Mechanism of Action and Structural Requirements of Constrained Peptide Inhibitors of RGS Proteins

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66199/1/j.1747-0285.2006.00373.x.pd

α-Synuclein-specific T cell reactivity is associated with preclinical and early Parkinson’s disease

A diagnosis of motor Parkinson’s disease (PD) is preceded by a prolonged premotor phase with accumulating neuronal damage. Here we examined the temporal relation between α-synuclein (α-syn) T cell reactivity and PD. A longitudinal case study revealed that elevated α-syn-specific T cell responses were detected prior to the diagnosis of motor PD, and declined after. The relationship between T cell reactivity and early PD in two independent cohorts showed that α-syn-specific T cell responses were highest shortly after diagnosis of motor PD and then decreased. Additional analysis revealed significant association of α-syn-specific T cell responses with age and lower levodopa equivalent dose. These results confirm the presence of α-syn-reactive T cells in PD and show that they are most abundant immediately after diagnosis of motor PD. These cells may be present years before the diagnosis of motor PD, suggesting avenues of investigation into PD pathogenesis and potential early diagnosis

The TCR repertoire of α-synuclein-specific T cells in Parkinson’s disease is surprisingly diverse

The self-antigen α-synuclein (α-syn) was recently shown to be associated with Parkinson’s disease (PD). Here we mapped the T cell receptor (TCR) repertoire of α-syn-specific T cells from six PD patients. The self-antigen α-syn-specific repertoire was compared to the repertoire of T cells specific for pertussis (PT), as a representative foreign antigen that most individuals are exposed to, revealing that the repertoire for α-syn was as diverse as the repertoire for PT. The diversity of PT-specific clonotypes was similar between individuals with PD diagnosis and age-matched healthy controls. We found that the TCR repertoire was specific to each PD patient, and no shared TCRs among patients were defined, likely due to differences in HLA expression that select for different subsets of epitope-specific TCR rearrangements. This study provides the first characterization of α-syn-specific TCR clonotypes in individuals with PD. Antigen-specific TCRs can serve as immunotherapeutics and diagnostics, and means to track longitudinal changes in specific T cells, and disease progression

A Unified Framework for the Analysis of Side-Channel Key Recovery Attacks- extended version-

Abstract. The fair evaluation and comparison of side-channel attacks and countermeasures has been a long standing open question, limiting further developments in the field. Motivated by this challenge, this work makes a step in this direction and proposes a framework for the analysis of cryptographic implementations that includes a theoretical model and an application methodology. The model is based on commonly accepted hypotheses about side-channels that computations give rise to. It allows quantifying the effect of practically relevant leakage functions with a combination of information theoretic and security metrics, measuring the quality of an implementation and the strength of an adversary, respectively. From a theoretical point of view, we demonstrate formal connections between these metrics and discuss their intuitive meaning. From a practical point of view, the model implies a unified methodology for the analysis of side-channel key recovery attacks. The proposed solution allows getting rid of most of the subjective parameters that were limiting previous specialized and often ad hoc approaches in the evaluation of physically observable devices. It typically determines the extent to which basic (but practically essential) questions such as “How to compare two implementations? ” or “How to compare two side-channel adversaries? ” can be answered in a sound fashion.

Widespread Tau-Specific CD4 T Cell Reactivity in the General Population

Tau protein is found to be aggregated and hyperphosphorylated (p-tau) in many neurologic disorders, including Parkinson disease (PD) and related parkinsonisms, Alzheimer disease, traumatic brain injury, and even in normal aging. Although not known to produce autoimmune responses, we hypothesized that the appearance of aggregated tau and p-tau with disease could activate the immune system. We thus compared T cell responses to tau and p-tau–derived peptides between PD patients, age-matched healthy controls, and young healthy controls (<35 y old; who are less likely to have high levels of tau aggregates). All groups exhibited CD4+ T cell responses to tau-derived peptides, which were associated with secretion of IFN-γ, IL-5, and/or IL-4. The PD and control participants exhibited a similar magnitude and breadth of responses. Some tau-derived epitopes, consisting of both unmodified and p-tau residues, were more highly represented in PD participants. These results were verified in an independent set of PD and control donors (either age-matched or young controls). Thus, T cells recognizing tau epitopes escape central and peripheral tolerance in relatively high numbers, and the magnitude and nature of these responses are not modulated by age or PD disease

Past, present, and future of Parkinson&apos;s disease: A special essay on the 200th Anniversary of the Shaking Palsy

This article reviews and summarizes 200 years of Parkinson&apos;s disease. It comprises a relevant history of Dr. James Parkinson&apos;s himself and what he described accurately and what he missed from today&apos;s perspective. Parkinson&apos;s disease today is understood as a multietiological condition with uncertain etiopathogenesis. Many advances have occurred regarding pathophysiology and symptomatic treatments, but critically important issues are still pending resolution. Among the latter, the need to modify disease progression is undoubtedly a priority. In sum, this multiple-author article, prepared to commemorate the bicentenary of the shaking palsy, provides a historical state-of-the-art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson&apos;s disease. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Societ