Efficient Gene Targeting Mediated by Adeno-Associated Virus and DNA Double-Strand Breaks

Gene targeting is the in situ manipulation of the sequence of an endogenous gene by the introduction of homologous exogenous DNA. Presently, the rate of gene targeting is too low for it to be broadly used in mammalian somatic cell genetics or to cure genetic diseases. Recently, it has been demonstrated that infection with recombinant adeno-associated virus (rAAV) vectors can mediate gene targeting in somatic cells, but the mechanism is unclear. This paper explores the balance between random integration and gene targeting with rAAV. Both random integration and spontaneous gene targeting are dependent on the multiplicity of infection (MOI) of rAAV. It has previously been shown that the introduction of a DNA double-stranded break (DSB) in a target gene can stimulate gene targeting by several-thousand-fold in somatic cells. Creation of a DSB stimulates the frequency of rAAV-mediated gene targeting by over 100-fold, suggesting that the mechanism of rAAV-mediated gene targeting involves, at least in part, the repair of DSBs by homologous recombination. Absolute gene targeting frequencies reach 0.8% with a dual vector system in which one rAAV vector provides a gene targeting substrate and a second vector expresses the nuclease that creates a DSB in the target gene. The frequencies of gene targeting that we achieved with relatively low MOIs suggest that combining rAAV vectors with DSBs is a promising strategy to broaden the application of gene targeting

Employee Stock Ownership and Financial Performance in European Countries: The Moderating Effects of Uncertainty Avoidance and Social Trust

This study investigates how the effect of employee stock ownership on financial performance may hinge on the diverse cultural and societal contexts of European countries. Based on agency and national culture theories, we hypothesize that the positive relationship between employee stock ownership and return on assets (ROA) is stronger in those nations with lower uncertainty avoidance and higher social trust. Using a multisource, time‐lagged, large‐scale dataset of 1,741 firms from 21 countries in Europe, our multilevel, random coefficient modeling analysis found evidence for these hypotheses, suggesting that uncertainty avoidance and social trust serve as important contextual cues in predicting the linkage between employee stock ownership and financial performance. Our supplemental analysis with distinction between the managerial and nonmanagerial employee stock ownership further indicates managerial employee stock ownership has a direct positive effect on ROA. Although nonmanagerial employee stock ownership had a nonsignificant association with ROA, the relationship was positive and significant when uncertainty avoidance was low and social trust was high. This research contributes to the existing literature by illuminating some of the contextual influences altering the effectiveness of employee stock ownership. Our findings also offer practical suggestions for effectively using employee stock ownership

The fundamental problem of command : plan and compliance in a partially centralised economy

When a principal gives an order to an agent and advances resources for its implementation, the temptations for the agent to shirk or steal from the principal rather than comply constitute the fundamental problem of command. Historically, partially centralised command economies enforced compliance in various ways, assisted by nesting the fundamental problem of exchange within that of command. The Soviet economy provides some relevant data. The Soviet command system combined several enforcement mechanisms in an equilibrium that shifted as agents learned and each mechanism's comparative costs and benefits changed. When the conditions for an equilibrium disappeared, the system collapsed.Comparative Economic Studies (2005) 47, 296–314. doi:10.1057/palgrave.ces.810011

Contributions from economics of adaptation to decision making: an example for the autonomous community of the Basque Country

As a consequence of Climate Change sea level rise as well as a change in the intensity and propensity of rain are expected in the Basque Country. Valuing the costs and benefits of adapting to these changes becomes an important piece of information for the planning process. This paper develops two methodological frameworks. The first one devoted to estimating the economic impacts to urban areas of an increase in the risk of flooding. The values estimated for the Nervión river in the city of Amurrio (Álava) indicate that the average expected damage will increase in 15 per cent as a consequence of CC (from €56,097 to €64,451). For an extreme episode the total loss could increase to €20 million. The second framework is oriented towards the valuation of the damages as a consequence of sea level rise for 2100. The values in this case range from €87 to €231 million, that is, between €0.87 and €2.3 million per hectare

Employee share ownership in a unionised duopoly

Profit sharing schemes have been analysed assuming Cournot competition and decentralised wage negotiations, and it has been found that firms share profits in equilibrium. This paper analyses a different remuneration system: employee share ownership. We find that whether firms choose to share ownership or not depends on both the type of competition in the product market and the way in which workers organise to negotiate wages. If wage setting is decentralised, under duopolistic Cournot competition both firms share ownership. If wage setting is centralised, only one firm shares ownership if the degree to which goods are substitutes takes an intermediate value; otherwise, the two firms share ownership. In this case, if the union sets the same wage for all workers neither firm shares ownership. Therefore, centralised wage setting discourages share ownership. Fi- nally, under Bertrand competition neither firm shares ownership regardless of how workers are organised to negotiate wages.info:eu-repo/semantics/publishedVersio

Common barriers, but temporal dissonance: Genomic tests suggest ecological and paleo‐landscape sieves structure a coastal riverine fish community

Assessments of spatial and temporal congruency across taxa from genetic data provide insights into the extent to which similar processes structure communities. However, for coastal regions that are affected continuously by cyclical sea‐level changes over the Pleistocene, congruent interspecific response will not only depend upon codistributions, but also on similar dispersal histories among taxa. Here, we use SNPs to test for concordant genetic structure among four codistributed taxa of freshwater fishes (Teleostei: Characidae) along the Brazilian Atlantic coastal drainages. Based on population relationships and hierarchical genetic structure analyses, we identify all taxa share the same geographic structure suggesting the fish utilized common passages in the past to move between river basins. In contrast to this strong spatial concordance, model‐based estimates of divergence times indicate that despite common routes for dispersal, these passages were traversed by each of the taxa at different times resulting in varying degrees of genetic differentiation across barriers with most divergences dating to the Upper Pleistocene, even when accounting for divergence with gene flow. Interestingly, when this temporal dissonance is viewed through the lens of the species‐specific ecologies, it suggests that an ecological sieve influenced whether species dispersed readily, with an ecological generalist showing the highest propensity for historical dispersal among the isolated rivers of the Brazilian coast (i.e., the most recent divergence times and frequent gene flow estimated for barriers). We discuss how our findings, and in particular what the temporal dissonance, despite common geographic passages, suggest about past dispersal structuring coastal communities as a function of ecological and paleo‐landscape sieves.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154255/1/mec15357_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154255/2/mec15357.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154255/3/mec15357-sup-0001-Supinfo.pd