Synaptic Protection in the Brain of WldS Mice Occurs Independently of Age but Is Sensitive to Gene-Dose

Disruption of synaptic connectivity is a significant early event in many neurodegenerative conditions affecting the aging CNS, including Alzheimer's disease and Parkinson's disease. Therapeutic approaches that protect synapses from degeneration in the aging brain offer the potential to slow or halt the progression of such conditions. A range of animal models expressing the slow Wallerian Degeneration (Wld(S)) gene show robust neuroprotection of synapses and axons from a wide variety of traumatic and genetic neurodegenerative stimuli in both the central and peripheral nervous systems, raising that possibility that Wld(S) may be useful as a neuroprotective agent in diseases with synaptic pathology. However, previous studies of neuromuscular junctions revealed significant negative effects of increasing age and positive effects of gene-dose on Wld(S)-mediated synaptic protection in the peripheral nervous system, raising doubts as to whether Wld(S) is capable of directly conferring synapse protection in the aging brain.We examined the influence of age and gene-dose on synaptic protection in the brain of mice expressing the Wld(S) gene using an established cortical lesion model to induce synaptic degeneration in the striatum. Synaptic protection was found to be sensitive to Wld(S) gene-dose, with heterozygous Wld(S) mice showing approximately half the level of protection observed in homozygous Wld(S) mice. Increasing age had no influence on levels of synaptic protection. In contrast to previous findings in the periphery, synapses in the brain of old Wld(S) mice were just as strongly protected as those in young mice.Our study demonstrates that Wld(S)-mediated synaptic protection in the CNS occurs independently of age, but is sensitive to gene dose. This suggests that the Wld(S) gene, and in particular its downstream endogenous effector pathways, may be potentially useful therapeutic agents for conferring synaptic protection in the aging brain

Morphologic and functional correlates of synaptic pathology in the cathepsin D knockout mouse model of congenital neuronal ceroid lipofuscinosis

Mutations in the cathepsin D (CTSD) gene cause an aggressive neurodegenerative disease (congenital neuronal ceroid lipofuscinosis) that leads to early death. Recent evidence suggests that presynaptic abnormalities play a major role in the pathogenesis of CTSD deficiencies. To identify the early events that lead to synaptic alterations, we investigated synaptic ultrastructure and function in pre-symptomatic CTSD knock-out (Ctsd(−/−)) mice. Electron microscopy revealed that there were significantly greater numbers of readily releasable synaptic vesicles present in Ctsd(−/−) mice than in wild-type control mice as early as postnatal day 16. The size of this synaptic vesicle pool continued to increase with disease progression in the hippocampus and thalamus of the Ctsd(−/−) mice. Electrophysiology revealed a markedly decreased frequency of miniature excitatory postsynaptic currents (EPSCs) with no effect on pair-pulse modulation of the evoked EPSPs in the hippocampus of Ctsd(−/−) mice. The reduced miniature EPSC frequency was observed before the appearance of epilepsy or any morphological sign of synaptic degeneration. Taken together, the data indicate that CTSD is required for normal synaptic function, and that a failure in synaptic trafficking or recycling may be an early and important pathological mechanism in Ctsd(−/−) mice; these presynaptic abnormalities may initiate synaptic degeneration in advance of subsequent neuronal loss

Water warming garment versus forced air warming system in prevention of intraoperative hypothermia during liver transplantation: a randomized controlled trial [ISRCTN32154832]

BACKGROUND: The authors compared two strategies for the maintenance of intraoperative normothermia during orthotopic liver transplantation (OLT): the routine forced-air warming system and the newly developed, whole body water garment. METHODS: In this prospective, randomized and open-labelled study, 24 adult patients were enrolled in one of two intraoperative temperature management groups during OLT. The water-garment group (N = 12) received warming with a body temperature (esophageal) set point of 36.8°C. The forced air-warmer group (N = 12) received routine warming therapy using upper- and lower-body forced-air warming system. Body core temperature (primary outcome) was recorded intraoperatively and during the two hours after surgery in both groups. RESULTS: The mean core temperatures during incision, one hour after incision and during the skin closing were significantly higher (p < 0.05, t test with Bonferroni corrections for the individual tests) in the water warmer group compared to the control group (36.7 ± 0.1, 36.7 ± 0.2, 36.8 ± 0.1 vs 36.1 ± 0.4, 36.1 ± 0.4, 36.07 ± 0.4°C, respectively). Moreover, significantly higher core temperatures were observed in the water warmer group than in the control group during the placement of cold liver allograft (36.75 ± 0.17 vs 36.09 ± 0.38°C, respectively) and during the allograft reperfusion period (36.3 ± 0.26 vs 35.52 ± 0.42°C, respectively). In addition, the core temperatures immediately after admission to the SICU (36.75 ± 0.13 vs 36.22 ± 0.3°C, respectively) and at one hr (36.95 ± 0.13 vs 36.46 ± 0.2°C, respectively) were significantly higher in the water warmer group, compared to the control group, whereas the core temperature did not differ significantly afte two hours in ICU in both groups. CONCLUSIONS: The investigated water warming system results in better maintenance of intraoperative normothermia than routine air forced warming applied to upper- and lower body

Healthy Homes Asthma Survey

Asthma is a serious health concern among older adults in Massachusetts, the age group with the highest number of deaths due to asthma. The objective of this research is to investigate the prevalence of asthma and respiratory illness as well as the presence of environmental respiratory irritants in public senior housing. A total of 57 survey participants were recruited from social events for senior citizens sponsored by the Lowell Housing Authority. A paper survey was used to collect data regarding respiratory health and the presence of respiratory irritants in the homes. The study found that a large portion of the study participants has one or more respiratory ailments, and the majority of the participants have respiratory irritants present in their homes. Seniors living in public housing may benefit from residential respiratory health interventions

Combining comparative proteomics and molecular genetics uncovers regulators of synaptic and axonal stability and degeneration in vivo.

Degeneration of synaptic and axonal compartments of neurons is an early event contributing to the pathogenesis of many neurodegenerative diseases, but the underlying molecular mechanisms remain unclear. Here, we demonstrate the effectiveness of a novel "top-down" approach for identifying proteins and functional pathways regulating neurodegeneration in distal compartments of neurons. A series of comparative quantitative proteomic screens on synapse-enriched fractions isolated from the mouse brain following injury identified dynamic perturbations occurring within the proteome during both initiation and onset phases of degeneration. In silico analyses highlighted significant clustering of proteins contributing to functional pathways regulating synaptic transmission and neurite development. Molecular markers of degeneration were conserved in injury and disease, with comparable responses observed in synapse-enriched fractions isolated from mouse models of Huntington's disease (HD) and spinocerebellar ataxia type 5. An initial screen targeting thirteen degeneration-associated proteins using mutant Drosophila lines revealed six potential regulators of synaptic and axonal degeneration in vivo. Mutations in CALB2, ROCK2, DNAJC5/CSP, and HIBCH partially delayed injury-induced neurodegeneration. Conversely, mutations in DNAJC6 and ALDHA1 led to spontaneous degeneration of distal axons and synapses. A more detailed genetic analysis of DNAJC5/CSP mutants confirmed that loss of DNAJC5/CSP was neuroprotective, robustly delaying degeneration in axonal and synaptic compartments. Our study has identified conserved molecular responses occurring within synapse-enriched fractions of the mouse brain during the early stages of neurodegeneration, focused on functional networks modulating synaptic transmission and incorporating molecular chaperones, cytoskeletal modifiers, and calcium-binding proteins. We propose that the proteins and functional pathways identified in the current study represent attractive targets for developing therapeutics aimed at modulating synaptic and axonal stability and neurodegeneration in vivo

Horizontal, Anomalous U(1) Symmetry for the More Minimal Supersymmetric Standard Model

We construct explicit examples with a horizontal, ``anomalous'' $U(1)$ gauge group, which, in a supersymmetric extension of the standard model, reproduce qualitative features of the fermion spectrum and CKM matrix, and suppress FCNC and proton decay rates without the imposition of global symmetries. We review the motivation for such ``more'' minimal supersymmetric standard models and their predictions for the sparticle spectrum. There is a mass hierarchy in the scalar sector which is the inverse of the fermion mass hierarchy. We show in detail why DeltaS = 2 FCNC are suppressed when compared with naive estimates for nondegenerate squarks.Comment: Revised version clarifies calculation of FCNC amplitudes and rules out one model considered previousl

The Spatial Distribution and Kinematics of Stellar Populations in E+A Galaxies

We use long-slit spectroscopic observations of the sample of E+A galaxies described by Zabludoff et al. to constrain the nature of the progenitors and remnants of the E+A phase of galaxy evolution. We measure spatially-resolved kinematic properties of the young ( few Gyr) stellar populations. The young stellar populations are more centrally concentrated than the older populations, but they are not confined to the galaxy core (radius <~ 1 kpc). The kinematics of the old stellar population place 16 of 20 of our E+As on a trend parallel to the Faber-Jackson relation that is offset by $\sim$ 0.6 mag in R. Eighteen of 20 E+As have v/sigma < 1. As the young stars in these systems evolve, the luminosity offset will disappear and the remnants will be pressure-supported systems that lie on the Faber-Jackson relation. Although Zabludoff et al. spectroscopically selected the most extreme E+A galaxies in the local volume, the sample is kinematically diverse: velocity dispersions range from <~ 30 km/s to ~ 200 km/s over a luminosity range of M_R = -19 to -22 + 5 log h. Combining these results with an estimate of the number of galaxies that experience an E+A phase, we conclude that the E+A phase of galaxy evolution is important in the development of a large fraction of spheroid-dominated galaxies over a wide range of luminosities and masses. Our kinematic observations, together with evidence that E+As have recently evolved from a vigorous star forming phase to a quiescent phase (e.g. Couch and Sharples, Caldwell et al.) and that many have tidal features consistent with disk-like progenitors (Zabludoff et al.), indicate that these galaxies are undergoing a transformation from star-forming, disk-dominated galaxies into quiescent, spheroid-dominated galaxies.Comment: ApJ accepted, 40 pages including 16 embedded figures; figure 5 now properly included and a small change made to figure 15 captio

Feasibility and acceptability of a technology-based, rural weight management int ervention in older adults with obesity

Background Older adults with obesity residing in rural areas have reduced access to weight management programs. We determined the feasibility, acceptability and preliminary outcomes of an integrated technology-based health promotion intervention in rural-living, older adults using remote monitoring and synchronous video-based technology. Methods A 6-month, non-randomized, non-blinded, single-arm study was conducted from October 2018 to May 2020 at a community-based aging center of adults aged ≥65 years with a body mass index (BMI) ≥30 kg/m2. Weekly dietitian visits focusing on behavior therapy and caloric restriction and twice-weekly physical therapist-led group strength, flexibility and balance training classes were delivered using video-conferencing to participants in their homes. Participants used a Fitbit Alta HR for remote monitoring with data feedback provided by the interventionists. An aerobic activity prescription was provided and monitored. Results Mean age was 72.9±3.9 years (82% female). Baseline anthropometric measures of weight, BMI, and waist circumference were 97.8±16.3 kg, 36.5±5.2 kg/m2, and 115.5±13.0 cm, respectively. A total of 142 participants were screened (n=27 ineligible), and 53 consented. There were nine dropouts (17%). Overall satisfaction with the trial (4.7+ 0.6, scale: 1 (low) to 5 (high)) and with Fitbit (4.2+ 0.9) were high. Fitbit was worn an average of 81.7±19.3% of intervention days. In completers, mean weight loss was 4.6±3.5 kg or 4.7±3.5% (p\u3c 0.001). Physical function measures of 30-s sit-to-stand repetitions increased from 13.5±5.7 to 16.7±5.9 (p\u3c 0.001), 6-min walk improved by 42.0±77.3 m (p=0.005) but no differences were observed in gait speed or grip strength. Subjective measures of late-life function improved (3.4±4.7 points, p\u3c 0.001). Conclusions A technology-based obesity intervention is feasible and acceptable to older adults with obesity and may lead to weight loss and improved physical function. Clinical trial registration Registered on Clinicaltrials.gov #NCT03104205. Registered on April 7, 2017. First participant enrolled on October 1st, 2018

A dedicated flavin-dependent monooxygenase catalyzes the hydroxylation of demethoxyubiquinone into ubiquinone (coenzyme Q) in \u3ci\u3eArabidopsis\u3c/i\u3e

Ubiquinone (Coenzyme Q) is a vital respiratory cofactor and liposoluble antioxidant. In plants, it is not known how the C-6 hydroxylation of demethoxyubiquinone, the penultimate step in ubiquinone biosynthesis, is catalyzed. The combination of cross-species gene network modeling along with mining of embryo-defective mutant databases of Arabidopsis thaliana identified the embryo lethal locus EMB2421 (At1g24340) as a top candidate for the missing plant demethoxyubiquinone hydroxylase. In marked contrast with prototypical eukaryotic demethoxyubiquinone hydroxylases, the catalytic mechanism of which depends on a carboxylatebridged di-iron domain, At1g24340 is homologous to FADdependent oxidoreductases that instead use NAD(P)H as an electron donor. Complementation assays in Saccharomyces cerevisiae and Escherichia coli demonstrated that At1g24340 encodes a functional demethoxyubiquinone hydroxylase and that the enzyme displays strict specificity for the C-6 position of the benzoquinone ring. Laser-scanning confocal microscopy also showed that GFP-tagged At1g24340 is targeted to mitochondria. Silencing of At1g24340 resulted in 40 to 74% decrease in ubiquinone content and de novo ubiquinone biosynthesis. Consistent with the role of At1g24340 as a benzenoid ring modification enzyme, this metabolic blockage could not be bypassed by supplementation with 4-hydroxybenzoate, the immediate precursor of ubiquinone’s ring. Unlike in yeast, in Arabidopsis overexpression of demethoxyubiquinone hydroxylase did not boost ubiquinone content. Phylogenetic reconstructions indicated that plant demethoxyubiquinone hydroxylase is most closely related to prokaryotic monooxygenases that act on halogenated aromatics and likely descends from an event of ho

Developing autonomous learning in first year university students using perspectives from positive psychology

Autonomous learning is a commonly occurring learning outcome from university study, and it is argued that students require confidence in their own abilities to achieve this. Using approaches from positive psychology, this study aimed to develop confidence in first‐year university students to facilitate autonomous learning. Psychological character strengths were assessed in 214 students on day one at university. Two weeks later their top three strengths were given to them in study skills modules as part of a psycho‐educational intervention designed to increase their self‐efficacy and self‐esteem. The impact of the intervention was assessed against a control group of 40 students who had not received the intervention. The results suggested that students were more confident after the intervention, and that levels of autonomous learning increased significantly compared to the controls. Character strengths were found to be associated with self‐efficacy, self‐esteem and autonomous learning in ways that were theoretically meaningful