination selectively at loxP sites in purified cardiac myocytes, but not cardiac fibroblasts. In vivo, this alphaMyHC-Cre transgene elicited recombination in cardiac muscle, but not other organs, as ascertained by PCR analysis and localization of a recombination-dependent reporter protein. Adenoviral delivery of Cre in vivo provoked recombination in postmitotic, adult ventricular myocytes. Recombination between loxP sites was not detected in the absence of Cre. These studies demonstrate the feasibility of using Cre-mediated recombination to regulate gene expression in myocardium, with efficient induction of recombination even in terminally differentiated, postmitotic muscle cells. Moreover, delivery of Cre by viral infection provides a simple strategy to control the timing of recombination in myocardium.
The Rad50 zinc-hook is a structure joining Mre11 complexes in DNA recombination and repair
The Mre11 complex (Mre11–Rad50–Nbs1) is central to chromosomal maintenance and functions in homologous recombination, telomere maintenance and sister chromatid association. These functions all imply that the linked binding of two DNA substrates occurs, although the molecular basis for this process remains unknown. Here we present a 2.2 Å crystal structure of the Rad50 coiled-coil region that reveals an unexpected dimer interface at the apex of the coiled coils in which pairs of conserved Cys-X-X-Cys motifs form interlocking hooks that bind one Zn2+ ion. Biochemical, X-ray and electron microscopy data indicate that these hooks can join oppositely protruding Rad50 coiled-coil domains to form a flexible bridge of up to 1,200 Å. This suggests a function for the long insertion in the Rad50 ABC-ATPase domain. The Rad50 hook is functional, because mutations in this motif confer radiation sensitivity in yeast and disrupt binding at the distant Mre11 nuclease interface. These data support an architectural role for the Rad50 coiled coils in forming metal-mediated bridging complexes between two DNA-binding heads. The resulting assemblies have appropriate lengths and conformational properties to link sister chromatids in homologous recombination and DNA ends in non-homologous end-joining.
Recombination within natural populations of pathogenic bacteria: short-term empirical estimates and long-term phylogenetic consequences.
The identification of clones within bacterial populations is often taken as evidence for a low rate of recombination, but the validity of this inference is rarely examined. We have used statistical tests of congruence between gene trees to examine the extent and significance of recombination in six bacterial pathogens. For Neisseria meningitidis, Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus, the congruence between the maximum likelihood trees reconstructed using seven house-keeping genes was in most cases no better than that between each tree and trees of random topology. The lack of congruence between gene trees in these four species, which include both naturally transformable and nontransformable species, is in three cases supported by high ratios of recombination to point mutation during clonal diversification (estimates of this parameter were not possible for Strep. pyogenes). In contrast, gene trees constructed for Hemophilus influenzae and pathogenic isolates of Escherichia coli showed a higher degree of congruence, suggesting lower rates of recombination. The impact of recombination therefore varies between bacterial species but in many species is sufficient to obliterate the phylogenetic signal in gene trees.
Distribution of recombination crossovers and the origin of haplotype blocks: the interplay of population history, recombination, and mutation.
Recent studies suggest that haplotypes are arranged into discrete blocklike structures throughout the human genome. Here, we present an alternative haplotype block definition that assumes no recombination within each block but allows for recombination between blocks, and we use it to study the combined effects of demographic history and various population genetic parameters on haplotype block characteristics. Through extensive coalescent simulations and analysis of published haplotype data on chromosome 21, we find that (1) the combined effects of population demographic history, recombination, and mutation dictate haplotype block characteristics and (2) haplotype blocks can arise in the absence of recombination hot spots. Finally, we provide practical guidelines for designing and interpreting studies investigating haplotype block structure.
Removing structural disorder from oriented TiO2 nanotube arrays: reducing the dimensionality of transport and recombination in dye-sensitized solar cells.
We report on the influence of morphological disorder, arising from bundling of nanotubes (NTs) and microcracks in films of oriented TiO2 NT arrays, on charge transport and recombination in dye-sensitized solar cells (DSSCs). Capillary stress created during evaporation of liquids from the mesopores of dense TiO2 NT arrays was of sufficient magnitude to induce bundling and microcrack formation. The average lateral deflection of the NTs in the bundles increased with the surface tension of the liquids and with the film thicknesses. The supercritical CO2 drying technique was used to produce bundle-free and crack-free NT films. Charge transport and recombination properties of sensitized films were studied by frequency-resolved modulated photocurrent/photovoltage spectroscopies. Transport became significantly faster with decreased clustering of the NTs, indicating that bundling creates additional pathways via intertube contacts. Removing such contacts alters the transport mechanism from a combination of one and three dimensions to the expected one dimension and shortens the electron-transport pathway. Reducing intertube contacts also resulted in a lower density of surface recombination centers by minimizing distortion-induced surface defects in bundled NTs. A causal connection between transport and recombination is observed. The dye coverage was greater in the more aligned NT arrays, suggesting that reducing intertube contacts increases the internal surface area of the films accessible to dye molecules. The solar conversion efficiency and photocurrent density were highest for DSSCs incorporating films with more aligned NT arrays owing to an enhanced light-harvesting efficiency. Removing structural disorder from other materials and devices consisting of nominally one-dimensional architectures (e.g., nanowire arrays) should produce similar effects.
V(D)J recombination: a functional definition of the joining signals.
Two conserved DNA sequences serve as joining signals in the assembly of immunoglobulins and T-cell receptors from V-, (D)-, and J-coding segments during lymphoid differentiation. We have examined V(D)J recombination as a function of joining signal sequence. Plasmid substrates with mutations in one or both of the heptamer-spacer-nonamer sequences were tested for recombination in a pre-B-cell line active in V(D)J recombination. No signal variant recombines more efficiently than the consensus forms of the joining signals. We find the heptamer sequence to be the most important; specifically, the three bases closest to the recombination crossover site are critical. The nonamer is not as rigidly defined, and it is not important to maintain the five consecutive As that distinguish the consensus nonamer sequence. Both types of signals display very similar sequence requirements and have in common an intolerance for changes in spacer length greater than 1 bp. Although the two signal types share sequence motifs, we find no evidence of a role in recombination for homology between the signals, suggesting that they serve primarily as protein recognition and binding sites.
Double-strand signal sequence breaks in V(D)J recombination are blunt, 5'-phosphorylated, RAG-dependent, and cell cycle regulated.
Immunoglobulin and T-cell receptor genes are assembled during lymphocyte development by a novel, highly regulated series of gene rearrangement reactions known as V(D)J recombination. All rearranging loci are flanked by conserved heptamer-nonamer recombination signal sequences. Gene rearrangement results in the imprecise fusion of coding sequences and the precise fusion of signal sequences. DNA molecules with double-stranded breaks near signal sequences have been detected in cells undergoing V(D)J recombination of the TCR delta locus. We have devised a ligation-mediated PCR assay that detects broken-ended molecules in purified genomic DNA. Using this assay we found that DNA breaks occurring precisely at the signal sequence-coding sequence junction are a general feature of V(D)J recombination, appearing in association with each type of rearranging immunoglobulin gene segment. We show that a significant fraction of these broken ends are blunt and 5'-phosphorylated. In addition, detection of these broken-ended signal sequences is dependent on the activity of RAG-1 and RAG-2, and is restricted to the G0/G1 phase of the cell cycle. The pattern of broken-ended molecules detected in cells at various stages of development reflects the activity of the V(D)J recombinase at different loci during B- and T-cell development.
Ku80 is required for immunoglobulin isotype switching
Isotype switching is the DNA recombination mechanism by which antibody genes diversify immunoglobulin effector functions. In contrast to V(D)J recombination, which is mediated by RAG1, RAG2 and DNA double‐stranded break (DSB) repair proteins, little is known about the mechanism of switching. We have investigated the role of DNA DSB repair in switch recombination in mice that are unable to repair DSBs due to a deficiency in Ku80 (Ku80−/−). B‐cell development is arrested at the pro‐B cell stage in Ku80−/− mice because of abnormalities in V(D)J recombination, and there are no mature B cells. To reconstitute the B‐cell compartment in Ku80−/− mice, pre‐rearranged VB1−8 DJH2 (μi) and V3−83JK2 (κi) genes were introduced into the Ku80−/− background (Ku80−/−μi/+κi/+). Ku80−/−μi/+ κi/+ mice develop mature mIgM+ B cells that respond normally to lipopolysaccharide (LPS) or LPS plus interleukin‐4 (IL‐4) by producing specific germline Ig constant region transcripts and by forming switch region‐specific DSBs. However, Ku80−/−μi/+κi/+ B cells are unable to produce immunoglobulins of secondary isotypes, and fail to complete switch recombination. Thus, Ku80 is essential for switch recombination in vivo, suggesting a significant overlap between the molecular machinery that mediates DNA DSB repair, V(D)J recombination and isotype switching.
Recombination and the population structures of bacterial pathogens.
The population structures of bacterial species are complex and often controversial. To a large extent, this is due to uncertainty about the frequency and impact of recombination in bacteria. The existence of clones within bacterial populations, and of linkage disequilibrium between alleles at different loci, is often cited as evidence for low rates of recombination. However, clones and linkage disequilibrium are almost inevitable in species that divide by binary fission and can be present in populations where recombination is frequent. In recent years, it has become possible to directly compare rates of recombination in different species. These studies indicate that in many bacterial species, including Neisseria meningitidis, Streptococcus pneumoniae, and Staphylococcus aureus, evolutionary change at neutral (housekeeping) loci is more likely to occur by recombination than mutation and can result in the elimination of any deep-rooted phylogenetic signal. In such species, the long-term evolution of the population is dominated by recombination, but this does not occur at a sufficiently high frequency to prevent the emergence of adaptive clones, although these are relatively short-lived and rapidly diversify.
Boosting power conversion efficiencies of quantum-dot-sensitized solar cells beyond 8% by recombination control.
At present, quantum-dot-sensitized solar cells (QDSCs) still exhibit moderate power conversion efficiency (with record efficiency of 6-7%), limited primarily by charge recombination. Therefore, suppressing recombination processes is a mandatory requirement to boost the performance of QDSCs. Herein, we demonstrate the ability of a novel sequential inorganic ZnS/SiO2 double layer treatment onto the QD-sensitized photoanode for strongly inhibiting interfacial recombination processes in QDSCs while providing improved cell stability. Theoretical modeling and impedance spectroscopy reveal that the combined ZnS/SiO2 treatment reduces interfacial recombination and increases charge collection efficiency when compared with conventional ZnS treatment alone. In line with those results, subpicosecond THz spectroscopy demonstrates that while QD to TiO2 electron-transfer rates and yields are insensitive to inorganic photoanode overcoating, back recombination at the oxide surface is strongly suppressed by subsequent inorganic treatments. By exploiting this approach, CdSe(x)Te(1-x) QDSCs exhibit a certified record efficiency of 8.21% (8.55% for a champion cell), an improvement of 20% over the previous record high efficiency of 6.8%, together with an additional beneficial effect of improved cell stability.
High-Resolution Mapping of Crossovers Reveals Extensive Variation in Fine-Scale Recombination Patterns Among Humans
Recombination plays a crucial role in meiosis, ensuring the proper segregation of chromosomes. Recent linkage disequilibrium (LD) and sperm-typing studies suggest that recombination rates vary tremendously across the human genome, with most events occurring in narrow “hotspots.” To examine variation in fine-scale recombination patterns among individuals, we used dense, genome-wide single-nucleotide polymorphism data collected in nuclear families to localize crossovers with high spatial resolution. This analysis revealed that overall recombination hotspot usage is similar in males and females, with individual hotspots often active in both sexes. Across the genome, roughly 60% of crossovers occurred in hotspots inferred from LD studies. Notably, however, we found extensive and heritable variation among both males and females in the proportion of crossovers occurring in these hotspots.
V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations.
Severe combined immunodeficiency (SCID) comprises a heterogeneous group of primary immunodeficiencies, a proportion of which are due to mutations in either of the 2 recombination activating genes (RAG)-1 and -2, which mediate the process of V(D)J recombination leading to the assembly of antigen receptor genes. It is reported here that the clinical and immunologic phenotypes of patients bearing mutations in RAGs are more diverse than previously thought and that this variability is related, in part, to the specific type of RAG mutation. By analyzing 44 such patients from 41 families, the following conclusions were reached: (1) null mutations on both alleles lead to the T-B-SCID phenotype; (2) patients manifesting classic Omenn syndrome (OS) have missense mutations on at least one allele and maintain partial V(D)J recombination activity, which accounts for the generation of residual, oligoclonal T-lymphocytes; (3) in a third group of patients, findings were only partially compatible with OS, and these patients, who also carried at least one missense mutation, may be considered to have atypical SCID/OS; (4) patients with engraftment of maternal T cells as a complication of a transplacental transfusion represented a fourth group, and these patients, who often presented with a clinical phenotype mimicking OS, may be observed regardless of the type of RAG gene mutation. Analysis of the RAG genes by direct sequencing is an effective way to provide accurate diagnosis of RAG-deficient as opposed to RAG-independent V(D)J recombination defects, a distinction that cannot be made based on clinical and immunologic phenotype alone.
genetic algorithm positioning system process control sample size solar cell visible light dna sequence learning object indoor positioning received signal strength statistical process control indoor localization quantum dot statistical proces indoor positioning system count datum hecke algebra factorial design ieee standard binding site escherichia coli weighted moving average knowledge structure statistical quality control poisson structure cell cycle choice behavior econometric model quality level exponentially weighted moving fractional factorial design saccharomyces cerevisiae selection bia affine weyl group statistical process monitoring power conversion efficiency dye-sensitized solar cell charge transport uniform resource identifier learning object metadatum embryonic stem cell moving average control object class dye-sensitized solar reusable learning object linkage disequilibrium quantity discount spatial process spatial econometric population parameter embryonic stem reusable learning object metadatum heterojunction solar cell dna repair location fingerprinting cell development indoor positioning technique spatial econometric model radiation tolerance heterojunction solar genetic linkage signal peptide bulk heterojunction dna segment recombination rate bulk heterojunction solar dna recombination wifi-based indoor localization surface recombination escherichia coli. low-density lipoprotein indoor positioning solution proposed positioning system surface recombination velocity solar cells. neisseria meningitidi genetic heterogeneity learning object review dna break xrcc5 wt allele xrcc5 gene t cell receptor v(d)j recombination v(d)j recombination-activating protein 1 excretory function neuritis, autoimmune, experimental leukemia, b-cell dna sequence rearrangement immunoglobulin class switch recombination immunoglobulin class switching lipoprotein receptor dna breaks, double-stranded telomere maintenance v(d)j recombination genome encoded entity vdj recombinase recombination, genetic crossover (genetic algorithm) meiotic recombination homologous recombination