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Sixty billion chickens are produced worldwide each year, and all are at risk from Eimeria , parasites that cause coccidiosis. Control relies widely on chemoprophylaxis, but pressure to reduce drug use in farming urges development of cost-effective vaccines. Antigens such as apical membrane antigen 1 (AMA1) offer promise as anticoccidial vaccine candidates, but experience with related apicomplexans such as Plasmodium , in which pre-existing antigenic diversity and incompatible population structure have undermined vaccine development, tempers confidence. Parasite genotyping identified enormous region-specific variation in haplotype diversity for Eimeria tenella but a contrastingly low level of polymorphism for Et AMA1. Although high levels of polyclonal Eimeria infection and hybridization indicate an ability to disseminate vaccine resistance rapidly, the low level of Et AMA1 diversity promotes vaccine development. The phylum Apicomplexa includes serious pathogens of humans and animals. Understanding the distribution and population structure of these protozoan parasites is of fundamental importance to explain disease epidemiology and develop sustainable controls. Predicting the likely efficacy and longevity of subunit vaccines in field populations relies on knowledge of relevant preexisting antigenic diversity, population structure, the likelihood of coinfection by genetically distinct strains, and the efficiency of cross-fertilization. All four of these factors have been investigated for Plasmodium species parasites, revealing both clonal and panmictic population structures with exceptional polymorphism associated with immunoprotective antigens such as apical membrane antigen 1 (AMA1). For the coccidian Toxoplasma gondii only genomic diversity and population structure have been defined in depth so far; for the closely related Eimeria species, all four variables are currently unknown. Using Eimeria tenella , a major cause of the enteric disease coccidiosis, which exerts a profound effect on chicken productivity and welfare, we determined population structure, genotype distribution, and likelihood of cross-fertilization during coinfection and also investigated the extent of naturally occurring antigenic diversity for the E . tenella AMA1 homolog. Using genome-wide Sequenom SNP-based haplotyping, targeted sequencing, and single-cell genotyping, we show that in this coccidian the functionality of Et AMA1 appears to outweigh immune evasion. This result is in direct contrast to the situation in Plasmodium and most likely is underpinned by the biology of the direct and acute coccidian life cycle in the definitive host.

Elevated mitochondrial O -GlcNAcylation caused by hyperglycemia, as occurs in diabetes, significantly contributes to mitochondrial dysfunction and to diabetic cardiomyopathy. However, little is known about the enzymology of mitochondrial O -GlcNAcylation. Herein, we investigated the enzymes responsible for cycling O -GlcNAc on mitochondrial proteins and studied the mitochondrial transport of UDP-GlcNAc. Analyses of purified rat heart mitochondria from normal and streptozocin-treated diabetic rats show increased mitochondrial O -GlcNAc transferase (OGT) and a concomitant decrease in the mito-specific O-GlcNAcase (OGA). Strikingly, OGT is mislocalized in cardiac mitochondria from diabetic rats. Interaction of OGT and complex IV observed in normal rat heart mitochondria is visibly reduced in diabetic samples, where OGT is mislocalized to the matrix. Live cell OGA activity assays establish the presence of O-GlcNAcase within the mitochondria. Furthermore, we establish that the inner mitochondrial membrane transporter, pyrimidine nucleotide carrier, transports UDP-GlcNAc from the cytosol to the inside of the mitochondria. Knockdown of this transporter substantially lowers mitochondrial O -GlcNAcylation. Inhibition of OGT or OGA activity within neonatal rat cardiomyocytes significantly affects energy production, mitochondrial membrane potential, and mitochondrial oxygen consumption. These data suggest that cardiac mitochondria not only have robust O -GlcNAc cycling, but also that dysregulation of O -GlcNAcylation likely plays a key role in mitochondrial dysfunction associated with diabetes. Significance Mitochondrial dysfunction contributes significantly to glucose toxicity in diabetes. Increased O -GlcNAcylation is emerging as a major molecular cause of glucose toxicity via many mechanisms. The studies herein provide a direct molecular link between hyperglycemia and mitochondrial dysfunction. We show that mitochondrial O -GlcNAc transferase (OGT) and O-GlcNAcase (OGA) expression levels and localizations are strikingly different between normal and diabetic rat hearts. We also discover how UDP-GlcNAc enters the mitochondrial space. Finally our data demonstrate that OGT and OGA play significant roles in ATP production, mitochondrial membrane potential, and oxygen consumption. These studies are of general interest not only with respect to nutrient regulation of mitochondrial function, but also are important to elucidate mechanisms of diabetic complications.

In an increasingly volatile, uncertain, complex and ambiguous (VUCA) world, managers of capital projects are under relentless pressure to consistently meet their performance expectations. At the execution stage, managers have to constantly orchestrate competing demands on scare resources and, simultaneously, manage project operations to meet time, costs and quality compliances. This calls for simple methods to distinguish factors that could cause execution stage delays and prioritise their remedial actions. The objective, therefore, was to propose and test a methodology through empirical evidence, which could be useful for managers to focus on the distinguishing factors (rather than on all factors) to achieve execution excellence. We used a three-stage methodology leveraging the existing Project Management Institute (PMI) framework to define variables and then tested the methodology using case data generated from projects adopting a grounded theory approach. A set-theoretic, multi-value qualitative comparative analysis (QCA) tool helped appropriately configure this empirical case data and a subsequent Boolean minimisation technique then identified the distinguishing factor(s) that explained superior project schedule performance. The results corroborated literature findings. Two contributions emerged from this study: (a) our methodology enabled a richer analysis of the case than what would have been possible by adopting a more conventional approach; and (b) there is a potential for a domain-specific extension of the PMI framework to cover technology transfer projects having their unique knowledge areas.

Diabetes mellitus (DM) and atrial fibrillation (AF) are major unsolved public health problems, and diabetes is an independent risk factor for AF. However, the mechanism(s) underlying this clinical association is unknown. ROS and protein O-GlcNAcylation (OGN) are increased in diabetic hearts, and calmodulin kinase II (CaMKII) is a proarrhythmic signal that may be activated by ROS (oxidized CaMKII, ox-CaMKII) and OGN (OGN-CaMKII). We induced type 1 (T1D) and type 2 DM (T2D) in a portfolio of genetic mouse models capable of dissecting the role of ROS and OGN at CaMKII and global OGN in diabetic AF. Here, we showed that T1D and T2D significantly increased AF, and this increase required CaMKII and OGN. T1D and T2D both required ox-CaMKII to increase AF; however, we did not detect OGN-CaMKII or a role for OGN-CaMKII in diabetic AF. Collectively, our data affirm CaMKII as a critical proarrhythmic signal in diabetic AF and suggest ROS primarily promotes AF by ox-CaMKII, while OGN promotes AF by a CaMKII-independent mechanism(s). These results provide insights into the mechanisms for increased AF in DM and suggest potential benefits for future CaMKII and OGN targeted therapies.

Planning deficiencies and consequent execution delays are likely to persist in infrastructure development projects. However, recovery of schedule delay is a less researched area. This case research, using a two-stage inquiry modeled on the grounded theory, studied the schedule delay recovery during the execution phase of a brownfield airport construction project. The analyses generated contextual evidence and ambidexterity was found to be the key underlying phenomenon for successful recovery measures. The empirical learning was validated with literature and can be used by practitioners looking to institute schedule recovery measures.

Achieving success in technology transfer (TT) projects remains a difficult proposition in developing economies. Such projects need to accomplish not only their TT objectives, but also get delivered within schedule and costs. Literature is replete with TT models, analysis of contractual arrangements, governing processes and influencing factors. Earlier studies have conceptualized TT outcome enablers and validated through practitioner surveys. However, studying sector-wide TT programs in their natural settings for developing economies has remained an unexplored area. This study adopted a seven step Grounded Theory methodology, applied inductive and deductive reasoning on open-coded granular case data to derive causal factors. These factors were then classified into facilitators and inhibitors and mapped onto TT outcome enablers. Findings from an independent survey of equipment manufacturers were used to finalize the set of causal factors for TT outcome enablers, which were then taken forward for structural equation modeling (SEM). Inferences drawn from successive SEMs, validated by findings from equipment manufacturer survey, distinguished the dominant TT outcome enabler. Further, it established two significant facilitators and one inhibitor. Insights drawn showed that absorptive capacities of ‘mid-range’ economies may have accelerated thereby beginning to differentiate them from other developing economies. The study findings can provide insights to policy makers and leaders for improving effectiveness of sector-wide TT programs.

Diabetes mellitus (DM) and atrial fibrillation (AF) are major unsolved public health problems, and diabetes is an independent risk factor for AF. However, the mechanism(s) underlying this clinical association is unknown. ROS and protein OGlcNAcylation (OGN) are increased in diabetic hearts, and calmodulin kinase II (CaMKII) is a proarrhythmic signal that may be activated by ROS (oxidized CaMKII, ox-CaMKII) and OGN (OGN-CaMKII). We induced type 1 (T1D) and type 2 DM (T2D) in a portfolio of genetic mouse models capable of dissecting the role of ROS and OGN at CaMKII and global OGN in diabetic AF. Here, we showed that T1D and T2D significantly increased AF, and this increase required CaMKII and OGN. T1D and T2D both required ox-CaMKII to increase AF; however, we did not detect OGN-CaMKII or a role for OGN-CaMKII in diabetic AF. Collectively, our data affirm CaMKII as a critical proarrhythmic signal in diabetic AF and suggest ROS primarily promotes AF by ox-CaMKII, while OGN promotes AF by a CaMKII-independent mechanism(s). These results provide insights into the mechanisms for increased AF in DM and suggest potential benefits for future CaMKII and OGN targeted therapies.

This study describes development and evaluation of a multiplex PCR assay for simultaneous detection of Theileria annulata, Babesia bigemina and Anaplasma marginale infections in bovines. The assay was developed using parasites specific genomic DNA and three sets of PCR primers targeting the Tams1, 18S rRNA and 16S rRNA genes of T. annulata, B. bigemina and A. marginale, respectively. Blood samples collected from a total of 461 bovines, suspected for haemoparasitic infections, were examined microscopically to record the status of infection and simultaneously, genomic DNA extracted from these blood samples were utilized for the optimization and validation of multiplex PCR assay. Microscopic examination of blood samples revealed presence of single and multiple species of haemoparasites in 25.8% and 2.4% samples, respectively. Results of multiplex PCR revealed the presence of single haemoparasitic species infection in 159 cases (34.5%), whereas mixed infection was recorded in 82 (17.8%) samples. Occurrence of individual species infection detected by mPCR in the study was 26.03% (120/461) for T. annulata, 3.25% (15/461) for B. bigemina and 5.20% (24/461) for A. marginale. The detection limit of multiplex PCR assay was at the template dilutions of 10−6, 10−6 and 10−4, which corresponded to 0.1 pg, 0.1 pg and 10.0 pg of DNA for T. annulata, A. marginale, and B. bigemina, respectively. Based on the high diagnostic sensitivity and throughput, multiplex PCR assay developed in the present study could be exploited as a tool to conduct large-scale epidemiological survey for tick-borne haemoparasitic infection of bovines.

Elevated mitochondrialO-GlcNAcylation caused by hyperglycemia, as occurs in diabetes, significantly contributes to mitochondrial dysfunction and to diabetic cardiomyopathy. However, little is known about the enzymology of mitochondrialO-GlcNAcylation. Herein, we investigated the enzymes responsible for cyclingO-GlcNAc on mitochondrial proteins and studied the mitochondrial transport of UDP-GlcNAc. Analyses of purified rat heart mitochondria from normal and streptozocin-treated diabetic rats show increased mitochondrialO-GlcNAc transferase (OGT) and a concomitant decrease in the mito-specific O-GlcNAcase (OGA). Strikingly, OGT is mislocalized in cardiac mitochondria from diabetic rats. Interaction of OGT and complex IV observed in normal rat heart mitochondria is visibly reduced in diabetic samples, where OGT is mislocalized to thematrix. Live cell OGA activity assays establish the presence of O-GlcNAcase within the mitochondria. Furthermore, we establish that the inner mitochondrial membrane transporter, pyrimidine nucleotide carrier, transports UDP-GlcNAc from the cytosol to the inside of the mitochondria. Knockdown of this transporter substantially lowers mitochondrialO-GlcNAcylation. Inhibition of OGT or OGA activity within neonatal rat cardiomyocytes significantly affects energy production, mitochondrial membrane potential, and mitochondrial oxygen consumption. These data suggest that cardiac mitochondria not only have robustO-GlcNAc cycling, but also that dysregulation ofO-GlcNAcylation likely plays a key role in mitochondrial dysfunction associated with diabetes.

The phylum Apicomplexa includes serious pathogens of humans and animals. Understanding the distribution and population structure of these protozoan parasites is of fundamental importance to explain disease epidemiology and develop sustainable controls. Predicting the likely efficacy and longevity of subunit vaccines in field populations relies on knowledge of relevant preexisting antigenic diversity, population structure, the likelihood of coinfection by genetically distinct strains, and the efficiency of cross-fertilization. All four of these factors have been investigated forPlasmodiumspecies parasites, revealing both clonal and panmictic population structures with exceptional polymorphism associated with immunoprotective antigens such as apical membrane antigen 1 (AMA1). For the coccidianToxoplasma gondiionly genomic diversity and population structure have been defined in depth so far; for the closely relatedEimeriaspecies, all four variables are currently unknown. UsingEimeria tenella, a major cause of the enteric disease coccidiosis, which exerts a profound effect on chicken productivity and welfare, we determined population structure, genotype distribution, and likelihood of cross-fertilization during coinfection and also investigated the extent of naturally occurring antigenic diversity for theE. tenellaAMA1 homolog. Using genome-wide Sequenom SNP-based haplotyping, targeted sequencing, and single-cell genotyping, we show that in this coccidian the functionality ofEtAMA1 appears to outweigh immune evasion. This result is in direct contrast to the situation inPlasmodiumand most likely is underpinned by the biology of the direct and acute coccidian life cycle in the definitive host.