Biology subjects

Carrera, S.

Publications and source records attributed to Carrera, S..

4 recordsLinked to original sources

bioRxiv2026

Grey matter microstructural alterations distinguish cognitive impairment in Lewy body diseases

INTRODUCTION.Despite widespread cortical involvement in Lewy body diseases, conventional grey matter MRI measures have limited sensitivity. Microstructural measures from diffusion MRI may be more sensitive to early changes. METHODS.We examined grey matter microstructure in 197 participants across the Lewy body diseases spectrum: 88 Lewy body dementia (LBD), 109 Parkinsons normal cognition (PD-NC), and 46 controls. We compared tissue-weighted neurite density (tNDI), orientation dispersion index (tODI), and free water fraction (FWF) cross-sectionally and longitudinally. We examined relationships between microstructure, disease severity and plasma p-tau217. RESULTS.LBD participants showed widespread cortical and subcortical tODI and FWF increases compared to controls and PD-NC, despite minimal atrophy. These changes correlated with cognitive (but not motor severity) and with p-tau217. In 100 Parkinsons patients followed-up over 3 years, cortical FWF increased in those developing cognitive decline. DISCUSSION.Microstructural measures capture early grey matter changes, offering a sensitive marker of grey matter integrity in Lewy body diseases.

neuroscience↗

bioRxiv2024

PYR1 biosensor-driven genome-wide CRISPR screens for improved monoterpenoid production in Kluyveromyces marxianus

Monoterpenoids are valued for their roles as flavors, fragrances, insecticides, and energy-dense fuels. Microbial biosynthesis offers sustainable biosynthesis routes for these important molecules, but production levels remain limited. Here, we introduce a biosensor-driven microbial engineering strategy to enhance monoterpenoid production, specifically targeting geraniol. Using mutagenized libraries of the PYR1 receptor--a versatile biosensor from plant ABA signaling pathways with a malleable binding pocket--we screened 24 monoterpenoids and identified PYR1 variants responsive to eight, including geraniol. A low background, highly selective geraniol-sensitive PYR1 variant was expressed in the thermotolerant yeast Kluyveromyces marxianus as a growth-based biosensor circuit, allowing for rapid strain engineering. By coupling the geraniol-sensitive PYR1 sensor with a genome-wide CRISPR-Cas9 mutagenesis approach, we identified six gene knockouts that enhance geraniol production, achieving up to a 2-fold increase in titer. This study demonstrates the power of the PYR1 biosensor platform to enable rapid strain engineering and the identification of mutants that improve titer of a desired metabolite.

synthetic biology↗

bioRxiv2021

Complexities in the role of acetylation dynamics in modifying inducible gene activation parameters

High levels of histone acetylation are associated with the regulatory elements of active genes, suggesting a link between acetylation and gene activation. However, several studies have shown that histone acetylation dynamics rather than hyperacetylation per se are important determinants in gene activation, particularly at inducible genes. We revisited this model, in the context of EGF-inducible gene expression and found that rather than a simple unifying model, there are two broad classes of genes; one in which high lysine acetylation activity is required for efficient gene activation, and a second group where the opposite occurs and high acetylation activity is inhibitory. We examined the latter class in more detail using EGR2 as a model gene and found that lysine acetylation levels are critical for several activation parameters, including the timing of expression onset, and overall amplitudes of the transcriptional response. In contrast, DUSP1 responds in the canonical manner and its transcriptional activity is promoted by acetylation. Single cell approaches demonstrate heterogenous DUSP1 activation kinetics and that acetylation levels influence allele activation frequencies. Our data therefore point to a complex interplay between acetylation dynamics and target gene induction, which cannot simply be explained by a unified response to acetylation activity. Instead, acetylation level thresholds are an important determinant of transcriptional induction dynamics that are sensed in a gene-specific manner.

molecular biology↗

bioRxiv2021

Nuclear cholesterol is required for transcriptional repression by BASP1

Lipids are present within the cell nucleus where they engage with factors involved in gene regulation. Cholesterol associates with chromatin in vivo and stimulates nucleosome packing in-vitro, but its effects on specific transcriptional responses are not clear. Here we show that the lipidated WT1 transcriptional corepressor, BASP1, interacts with cholesterol in the cell nucleus through a conserved cholesterol interaction motif. We demonstrate that BASP1 directly recruits cholesterol to the promoter region of WT1 target genes. Mutation of BASP1 to ablate its interaction with cholesterol or the treatment of cells with drugs that block cholesterol biosynthesis inhibit the transcriptional repressor function of BASP1. We find that the BASP1-cholesterol interaction is required for BASP1-dependent chromatin remodelling and the direction of transcription programs that control cell differentiation. Our study uncovers a mechanism for gene-specific targeting of cholesterol where it is required to mediate transcriptional repression. SignificanceCholesterol is present within the cell nucleus where it associates with chromatin but to date, a direct role for cholesterol in nuclear processes has not been identified. We demonstrate that the transcriptional repressor BASP1 directly interacts with cholesterol within the cell nucleus through a consensus cholesterol interaction motif. BASP1 recruits cholesterol to the promoter region of target genes where it is required to mediate chromatin remodelling and transcriptional repression. Our work demonstrates that nuclear cholesterol plays a direct role in transcriptional regulation.

biochemistry↗