Biology subjects

Padula, M. P.

Publications and source records attributed to Padula, M. P..

4 recordsLinked to original sources

bioRxiv2024

Quorum sensing and DNA methylation play active roles in clinical Burkholderia phase variation

Phenotypic diversity in bacteria often results from adaptation to changing environmental conditions and is exemplified by variable colony morphotypes. Discrete genomic changes and modulation in gene expression occur in Burkholderia pseudomallei undergoing adaptation. Alternatively, adapted colony morphotype variants of species belonging to the Burkholderia cepacia complex (Bcc) lose a complete replicon (the pC3 virulence megaplasmid), which affects their production of virulence factors. We report that variants arising in Burkholderia ambifaria clinical isolates - with affected phenotypes - have retained their pC3, suggesting that another phase variation mechanism can take place in this Bcc species. Proteomic and phenotypic characterisation showed that morphotype variants of B. ambifaria strains CEP0996 (pC3-null) and HSJ1 (pC3-positive) share similarities in phenotypes controlled by the Cep quorum sensing system. Thus, we determined the role of quorum sensing in B. ambifaria HSJ1 phase variation and confirmed that the main quorum sensing system Cep is important for the emergence of variants. As DNA methylation is one of the main epigenetic factors involved in bacterial phase variation that regulates some virulence factors of the Bcc species Burkholderia cenocepacia, we hypothesized that B. ambifaria HSJ1 phase variation could also be regulated by adenosine DNA methylation. By deleting the three putative adenosine DNA methyltransferases, we found that an orphan type II DNA methyltransferase prevents the emergence of phase variants. This is the first study to report quorum sensing and adenosine DNA methylation as two antagonistic systems independently controlling phase variation. ImportanceSome Burkholderia species are pathogenic to plants, animals, or humans. In immunocompromised individuals, such as those with cystic fibrosis, infection with Burkholderia cepacia complex (Bcc) bacteria can lead to "cepacia syndrome." In the Australian Aboriginal population, melioidosis caused by B. pseudomallei is prevalent, particularly among those with diabetes or alcoholism. Burkholderias phenotypic plasticity, including colony morphotype variation (CMV), enables rapid adaptation to diverse environments, enhancing survival and pathogenicity. This study reveals phase variation as a new CMV mechanism within the Bcc group. We found that quorum sensing and DNA methylation are involved in phase variation. Understanding the underlying CMV mechanisms could lead to the development of targeted therapies against these highly antibiotic-resistant bacteria.

microbiology↗

bioRxiv2024

Deep Visual Proteomics reveals DNA replication stress as a hallmark of Signet Ring Cell Carcinoma

Signet Ring Cell Carcinoma (SRCC) is a rare and highly malignant form of adenocarcinoma with increasing incidence and poor prognosis due to late diagnosis and limited treatment options. We employed Deep Visual Proteomics (DVP), which combines AI directed cell segmentation and classification with laser microdissection and ultra-high sensitivity mass spectrometry, for cell-type specific proteomic analysis of SRCC across the bladder, prostate, liver, and lymph nodes of a single patient. DVP identified significant alterations in DNA damage response (DDR) proteins, particularly within the ATR and mismatch repair (MMR) pathways, indicating replication stress as a crucial factor in SRCC mutagenicity. Additionally, we observed substantial enrichment of immune-related proteins, reflecting high levels of cytotoxic T lymphocyte infiltration and elevated PD-1 expression. These findings suggest that pembrolizumab immunotherapy may be more effective than conventional chemotherapy for this patient. Our results provide novel insights into the proteomic landscape of SRCC, identifying potential targets and open up for personalized therapeutic strategies in managing SRCC.

cancer biology↗

bioRxiv2023

Colchicine promotes atherosclerotic plaque stability independently of inflammation

Atherosclerosis is a chronic inflammatory disease which is driven in part by the aberrant trans-differentiation of vascular smooth muscle cells (SMCs). No therapeutic drug has been shown to reverse detrimental SMC-derived cell phenotypes into protective phenotypes, a hypothesized enabler of plaque regression and improved patient outcome. Herein, we describe a novel function of colchicine in the beneficial modulation of SMC-derived cell phenotype, independent of its conventional anti-inflammatory effects. Using SMC fate mapping in an advanced atherosclerotic lesion model, colchicine induced plaque regression by converting pathogenic SMC-derived macrophage-like and osteoblast-like cells into protective myofibroblast-like cells which thickened, and thereby stabilized, the fibrous cap. This was dependent on Notch3 signaling in SMC-derived plaque cells. These findings may help explain the success of colchicine in clinical trials relative to other anti-inflammatory drugs. Thus, we demonstrate the potential of regulating SMC phenotype in advanced plaque regression through Notch3 signaling, in addition to the canonical anti-inflammatory actions of drugs to treat atherosclerosis.

cell biology↗

bioRxiv2019

MKPV (aka MuCPV) and related chapparvoviruses are nephro-tropic and encode novel accessory proteins p15 and NS2

Mouse kidney parvovirus (MKPV) is a member of the provisional Chapparvovirus genus that causes renal disease in immune-compromised mice, with a disease course reminiscent of polyomavirus-associated nephropathy in immune-suppressed kidney transplant patients. Here we map four MKPV transcripts, created by alternative splicing, to a common transcription initiation region, and use mass spectrometry to identify \"p10\" and \"p15\" as novel chapparvovirus accessory proteins produced in MKPV-infected kidneys. p15 and a splicing-dependent putative accessory protein NS2 are conserved in all near-complete tetrapod chapparvovirus genomes currently available (from mammals, birds and a reptile). In contrast, p10 may be encoded only by viruses with >60% amino acid identity to MKPV. We show that MKPV is kidney-tropic and that the bat chapparvovirus DrPV-1 and a non-human primate chapparvovirus, CKPV, are also found in the kidneys of their hosts. We propose, therefore, that chapparvoviruses with >60% VP1 amino acid identity to MKPV be classified into a genus dubbed Nephroparvovirus, which is consistent with nomenclature for the genus Erythroparvovirus.

microbiology↗