Complement protein levels in plasma astrocyte-derived exosomes are abnormal in conversion from mild cognitive impairment to Alzheimer's disease dementia.

IntroductionLevels of complement proteins (CPs) in plasma astrocyte-derived exosomes (ADEs) that are abnormal in Alzheimer's disease (AD) have not been assessed in mild cognitive impairment (MCI).MethodsParticipants (n = 20 per group) had either MCI converting to dementia within 3 years (MCIC), MCI remaining stable over 3 years (MCIS), Alzheimer's disease, or were controls. CPs of ADEs isolated from plasmas by anti-human glutamine aspartate transporter antibody absorption were quantified by ELISAs.ResultsADE levels of C1q and C4b of the classical pathway, factor D and fragment Bb of the alternative pathway, and C5b, C3b, and C5b-C9 of both pathways were significantly higher in patients with MCIC than those with MCIS. ADE levels of inhibitory CPs decay-accelerating factor, CD46, CD59, and type 1 complement receptor were significantly lower in patients with MCIC than those with MCIS.DiscussionADE CPs are components of neurotoxic neuroinflammation that may be predictive biomarkers of MCI conversion to Alzheimer's disease

Geothermal Heating and Cooling Networks for Green and Livable Urban Transformations – Part II

As stated in part one of “how geothermal heating and cooling networks may support the green and livable urban transformation,” geothermal energy can be very efficiently used as a resource for district heating and cooling networks and can have the ability to be a key technology for a necessary heat energy transition. Compared to natural gas, the reduction of CO2-emissions using geothermal energy in an average project can be up to 88 percent (Stichting Platform Geothermie et al., 2018), hence the implementation of geothermal energy could be an important step to reach EU climate goals. In the Netherlands, for instance, it is predicted that geothermal energy can contribute 15 percent to the necessary CO2-emission reduction in the heat sector by 2030 and up to 25 percent by 2050 (Stichting Platform Geothermie et al., 2018). In contrast to that, geothermal energy only plays a minor role in the European heating and cooling sector. Hence there is a need to strengthen the role of geothermal energy and to intensify a know-how transfer about the potential of this technology. Therefore, the COST Action Geothermal-DHC wants to foster this knowledge exchange and will develop a roadmap towards a better integration of geothermally supplied heating and cooling networks in Europe in the next three years. Showcases and good practice examples offer a reliable option to exchange experiences and achieved success and can incentivize stakeholders to integrate similar solutions in their concepts and strategies. Some of such practice examples, implementing geothermal energy for heating and cooling in various European countries, are described in the following, which show a high variety of application possibilities

FORMATION OF SLOW-REACTING SUBSTANCE OF ANAPHYLAXIS IN HUMAN LUNG TISSUE AND CELLS BEFORE RELEASE

The capacity to extract slow-reacting substance of anaphylaxis (SRS-A) from human lung tissue or cells after immunologic activation, together with the measurement of SRS-A in both the extract and the surrounding fluid, permits study of total SRS-A generation. That the material extracted is SRS-A was established by both differential bioassay and purification. SRS-A accumulation was entirely intracellular after limited IgE-dependent direct or reversed anaphylactic activation. Intracellular accumulation also generally preceded release, with generation of SRS-A continuing well beyond a plateau in the cellular SRS-A level and the release of preformed mediators. The quantity of SRS-A generated after immunologic activation was modulated by the introduction of exogenous cyclic nucleotides, revealing a site of cyclic nucleotide action distinct from that on mediator release. The capacity to determine not only the release of preformed mediators but also the generation of a newly formed mediator, the sum of SRS-A in cells and supernate, adds an additional dimension to the analysis of the cellular events of immediate hypersensitivity

Plasma Neuronal Exosomal Levels of Alzheimer\u27s Disease Biomarkers in Normal Aging

Plasma neuronal exosomal levels of pathogenic Alzheimer\u27s disease (AD) proteins, cellular survival factors, and lysosomal proteins distinguish AD patients from control subjects, but changes in these exosomal proteins associated with normal aging have not been described for cognitively intact subjects. Plasma neuronal exosomal levels of P-T181-tau, P-S396-tau, Aβ1-42, cathepsin D, repressor element 1-silencing transcription factor, and neurogranin were quantified longitudinally in cognitively intact older adults using two samples collected at 3- to 11-year intervals. Except for P-S396-tau, exosomal protein levels changed significantly with aging, but were largely outside the range observed in AD patients

Structural identification of oxidized acyl-phosphatidylcholines that induce platelet activation

Oxidation of low-density lipoprotein (LDL) generates proinflammatory and prothrombotic mediators that may play a crucial role in cardiovascular and inflammatory diseases. In order to study platelet-activating components of oxidized LDL 1-stearoyl-2-arachidonoyl-sn-glycero-3- phosphocholine, a representative of the major phospholipid species in LDL, the 1-acyl-phosphatidylcholines (PC), was oxidized by CuCl2 and H2O2. After separation by high-performance liquid chromatography, three compounds were detected which induced platelet shape change at low micromolar concentrations. Platelet activation by these compounds was distinct from the pathways stimulated by platelet-activating factor, lysophosphatidic acid, lyso-PC and thromboxane A(2), as evidenced by the use of specific receptor antagonists. Further analyses of the oxidized phospholipids by electrospray ionization mass spectrometry structurally identified them as 1-stearoyl-2-azelaoyl-sn-glycero-3-phosphocholine (m/z 694; SAzPC), 1-stearoyl-2-glutaroyl-snglycero-3- phosphocholine (m/z 638; SGPC), and 1-stearoyl-2-( 5-oxovaleroyl)-sn-glycero-3-phosphocholine (m/z 622; SOVPC). These observations demonstrate that novel 1-acyl-PC which had previously been found to stimulate interaction of monocytes with endothelial cells also induce platelet activation, a central step in acute thrombogenic and atherogenic processes. Copyright (C) 2005 S. Karger AG, Basel

Chemotactic Activity and Receptor Binding of Neutrophil Attractant/Activation Protein‐1 (NAP‐1) and Structurally Related Host Defense Cytokines: Interaction of NAP‐2 With the NAP‐1 Receptor

Neutrophil attractant/activation protein‐1 (NAP‐1) has sequence similarity to platelet factor‐4 (PF‐4) and to NAP‐2 (a truncated form of connective tissue activating protein‐Ill [CTAP‐III(des 1–15)]. We compared chemotactic activity for neutrophils of these related proteins. We also included for comparison CTAP‐III, CTAP‐III(des 1–13), the C‐terminal dodecapeptide of PF‐4 [PF‐4(59–70)], and C5a. Chemotactic potency (EC50) was highest for NAP‐1 and C5a. Although chemotactic efficacy (peak percentage of neutrophils migrating) was comparable for C5a, NAP‐1, and NAP‐2, the NAP‐2 response occurred only at concentrations 100‐fold higher than the NAP‐1 EC50 of 10‐8 M. Data for the CTAP‐III proteins confirmed that CTAP‐III is not an attractant and that chemotactic activity appears as a result of cleavage of residues at the N‐terminus to make CTAP‐III(des 1–13) or NAP‐2 [CTAP‐III(des 1–15)]. Chemotactic activity of PF‐4 was low and variable, with no significant response by neutrophils from six of nine subjects. In contrast, PF‐4(59–70) regularly induced high chemotactic responses, although the EC50 of 1.6 × 10‐5 M was 1,000‐fold greater than that of NAP‐1. The binding of fluoresceinated NAP‐1 to neutrophils was inhibited by unlabeled NAP‐1 or NAP‐2 but not by PF‐4 or PF‐4 (59–70). This suggests that NAP‐2 interacts with the neutrophil NAP‐1 receptor. Despite the low chemotactic potency of NAP‐2, it is a potential attractant at sites of injury because of the relatively large amounts of the parent CTAP‐III released from platelets, as indicated by a serum concentration of approximately 10‐6 M.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141697/1/jlb0258.pd

VIP and PACAP receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Vasoactive Intestinal Peptide Receptors [64, 65]) are activated by the endogenous peptides VIP, PACAP-38, PACAP-27, peptide histidine isoleucineamide (PHI), peptide histidine methionineamide (PHM) and peptide histidine valine (PHV). VPAC1 and VPAC2 receptors display comparable affinity for the PACAP peptides, PACAP-27 and PACAP-38, and VIP, whereas PACAP-27 and PACAP-38 are >100 fold more potent than VIP as agonists of most isoforms of the PAC1 receptor. However, one splice variant of the human PAC1 receptor has been reported to respond to PACAP-38, PACAP-27 and VIP with comparable affinity [29]. PG 99-465 [115] has been used as a selective VPAC2 receptor antagonist in a number of physiological studies, but has been reported to have significant activity at VPAC1 and PAC1 receptors [35]. The selective PAC1 receptor agonist maxadilan, was extracted from the salivary glands of sand flies (Lutzomyia longipalpis) and has no sequence homology to VIP or the PACAP peptides [116]. Two deletion variants of maxadilan, M65 [180] and Max.d.4 [117] have been reported to be PAC1 receptor antagonists, but these peptides have not been extensively characterised

VIP and PACAP receptors in GtoPdb v.2023.1

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Vasoactive Intestinal Peptide Receptors [65, 66]) are activated by the endogenous peptides VIP, PACAP-38, PACAP-27, peptide histidine isoleucineamide (PHI), peptide histidine methionineamide (PHM) and peptide histidine valine (PHV). VPAC1 and VPAC2 receptors display comparable affinity for the PACAP peptides, PACAP-27 and PACAP-38, and VIP, whereas PACAP-27 and PACAP-38 are >100 fold more potent than VIP as agonists of most isoforms of the PAC1 receptor. However, one splice variant of the human PAC1 receptor has been reported to respond to PACAP-38, PACAP-27 and VIP with comparable affinity [30]. PG 99-465 [117] has been used as a selective VPAC2 receptor antagonist in a number of physiological studies, but has been reported to have significant activity at VPAC1 and PAC1 receptors [36]. The selective PAC1 receptor agonist maxadilan, was extracted from the salivary glands of sand flies (Lutzomyia longipalpis) and has no sequence homology to VIP or the PACAP peptides [118]. Two deletion variants of maxadilan, M65 [183] and Max.d.4 [119] have been reported to be PAC1 receptor antagonists, but these peptides have not been extensively characterised