Biology subjects

Berry, A.

Publications and source records attributed to Berry, A..

3 recordsLinked to original sources

bioRxiv2018

Insertion sequences drive the emergence of a highly adapted human pathogen

Taxonomic outliers of Pseudomonas aeruginosa of environmental origin have recently emerged as infectious for humans. Here we present the first genome-wide analysis of an isolate that caused fatal hemorrhagic pneumonia. We demonstrate that, in two sequential clones, CLJ1 and CLJ3, recovered from a patient with chronic pulmonary disease, insertion of a mobile genetic element into the P. aeruginosa chromosome affected major virulence-associated phenotypes and led to increased resistance to antibiotics used to treat the patient. Comparative proteome and transcriptome analyses revealed that this insertion sequence, ISL3, disrupted genes encoding flagellar components, type IV pili, O-specific antigens, translesion polymerase and enzymes producing hydrogen cyanide. CLJ3 possessed seven fold more IS insertions than CLJ1, some modifying its susceptibility to antibiotics by disrupting the genes for the outer-membrane porin OprD and the regulator of {beta}-lactamase expression AmpD. In the Galleria mellonella larvae model, the two strains displayed different levels of virulence, with CLJ1 being highly pathogenic. This work reveals ISs as major players in enhancing the pathogenic potential of a P. aeruginosa taxonomic outlier by modulating both, the virulence and the resistance to antimicrobials, and explains the ability of this bacterium to adapt from the environment to a human host.

microbiology↗

bioRxiv2018

Molecular basis of human asparagine synthetase inhibitor specificity

Expression of the enzyme human asparagine synthetase (ASNS) promotes metastatic progression in breast cancer, which affects L-asparagine levels and tumor cell invasiveness. Human ASNS has therefore emerged as a bona fide drug target for cancer therapy. We have reported a slow-onset, tight binding ASNS inhibitor with nanomolar affinity, but our compound exhibits poor cell permeability. On the other hand, we show here that this inhibitor exhibits remarkable selectivity for the human ASNS in HCT-116 cell lysates. By determining the first high-resolution (1.85 [A]) X-ray crystal structure for human ASNS, we have built a computational model of the enzyme complexed to our inhibitor, which provides the first insights into the intermolecular interactions mediating specificity. These findings should facilitate the development of a second generation of ASNS inhibitors, leading to the discovery of drugs to prevent metastasis.

biochemistry↗

bioRxiv2018

Healthspan pathway maps in C. elegans and humans highlight transcription, prolifera-tion/biosynthesis and lipids

The molecular basis of aging and of aging-associated diseases is being unraveled at an increasing pace. An extended healthspan, and not merely an extension of lifespan, has become the aim of medical practice. However, a precise definition of health and healthspan is not straightforward, and the causal molecular basis of health \"per se\" is largely unknown. Here, we define health based on the absence of diseases and dysfunctions. Based on an extensive review of the literature, in particular for humans and C. elegans, we compile a list of features of health and of the genes associated with them. Clusters of these genes based on molecular interaction data give rise to maps of healthspan pathways for humans, featuring the themes transcription initiation, proliferation and cholesterol/lipid processing, and for C. elegans, featuring the themes immune response, mitochondrion and biosynthesis based on genetic and compound intervention data, and lipids, biosynthesis and transcription based on WormBase compound intervention data. Overlaying healthspan-related gene expression data (describing effects of metabolic intervention associated with improvements in health) onto the aforementioned healthspan pathway maps, we observe the downregulation of Notch signalling in humans and of proliferation/cell-cycle in C. elegans. The former reflects the proinflammatory role of the Notch pathway. We identify transcription, proliferation/biosynthesis and lipids as a common theme on the annotation level, and proliferation-related kinases on the gene/protein level. Our literature-based data corpus, including visualization, is available as a reference for future investigations, at http://www.h2020awe.eu/index.php/pathways/.

bioinformatics↗