A New Anti-Depressive Strategy for the Elderly: Ablation of FKBP5/FKBP51

The gene FKBP5 codes for FKBP51, a co-chaperone protein of the Hsp90 complex that increases with age. Through its association with Hsp90, FKBP51 regulates the glucocorticoid receptor (GR). Single nucleotide polymorphisms (SNPs) in the FKBP5 gene associate with increased recurrence of depressive episodes, increased susceptibility to post-traumatic stress disorder, bipolar disorder, attempt of suicide, and major depressive disorder in HIV patients. Variation in one of these SNPs correlates with increased levels of FKBP51. FKBP51 is also increased in HIV patients. Moreover, increases in FKBP51 in the amygdala produce an anxiety phenotype in mice. Therefore, we tested the behavioral consequences of FKBP5 deletion in aged mice. Similar to that of naïve animals treated with classical antidepressants FKBP5−/− mice showed antidepressant behavior without affecting cognition and other basic motor functions. Reduced corticosterone levels following stress accompanied these observed effects on depression. Age-dependent anxiety was also modulated by FKBP5 deletion. Therefore, drug discovery efforts focused on depleting FKBP51 levels may yield novel antidepressant therapies

Gene expression profiling in brain of mice exposed to the marine neurotoxin ciguatoxin reveals an acute anti-inflammatory, neuroprotective response

<p>Abstract</p> <p>Background</p> <p>Ciguatoxins (CTXs) are polyether marine neurotoxins and potent activators of voltage-gated sodium channels. This toxin is carried by multiple reef-fish species and human consumption of ciguatoxins can result in an explosive gastrointestinal/neurologic illness. This study characterizes the global transcriptional response in mouse brain to a symptomatic dose of the highly toxic Pacific ciguatoxin P-CTX-1 and additionally compares this data to transcriptional profiles from liver and whole blood examined previously. Adult male C57/BL6 mice were injected with 0.26 ng/g P-CTX-1 while controls received only vehicle. Animals were sacrificed at 1, 4 and 24 hrs and transcriptional profiling was performed on brain RNA with Agilent whole genome microarrays. RT-PCR was used to independently validate gene expression and the web tool DAVID was used to analyze gene ontology (GO) and molecular pathway enrichment of the gene expression data.</p> <p>Results</p> <p>A pronounced 4°C hypothermic response was recorded in these mice, reaching a minimum at 1 hr and lasting for 8 hrs post toxin exposure. Ratio expression data were filtered by intensity, fold change and p-value, with the resulting data used for time course analysis, K-means clustering, ontology classification and KEGG pathway enrichment. Top GO hits for this gene set included acute phase response and mono-oxygenase activity. Molecular pathway analysis showed enrichment for complement/coagulation cascades and metabolism of xenobiotics. Many immediate early genes such as Fos, Jun and Early Growth Response isoforms were down-regulated although others associated with stress such as glucocorticoid responsive genes were up-regulated. Real time PCR confirmation was performed on 22 differentially expressed genes with a correlation of 0.9 (Spearman's Rho, p < 0.0001) with microarray results.</p> <p>Conclusions</p> <p>Many of the genes differentially expressed in this study, in parallel with the hypothermia, figure prominently in protection against neuroinflammation. Pathologic activity of the complement/coagulation cascade has been shown in patients suffering from a chronic form of ciguatera poisoning and is of particular interest in this model. Anti-inflammatory processes were at work not only in the brain but were also seen in whole blood and liver of these animals, creating a systemic anti-inflammatory environment to protect against the initial cellular damage caused by the toxin.</p

Control of Alzheimer's Amyloid Beta Toxicity by the High Molecular Weight Immunophilin FKBP52 and Copper Homeostasis in Drosophila

FK506 binding proteins (FKBPs), also called immunophilins, are prolyl-isomerases (PPIases) that participate in a wide variety of cellular functions including hormone signaling and protein folding. Recent studies indicate that proteins that contain PPIase activity can also alter the processing of Alzheimer's Amyloid Precursor Protein (APP). Originally identified in hematopoietic cells, FKBP52 is much more abundantly expressed in neurons, including the hippocampus, frontal cortex, and basal ganglia. Given the fact that the high molecular weight immunophilin FKBP52 is highly expressed in CNS regions susceptible to Alzheimer's, we investigated its role in Aβ toxicity. Towards this goal, we generated Aβ transgenic Drosophila that harbor gain of function or loss of function mutations of FKBP52. FKBP52 overexpression reduced the toxicity of Aβ and increased lifespan in Aβ flies, whereas loss of function of FKBP52 exacerbated these Aβ phenotypes. Interestingly, the Aβ pathology was enhanced by mutations in the copper transporters Atox1, which interacts with FKBP52, and Ctr1A and was suppressed in FKBP52 mutant flies raised on a copper chelator diet. Using mammalian cultures, we show that FKBP52 (−/−) cells have increased intracellular copper and higher levels of Aβ. This effect is reversed by reconstitution of FKBP52. Finally, we also found that FKBP52 formed stable complexes with APP through its FK506 interacting domain. Taken together, these studies identify a novel role for FKBP52 in modulating toxicity of Aβ peptides

Changes in Ultrafine Particle Concentrations near a Major Airport Following Reduced Transportation Activity during the COVID-19 Pandemic

13-C-AJFF-BU-07, 11, 20This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)) license https://creativecommons.org/licenses/by-nc-nd/4.0/. Please cite this article as: Sean C. Mueller, Neelakshi Hudda, Jonathan I. Levy, John L. Durant, Prasad Patil, Nina Franzen Lee, Ida Weiss, Tyler Tatro, Tiffany Duhl, and Kevin Lane Environmental Science & Technology Letters 2022 9 (9), 706-711 DOI: 10.1021/acs.estlett.2c00322Mobility reductions following the COVID-19 pandemic in the United States were higher, and sustained longer, for aviation than ground transportation activity. We evaluate changes in ultrafine particle (UFP, Dp < 100 nm, a marker of fuel combustion emissions) concentrations at a site near Logan Airport (Boston, Massachusetts) in relation to mobility reductions. Several years of particle number concentration (PNC) data prepandemic [1/2017 129/2018] and during the state-of-emergency (SOE) phase of the pandemic [4/2020 126/2021] were analyzed to assess the emissions reduction impact on PNC, controlling for season and wind direction. Mean PNC was 48% lower during the first three months of the SOE than prepandemic, consistent with 74% lower flight activity and 39% (local) 1251% (highway) lower traffic volume. Traffic volume and mean PNC for all wind directions returned to prepandemic levels by 6/2021; however, when the site was downwind from Logan Airport, PNC remained lower than prepandemic levels (by 23%), consistent with lower-than-normal flight activity (44% below prepandemic levels). Our study shows the effect of pandemic-related mobility changes on PNC in a near-airport community, and it distinguishes aviation-related and ground transportation source contributions

Toward an energy surety future.

Because of the inevitable depletion of fossil fuels and the corresponding release of carbon to the environment, the global energy future is complex. Some of the consequences may be politically and economically disruptive, and expensive to remedy. For the next several centuries, fuel requirements will increase with population, land use, and ecosystem degradation. Current or projected levels of aggregated energy resource use will not sustain civilization as we know it beyond a few more generations. At the same time, issues of energy security, reliability, sustainability, recoverability, and safety need attention. We supply a top-down, qualitative model--the surety model--to balance expenditures of limited resources to assure success while at the same time avoiding catastrophic failure. Looking at U.S. energy challenges from a surety perspective offers new insights on possible strategies for developing solutions to challenges. The energy surety model with its focus on the attributes of security and sustainability could be extrapolated into a global energy system using a more comprehensive energy surety model than that used here. In fact, the success of the energy surety strategy ultimately requires a more global perspective. We use a 200 year time frame for sustainability because extending farther into the future would almost certainly miss the advent and perfection of new technologies or changing needs of society

Different Classes of Proteoglycans Contribute to the Attachment of Borrelia burgdorferi to Cultured Endothelial and Brain Cells

The Lyme disease spirochete, Borrelia burgdorferi, infects multiple tissues, such as the heart, joint, skin, and nervous system and has been shown to recognize heparan sulfate and dermatan sulfate proteoglycans. In this study, we examined the contribution of different classes of proteoglycans to the attachment of the infectious B. burgdorferi strain N40 to several immortalized cell lines and primary cultured cells, including endothelial cells and brain cells. Bacterial attachment was inhibited by exogenous proteoglycans or by treatment of host cells with inhibitors of proteoglycan synthesis or sulfation, indicating that proteoglycans play a critical role in bacterial binding to diverse cell types. Binding to primary bovine capillary endothelial cells or a human endothelial cell line was also inhibited by digestion with heparinase or heparitinase but not with chondroitinase ABC. In contrast, binding to glial cell-enriched brain cell cultures or to a neuronal cell line was inhibited by all three lyases. Binding of strain N40 to immobilized heparin could be completely inhibited by dermatan sulfate, and conversely, binding to dermatan sulfate could be completely blocked by heparin. As measured by 50% inhibitory dose, heparin was a better inhibitor of binding than dermatan sulfate, regardless of whether the substrate was heparin or dermatan sulfate. These results are consistent with the hypotheses that the species of proteoglycans recognized by B. burgdorferi vary with cell type and that bacterial recognition of different proteoglycans is mediated by the same bacterial molecule(s)

Changes in Ultrafine Particle Concentrations near a Major Airport Following Reduced Transportation Activity during the COVID-19 Pandemic

Mobility reductions following the COVID-19 pandemic in the United States were higher, and sustained longer, for aviation than ground transportation activity. We evaluate changes in ultrafine particle (UFP, Dp < 100 nm, a marker of fuel-combustion emissions) concentrations at a site near Logan Airport (Boston, Massachusetts) in relation to mobility reductions. Several years of particle number concentration (PNC) data prepandemic [1/2017–9/2018] and during the state-of-emergency (SOE) phase of the pandemic [4/2020–6/2021] were analyzed to assess the emissions reduction impact on PNC, controlling for season and wind direction. Mean PNC was 48% lower during the first three months of the SOE than prepandemic, consistent with 74% lower flight activity and 39% (local)–51% (highway) lower traffic volume. Traffic volume and mean PNC for all wind directions returned to prepandemic levels by 6/2021; however, when the site was downwind from Logan Airport, PNC remained lower than prepandemic levels (by 23%), consistent with lower-than-normal flight activity (44% below prepandemic levels). Our study shows the effect of pandemic-related mobility changes on PNC in a near-airport community, and it distinguishes aviation-related and ground transportation source contributions