Post hoc experimental designs improve genetic trial analyses: A case study of cherrybark oak (Quercus pagoda Raf.) genetic evaluation in the western Gulf region, USA.

Oaks (Quercus spp.) are widespread hardwood trees in the Northern Hemisphere and of high ecological, economic, and social values. Optimal experimental design of genetic trials is essential for accurate estimates of genetic parameters and improving the genetic merit of breeding stock. Here, we evaluate the use of post hoc row-column factors combined with spatial adjustment to improve genetic analyses of parents and individual trees in field progeny tests of plantation hardwoods, using cherrybark oak (Quercus pagoda Raf.) as an example. For tree height, post hoc incomplete blocking reduced ~14% more of the within-block environmental variance compared to the randomized complete block design (RCBD) model. Incomplete blocking also improved the heritability estimates for height by 7% to 14% compared to the original RCBD model. No clinal trend for growth breeding values was identified due to provenances. Our approach warrants the initial selection for height as early as age ~10 based on its moderate narrow-sense heritability of 0.2; however, diameter and volume need longer evaluation times. The post hoc incomplete blocking is more efficient and promising to improve the genetic analysis of Q. pagoda to minimize the environmental heterogeneity influences. Adjusting competition and spatial effects, including the distance principal components and autoregressive residual structure notably improves the model fit based on the observed reductions in AICs and BICs. Employing our approach is promising for hardwood genetic improvement in the southern USA.

A multiple comorbidities mouse lung infection model in ApoE­deficient mice.

Acute pneumonia is characterised by a period of intense inflammation. Inflammation is now considered to be a key step in atherosclerosis progression. In addition, pre-existing atherosclerotic inflammation is considered to play a role in pneumonia progression and risk. In the present study, a multiple comorbidities murine model was used to study respiratory and systemic inflammation that results from pneumonia in the setting of atherosclerosis. Firstly, a minimal infectious dose of Streptococcus pneumoniae (TIGR4 strain) to produce clinical pneumonia with a low mortality rate (20%) was established. C57Bl/6 ApoE -/- mice were fed a high-fat diet prior to administering intranasally 105 colony forming units of TIGR4 or phosphate-buffered saline (PBS). At days 2, 7 and 28 post inoculation (PI), the lungs of mice were imaged by magnetic resonance imaging (MRI) and positron emission tomography (PET). Mice were euthanised and investigated for changes in lung morphology and changes in systemic inflammation using ELISA, Luminex assay and real-time PCR. TIGR4-inoculated mice presented with varying degrees of lung infiltrate, pleural effusion and consolidation on MRI at all time points up to 28 days PI. Moreover, PET scans identified significantly higher FDG uptake in the lungs of TIGR4-inoculated mice up to 28 days PI. The majority (90%) TIGR4-inoculated mice developed pneumococcal-specific IgG antibody response at 28 days PI. Consistent with these observations, TIGR4-inoculated mice displayed significantly increased inflammatory gene expression [interleukin (IL)-1ß and IL-6] in the lungs and significantly increased levels of circulating inflammatory protein (CCL3) at 7 and 28 days PI respectively. The mouse model developed by the authors presents a discovery tool to understand the link between inflammation related to acute infection such as pneumonia and increased risk of cardiovascular disease observed in humans.

Cardiovascular changes after pneumonia in a dual disease mouse model.

Residual inflammation in cardiovascular organs is thought to be one of the catalysts for the increased risk of cardiovascular complications seen following pneumonia. To test this hypothesis, we investigated changes in plaque characteristics and inflammatory features in ApoE-/- mouse aorta and heart following pneumonia. Male ApoE-/- mice were fed a high fat diet for 8 weeks before intranasal inoculation with either Streptococcus pneumoniae serotype 4 (test group) or phosphate buffered saline (control group). Mice were sacrificed at 2-, 7- and 28-days post-challenge. Changes in plaque burden and characteristics in aortic root and thoracic aorta were characterized by Oil red O and Trichrome stains. Inflammatory changes were investigated by FDG-PET imaging and immunofluorescence staining. We found TIGR4-infected mice present with increased plaque presence in the aortic root and thoracic aorta at 2- and 28-days post-inoculation, respectively. Aortic wall remodelling was also more pronounced in mice challenged with pneumococci at 28 days post-inoculation. Aortic root plaques of infected mice had reduced collagen and smooth muscle cells, consistent with an unstable plaque phenotype. Pneumonia alters plaque burden, plaque characteristics, and aortic wall remodelling in ApoE-/- mice. These effects caused by Streptococcus pneumoniae TIGR4, may contribute to the increased risk of cardiovascular complications seen in survivors of this infection.

Imaging Inflammation in Patients and Animals: Focus on PET Imaging the Vulnerable Plaque.

Acute coronary syndrome (ACS) describes a range of conditions associated with the rupture of high-risk or vulnerable plaque. Vulnerable atherosclerotic plaque is associated with many changes in its microenvironment which could potentially cause rapid plaque progression. Present-day PET imaging presents a plethora of radiopharmaceuticals designed to image different characteristics throughout plaque progression. Improved knowledge of atherosclerotic disease pathways has facilitated a growing number of pathophysiological targets for more innovative radiotracer design aimed at identifying at-risk vulnerable plaque and earlier intervention opportunity. This paper reviews the efficacy of PET imaging radiotracers 18F-FDG, 18F-NaF, 68Ga-DOTATATE, 64Cu-DOTATATE and 68Ga-pentixafor in plaque characterisation and risk assessment, as well as the translational potential of novel radiotracers in animal studies. Finally, we discuss our murine PET imaging experience and the challenges encountered.

A New Argument for No-Fault Compensation in Health Care: The Introduction of Artificial Intelligence Systems.

Artificial intelligence (AI) systems advising healthcare professionals will be widely introduced into healthcare settings within the next 5-10 years. This paper considers how this will sit with tort/negligence based legal approaches to compensation for medical error. It argues that the introduction of AI systems will provide an additional argument pointing towards no-fault compensation as the better legal solution to compensation for medical error in modern health care systems. The paper falls into four parts. The first part rehearses the main arguments for and against no-fault compensation. The second explains why it is likely that AI systems will be widely introduced. The third part analyses why it is difficult to fit AI systems into fault-based compensation systems while the final part suggests how no-fault compensation could provide a possible solution to such challenges.

Relevance of a Truncated PRESENILIN 2 Transcript to Alzheimer's Disease and Neurodegeneration.

BACKGROUND: The PRESENILIN genes (PSEN1, PSEN2) encoding for their respective proteins have critical roles in many aspects of Alzheimer's disease (AD) pathogenesis. The PS2V transcript of PSEN2 encodes a truncated protein and is upregulated in AD brains; however, its relevance to AD and disease progression remains to be determined. OBJECTIVE: Assess transcript levels in postmortem AD and non-AD brain tissue and in lymphocytes collected under the Australian Imaging Biomarker and Lifestyle (AIBL) study. METHODS: Full length PSEN2 and PS2V transcript levels were assessed by quantitative digital PCR in postmortem brain tissue (frontal cortex and hippocampus) from control, AD, frontotemporal dementia (FTD), and Lewy body dementia (LBD). Transcript levels were also assessed in lymphocytes obtained from the Perth subset of the AIBL study (n = 160). Linear regression analysis was used to assess correlations between transcript copy number and brain volume and neocortical amyloid load. RESULTS: PS2V levels increased in AD postmortem brain but PS2V was also present at significant levels in FTD and LBD brains. PS2V transcript was detected in lymphocytes and PS2V/PSEN2 ratios were increased in mild cognitive impairment (p = 0.024) and AD (p = 0.019) groups compared to control group. Increased ratios were significantly correlated with hippocampal volumes only (n = 62, ß= -0.269, p = 0.03). CONCLUSION: Taken together, these results suggest that PS2V may be a marker of overall neurodegeneration.

Adaptive Immune Responses in Human Atherosclerosis.

Atherosclerosis is a chronic inflammatory disease that is initiated by the deposition and accumulation of low-density lipoproteins in the artery wall. In this review, we will discuss the role of T- and B-cells in human plaques at different stages of atherosclerosis and the utility of profiling circulating immune cells to monitor atherosclerosis progression. Evidence supports a proatherogenic role for intraplaque T helper type 1 (Th1) cells, CD4+CD28null T-cells, and natural killer T-cells, whereas Th2 cells and regulatory T-cells (Treg) have an atheroprotective role. Several studies indicate that intraplaque T-cells are activated upon recognition of endogenous antigens including heat shock protein 60 and oxidized low-density lipoprotein, but antigens derived from pathogens can also trigger T-cell proliferation and cytokine production. Future studies are needed to assess whether circulating cellular biomarkers can improve identification of vulnerable lesions so that effective intervention can be implemented before clinical manifestations are apparent.

Macrophages and T cells in atherosclerosis: a translational perspective.

Atherosclerosis is now considered a chronic maladaptive inflammatory disease. The hallmark feature in both human and murine disease is atherosclerotic plaques. Macrophages and various T-cell lineages play a crucial role in atherosclerotic plaque establishment and disease progression. Humans and mice share many of the same processes that occur within atherogenesis. The various similarities enable considerable insight into disease mechanisms and those which contribute to cardiovascular complications. The apolipoprotein E-null and low-density lipoprotein receptor-null mice have served as the foundation for further immunological pathway manipulation to identify pro- and antiatherogenic pathways in attempt to reveal more novel therapeutic targets. In this review, we provide a translational perspective and discuss the roles of macrophages and various T-cell lineages in contrasting proatherosclerotic and atheroprotective settings.

A genomic resource for the sedentary semi-endoparasitic reniform nematode, Rotylenchulus reniformis Linford & Oliveira.

The reniform nematode (Rotylenchulus reniformis) is a sedentary semi-endoparasitic species that is pathogenic on many row crops, fruits, and vegetables. Here, the authors present a draft genome assembly of R. reniformis using small- and large-insert libraries sequenced on the Illumina GAIIx and MiSeq platforms.The reniform nematode (Rotylenchulus reniformis) is a sedentary semi-endoparasitic species that is pathogenic on many row crops, fruits, and vegetables. Here, the authors present a draft genome assembly of R. reniformis using small- and large-insert libraries sequenced on the Illumina GAIIx and MiSeq platforms.

Cardiovascular complications following pneumonia: focus on pneumococcus and heart failure.

PURPOSE OF REVIEW: Pneumonia, an inflammatory disease, is the single largest infectious cause of death. Pneumonia has recently been established as an important contributing factor to major adverse cardiovascular events including heart failure. Developing an intermechanistic understanding of pneumonia and cardiovascular disease is crucial for successful future drug therapy and reducing healthcare expenditure. RECENT FINDINGS: Up to 30% of patients admitted with pneumonia develop cardiovascular complications such as heart failure within 10 years of hospital discharge. Recent mechanistic studies have identified inflammation, pneumolysin, platelet activation, and thrombus formation at the center of cardiovascular disease progression. SUMMARY: In this review, we will detail current knowledge of the mechanistic interaction between pneumonia and development of cardiovascular disease as well as discuss the current and potential drug therapy targets.

Review of the Michigan Upper Peninsula bovine viral diarrhea virus eradication project.

OBJECTIVE: To evaluate the effects of a voluntary regional bovine viral diarrhea virus (BVDV) control project implemented in the Upper Peninsula of Michigan. DESIGN: Longitudinal study. Sample-294 cattle producers and 11,917 cattle from the Upper Peninsula. PROCEDURES: Producer participation was assessed to determine the effectiveness of the project's promotional and educational campaigns. Participating herds were screened for cattle persistently infected (PI) with BVDV by real-time reverse transcriptase PCR assay on ear notch specimens from all newborn calves and cattle that did not calve (bulls and young stock) during the year of enrollment. Responses to a survey administered to producers 4 years after project initiation were evaluated to assess the project's effect on BVDV management practices implemented by producers. RESULTS: 294 of 495 (59%) known cattle producers in the Upper Peninsula participated in the project, and 11,917 cattle from 232 herds were tested for BVDV, of which 22 (0.18%) cattle from 9 (3.9%) herds were identified as PI with BVDV and euthanized or slaughtered. Of 140 survey respondents, 85 (61%) indicated they would test all new herd additions for BVDV, 83 (59%) would quarantine new herd additions for 30 days before introducing them to the main herd, and 81 (58%) would use the fact that their herd was free of cattle PI with BVDV for marketing purposes. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that the project enhanced producer knowledge about BVDV and led to changes in producer behavior regarding BVDV management. Stakeholder engagement was as critical to project success as was increased BVDV knowledge.

Adventures in the enormous: a 1.8 million clone BAC library for the 21.7 Gb genome of loblolly pine.

Loblolly pine (LP; Pinus taeda L.) is the most economically important tree in the U.S. and a cornerstone species in southeastern forests. However, genomics research on LP and other conifers has lagged behind studies on flowering plants due, in part, to the large size of conifer genomes. As a means to accelerate conifer genome research, we constructed a BAC library for the LP genotype 7-56. The LP BAC library consists of 1,824,768 individually-archived clones making it the largest single BAC library constructed to date, has a mean insert size of 96 kb, and affords 7.6X coverage of the 21.7 Gb LP genome. To demonstrate the efficacy of the library in gene isolation, we screened macroarrays with overgos designed from a pine EST anchored on LP chromosome 10. A positive BAC was sequenced and found to contain the expected full-length target gene, several gene-like regions, and both known and novel repeats. Macroarray analysis using the retrotransposon IFG-7 (the most abundant repeat in the sequenced BAC) as a probe indicates that IFG-7 is found in roughly 210,557 copies and constitutes about 5.8% or 1.26 Gb of LP nuclear DNA; this DNA quantity is eight times the Arabidopsis genome. In addition to its use in genome characterization and gene isolation as demonstrated herein, the BAC library should hasten whole genome sequencing of LP via next-generation sequencing strategies/technologies and facilitate improvement of trees through molecular breeding and genetic engineering. The library and associated products are distributed by the Clemson University Genomics Institute (www.genome.clemson.edu).