Alien Registration- Hazlett, Miles L. (Portland, Cumberland County)

https://digitalmaine.com/alien_docs/24524/thumbnail.jp

A Family of Helminth Molecules that Modulate Innate Cell Responses via Molecular Mimicry of Host Antimicrobial Peptides

Over the last decade a significant number of studies have highlighted the central role of host antimicrobial (or defence) peptides in modulating the response of innate immune cells to pathogen-associated ligands. In humans, the most widely studied antimicrobial peptide is LL-37, a 37-residue peptide containing an amphipathic helix that is released via proteolytic cleavage of the precursor protein CAP18. Owing to its ability to protect against lethal endotoxaemia and clinically-relevant bacterial infections, LL-37 and its derivatives are seen as attractive candidates for anti-sepsis therapies. We have identified a novel family of molecules secreted by parasitic helminths (helminth defence molecules; HDMs) that exhibit similar biochemical and functional characteristics to human defence peptides, particularly CAP18. The HDM secreted by Fasciola hepatica (FhHDM-1) adopts a predominantly α-helical structure in solution. Processing of FhHDM-1 by F. hepatica cathepsin L1 releases a 34-residue C-terminal fragment containing a conserved amphipathic helix. This is analogous to the proteolytic processing of CAP18 to release LL-37, which modulates innate cell activation by classical toll-like receptor (TLR) ligands such as lipopolysaccharide (LPS). We show that full-length recombinant FhHDM-1 and a peptide analogue of the amphipathic C-terminus bind directly to LPS in a concentration-dependent manner, reducing its interaction with both LPS-binding protein (LBP) and the surface of macrophages. Furthermore, FhHDM-1 and the amphipathic C-terminal peptide protect mice against LPS-induced inflammation by significantly reducing the release of inflammatory mediators from macrophages. We propose that HDMs, by mimicking the function of host defence peptides, represent a novel family of innate cell modulators with therapeutic potential in anti-sepsis treatments and prevention of inflammation

Alien Registration- Hazlett, Miles L. (Portland, Cumberland County)

https://digitalmaine.com/alien_docs/24524/thumbnail.jp

The “outer dimensions”: impulsivity, anger/aggressiveness, activation

The “outer” SVARAD dimensions, impulsivity, anger/aggressiveness, and activation, represent trans-diagnostic psychological and behavioural domains that span traditional categorical boundaries. At the neurobiological level, the fronto-limbic and the fronto-cerebellar circuitry, as well as molecular pathways involving dopamine, serotonin, testosterone, and inflammatory mediators, play a crucial role in mediating the biological underpinnings of these psychopathological dimensions. From a clinical perspective, as the combination of clusters of symptoms differs from patient to patient and gives rise to a wide variety of clinical pictures even among subjects with the same diagnosis, it is important that the clinical features related to impulsivity, anger, aggressiveness, and activation are specifically and multiparametrically investigated and treated. The aim of the present chapter is to discuss the psychopathological aspects, the neurobiological underpinnings, and the clinical implications related to the “outer dimensions” in clinical psychiatry