Biology subjects

Laurie, S.

Publications and source records attributed to Laurie, S..

5 recordsLinked to original sources

bioRxiv2024

Tumor microenvironment immunomodulation by nanoformulated TLR 7/8 agonist and PI3k delta inhibitor enhances therapeutic benefits of radiotherapy

Infiltration of immunosuppressive cells into the breast tumor microenvironment (TME) is associated with suppressed effector T cell (Teff) responses, accelerated tumor growth, and poor clinical outcomes. Previous studies from our group and others identified infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) as critical contributors to immune dysfunction in the orthotopic triple-negative breast cancer (TNBC) tumor model limiting the efficacy of adoptive cellular therapy. However, approaches to target these cells specifically in the TME are currently lacking. To overcome this barrier, polymeric micelles nanoparticles (PMNPs) were used for co-delivery of small molecule drugs activating Toll-like receptors 7 and 8 (TLR7/8) and inhibiting PI3K delta. The immunomodulation of the TME by TLR7/8 agonist and PI3K inhibitor altered macrophage polarization, reduced MDSC accumulation and selectively decreased tissue-resident Tregs in the TME, while enhancing the T and B cell adaptive immune response. PMNPs significantly enhanced the anti-tumor activity of local radiation therapy (RT) in mice bearing orthotopic TNBC tumors compared to RT alone. Taken together, these data demonstrate that RT combined with a nanoformulated immunostimulant restructured the TME and has promising potential for future translation combined with RT for patients with TNBC.

immunology↗

bioRxiv2024

Turmeric shortens lifespan in houseflies

Climate change poses a significant threat to food security and global public health with the increasing likelihood of insect pest outbreaks. Alternative ways to control insect populations, preferably using environmental-friendly compounds, are needed. Turmeric has been suggested as a natural insecticide with toxicity properties in some insect groups. However, empirical evidence of the effects turmeric - and their interaction with other ecological factors such as diet - on insect survival has been limited. Here, we tested the effects of turmeric and its interactions with diets differing in protein source in the common housefly, Musca domestica. We found that turmeric shortened lifespan independent of diet and sex. Females in turmeric diets were heavier at death, which was likely driven by a combination of relatively lower rates of body mass loss during their lifetime and a higher percentage of water content at death. Each sex responded differently to the protein source in the diet, and the magnitude of the difference in lifespan between sexes were greatest in diets in which protein source was hydrolysed yeast; individuals from both sexes lived longest in sucrose-milk diets and shortest in diets with hydrolysed yeast. There was no evidence of an interaction between turmeric and diet, suggesting that the toxicity effects are independent of protein source in the diet. Given the seemingly opposing effects of turmeric in insects and mammals being uncovered in the literature, our findings provide further evidence in support of turmeric as a potential natural insecticide.

zoology↗

bioRxiv2023

Rare disease research workflow using multilayer networks elucidates the molecular determinants of severity in Congenital Myasthenic Syndromes

Exploring the molecular basis of disease severity in rare disease scenarios is a challenging task provided the limitations on data availability. Causative genes have been described for Congenital Myasthenic Syndromes (CMS), a group of diverse minority neuromuscular junction (NMJ) disorders; yet a molecular explanation for the phenotypic severity differences remains unclear. Here, we present a workflow to explore the functional relationships between CMS causal genes and altered genes from each patient, based on multilayer network analysis of protein-protein interactions, pathways and metabolomics. Our results show that CMS severity can be ascribed to the personalized impairment of extracellular matrix components and postsynaptic modulators of acetylcholine receptor (AChR) clustering. We explore this in more detail for one of the proteins not previously associated with the NMJ, USH2A. Loss of the zebrafish USH2A ortholog revealed some effects on early movement and gross NMJ morphology. This work showcases how coupling multilayer network analysis with personalized -omics information provides molecular explanations to the varying severity of rare diseases; paving the way for sorting out similar cases in other rare diseases.

bioinformatics↗

bioRxiv2021

VarGenius-HZD allows accurate detection of rare homozygous or hemizygous deletions in targeted sequencing leveraging breadth of coverage

MotivationHomozygous deletions (HDs) may be the cause of rare diseases and cancer and their discovery in targeted sequencing is a challenging task. Different tools have been developed to disentangle HD discovery but a sensitive caller is still lacking. ResultsWe present VarGenius-HZD, a sensitive and scalable algorithm that leverages breadth-of-coverage for the detection of rare homozygous and hemizygous single-exon deletions (HDs). To assess its effectiveness we detected both real and synthetic rare HDs in fifty exomes from the 1000 Genomes Project obtaining higher sensitivity in comparison with state-of-the-art algorithms which missed at least one event each. We then applied our tool on targeted sequencing data from patients with Inherited Retinal Dystrophies and solved five cases that still lacked a genetic diagnosis. Availability and implementationWe provide VarGenius-HZD either stand-alone or integrated within our recently developed software enabling the automated selection of samples using the internal database. Hence, it could be extremely useful for both diagnostic and research purposes. Our tool is available under GNU General Public License, version 3 at: https://github.com/frankMusacchia/VarGenius-HZD Contact: francesco.musacchia@iit.it Supplementary information is available online.

genomics↗

bioRxiv2020

New genes involved in Angelman syndrome-like: expanding the genetic spectrum

Angelman syndrome (AS) is a neurogenetic disorder characterized by severe developmental delay with absence of speech, happy disposition, frequent laughter, hyperactivity, stereotypies, ataxia and seizures with specific EEG abnormalities. There is a 10-15% of patients with an AS phenotype whose genetic cause remains unknown (Angelman-like syndrome, AS-like). Whole-exome sequencing (WES) was performed on a cohort of 14 patients with clinical features of AS and no molecular diagnosis. As a result, we identified 10 de novo and 1 X-linked pathogenic/likely pathogenic variants in 10 neurodevelopmental genes (SYNGAP1, VAMP2, TBL1XR1, ASXL3, SATB2, SMARCE1, SPTAN1, KCNQ3, SLC6A1 and LAS1L) and one deleterious de novo variant in a candidate gene (HSF2). Our results highlight the wide genetic heterogeneity in AS-like patients and expands the differential diagnosis. New AS-like genes do not interact directly with UBE3A gene product but are involved in synapsis and neuron system development.

genetics↗