Novel Calcium-Related Targets of Insulin in Hippocampal Neurons

Both insulin signaling disruption and Ca2+ dysregulation are closely related to memory loss during aging and increase the vulnerability to Alzheimer\u27s disease (AD). In hippocampal neurons, aging-related changes in calcium regulatory pathways have been shown to lead to higher intracellular calcium levels and an increase in the Ca2+-dependent afterhyperpolarization (AHP), which is associated with cognitive decline. Recent studies suggest that insulin reduces the Ca2+-dependent AHP. Given the sensitivity of neurons to insulin and evidence that brain insulin signaling is reduced with age, insulin-mediated alterations in calcium homeostasis may underlie the beneficial actions of insulin in the brain. Indeed, increasing insulin signaling in the brain via intranasal delivery has yielded promising results such as improving memory in both clinical and animal studies. However, while several mechanisms have been proposed, few have focused on regulation on intracellular Ca2+. In the present study, we further examined the effects of acute insulin on calcium pathways in primary hippocampal neurons in culture. Using the whole-cell patch-clamp technique, we found that acute insulin delivery reduced voltage-gated calcium currents. Fura-2 imaging was used to also address acute insulin effects on spontaneous and depolarization-mediated Ca2+ transients. Results indicate that insulin reduced Ca2+ transients, which appears to have involved a reduction in ryanodine receptor function. Together, these results suggest insulin regulates pathways that control intracellular Ca2+ which may reduce the AHP and improve memory. This may be one mechanism contributing to improved memory recall in response to intranasal insulin therapy in the clinic

Calcium\u27s Role as Nuanced Modulator of Cellular Physiology in the Brain

Neuroscientists studying normal brain aging, spinal cord injury, Alzheimer’s disease (AD) and other neurodegenerative diseases have focused considerable effort on carefully characterizing intracellular perturbations in calcium dynamics or levels. At the cellular level, calcium is known for controlling life and death and orchestrating most events in between. For many years, intracellular calcium has been recognized as an essential ion associated with nearly all cellular functions from cell growth to degeneration. Often the emphasis is on the negative impact of calcium dysregulation and the typical worse-case-scenario leading inevitably to cell death. However, even high amplitude calcium transients, when executed acutely can alter neuronal communication and synaptic strength in positive ways, without necessarily killing neurons. Here, we focus on the evidence that calcium has a subtle and distinctive role in shaping and controlling synaptic events that underpin neuronal communication and that these subtle changes in aging or AD may contribute to cognitive decline. We emphasize that calcium imaging in dendritic components is ultimately necessary to directly test for the presence of age- or disease-associated alterations during periods of synaptic activation

Preparing for a Northwest Passage: A Workshop on the Role of New England in Navigating the New Arctic

Preparing for a Northwest Passage: A Workshop on the Role of New England in Navigating the New Arctic (March 25 - 27, 2018 -- The University of New Hampshire) paired two of NSF\u27s 10 Big Ideas: Navigating the New Arctic and Growing Convergence Research at NSF. During this event, participants assessed economic, environmental, and social impacts of Arctic change on New England and established convergence research initiatives to prepare for, adapt to, and respond to these effects. Shipping routes through an ice-free Northwest Passage in combination with modifications to ocean circulation and regional climate patterns linked to Arctic ice melt will affect trade, fisheries, tourism, coastal ecology, air and water quality, animal migration, and demographics not only in the Arctic but also in lower latitude coastal regions such as New England. With profound changes on the horizon, this is a critical opportunity for New England to prepare for uncertain yet inevitable economic and environmental impacts of Arctic change

Hippocampal CA1 Transcriptional Profile of Sleep Deprivation: Relation to Aging and Stress

BACKGROUND: Many aging changes seem similar to those elicited by sleep-deprivation and psychosocial stress. Further, sleep architecture changes with age suggest an age-related loss of sleep. Here, we hypothesized that sleep deprivation in young subjects would elicit both stress and aging-like transcriptional responses. METHODOLOGY/PRINCIPAL FINDINGS: F344 rats were divided into control and sleep deprivation groups. Body weight, adrenal weight, corticosterone level and hippocampal CA1 transcriptional profiles were measured. A second group of animals was exposed to novel environment stress (NES), and their hippocampal transcriptional profiles measured. A third cohort exposed to control or SD was used to validate transcriptional results with Western blots. Microarray results were statistically contrasted with prior transcriptional studies. Microarray results pointed to sleep pressure signaling and macromolecular synthesis disruptions in the hippocampal CA1 region. Animals exposed to NES recapitulated nearly one third of the SD transcriptional profile. However, the SD-aging relationship was more complex. Compared to aging, SD profiles influenced a significant subset of genes. mRNA associated with neurogenesis and energy pathways showed agreement between aging and SD, while immune, glial, and macromolecular synthesis pathways showed SD profiles that opposed those seen in aging. CONCLUSIONS/SIGNIFICANCE: We conclude that although NES and SD exert similar transcriptional changes, selective presynaptic release machinery and Homer1 expression changes are seen in SD. Among other changes, the marked decrease in Homer1 expression with age may represent an important divergence between young and aged brain response to SD. Based on this, it seems reasonable to conclude that therapeutic strategies designed to promote sleep in young subjects may have off-target effects in the aged. Finally, this work identifies presynaptic vesicular release and intercellular adhesion molecular signatures as novel therapeutic targets to counter effects of SD in young subjects

Inhibition of the Integrin/FAK Signaling Axis and c-Myc Synergistically Disrupts Ovarian Cancer Malignancy

Integrins, a family of heterodimeric receptors for extracellular matrix, are promising therapeutic targets for ovarian cancer, particularly high-grade serous-type (HGSOC), as they drive tumor cell attachment, migration, proliferation and survival by activating focal adhesion kinase (FAK)-dependent signaling. Owing to the potential off-target effects of FAK inhibitors, disruption of the integrin signaling axis remains to be a challenge. Here, we tackled this barrier by screening for inhibitors being functionally cooperative with small-molecule VS-6063, a phase II FAK inhibitor. From this screening, JQ1, a potent inhibitor of Myc oncogenic network, emerged as the most robust collaborator. Treatment with a combination of VS-6063 and JQ1 synergistically caused an arrest of tumor cells at the G2/M phase and a decrease in the XIAP-linked cell survival. Our subsequent mechanistic analyses indicate that this functional cooperation was strongly associated with the concomitant disruption of activation or expression of FAK and c-Myc as well as their downstream signaling through the PI3K/Akt pathway. In line with these observations, we detected a strong co-amplification or upregulation at genomic or protein level for FAK and c-Myc in a large portion of primary tumors in the TCGA or a local HGSOC patient cohort. Taken together, our results suggest that the integrin–FAK signaling axis and c-Myc synergistically drive cell proliferation, survival and oncogenic potential in HGSOC. As such, our study provides key genetic, functional and signaling bases for the small-molecule-based co-targeting of these two distinct oncogenic drivers as a new line of targeted therapy against human ovarian cancer

Obesity and Diabetes Cause Cognitive Dysfunction in the Absence of Accelerated β-Amyloid Deposition in a Novel Murine Model of Mixed or Vascular Dementia

Mid-life obesity and type 2 diabetes mellitus (T2DM) confer a modest, increased risk for Alzheimer\u27s disease (AD), though the underlying mechanisms are unknown. We have created a novel mouse model that recapitulates features of T2DM and AD by crossing morbidly obese and diabetic db/db mice with APPΔNL/ΔNLx PS1P264L/P264L knock-in mice. These mice (db/AD) retain many features of the parental lines (e.g. extreme obesity, diabetes, and parenchymal deposition of β-amyloid (Aβ)). The combination of the two diseases led to additional pathologies-perhaps most striking of which was the presence of severe cerebrovascular pathology, including aneurysms and small strokes. Cortical Aβ deposition was not significantly increased in the diabetic mice, though overall expression of presenilin was elevated. Surprisingly, Aβ was not deposited in the vasculature or removed to the plasma, and there was no stimulation of activity or expression of major Aβ-clearing enzymes (neprilysin, insulin degrading enzyme, or endothelin-converting enzyme). The db/AD mice displayed marked cognitive impairment in the Morris Water Maze, compared to either db/db or APPΔNLx PS1P264L mice. We conclude that the diabetes and/or obesity in these mice leads to a destabilization of the vasculature, leading to strokes and that this, in turn, leads to a profound cognitive impairment and that this is unlikely to be directly dependent on Aβ deposition. This model of mixed or vascular dementia provides an exciting new avenue of research into the mechanisms underlying the obesity-related risk for age-related dementia, and will provide a useful tool for the future development of therapeutics

Atomic Resonance and Scattering

Contains reports on eight research projects.National Science Foundation (Grant PHY79-09743)National Bureau of Standards (Grant NB-8-NAHA-3017)Joint Services Electronics Program (Contract DAAG29-80-C-0104)National Science Foundation (Grant PHY82-10486)U.S. Navy - Office of Naval Research (Contract N00014-79-C-0183)National Science Foundation (Grant CHE79-02967-A04)U.S. Air Force - Office of Scientific Research (Contract AFOSR-81-0067)Joint Services Electronics Program (Contract DAAG29-83-K-0003

Pristup procjeni zdravstvenoga rizika za ljude prilikom izgradnje gradskoga parka

A Human Health Risk Assessment (HHRA) was undertaken for a proposed park development “River Landing”, to be constructed along the north bank of the South Saskatchewan River in the City of Saskatoon, Saskatchewan, Canada. The purpose of the HHRA was to determine whether chemical constituents identified at the site, including polycyclic aromatic hydrocarbons (PAHs), petroleum hydrocarbons (PHCs), and toxic and heavy metals, would adversely affect the health of construction workers and potential park users. Although more traditional remediation options were considered, the risk assessment approach was chosen since it represented the best available technology. The HHRA was undertaken using protocols and methodologies proposed and readily accepted by the Canadian Council of Ministers of the Environment (CCME), Health Canada, and the United States Environmental Protection Agency (US EPA). Results of the risk assessment revealed that the magnitude and distribution of the chemicals at the site were such that extensive remediation was not required, and that the site could be developed without any significant restrictions on the proposed use. The assessment revealed that potential exposure to soil constituents would not result in adverse health risk to construction workers involved in park development or future park users.Napravljena je procjena zdravstvenoga rizika za ljude (izv. human health risk assessment, HHRA) za projekt gradskoga parka “River Landing” koji bi se trebao izgraditi duž sjeverne obale rijeke South Saskatchewan u Saskatoonu, saveznoj državi Saskatchewan u Kanadi. Svrha je procjene bila utvrditi mogu li kemijski spojevi zatečeni na gradilištu, uključujući policikličke aromatske ugljikovodike, naftne ugljikovodike te toksične i teške metale, štetno utjecati na zdravlje građevinskih radnika i korisnika parka. Premda je razmotrena i uporaba tradicionalnijih metoda sanacije, izabran je ovaj pristup procjeni rizika zbog toga što rabi najbolju dostupnu tehnologiju. Procjena rizika provedena je prema protokolima i metodama koje je odmah usvojio Kanadski savjet ministara za zaštitu okoliša (izv. Canadian Council of Ministers of the Environment, CCME), savezni ured za zdravlje Health Canada te Agencija za zaštitu okoliša Sjedinjenih Država (izv. United States Environmental Protection Agency, US EPA). Procjena rizika pokazala je da količina i rasprostranjenost kemikalija na gradilištu nisu takvi da zahtijevaju opsežniju sanaciju, te da se lokacija može izgraditi bez značajnih ograničenja u namjeni. Procjenom je također utvrđeno da eventualno izlaganje sastavnicama tla neće dovesti do štetnih posljedica za zdravlje građevinskih radnika koji rade na parku, a niti za buduće korisnike parka

Anti-Tuberculosis Therapy-Induced Hepatotoxicity among Ethiopian HIV-Positive and Negative Patients

Background: To assess and compare the prevalence, severity and prognosis of anti-TB drug induced hepatotoxicity (DIH) in HIV positive and HIV negative tuberculosis (TB) patients in Ethiopia. Methodology/Principal Findings: In this study, 103 HIV positive and 94 HIV negative TB patients were enrolled. All patients were evaluated for different risk factors and monitored biochemically and clinically for development of DIH. Sub-clinical hepatotoxicity was observed in 17.3 % of the patients and 8 out of the 197 (4.1%) developed clinical hepatotoxicity. Seven of the 8 were HIV positive and 2 were positive for HBsAg. Conclusions/Significance: Sub-clinical hepatotoxicity was significantly associated with HIV co-infection (p = 0.002), concomitant drug intake (p = 0.008), and decrease in CD4 count (p = 0.001). Stepwise restarting of anti TB treatment was also successful in almost all the patients who developed clinical DIH. We therefore conclude that anti-TB DIH is a major problem in HIV-associated TB with a decline in immune status and that there is a need for a regular biochemical and clinical follow up for those patients who are at risk

Atomic Resonance and Scattering

Contains reports on eight research projects.National Science Foundation (Grant PHY83-06273)National Bureau of Standards (Grant NB83-NAHA-4058)National Science Foundation (Grant PHY84-11483)Joint Services Electronics Program (Contract DAAG29-83-K-0003)U.S. Navy - Office of Naval Research (Contract NO0014-79-C-0183)U.S. Navy - Office of Naval Research (Contract N00014-83-K-0695)National Science Foundation (Grant PHY83-07172-A01