Neuroinflammation and Neuronal Loss Precede Aβ Plaque Deposition in the hAPP-J20 Mouse Model of Alzheimer’s Disease

Recent human trials of treatments for Alzheimer's disease (AD) have been largely unsuccessful, raising the idea that treatment may need to be started earlier in the disease, well before cognitive symptoms appear. An early marker of AD pathology is therefore needed and it is debated as to whether amyloid-βAβ? plaque load may serve this purpose. We investigated this in the hAPP-J20 AD mouse model by studying disease pathology at 6, 12, 24 and 36 weeks. Using robust stereological methods, we found there is no neuron loss in the hippocampal CA3 region at any age. However loss of neurons from the hippocampal CA1 region begins as early as 12 weeks of age. The extent of neuron loss increases with age, correlating with the number of activated microglia. Gliosis was also present, but plateaued during aging. Increased hyperactivity and spatial memory deficits occurred at 16 and 24 weeks. Meanwhile, the appearance of plaques and oligomeric Aβ were essentially the last pathological changes, with significant changes only observed at 36 weeks of age. This is surprising given that the hAPP-J20 AD mouse model is engineered to over-expresses Aβ. Our data raises the possibility that plaque load may not be the best marker for early AD and suggests that activated microglia could be a valuable marker to track disease progression.Funding provided by Iain S. Gray Foundation, Stanley and John Roth, Patricia A. Quick foundation, David King, Doug Battersby, Tony and Vivian Howland-Rose, Walter and Edith Sheldon, Gleneagle Securities, Bill Gruy, Geoffrey Towner, Amadeus Energy Ltd., Nick and Melanie Kell, J. O. and J. R. Wicking Trust and the Mason Foundation, the New South Wales Government, through their office for Science and Medical Research, and SpinalCure Australia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Maternal Restricted- and Over-Feeding During Gestation Result in Distinct Lipid and Amino Acid Metabolite Profiles in the Longissimus Muscle of the Offspring

Maternal over- and restricted-feeding during gestation have similar negative consequences for the offspring, including decreased muscularity, increased adiposity, and altered metabolism. Our objective was to determine the effects of poor maternal nutrition during gestation (over- and restricted-feeding) on the offspring muscle metabolite profile. Pregnant ewes (n = 47) were fed 60% (RES), 100% (CON), or 140% (OVER) of NRC requirements starting at day 30.2 ± 0.2 of gestation. Offspring sample collection occurred at days 90 and 135 of gestation, and within 24 h of birth. C2C12 myoblasts were cultured in serum collected from offspring at birth (n = 18; 6 offspring per treatment) for analysis of oxidative and glycolytic capacity. Unbiased metabolite analysis of longissimus muscle samples (n = 72; 8 fetuses per treatment per time point) was performed using mass spectrometry. Data were analyzed by ANOVA for main effects of treatment, time point, and their interaction. Cells cultured in serum from RES offspring exhibited increased proton leak 49% (p = 0.01) compared with CON, but no other variables of mitochondrial respiration or glycolytic function were altered. Mass spectrometry identified 612 metabolites. Principle component analysis identified day of gestation as the primary driver of metabolic change; however, maternal diet also altered the lipid and amino acid profiles in offspring. The abundance of 53 amino acid metabolites and 89 lipid metabolites was altered in RES compared with CON (p ≤ 0.05), including phospholipids, sphingolipids, and ceramides within the lipid metabolism pathway and metabolites involved in glutamate, histidine, and glutathione metabolism. Similarly, abundance of 63 amino acid metabolites and 70 lipid metabolites was altered in OVER compared with CON (p ≤ 0.05). These include metabolites involved in glutamate, histidine, lysine, and tryptophan metabolism and phosphatidylethanolamine, lysophospholipids, and fatty acids involved in lipid metabolism. Further, the amino acid and lipid profiles diverged between RES and OVER, with 69 amino acid and 118 lipid metabolites differing (p ≤ 0.05) between groups. Therefore, maternal diet affects metabolite abundance in offspring longissimus muscle, specifically metabolites involved in lipid and amino metabolism. These changes may impact post-natal skeletal muscle metabolism, possibly altering energy efficiency and long-term health

Breaking Free from Smoking: A Novel Digital Smoking Cessation Intervention for Offenders in UK Prisons

Introduction: The level of smoking cessation support across UK prisons is variable, with most offering pharmacological support, such as nicotine replacement therapy. However, with a complete smoking ban in prisons in England now imminent, additional standardised behavioural support is necessary to help offenders go smoke-free. Aims: This study used the Behaviour Change Wheel to aim to develop the content of an online smoking cessation intervention for offenders, with consideration of their capability, motivation and opportunity for behaviour change. Methods: This was an intervention development study. The Behaviour Change Wheel was used to map cognitive, behavioural, physiological and social targets for the intervention, onto appropriate intervention techniques for inclusion in the smoking cessation programme for offenders. Results: Psychological capability, social opportunity and reflective and automatic motivation were identified through deductive thematic analysis as areas of change required to achieve smoking cessation. A total of 27 behavioural change techniques were chosen for this smoking cessation intervention and were mapped onto the Lifestyle Balance Model which provided the theoretical basis on which the components of the programme are conceptualised. This included strategies around increasing motivation to quit, anticipating smoking triggers, modifying smoking-related thoughts, regulating emotions, managing cravings, replacing smoking and rewarding nicotine abstinence and adopting a healthier lifestyle. Conclusions: Through the utilisation of the Behaviour Change Wheel, the development process of this digital smoking cessation intervention was achieved. Further research is planned to evaluate the clinical effectiveness of this intervention and to explore how the programme is implemented in practice within prison settings

Examining mindfulness-based stress reduction: Perceptions from minority older adults residing in a low-income housing facility

<p>Abstract</p> <p>Background</p> <p>Mindfulness-based stress reduction (MBSR) programs are becoming increasingly common, but have not been studied in low income minority older populations. We sought to understand which parts of MBSR were most important to practicing MBSR members of this population, and to understand whether they apply their training to daily challenges.</p> <p>Methods</p> <p>We conducted three focus groups with 13 current members of an MBSR program. Participants were African American women over the age of 60 in a low-income housing residence. We tape recorded each session and subsequently used inductive content analysis to identify primary themes.</p> <p>Results and discussion</p> <p>Analysis of the focus group responses revealed three primary themes stress management, applying mindfulness, and the social support of the group meditation. The stressors they cited using MBSR with included growing older with physical pain, medical tests, financial strain, and having grandchildren with significant mental, physical, financial or legal hardships. We found that participants particularly used their MBSR training for coping with medical procedures, and managing both depression and anger.</p> <p>Conclusion</p> <p>A reflective stationary intervention delivered in-residence could be an ideal mechanism to decrease stress in low-income older adult's lives and improve their health.</p

A Human IgSF Cell-Surface Interactome Reveals a Complex Network of Protein-Protein Interactions

Cell-surface protein-protein interactions (PPIs) mediate cell-cell communication, recognition, and responses. We executed an interactome screen of 564 human cell-surface and secreted proteins, most of which are immunoglobulin superfamily (IgSF) proteins, using a high-throughput, automated ELISA-based screening platform employing a pooled-protein strategy to test all 318,096 PPI combinations. Screen results, augmented by phylogenetic homology analysis, revealed ∼380 previously unreported PPIs. We validated a subset using surface plasmon resonance and cell binding assays. Observed PPIs reveal a large and complex network of interactions both within and across biological systems. We identified new PPIs for receptors with well-characterized ligands and binding partners for “orphan” receptors. New PPIs include proteins expressed on multiple cell types and involved in diverse processes including immune and nervous system development and function, differentiation/proliferation, metabolism, vascularization, and reproduction. These PPIs provide a resource for further biological investigation into their functional relevance and may offer new therapeutic drug targets

A Human IgSF Cell-Surface Interactome Reveals a Complex Network of Protein-Protein Interactions

Cell-surface protein-protein interactions (PPIs) mediate cell-cell communication, recognition, and responses. We executed an interactome screen of 564 human cell-surface and secreted proteins, most of which are immunoglobulin superfamily (IgSF) proteins, using a high-throughput, automated ELISA-based screening platform employing a pooled-protein strategy to test all 318,096 PPI combinations. Screen results, augmented by phylogenetic homology analysis, revealed ∼380 previously unreported PPIs. We validated a subset using surface plasmon resonance and cell binding assays. Observed PPIs reveal a large and complex network of interactions both within and across biological systems. We identified new PPIs for receptors with well-characterized ligands and binding partners for “orphan” receptors. New PPIs include proteins expressed on multiple cell types and involved in diverse processes including immune and nervous system development and function, differentiation/proliferation, metabolism, vascularization, and reproduction. These PPIs provide a resource for further biological investigation into their functional relevance and may offer new therapeutic drug targets

The K2-HERMES Survey: Age and Metallicity of the Thick Disc

Asteroseismology is a promising tool to study Galactic structure and evolution because it can probe the ages of stars. Earlier attempts comparing seismic data from the {\it Kepler} satellite with predictions from Galaxy models found that the models predicted more low-mass stars compared to the observed distribution of masses. It was unclear if the mismatch was due to inaccuracies in the Galactic models, or the unknown aspects of the selection function of the stars. Using new data from the K2 mission, which has a well-defined selection function, we find that an old metal-poor thick disc, as used in previous Galactic models, is incompatible with the asteroseismic information. We show that spectroscopic measurements of [Fe/H] and [$\alpha$/Fe] elemental abundances from the GALAH survey indicate a mean metallicity of $\log (Z/Z_{\odot})=-0.16$ for the thick disc. Here $Z$ is the effective solar-scaled metallicity, which is a function of [Fe/H] and [$\alpha$/Fe]. With the revised disc metallicities, for the first time, the theoretically predicted distribution of seismic masses show excellent agreement with the observed distribution of masses. This provides an indirect verification of the asteroseismic mass scaling relation is good to within five percent. Using an importance-sampling framework that takes the selection function into account, we fit a population synthesis model of the Galaxy to the observed seismic and spectroscopic data. Assuming the asteroseismic scaling relations are correct, we estimate the mean age of the thick disc to be about 10 Gyr, in agreement with the traditional idea of an old $\alpha$-enhanced thick disc.Comment: 21 pages, submitted to MNRA

Mutational analyses of UPIIIA, SHH, EFNB2, and HNF1β in persistent cloaca and associated kidney malformations

OBJECTIVES: ‘Persistent cloaca’ is a severe malformation affecting females in which the urinary, genital and alimentary tracts share a single conduit. Previously, a Uroplakin IIIA (UPIIIA) mutation was reported in one individual with persistent cloaca, and UPIIIA, Sonic Hedgehog (SHH), Ephrin B2 (EFNB2) and Hepatocyte Nuclear Factor 1β (HNF1β) are expressed during the normal development of organs that are affected in this condition. HNF1β mutations have been associated with uterine malformations in humans, and mutations of genes homologous to human SHH or EFNB2 cause persistent cloaca in mice. PATIENTS AND METHODS: We sought mutations of coding regions of UPIIIA, SHH, EFNB2 and HNF1β genes by direct sequencing in a group of 20 patients with persistent cloaca. Most had associated malformations of the upper renal tract and over half had impaired renal excretory function. The majority of patients had congenital anomalies outside the renal/genital tracts and two had the VACTERL association. RESULTS: Apart from a previously described index case, we failed to find UPIIIA mutations, and no patient had a SHH, EFNB2 or HNF1β mutation. CONCLUSION: Persistent cloaca is only rarely associated with UPIIIA mutation. Despite the fact that SHH and EFNB2 are appealing candidate genes, based on their expression patterns and mutant mice phenotypes, they were not mutated in these humans with persistent cloaca. Although HNF1β mutations can perturb paramesonephric duct fusion in humans, HNF1β was not mutated in persistent cloaca

Enhanced psychological flexibility and improved quality of life in chronic fatigue syndrome/myalgic encephalomyelitis.

OBJECTIVE: Psychological Flexibility (PF) is a relatively new concept in physical health. It can be defined as an overarching process of being able to accept the presence of wanted/unwanted experiences, choosing whether to change or persist in behaviour in response to those experiences. Associations between processes of PF and quality of life (QoL) have been found in long-term health conditions such as chronic pain, PF has not yet been applied to Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). METHODS: Changes in PF, fatigue severity and QoL were examined in one hundred and sixty-five patients with CFS/ME engaged in a six-week outpatient interdisciplinary group treatment programme. Participants were assessed using a series of self-report measures at the start of the start (T1) and end of a six-week programme (T2) and at six months follow up (T3). RESULTS: Significant changes in PF and QoL were observed from pre-treatment (T1) to post treatment follow-up (T2 and T3); changes in fatigue severity were observed from T1 to T3 only. Controlling for fatigue severity, changes in the PF dimension of activity/occupational engagement were associated with improvement in QoL at six month follow up (T3) but not at six weeks post programme (T2). CONCLUSION: Findings indicate an interdisciplinary group treatment approach for people with CFS/ME may be associated with improved QoL, processes of PF and fatigue severity, supporting a link between PF and long term health conditions. Results highlight links between PF and patient QoL in CFS/ME and the value of interdisciplinary treatment approaches in this patient population