Biology subjects

Piccoli, L.

Publications and source records attributed to Piccoli, L..

3 recordsLinked to original sources

bioRxiv2019

Machine learning predicts immunoglobulin light chain toxicity through somatic mutations

In systemic light chain amyloidosis (AL), pathogenic monoclonal immunoglobulin light chains (LCs) form toxic aggregates and amyloid fibrils in target organs. Prompt diagnosis is crucial to avoid permanent organ damage. However, delays in diagnosis are common, with a consequent poor patients prognosis, as symptoms usually appear only after strong organ involvement. Here, we present LICTOR, a machine learning approach predicting LC toxicity in AL, based on the distribution of somatic mutations acquired during clonal selection. LICTOR achieved a specificity and a sensitivity of 0.82 and 0.76, respectively, with an area under the receiver operating characteristic curve (AUC) of 0.87. Tested on an independent set of 12 LCs sequences with known clinical phenotypes, LICTOR achieved a prediction accuracy of 83%. Furthermore, we were able to abolish the toxic phenotype of an LC by in silico reverting two germline-specific somatic mutations identified by LICTOR and by experimentally assessing the loss of in vivo toxicity in a Caenorhabditis elegans model. Therefore, LICTOR represents a promising strategy for AL diagnosis and reducing high mortality rates in AL.

bioinformatics↗

bioRxiv2019

Rationally designed oral vaccines can set an evolutionary trap for Salmonella Typhimurium

Introductory paragraphThe ability of gut bacterial pathogens to escape immunity by antigenic variation, particularly via changes to surface-exposed antigens, is a major barrier to immune clearance1. However, not all variants are equally fit in all environments2, 3. It should therefore be possible to exploit such immune escape mechanisms to direct an evolutionary trade-off. Here we demonstrated this phenomenon using Salmonella enterica subspecies enterica serovar Typhimurium (S.Tm). A dominant surface antigen of S.Tm is its O-antigen: A long, repetitive glycan that can be rapidly varied by mutations in biosynthetic pathways or by phase-variation4, 5. We quantified the selective advantage of O-antigen variants in the presence and absence of O-antigen specific IgA and identified a set of evolutionary trajectories allowing immune escape without an associated fitness cost in naive mice. Through the use of oral vaccines, we rationally induced IgA responses blocking all of these trajectories, which selected for Salmonella mutants carrying deletions of the O-antigen polymerase wzyB. Due to their short O-antigen, these evolved mutants were more susceptible to environmental stressors (detergents, complement), predation (bacteriophages), and were impaired in gut colonization and virulence in mice. Therefore, a rationally induced cocktail of intestinal antibodies can direct an evolutionary trade-off in S.Tm. This lays the foundations for the exploration of mucosal vaccines capable of setting evolutionary traps as a prophylactic strategy.

immunology↗

bioRxiv2019

Mindfulness meditators show enhanced working memory performance concurrent with different brain region engagement patterns during recall

Mindfulness meditation has been shown to improve working memory (WM). However, the altered brain activity underpinning these improvements is underexplored. In non-meditating individuals, modulation of theta and alpha oscillations and 1/f aperiodic activity during WM has been found to be related to WM performance. Resting theta and alpha oscillations have been found to differ in meditators, but WM related oscillation changes and 1/f aperiodic activity have not yet been examined. Additionally, WM event-related-potentials (ERPs) are modulated by attention, which is also enhanced by meditation, so these neural measures are candidates for exploring neural activity underpinning WM improvement in meditators. We recorded EEG from 29 controls and 29 meditators during a modified Sternberg WM task and compared theta, alpha, and 1/f aperiodic activity during the WM delay, and ERPs time-locked to the WM probe. Meditators responded more accurately (p = 0.008, Cohens d = 0.688). Meditators also showed different ERP distributions with earlier left-temporal activation and more frontal distribution of activity (FDR-p = 0.0186, {eta}2 = 0.0903), as well as a reduction in overall neural response strength (FDR-p = 0.0098, {eta}2 = 0.1251). While a higher proportion of meditators showed theta oscillations during the WM delay, no other differences in theta, alpha or 1/f aperiodic activity were present. These results suggest that increased WM performance in meditators might not be the result of higher amplitudes of typical WM activity, but instead due to an alternative neural strategy during WM decision making, which may allow more accurate responses with less neural activation.\n\nHighlights- Long term mindfulness meditators showed improved working memory (WM) accuracy\n- This was concurrent with earlier left temporal activation following probe stimuli\n- As well as a more frontal distribution and reduced overall neural response strength\n- No oscillation differences were present in the working memory delay period\n- Improved WM from altered neural strategy rather than increased neural activity

neuroscience↗