Biology subjects

Samson, S.

Publications and source records attributed to Samson, S..

4 recordsLinked to original sources

bioRxiv2024

An anti-virulence drug targeting the evolvability protein Mfd protects against infections with antimicrobial resistant ESKAPE pathogens

The increased incidence of antibiotic resistance and declining discovery of new antibiotics have created a global health crisis, especially for the treatment of infections caused by Gram-negative bacteria. Here, we identify and characterize a molecule, NM102, that displays antimicrobial activity exclusively in the context of infection. NM102 inhibits the activity of the non-essential Mutation Frequency Decline (Mfd) protein by competing with ATP binding to its active site. Inhibition of Mfd by NM102 sensitizes pathogenic bacteria to the host immune response and blocks infections with clinically- relevant Klebsiella pneumoniae and Pseudomonas aeruginosa, without inducing host toxicity. Finally, NM102 inhibits the function of Mfd as a mutation and evolvability factor, thus reducing the bacterial capacity to develop antimicrobial resistance. These data provide a potential roadmap to expand the arsenal of drugs to combat antimicrobial resistance. HighlightO_LINM102 is a "first in class" molecule specifically targeting the active site of the bacterial Mfd protein C_LIO_LINM102 has a new mode of action: it inhibits Mfd function during immune stress response C_LIO_LINM102 also inhibits Mfd evolvability function and thereby decreases bacterial resistance to known antibiotics C_LIO_LINM102 effectively treats Gram-negative infections in animal models C_LIO_LINM102 is efficient against clinically relevant resistant bacteria and provides an increased efficacy in combination with the {beta}-lactam meropenem C_LI

microbiology↗

bioRxiv2023

Sensorimotor Impairment in Ageing and Neurocognitive Disorders: Beat Synchronisation and Adaptation to Tempo Changes

BackgroundUnderstanding the nature and extent of sensorimotor decline in ageing individuals and those with neurocognitive disorders NCD, such as Alzheimers disease, is essential for designing effective music-based interventions. ObjectiveOur understanding of rhythmic functions remains incomplete, particularly in how ageing and NCD affect sensorimotor synchronisation and adaptation to tempo changes. This study aims to fill this knowledge gap. MethodsPatients from a memory clinic participated in a tapping task, synchronising with metronomic and musical sequences, some of which contained sudden tempo changes. After exclusions, 51 patients were included in the final analysis. ResultsParticipants mini-mental state examination scores were associated with tapping consistency. Additionally, age negatively influenced consistency when synchronising with a musical beat, whereas consistency remained stable across age when tapping with a metronome. ConclusionsThe ability to extract a beat from a musical signal diminishes with age, whereas the capacity to maintain a beat remains relatively constant. However, both processes may decline at moderate or severe stages of NCD. Moreover, the results indicate that the initial decline of attention and working memory with age may impact perception and synchronisation to a musical beat, whereas progressive NCD-related cognitive decline results in more widespread sensorimotor decline, affecting tapping irrespective of audio type. These findings underline the importance of customising rhythm-based interventions to the needs of older adults and individuals with NCD, taking into consideration their cognitive as well as their rhythmic aptitudes. This study was registered at clinicaltrials.gov (NCT04146688).

neuroscience↗

bioRxiv2022

Mechanosensitive hormone signaling promotes mammary progenitor expansion and breast cancer progression

Tissue stem-progenitor cell frequency has been implicated in tumor risk and progression. Tissue-specific factors linking stem-progenitor cell frequency to cancer risk and progression remain ill defined. Using a genetically engineered mouse model that promotes integrin mechanosignaling with syngeneic manipulations, spheroid models, and patient-derived xenografts we determined that a stiff extracellular matrix and high integrin mechanosignaling increase stem-progenitor cell frequency to enhance breast tumor risk and progression. Studies revealed that high integrin-mechanosignaling expands breast epithelial stem-progenitor cell number by potentiating progesterone receptor-dependent RANK signaling. Consistently, we observed that the stiff breast tissue from women with high mammographic density, who exhibit an increased lifetime risk for breast cancer, also have elevated RANK signaling and a high frequency of stem-progenitor epithelial cells. The findings link tissue fibrosis and integrin mechanosignaling to stem-progenitor cell frequency and causally implicate hormone signaling in this phenotype. Accordingly, inhibiting RANK signaling could temper the tumor promoting impact of fibrosis on breast cancer and reduce the elevated breast cancer risk exhibited by women with high mammographic density. SummaryElevated mechano-signaling and matrix stiffness promote progesterone and RANK mediated expansion of mammary progenitors and breast cancer risk and progression.

cancer biology↗

bioRxiv2021

Combinatorial immunotherapies overcome MYC-driven immune evasion

For many human cancers, including triple negative breast cancer (TNBC), a modest number of patients benefit from immune checkpoint inhibitors, and few experience cancer remission1. Expression of programed death-ligand 1 (PD-L1), tumor immune infiltration, or tumor mutation burden have been widely investigated for predicting cancer immunotherapy response1-5. Whether specific oncogenes diminish response to immunotherapy6-10 and whether these effects are reversible remains poorly understood. We predicted that MYC, an oncogene that is frequently overexpressed11,12 and is associated with worse prognosis12, may predict immunotherapy response in patients with TNBC. Here, we report that MYC-elevated TNBCs are resistant to immune checkpoint inhibitors. Using mouse models of TNBC and patient data we report that MYC signaling is associated with low tumor cell PD-L1, low overall immune cell infiltration, and low tumor cell MHC-I expression. Restoring interferon signaling in the tumor reduces MYC expression and increases MHC-I expression. By combining a TLR9 agonist and an agonistic antibody against OX40 with anti-PD-L1, most mice experience complete tumor regression and are protected from new TNBC tumor outgrowth. Our findings demonstrate that MYC-dependent immune evasion is reversible and druggable, and if strategically targeted, may improve outcomes for patients treated with immune checkpoint inhibitors.

cancer biology↗