Analysis of hidradenitis suppurativa-linked mutations in four genes and the effects of PSEN1-P242LfsX11 on cytokine and chemokine expression in macrophages.

Hidradenitis suppurativa (HS), or acne inversa, is a chronic inflammatory skin disorder characterized clinically with acne-like lesions in apocrine gland-bearing skin, follicular occlusion and recurrent inflammation. Thirty-four unique mutations in patients with HS have been found in three genes encoding the γ-secretase complex: nicastrin (NCSTN), presenilin 1 (PSEN1), presenilin enhancer 2 (PSENEN) and in POGLUT1, an endoplasmic reticulum O-glucosyltransferase involved in Notch signaling. We have carried out a system review and have performed a functional analysis of the 34 unique reported HS-linked mutations in NCSTN, PSEN1, PSENEN and POGLUT1. We have also examined the effects of the HS-linked PSEN1-P242LfsX11 mutation on cytokine and chemokine expression in macrophages. Mutations in NCSTN are predicted to cause loss of function, to result in loss of transmembrane (TM) domain, to affect NCSTN substrate recruitment sites, to cause loss or creation of new ligand binging sites and to alter post-translational modifications and disulfide bonds. PSEN1-P242LfsX11 occurs at the opposite side of TM5 from Alzheimer's disease-linked PSEN1 mutations. All of the PSENEN mutations occur on TM regions that are predicted to disrupt membrane function. POGLUT1 mutations lead to an early termination of protein synthesis and are predicted to affect ligand binding function. In addition, PSEN1-P242LfsX11 mediates cytokine and chemokine expression and prolongs tumor necrosis factor α production on the inflammatory processes in THP-1 cells and phorbol-12-myristate-13-acetate-differentiated macrophages in response to lipopolysaccharide stimulation. These in silico analyses are instructive for functional studies of the HS-linked mutations. The PSEN1-P242LfsX11 mutation mediates cytokine and chemokine expression in macrophages.

Disentangling Function from Benefit: Participant Perspectives from an Early Feasibility Trial for a Novel Visual Cortical Prosthesis.

Visual cortical prostheses (VCPs) have the potential to provide artificial vision for visually impaired persons. However, the nature and utility of this form of vision is not yet fully understood. Participants in the early feasibility trial for the Orion VCP were interviewed to gain insight into their experiences using artificial vision, their motivations for participation, as well as their expectations and assessments of risks and benefits. Analyzed using principles of grounded theory and an interpretive description approach, these interviews yielded six themes, including: the irreducibility of benefit to device functionality, mixed expectations for short-term device functionality and long-term technological advancement of visual prostheses, and a broad range of risks, concerns, and fears related to trial participation. We argue that these narratives motivate a nuanced set of ethical considerations related to the complex relationship between functionality and benefit, the intersection of user experience with disability justice, and the import of expectations and indirect risks on consent.

"They were already inside my head to begin with": Trust, Translational Misconception, and Intraoperative Brain Research.

Background: Patients undergoing invasive neurosurgical procedures offer researchers unique opportunities to study the brain. Deep brain stimulation patients, for example, may participate in research during the surgical implantation of the stimulator device. Although this research raises many ethical concerns, little attention has been paid to basic studies, which offer no therapeutic benefits, and the value of patient-participant perspectives.Methods: Semi-structured interviews were conducted with fourteen individuals across two studies who participated in basic intraoperative research during their deep brain stimulator surgery. Interviews explored interpretations of risks and benefits, enrollment motivations, and experiences of participating in awake brain research. Reflexive thematic analysis was conducted.Results: Seven themes were identified from participant narratives, including robust attitudes of trust, high valuations of basic science research, impacts of the surgical context, and mixed experiences of participation.Conclusion: We argue that these narratives raise the potential for a translational misconception and motivate intraoperative re-consent procedures.