Molecular Determinants Defining the Triggering Range of Prefusion F Complexes of Canine Distemper Virus

The morbillivirus cell entry machinery consists of a fusion (F) protein trimer that refolds to mediate membrane fusion following receptor-induced conformational changes in its binding partner, the tetrameric attachment (H) protein. To identify molecular determinants that control F refolding, we generated F chimeras between measles virus (MeV) and canine distemper virus (CDV). We located a central pocket in the globular head domain of CDV F that regulates the stability of the metastable, prefusion conformational state of the F trimer. Most mutations introduced into this "pocket'" appeared to mediate a destabilizing effect, a phenotype associated with enhanced membrane fusion activity. Strikingly, under specific triggering conditions (i.e., variation of receptor type and H protein origin), some F mutants also exhibited resistance to a potent morbillivirus entry inhibitor, which is known to block F triggering by enhancing the stability of prefusion F trimers. Our data reveal that the molecular nature of the F stimulus and the intrinsic stability of metastable prefusion F both regulate the efficiency of F refolding and escape from small-molecule refolding blockers. IMPORTANCE: With the aim to better characterize the thermodynamic basis of morbillivirus membrane fusion for cell entry and spread, we report here that the activation energy barrier of prefusion F trimers together with the molecular nature of the triggering "stimulus" (attachment protein and receptor types) define a "triggering range," which governs the initiation of the membrane fusion process. A central "pocket" microdomain in the globular F head contributes substantially to the regulation of the conformational stability of the prefusion complexes. The triggering range also defines the mechanism of viral escape from entry inhibitors and describes how the cellular environment can affect membrane fusion efficiency.

Systemic Determinants of the Information Systems Outsourcing Decision: A Comparative Study of German and United States Firms

The practice of information systems (IS) outsourcing is widely established among organizations. Nonetheless, evidence suggests that organizations differ considerably in the extent to which they deploy IS outsourcing. This variation has motivated research into the determinants of the IS outsourcing decision. Most of this research is based on the assumption that a decision on the outsourcing of a particular IS function is made independently of other IS functions. This modular view ignores the systemic nature of the IS function, which posits that IS effectiveness depends on how the various IS functions work together effectively. This study proposes that systemic influences are important criteria in evaluating the outsourcing option. It further proposes that the recognition of systemic influences in outsourcing decisions is culturally sensitive. Specifically, we provide evidence that systemic effects are factored into the IS outsourcing decision differently in more individualist cultures than in collectivist ones. Our results of a survey of United States and German firms indicate that perceived in-house advantages in the systemic impact of an IS function are, indeed, a significant determinant of IS outsourcing in a moderately individualist country (i.e., Germany), whereas insignificant in a strongly individualist country (i.e., the United States). The country differences are even stronger with regard to perceived in-house advantages in the systemic view of IS professionals. In fact, the direction of this impact is reversed in the United States sample. Other IS outsourcing determinants that were included as controls, such as cost efficiency, did not show significant country differences.

{\it cis\/} -acting determinants in the control of MuSVts110 RNA splicing

Like other simple retroviruses the murine sarcoma virus ts110 (MuSVts110) displays an inefficient mode of genome splicing. But, unlike the splicing phenotypic of other retroviruses, the splicing event effected upon the transcript of MuSVts110 is temperature sensitive. Previous work in this laboratory has established that the conditionally defective nature of MuSVts110 RNA splicing is mediated in cis by features in the viral transcript. Here we show that the 5$\sp\prime$ splice site of the MuSVts110 transcript acts as a point of control of the overall splicing efficiency at both permissive and nonpermissive temperatures for splicing. We strengthened and simultaneously weakened the nucleotide structure of the 5$\sp\prime$ splice site in an attempt to elucidate the differential effects each of the two known critical splicing components which interact with the 5$\sp\prime$ splice site have on the overall efficiency of intron excision. We found that a transversion of the sixth nucleotide, resulting in the formation of a near-consensus 5$\sp\prime$ splice site, dramatically increased the overall efficiency of MuSVts110 RNA splicing and abrogated the thermosensitive nature of this splicing event. Various secondary mutations within this original transversion mutant, designed to selectively decrease specific splicing component interactions, lead to recovery of inefficient and thermosensitive splicing. We have further shown that a sequence of 415 nucleotides lying in the downstream exon of the viral RNA and hypothesized to act as an element in the temperature-dependent inhibition of splicing displays a functional redundancy throughout its length; loss and/or replacement of any one sequence of 100 nucleotides within this sequence does not, with one exception detailed below, diminish the degree to which MuSVts110 RNA is inhibited to splice at the restrictive temperature. One specific deletion, though, fortuitously juxtaposed and activated cryptic consensus splicing signals for the excision of a cryptic intron within the downstream exon and markedly potentiated--across a newly defined cryptic exon--the splicing event effected upon the upstream, native intron. We have exploited this mutant of MuSVts110 to further an understanding of the process of exon definition and intron definition and show that the polypyrimidine tract and consensus 3$\sp\prime$ splice site, as well as the 5$\sp\prime$ splice site, within the intron at the 3$\sp\prime$ flank of the defined exon are required for the exon's definition; implying that definition of the downstream intron is required for the in vivo definition of the proximal, upstream exon. Finally; we have shown, through the construction of heterologous mutants of MuSVts110 employing a foreign 3$\sp\prime$ end-forming sequence, that efficiency of transcript splicing can be increased--to a degree which abrogates its thermosensitive nature--in direct proportion to increasing proximity of the 3$\sp\prime$ end-forming signal to the terminal 3$\sp\prime$ splice site. ^

Structural determinants of subunit -subunit interactions and subcellular localization of the calcium /calmodulin -dependent protein kinase II

The multifunctional Ca$\sp{2+}$/calmodulin-dependent protein kinase II (CaM kinase) is a Ser/Thr directed protein kinase that participates in diverse Ca$\sp{2+}$ signaling pathways in neurons. The function of CaM kinase depends upon the ability of subunits to form oligomers and to interact with other proteins. Oligomerization is required for autophosphorylation which produces significant functional changes that include Ca$\sp{2+}$/calmodulin-independent activity and calmodulin trapping. Associations with other proteins localize CaM kinase to specific substrates and effectors which serves to optimize the efficiency and speed of signal transduction. In this thesis, we investigate the interactions that underlie the appropriate positioning of CaM kinase activity in cells. We demonstrate that the subcellular distribution of CaM kinase is dynamic in hippocampal slices exposed to anoxic/aglycemic insults and to high K$\sp{+}$-induced depolarization. We determine the localization of CaM kinase domains expressed in neurons and PC-12 cells and find that the C-terminal domain of the $\alpha$ subunit is necessary for localization to dendrites. Moreover, monomeric forms of the enzyme gain access to the nucleus. Attempts made to identify novel CaM kinase binding proteins using the yeast two-hybrid system resulted in the isolation of hundreds of positive clones. Those that have been sequenced are identical to CaM kinase isoforms. Finally, we report the discovery of specific regions within the C-terminal domain that are necessary and sufficient for subunit-subunit interactions. Differences between the $\alpha$ and $\beta$ isoforms were discovered that indicate unique structural requirements for oligomerization. A model for how CaM kinase subunits interact to form holoenzymes and how structural heterogeneity might influence CaM kinase function is presented. ^

Determinants of the phagocytic signal mediated by the type IIIA Fc gamma receptor, Fc gamma RIIIA: sequence requirements and interaction with protein-tyrosine kinases.

The Fc gamma receptor-associated gamma and zeta subunits contain a conserved cytoplasmic motif, termed the immunoglobulin gene tyrosine activation motif, which contains a pair of YXXL sequences. The tyrosine residues within these YXXL sequences have been shown to be required for transduction of a phagocytic signal. We have previously reported that the gamma subunit of the type IIIA Fc gamma receptor (Fc gamma RIIIA) is approximately 6 times more efficient in mediating phagocytosis than the zeta subunit of Fc gamma RIIIA. By exchanging regions of the cytoplasmic domains of the homologous gamma and zeta chains, we observed that the cytoplasmic area of the gamma chain bearing a pair of the conserved YXXL sequences is important in phagocytic signaling. Further specificity of phagocytic signaling is largely determined by the two internal XX amino acids in the YXXL sequences. In contrast, the flanking amino acids of the YXXL sequences including the seven intervening amino acids between the two YXXL sequences do not significantly affect the phagocytic signal. Furthermore, the protein-tyrosine kinase Syk, but not the related kinase ZAP-70, stimulated Fc gamma RIIIA-mediated phagocytosis. ZAP-70, however, increased phagocytosis when coexpressed with the Src family kinase Fyn. These data demonstrate the importance of the two specific amino acids within the gamma subunit YXXL cytoplasmic sequences in phagocytic signaling and explain the difference in phagocytic efficiency of the gamma and zeta chains. These results indicate the importance of Syk in Fc gamma RIIIA-mediated phagocytosis and demonstrate that ZAP-70 and syk differ in their requirement for a Src-related kinase in signal transduction.

Trade liberalisation and technical efficiency: Evidence from Bangladesh manufacturing industries

The paper investigates the effects of trade liberalisation on the technical efficiency of the Bangladesh manufacturing sector by estimating a combined stochastic frontier-inefficiency model using panel data for the period 197894 for 25 three-digit level industries. The results show that the overall technical efficiency of the manufacturing sector as well as the technical efficiencies of the majority of the individual industries has increased over time. The findings also clearly suggest that trade liberalisation, proxied by export orientation and capital deepening, has had significant impact on the reduction of the overall technical inefficiency. Similarly, the scale of operation and the proportion of non-production labour in total employment appear as important determinants of technical inefficiency. The evidence also indicates that both export-promoting and import-substituting industries have experienced rises in technical efficiencies over time. Besides, the results are suggestive of neutral technical change, although (at the 5 per cent level of significance) the empirical results indicate that there was no technical change in the manufacturing industries. Finally, the joint test based on the likelihood ratio (LR) test rejects the Cobb-Douglas production technology as description of the database given the specification of the translog production technology.

Trade liberalization and the efficiency of firms in Indian manufacturing

Has the efficiency of firms in India improved since its liberalization in 1991? The authors attempt to answer this question by analyzing the determinants of firm-level efficiency in six manufacturing sectors in India while focusing on the effects of liberalization and domestic competition. They find that there was an increase in overall efficiency in the post-reform period in India in five out of six sectors. While imports do not seem to improve efficiency, liberalization did increase efficiency in four of the sectors.

Organizational capital, product market competition and technical efficiency in Italian cooperatives

This paper tries to identify under which conditions increasing market competition may help cooperatives to improve technical efficiency to guarantee positive profits. This hypothesis is first formalized in a partial equilibrium framework and then is tested on a sample of Italian conventional and cooperative firms, using frontier analysis. Technical efficiency indexes are computed by using the one-stage approach as suggested by Battese and Coelli (1995), where proxies for competition are introduced as determinants of efficiency, along with other exogenous factors accounting for the firms’ heterogeneity. However, the overall impact of increasing competition on efficiency is negative.

An empirical investigation of the effect of rights issue announcements on share returns and the determinants of abnormal returns on the Kuala Lumpur Stock Exchange

This thesis examines the effect of rights issue announcements on stock prices by companies listed on the Kuala Lumpur Stock Exchange (KLSE) between 1987 to 1996. The emphasis is to report whether the KLSE is semi strongly efficient with respect to the announcement of rights issues and to check whether the implications of corporate finance theories on the effect of an event can be supported in the context of an emerging market. Once the effect is established, potential determinants of abnormal returns identified by previous empirical work and corporate financial theory are analysed. By examining 70 companies making clean rights issue announcements, this thesis will hopefully shed light on some important issues in long term corporate financing. Event study analysis is used to check on the efficiency of the Malaysian stock market; while cross-sectional regression analysis is executed to identify possible explanators of the rights issue announcements' effect. To ensure the results presented are not contaminated, econometric and statistical issues raised in both analyses have been taken into account. Given the small amount of empirical research conducted in this part of the world, the results of this study will hopefully be of use to investors, security analysts, corporate financial managements, regulators and policy makers as well as those who are interested in capital market based research of an emerging market. It is found that the Malaysian stock market is not semi strongly efficient since there exists a persistent non-zero abnormal return. This finding is not consistent with the hypothesis that security returns adjust rapidly to reflect new information. It may be possible that the result is influenced by the sample, consisting mainly of below average size companies which tend to be thinly traded. Nevertheless, these issues have been addressed. Another important issue which has emerged from the study is that there is some evidence to suggest that insider trading activity existed in this market. In addition to these findings, when the rights issue announcements' effect is compared to the implications of corporate finance theories in predicting the sign of abnormal returns, the signalling model, asymmetric information model, perfect substitution hypothesis and Scholes' information hypothesis cannot be supported.

Derivation of marginal effects of determinants of technical inefficiency

In efficiency studies using the stochastic frontier approach, the main focus is to explain inefficiency in terms of some exogenous variables and computation of marginal effects of each of these determinants. Although inefficiency is estimated by its mean conditional on the composed error term (the Jondrow et al., 1982 estimator), the marginal effects are computed from the unconditional mean of inefficiency (Wang, 2002). In this paper we derive the marginal effects based on the Jondrow et al. estimator and use the bootstrap method to compute confidence intervals of the marginal effects.

Public sector efficiency, foreign aid and small island development states

This paper examines the efficiency of public sector expenditures and foreign aid at achieving social sector outcomes in Small Island Developing States (SIDS). Efficiency is estimated using a Stochastic Production Function (SPF) approach and panel data since 1990. A second stage of the analysis examines the determinants of efficiency. Results indicate that the efficiency of aid and public sectors at improving life expectancy has deteriorated during the 1990s but efficiency at improving school enrolments has increased. Higher levels of governance are associated with higher efficiency. There is also evidence to suggest that efficiency is lower in SIDS, as well as in Sub-Saharan Africa.

Determinants of confidence and their effect on epistemic judgments: Implications for auditor calibration bias

Auditor decisions regarding the causes of accounting misstatements can have an audit effectiveness and efficiency. Specifically, overconfidence in one's decision can lead to an ineffective audit, whereas underconfidence in one's decision can lead to an inefficient audit. This dissertation explored the implications of providing various types of information cues to decision-makers regarding an Analytical Procedure task and investigated the relationship between different types of evidence cues (confirming, disconfirming, redundant or non-redundant) and the reduction in calibration bias. Information was collected using a laboratory experiment, from 45 accounting students participants. Research questions were analyzed using a 2 x 2 x 2 between-subject and within-subject analysis of covariance (ANCOVA). ^ Results indicated that presenting subjects with information cues dissimilar to the choice they made is an effective intervention in reducing the common overconfidence found in decision-making. In addition, other information characteristics, specifically non-redundant information can help in reducing a decision-maker's overconfidence/calibration bias for difficulty (compared to easy) decision-tasks. ^

Social service provision, efficiency labor and economic development

This dissertation provides a theory of the effects and determinants of an economy's level of social services. The dissertation focuses on how the provision of social services will affect the effort decisions of workers, which will ultimately determine the economy's level of output. A worker decides on how much effort to contribute in relation to the level of social services he/she receives. The higher the level of social services received, the lower the cost—disutility—from providing effort will be. The government provides public infrastructure and social services (i.e. health services) in accordance with the economy's endowment of effort. In doing so, the government takes the aggregate effort endowment as given. Since, with higher individual work effort the higher the economy's total level of effort, failure by workers to coordinate effort levels will result in possible instances of low effort, low social services and low output; and, other instances of high effort, high social services and high output. Therefore, this dissertation predicts that in the context of social services, coordination failures in effort levels can lead to development traps. ^

Energy efficiency in the Chinese provinces: a fixed effects stochastic frontier spatial Durbin error panel analysis

Energy efficiency improvement has been a key objective of China’s long-term energy policy. In this paper, we derive single-factor technical energy efficiency (abbreviated as energy efficiency) in China from multi-factor efficiency estimated by means of a translog production function and a stochastic frontier model on the basis of panel data on 29 Chinese provinces over the period 2003–2011. We find that average energy efficiency has been increasing over the research period and that the provinces with the highest energy efficiency are at the east coast and the ones with the lowest in the west, with an intermediate corridor in between. In the analysis of the determinants of energy efficiency by means of a spatial Durbin error model both factors in the own province and in first-order neighboring provinces are considered. Per capita income in the own province has a positive effect. Furthermore, foreign direct investment and population density in the own province and in neighboring provinces have positive effects, whereas the share of state-owned enterprises in Gross Provincial Product in the own province and in neighboring provinces has negative effects. From the analysis it follows that inflow of foreign direct investment and reform of state-owned enterprises are important policy handles.

Agricultural microcredit and technical efficiency: The case of smallholder rice farmers in Northern Ghana

In the current study, we compared technical efficiency of smallholder rice farmers with and without credit in northern Ghana using data from a farm household survey. We fitted a stochastic frontier production function to input and output data to measure technical efficiency. We addressed self-selection into credit participation using propensity score matching and found that the mean efficiency did not differ between credit users and non-users. Credit-participating households had an efficiency of 63.0 percent compared to 61.7 percent for non-participants. The results indicate significant inefficiencies in production and thus a high scope for improving farmers’ technical efficiency through better use of available resources at the current level of technology. Apart from labour and capital, all the conventional farm inputs had a significant effect on rice production. The determinants of efficiency included the respondent’s age, sex, educational status, distance to the nearest market, herd ownership, access to irrigation and specialisation in rice production. From a policy perspective, we recommend that the credit should be channelled to farmers who demonstrate the need for it and show the commitment to improve their production through external financing. Such a screening mechanism will ensure that the credit goes to the right farmers who need it to improve their technical efficiency.