Corticotropin-releasing factor receptor 1 activation during exposure to novelty stress protects against alzheimer's disease-like cognitive decline in AβPP/PS1 Mice

A lifestyle rich in physical and mental activities protects against Alzheimer's disease (AD) but the underlying mechanisms are unclear. We have proposed that this is mediated by a stress response and have shown that repeated exposure to novelty stress, which induces physical and exploratory activities, delays the progression of AD-like pathology in the TASTPM mouse model. Here, we aimed to establish the role played by corticotrophin-releasing factor receptor 1 (CRFR1), a major component of the stress axis, in TASTPM's behavioral and neuroendocrine responses to novelty and related protective effects. We show that the stress response of TASTPM mice is altered with reduced CRFR1-mediated neuroendocrine and behavioral responses to novelty and a distinct profile of behavioral responses. Repeated novelty-induced CRFR1 activation, however, mediated the improved contextual fear memory and extinction performance of TASTPM mice and increased hippocampal and fronto-cortical levels of synaptophysin, a marker of synaptic density, and fronto-cortical levels of the post-synaptic marker PSD95. The N-methyl-D-aspartate receptor (NMDAR) is the major receptor for synaptic plasticity underlying learning and memory. Although novelty-induced NMDAR activation contributed to enhancement of fear memory and synaptophysin levels, antagonism of CRFR1 and NMDAR prevented the novelty-induced increase in hippocampal synaptophysin levels but reversed the other effects of CRFR1 inactivation, i.e., the enhancement of contextual fear extinction and fronto-cortical synaptophysin and PSD95 levels. These findings suggest a novel mechanism whereby a stimulating environment can delay AD symptoms through CRFR1 activation, facilitating NMDAR-mediated synaptic plasticity and synaptogenesis in a region-dependent manner, either directly, or indirectly, by modulating PSD95. © 2013 - IOS Press and the authors. All rights reserved

Magnetic Resonance Spectroscopy discriminates the response to microglial stimulation of wild type and Alzheimer's disease models.

Microglia activation has emerged as a potential key factor in the pathogenesis of Alzheimers disease. Metabolite levels assessed by magnetic resonance spectroscopy (MRS) are used as markers of neuroinflammation in neurodegenerative diseases, but how they relate to microglial activation in health and chronic disease is incompletely understood. Using MRS, we monitored the brain metabolic response to lipopolysaccharides (LPS)-induced microglia activation in vivo in a transgenic mouse model of Alzheimers disease (APP/PS1) and healthy controls (wild-type (WT) littermates) over 4 hours. We assessed reactive gliosis by immunohistochemistry and correlated metabolic and histological measures. In WT mice, LPS induced a microglial phenotype consistent with activation, associated with a sustained increase in macromolecule and lipid levels (ML9). This effect was not seen in APP/PS1 mice, where LPS did not lead to a microglial response measured by histology, but induced a late increase in the putative inflammation marker myoinositol (mI) and metabolic changes in total creatine and taurine previously reported to be associated with amyloid load. We argue that ML9 and mI distinguish the response of WT and APP/PS1 mice to immune mediators. Lipid and macromolecule levels may represent a biomarker of activation of healthy microglia, while mI may not be a glial marker

Structure of a bacterial type IV secretion core complex at subnanometre resolution

Type IV secretion (T4S) systems are able to transport DNAs and/or proteins through the membranes of bacteria. They form large multiprotein complexes consisting of 12 proteins termed VirB1-11 and VirD4. VirB7, 9 and 10 assemble into a 1.07 MegaDalton membrane-spanning core complex (CC), around which all other components assemble. This complex is made of two parts, the O-layer inserted in the outer membrane and the I-layer inserted in the inner membrane. While the structure of the O-layer has been solved by X-ray crystallography, there is no detailed structural information on the I-layer. Using high-resolution cryo-electron microscopy and molecular modelling combined with biochemical approaches, we determined the I-layer structure and located its various components in the electron density. Our results provide new structural insights on the CC, from which the essential features of T4S system mechanisms can be derived

Evidence of a high incidence of subclinically affected calves in a herd of cattle with fatal cases of Bovine Neonatal Pancytopenia (BNP).

BACKGROUND: Bovine Neonatal Pancytopenia (BNP) is a disease of calves characterised by bone marrow trilineage hypoplasia, mediated by ingestion of alloantibodies in colostrum. Suspected subclinical forms of BNP have been reported, suggesting that observed clinical cases may not represent the full extent of the disease. However to date there are no objective data available on the incidence of subclinical disease or its temporal distribution. This study aimed to 1) ascertain whether subclinical BNP occurs and, if so, to determine the incidence on an affected farm and 2) determine whether there is evidence of temporal clustering of BNP cases on this farm. To achieve these aims, haematological screening of calves born on the farm during one calving season was carried out, utilising blood samples collected at defined ages. These data were then analysed in comparison to data from both known BNP-free control animals and histopathologically confirmed BNP cases. An ordinal logistic regression model was used to create a composite haematology score to predict the probabilities of calves being normal, based on their haematology measurements at 10–14 days old. RESULTS: This study revealed that 15% (21 of 139) of the clinically normal calves on this farm had profoundly abnormal haematology (<5% chance of being normal) and could be defined as affected by subclinical BNP. Together with clinical BNP cases, this gave the study farm a BNP incidence of 18%. Calves with BNP were found to be distributed throughout the calving period, with no clustering, and no significant differences in the date of birth of cases or subclinical cases were found compared to the rest of the calves. This study did not find any evidence of increased mortality or increased time from birth to sale in subclinical BNP calves but, as the study only involved a single farm and adverse effects may be determined by other inter-current diseases it remains possible that subclinical BNP has a detrimental impact on the health and productivity of calves under certain circumstances. CONCLUSIONS: Subclinical BNP was found to occur at a high incidence in a herd of cattle with fatal cases of BNP

A state of delirium: deciphering the effect of inflammation on tau pathology in Alzheimer's disease

Alzheimer's disease (AD), the predominant form of dementia, is highly correlated with the abnormal hyperphosphorylation and aggregation of tau. Immune responses are key drivers of AD and how they contribute to tau pathology in human disease remains largely unknown. This review summarises current knowledge on the association between inflammatory processes and tau pathology. While, preclinical evidence suggests that inflammation can indeed induce tau hyperphosphorylation at both pre- and post-tangles epitopes, a better understanding of whether this develops into advanced pathological features such as neurofibrillary tangles is needed. Microglial cells, the immune phagocytes in the central nervous system, appear to play a key role in regulating tau pathology, but the underlying mechanisms are not fully understood. Their activation can be detrimental via the secretion of pro-inflammatory mediators, particularly interleukin-1β, but also potentially beneficial through phagocytosis of extracellular toxic tau oligomers. Nevertheless, anti-inflammatory treatments in animal models were found protective, but whether or not they affect microglial phagocytosis of tau species is unknown. However, one major challenge to our understanding of the role of inflammation in the progression of tau pathology is the preclinical models used to address this question. They mostly rely on the use of septic doses of lipopolysaccharide that do not reflect the inflammatory conditions experienced AD patients, questioning whether the impact of inflammation on tau pathology in these models is dose-dependent and relevant to the human disease. The use of more translational models of inflammation corroborated with verification in clinical investigations are necessary to progress our understanding of the interplay between inflammation and tau pathology

Increasing Tau 4R Tau Levels Exacerbates Hippocampal Tau Hyperphosphorylation in the hTau Model of Tauopathy but Also Tau Dephosphorylation Following Acute Systemic Inflammation

Copyright © 2020 Barron, Gartlon, Dawson, Atkinson and Pardon. Inflammation is considered a mechanistic driver of Alzheimer's disease, thought to increase tau phosphorylation, the first step to the formation of neurofibrillary tangles (NFTs). To further understand how inflammation impacts the development of tau pathology, we used (hTau) mice, which express all six, non-mutated, human tau isoforms, but with an altered ratio of tau isoforms favoring 3R tau due to the concomitant loss of murine tau (mTau) that is predominantly 4R. Such an imbalance pattern has been related to susceptibility to NFTs formation, but whether or not this also affects susceptibility to systemic inflammation and related changes in tau phosphorylation is not known. To reduce the predominance of 3R tau by increasing 4R tau availability, we bred hTau mice on a heterozygous mTau background and compared the impact of systemic inflammation induced by lipopolysaccharide (LPS) in hTau mice hetero- or homozygous mTau knockout. Three-month-old male wild-type (Wt), mTau+/-, mTau-/-, hTau/mTau+/-, and hTau/mTau-/- mice were administered 100, 250, or 330 μg/kg of LPS or its vehicle phosphate buffer saline (PBS) [intravenously (i.v.), n = 8-9/group]. Sickness behavior, reflected by behavioral suppression in the spontaneous alternation task, hippocampal tau phosphorylation, measured by western immunoblotting, and circulating cytokine levels were quantified 4 h after LPS administration. The persistence of the LPS effects (250 μg/kg) on these measures, and food burrowing behavior, was assessed at 24 h post-inoculation in Wt, mTau+/-, and hTau/mTau+/- mice (n = 9-10/group). In the absence of immune stimulation, increasing 4R tau levels in hTau/mTau+/- exacerbated pS202 and pS396/404 tau phosphorylation, without altering total tau levels or worsening early behavioral perturbations characteristic of hTau/mTau-/- mice. We also show for the first time that modulating 4R tau levels in hTau mice affects the response to systemic inflammation. Behavior was suppressed in all genotypes 4 h following LPS administration, but hTau/mTau+/- exhibited more severe sickness behavior at the 100 μg/kg dose and a milder behavioral and cytokine response than hTau/mTau-/- mice at the 330 μg/kg dose. All LPS doses decreased tau phosphorylation at both epitopes in hTau/mTau+/- mice, but pS202 levels were selectively reduced at the 100 μg/kg dose in hTau/mTau-/- mice. Behavioral suppression and decreased tau phosphorylation persisted at 24 h following LPS administration in hTau/mTau+/- mice

Student Employment Models for Undergraduate Nurses and Midwives in Australia: A Scoping Review

Introduction: Evidence has shown that throughout their undergraduate years, many nursing and midwifery students obtain paid employment in a wide variety of clinical and non-clinical positions. Across Australia, inconsistencies exist in the models of clinical employment available to these student groups. Previous Australian studies have described the employment of undergraduate nursing and midwifery students in regulated and unregulated clinical roles. No studies have reported on the various regulated roles available to both student nurses and midwives in Australia. The purpose of this scoping review is to identify and synthesize evidence related to nursing and/or midwifery students employed in regulated and unregulated clinical roles in Australia. Methods: This scoping review utilized published recommendations for data screening, abstraction, and synthesis. One of the authors, a librarian, undertook systematic searches in CINAHL Complete (1937–present), Emcare on Ovid (1995–present), Scopus (1969–present), and Ovid MEDLINE(R) (including Epub Ahead of Print, In-Process, and In-Data-Review & Other Non-Indexed Citations, 1946–present). The initial searches were completed in April 2019 and repeated in March 2021 and May 2022 to identify any new literature. Manual searching of reference lists in the included papers was also undertaken, together with selected organizational websites. The extracted data included the lead author, date, title, study design, study sample and location, and key findings. Results: From the 53 items retrieved, 23 peer-reviewed studies met the inclusion criteria and were included in the review. All items were published between 2011 and 2022. Only four of the studies focused upon student midwives. Undergraduate nursing and midwifery students in Australia obtain paid employment in a variety of regulated and unregulated clinical roles. Conclusion: The literature reported here demonstrates that there are differing models, nomenclature, educational requirements, and pay scales in place for student employment in clinical roles across Australian states and territories

Herd-level animal management factors associated with the occurrence of bovine neonatal pancytopenia in calves in a multicountry study

Since 2007, mortality associated with a previously unreported haemorrhagic disease has been observed in young calves in several European countries. The syndrome, which has been named ‘bovine neonatal pancytopenia’ (BNP), is characterised by thrombocytopenia, leukocytopenia and a panmyelophthisis. A herd-level case-control study was conducted in four BNP affected countries (Belgium, France, Germany and the Netherlands) to identify herd management risk factors for BNP occurrence. Data were collected using structured face-to-face and telephone interviews of farm managers and their local veterinarians. In total, 363 case farms and 887 control farms were included in a matched multivariable conditional logistic regression analysis. Case-control status was strongly associated with the odds of herd level use of the vaccine PregSure® BVD (PregSure, Pfizer Animal Health) (matched adjusted odds ratio (OR) 107.2; 95% CI: 41.0–280.1). This was also the case for the practices of feeding calves colostrum from the calf’s own dam (OR 2.0; 95% CI: 1.1–3.4) or feeding pooled colostrum (OR 4.1; 95% CI: 1.9–8.8). Given that the study had relatively high statistical power and represented a variety of cattle production and husbandry systems, it can be concluded with some confidence that no other herd level management factors are competent causes for a sufficient cause of BNP occurrence on herd level. It is suggested that genetic characteristics of the dams and BNP calves should be the focus of further investigations aimed at identifying the currently missing component causes that together with PregSure vaccination and colostrum feeding represent a sufficient cause for occurrence of BNP in calves

Effect of manganese-rich solid waste on soil phosphorus availability applied as monopotassium and rock phosphate in two contrasting soils

Manganese (Mn) mining produces a large amount of Mn-rich solid waste contributing to soil and groundwater pollution. Adding Mn-rich waste to soils could reduce mining pollution by allowing specialised plants to take up this mineral for growth, that is, phytoremediation. However, Mn interacts with other soil major and trace minerals. The interaction with phosphorus (P), a key element for plant nutrition and growth, has received less attention. In this study, we aimed to evaluate the effects of P sources (i.e. rock phosphate and monopotassium [KH2PO4]) and application rates on the P and Mn relationships in clay and sandy soils mixed with Mn-rich waste. Soils differing in texture were incubated for 60 days at room temperature (±20 °C), and changes in available P, Mn and soil pH were determined at 0, 30 and 60 days. The addition of Mn-rich solid waste significantly decreased available soil P in both soils with the greatest reduction of 62% and 52% from the sandy soil subjected to KH2PO4 and rock phosphate, respectively. In the clayey soil, the reduction was higher for the rock phosphate source implying more P was released from the rock phosphate in Mn-rich soils. This explanation was supported by the significant positive correlation between P and Mn for both soils when P is added in the form of rock phosphate. Our results suggest that Mn-rich waste is better in clay soils subjected to rock phosphate addition. Further research is needed to control Mn solid waste pollution levels in soils using specific crops with known phytoremediation properties. Significance: South African mining and smelting processes produce a lot of Mn-rich waste as a by-product that harms the environment if not appropriately managed. The efficient use of Mn-rich solid waste in agricultural soils is poorly studied; hence, this study focused on the role of soil type and Mn-rich waste addition on phosphorus release and availability

Crystal structure of the proteasomal deubiquitylation module Rpn8-Rpn11

The ATP-dependent degradation of polyubiquitylated proteins by the 26S proteasome is essential for the maintenance of proteome stability and the regulation of a plethora of cellular processes. Degradation of substrates is preceded by the removal of polyubiquitin moieties through the isopeptidase activity of the subunit Rpn11. Here we describe three crystal structures of the heterodimer of the Mpr1-Pad1-N-terminal domains of Rpn8 and Rpn11, crystallized as a fusion protein in complex with a nanobody. This fusion protein exhibits modest deubiquitylation activity toward a model substrate. Full activation requires incorporation of Rpn11 into the 26S proteasome and is dependent on ATP hydrolysis, suggesting that substrate processing and polyubiquitin removal are coupled. Based on our structures, we propose that premature activation is prevented by the combined effects of low intrinsic ubiquitin affinity, an insertion segment acting as a physical barrier across the substrate access channel, and a conformationally unstable catalytic loop in Rpn11. The docking of the structure into the proteasome EM density revealed contacts of Rpn11 with ATPase subunits, which likely stabilize the active conformation and boost the affinity for the proximal ubiquitin moiety. The narrow space around the Rpn11 active site at the entrance to the ATPase ring pore is likely to prevent erroneous deubiquitylation of folded proteins