Cognitive Dysfunction Precedes the Onset of Motor Symptoms in the MitoPark Mouse Model of Parkinson’s Disease

Parkinson’s disease (PD) is a neurodegenerative disorder primarily characterized by progressive loss of dopamine neurons, leading to loss of motor coordination. However, PD is associated with a high rate of non-motor neuropsychiatric comorbities that often develop before the onset of movement symptoms. The MitoPark transgenic mouse model is the first to recapitulate the cardinal clinical features, namely progressive neurodegeneration and death of neurons, loss of motor function and therapeutic response to L-DOPA. To investigate whether MitoPark mice exhibit early onset of cognitive impairment, a non-motor neuropsychiatric comorbidity, we measured performance on a spatial learning and memory task before (∼8 weeks) or after (∼20 weeks) the onset of locomotor decline in MitoPark mice or in littermate controls. Consistent with previous studies, we established that a progressive loss of spontaneous locomotor activity began at 12 weeks of age, which was followed by progressive loss of body weight beginning at 16–20 weeks. Spatial learning and memory was measured using the Barnes Maze. By 20 weeks of age, MitoPark mice displayed a substantial reduction in overall locomotor activity that impaired their ability to perform the task. However, in the 8-week-old mice, locomotor activity was no different between genotypes, yet MitoPark mice took longer, traveled further and committed more errors than same age control mice, while learning to successfully navigate the maze. The modest between-day learning deficit of MitoPark mice was characterized by impaired within-day learning during the first two days of testing. No difference was observed between genotypes during probe trials conducted one or twelve days after the final acquisition test. Additionally, 8-week-old MitoPark mice exhibited impaired novel object recognition when compared to control mice. Together, these data establish that mild cognitive impairment precedes the loss of motor function in a novel rodent model of PD, which may provide unique opportunities for therapeutic development.     

Evidence runs contrary to digestive stability predicting protein allergenicity

Transgenic Research - A dogma has persisted for over two decades that food allergens are more stable to digestion compared with non-allergenic proteins. This belief has become enshrined in...     

Meningococcal disease: A paradigm of type‐IV pilus dependent pathogenesis

Neisseria meningitidis (meningococcus) is a Gram‐negative bacterium responsible for two devastating forms of invasive diseases: purpura fulminans and meningitis. Interaction with both peripheral and cerebral microvascular endothelial cells is at the heart of meningococcal pathogenesis. During the last two decades, an essential role for meningococcal type IV pili in vascular colonisation and disease progression has been unravelled. This review summarises 20 years of research on meningococcal type IV pilus‐dependent virulence mechanisms, up to the identification of promising anti‐virulence compounds that target type IV pili.     

A critical evaluation of the Oscillayers methods and datasets

Here we evaluate Oscillayers, a new method that aims to estimate palaeoclimates for the past 5.4 Myr, and discuss the associated theoretical and methodological issues. We show that the theoretical foundation of Oscillayers is inherently limited, because the method cannot incorporate spatio‐temporal variation and different forcing mechanisms into climate reconstructions. In addition, several methodological weaknesses are clarified that entrench the palaeoclimatic reconstruction of Oscillayers to patterns of climate change observed between the Last Glacial Maximum and current climates. We test the utility of the Oscillayers method to produce palaeoclimatic reconstructions that are similar to general circulation model (GCM)‐based estimates. On average, only 55.6% of values in the mean annual temperature datasets across the Pliocene and Pleistocene were within ±3°C when compared with corresponding GCM‐based datasets. Furthermore, on average only 75.3% of values in the mean annual precipitation datasets across the Pliocene and Pleistocene were within ±200 mm of rainfall of the GCM‐based estimates. Our results demonstrate that the Oscillayers approach does not provide a robust approximation of palaeoclimatic conditions throughout the Plio‐Pleistocene. Thus, when these datasets are used for scientific analyses, the results should be interpreted with a full appreciation of their limitations, particularly for periods outside the last glacial cycle.     

Exercise training reverses cardiac aging phenotypes associated with heart failure with preserved ejection fraction in male mice

Heart failure with preserved ejection fraction (HFpEF) is the most common type of HF in older adults. Although no pharmacological therapy has yet improved survival in HFpEF, exercise training (ExT) has emerged as the most effective intervention to improving functional outcomes in this age‐related disease. The molecular mechanisms by which ExT induces its beneficial effects in HFpEF, however, remain largely unknown. Given the strong association between aging and HFpEF, we hypothesized that ExT might reverse cardiac aging phenotypes that contribute to HFpEF pathophysiology and additionally provide a platform for novel mechanistic and therapeutic discovery. Here, we show that aged (24–30 months) C57BL/6 male mice recapitulate many of the hallmark features of HFpEF, including preserved left ventricular ejection fraction, subclinical systolic dysfunction, diastolic dysfunction, impaired cardiac reserves, exercise intolerance, and pathologic cardiac hypertrophy. Similar to older humans, ExT in old mice improved exercise capacity, diastolic function, and contractile reserves, while reducing pulmonary congestion. Interestingly, RNAseq of explanted hearts showed that ExT did not significantly modulate biological pathways targeted by conventional HF medications. However, it reversed multiple age‐related pathways, including the global downregulation of cell cycle pathways seen in aged hearts, which was associated with increased capillary density, but no effects on cardiac mass or fibrosis. Taken together, these data demonstrate that the aged C57BL/6 male mouse is a valuable model for studying the role of aging biology in HFpEF pathophysiology, and provide a molecular framework for how ExT potentially reverses cardiac aging phenotypes in HFpEF.     

Review of impact categories and environmental indicators for life cycle assessment of geotechnical systems

Life cycle assessment (LCA) has only had limited application in the geotechnical engineering discipline, though it has been widely applied to civil engineering systems such as pavements and roadways. A review of previous geotechnical LCAs showed that most studies have tracked a small set of impact categories, such as energy and global warming potential. Accordingly, currently reported environmental indicators may not effectively or fully capture important environmental impacts and tradeoffs associated with geotechnical systems, including those associated with land and soil resources. This research reviewed previous studies, methods, and models for assessment of land use and soil‐related impacts to understand their applicability to geotechnical LCA. The results of this review show that critical gaps remain in current knowledge and practice. In particular, further development or refinement of environmental indicators, impact categories, and cause–effect pathways is needed as they pertain to geotechnical applications—specifically those related to soil quality, soil functions, and the ecosystem services soils provide. In addition, many existing methods emerge from research on land use and land use change related to other disciplines (e.g., agriculture). For applicability to geotechnical projects, the resolution of many of these methods and resulting indicators need to be downscaled from the landscape/macro scale to the project scale. In the near term, practitioners of geotechnical LCA should begin tracking changes to soil properties and report impacts to land and soil resources qualitatively.     

Canopy thinning,not agricultural history,determines early responses of wild bees to longleaf pine savanna restoration

Longleaf pine savannas are highly threatened, fire‐maintained ecosystems unique to the southeastern United States. Fire suppression and conversion to agriculture have strongly affected this ecosystem, altering overstory canopies, understory plant communities, and animal populations. Tree thinning to reinstate open canopies can benefit understory plant diversity, but effects on animal communities are less well understood. Moreover, agricultural land‐use legacies can have long‐lasting impacts on plant communities, but their effects on animal communities either alone or through interactions with restoration are unclear. Resolving these impacts is important due to the conservation potential of fire‐suppressed and post‐agricultural longleaf savannas. We evaluated how historical agricultural land use and canopy thinning affect the diversity and abundance of wild bees in longleaf pine savannas. We employed a replicated, large‐scale factorial block experiment in South Carolina, where canopy thinning was applied to longleaf pine savannas that were either post‐agricultural or remnant (no agricultural history). Bees were sampled using elevated bee bowls. In the second growing season after restoration, thinned plots supported a greater bee abundance and bee community richness. Additionally, restored plots had altered wild bee community composition when compared to unthinned plots, indicating that reduction of canopy cover by the thinning treatment best predicted wild bee diversity and composition. Conversely, we found little evidence for differences between sites with or without historical agricultural land use. Some abundant Lasioglossum species were the most sensitive to habitat changes. Our results highlight how restoration practices that reduce canopy cover in fire‐suppressed savannas can have rapid benefits for wild bee communities.