Activity-dependent trafficking of lysosomes in dendrites and dendritic spines.

In neurons, lysosomes, which degrade membrane and cytoplasmic components, are thought to primarily reside in somatic and axonal compartments, but there is little understanding of their distribution and function in dendrites. Here, we used conventional and two-photon imaging and electron microscopy to show that lysosomes traffic bidirectionally in dendrites and are present in dendritic spines. We find that lysosome inhibition alters their mobility and also decreases dendritic spine number. Furthermore, perturbing microtubule and actin cytoskeletal dynamics has an inverse relationship on the distribution and motility of lysosomes in dendrites. We also find trafficking of lysosomes is correlated with synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors. Strikingly, lysosomes traffic to dendritic spines in an activity-dependent manner and can be recruited to individual spines in response to local activation. These data indicate the position of lysosomes is regulated by synaptic activity and thus plays an instructive role in the turnover of synaptic membrane proteins

Self-Reported Tobacco Use and Correlation with Umbilical Cord Blood Cotinine levels at Delivery among Appalachian Gravidas

The detrimental effects of cigarette use during pregnancy are well documented. Studies have shown that cigarette smoking while pregnant is associated with multiple adverse outcomes including: pre-term birth, placental abruption, placenta previa, fetal growth restriction, stillbirth, increased rate of birth defects, and increased risk of sudden infant death syndrome. Cotinine is the primary metabolite of nicotine and allows for measurement of active as well as passive exposure. Cotinine freely cross the placental barrier and maternal concentrations are closely correlated with newborn plasma levels. The aim of this study was to compare maternally reported rates of tobacco use to fetal umbilical cord blood cotinine levels at the time of delivery. A cross-sectional study was conducted on 172 patients. Patients were asked a single yes or no question in regards to their cigarette use during pregnancy. Cord blood was collected at the time of delivery and analyzed for serum concentrations of cotinine. Cotinine levels greater than 3.0 ng/mL were considered consistent with the use of tobacco or tobacco cessation products. Maternal self-reporting of tobacco use indicates a reported tobacco use rate of 27.3% and an actual use rate of 30.2%. The reported tobacco non-use rate was 72.7% and the actual non-use rate was 66.3%. The prevalence of tobacco use during pregnancy in our study was 30.2%, while the overall rate in the United States is reported to be 12.3%. Our findings indicate that self-reported smoking prevalence and verified umbilical cord blood cotinine levels at the time of delivery have excellent correlation (kappa=0.76). Compared to the national average our study group also had nearly double the rate of tobacco use. Due to the deleterious effects of cigarette use during pregnancy continued efforts to educate patients regarding cigarette cessation is of utmost importance as cessation of tobacco products will improve and promote maternal and fetal well-being

Not In Our Backyard: Spectroscopic Support for the CLASH z=11 Candidate MACS0647-JD

We report on our first set of spectroscopic Hubble Space Telescope observations of the z~11 candidate galaxy strongly lensed by the MACSJ0647.7+7015 galaxy cluster. The three lensed images are faint and we show that these early slitless grism observations are of sufficient depth to investigate whether this high-redshift candidate, identified by its strong photometric break at ~1.5 micron, could possibly be an emission line galaxy at a much lower redshift. While such an interloper would imply the existence of a rather peculiar object, we show here that such strong emission lines would clearly have been detected. Comparing realistic, two-dimensional simulations to these new observations we would expect the necessary emission lines to be detected at >5 sigma while we see no evidence for such lines in the dispersed data of any of the three lensed images. We therefore exclude that this object could be a low redshift emission line interloper, which significantly increases the likelihood of this candidate being a bona fide z~11 galaxy.Comment: 14 Pages. 6 Figures. 2nd revised version. Accepted. To appear in ApJ. Please contact [email protected] for comments on this pape

Effective public involvement in the HoST-D Programme for dementia home care support: From proposal and design to methods of data collection (innovative practice)

Public involvement is an important element in health and social care research. However, it is little evaluated in research. This paper discusses the utility and impact of public involvement of carers and people with dementia in a five-year programme on effective home support in dementia, from proposal and design to methods of data collection, and provides a useful guide for future research on how to effectively involve the public. The Home SupporT in Dementia (HoST-D) Programme comprises two elements of public involvement, a small reference group and a virtual lay advisory group. Involving carers and people with dementia is based on the six key values of involvement – respect, support, transparency, responsiveness, fairness of opportunity, and accountability. Carers and people with dementia gave opinions on study information, methods of data collection, an economic model, case vignettes, and a memory aid booklet, which were all taken into account. Public involvement has provided benefits to the programme whilst being considerate of the time constraints and geographical locations of members

Within Subject Cross-Tissue Analyzes of Epigenetic Clocks in Substance Use Disorder Postmortem Brain and Blood

There is a possible accelerated biological aging in patients with substance use disorders (SUD). The evaluation of epigenetic clocks, which are accurate estimators of biological aging based on DNA methylation changes, has been limited to blood tissue in patients with SUD. Consequently, the impact of biological aging in the brain of individuals with SUD remains unknown. In this study, we evaluated multiple epigenetic clocks (DNAmAge, DNAmAgeHannum, DNAmAgeSkinBlood, DNAmPhenoAge, DNAmGrimAge, and DNAmTL) in individuals with SUD (n = 42), including alcohol (n = 10), opioid (n = 19), and stimulant use disorder (n = 13), and controls (n = 10) in postmortem brain (prefrontal cortex) and blood tissue obtained from the same individuals. We found a higher DNAmPhenoAge (β = 0.191, p-value = 0.0104) and a nominally lower DNAmTL (β = -0.149, p-value = 0.0603) in blood from individuals with SUD compared to controls. SUD subgroup analysis showed a nominally lower brain DNAmTL in subjects with alcohol use disorder, compared to stimulant use disorder and controls (β = 0.0150, p-value = 0.087). Cross-tissue analyzes indicated a lower blood DNAmTL and a higher blood DNAmAge compared to their respective brain values in the SUD group. This study highlights the relevance of tissue specificity in biological aging studies and suggests that peripheral measures of epigenetic clocks in SUD may depend on the specific type of drug used

Within Subject Cross-Tissue Analyzes of Epigenetic Clocks in Substance Use Disorder Postmortem Brain and Blood.

There is a possible accelerated biological aging in patients with substance use disorders (SUD). The evaluation of epigenetic clocks, which are accurate estimators of biological aging based on DNA methylation changes, has been limited to blood tissue in patients with SUD. Consequently, the impact of biological aging in the brain of individuals with SUD remains unknown. In this study, we evaluated multiple epigenetic clocks (DNAmAge, DNAmAgeHannum, DNAmAgeSkinBlood, DNAmPhenoAge, DNAmGrimAge, and DNAmTL) in individuals with SUD (n=42), including alcohol (n=10), opioid (n=19), and stimulant use disorder (n=13), and controls (n=10) in postmortem brain (prefrontal cortex) and blood tissue obtained from the same individuals. We found a higher DNAmPhenoAge (beta=0.191, p-value=0.0104) and a nominally lower DNAmTL (beta=−0.149, p-value=0.0603) in blood from individuals with SUD compared to controls. SUD subgroup analysis showed a nominally lower brain DNAmTL in subjects with alcohol use disorder, compared to stimulant use disorder and controls (beta=0.0150, p-value=0.087). Cross-tissue analyses indicated a lower blood DNAmTL and a higher blood DNAmAge compared to their respective brain values in the SUD group. This study highlights the relevance of tissue specificity in biological aging studies and suggests that peripheral measures of epigenetic clocks in SUD may depend on the specific type of drug used