Biology subjects

Zhu, K.

Publications and source records attributed to Zhu, K..

5 recordsLinked to original sources

bioRxiv2018

Universal antibiotic tolerance arising from antibiotic-triggered accumulation of redox metabolites

Pseudomonas aeruginosa is an opportunistic pathogen that often infects open wounds or patients with cystic fibrosis. Once established, P. aeruginosa infections are notoriously difficult to eradicate. This difficulty is in part due to the ability of P. aeruginosa to tolerate antibiotic treatment at the individual-cell level or through collective behaviors. Here we describe a new mechanism by which P. aeruginosa tolerates antibiotic treatment by modulating its global cellular metabolism. In particular, treatment of P. aeruginosa with sublethal concentrations of antibiotics covering all major classes promoted accumulation of the redox-sensitive phenazine - pyocyanin (PYO). PYO in turn conferred general tolerance against diverse antibiotics for both P. aeruginosa and other Gram-negative and Gram-positive bacteria. We show that PYO promotes energy generation to enhance the activity of efflux pumps, leading to enhanced antibiotic tolerance. This property is shared by other redox-active phenazines produced by P. aeruginosa. Our discovery sheds new insights into the physiological functions of phenazines and has implications for designing effective antibiotic treatment protocols.\n\nAuthor SummaryAntibiotic tolerance can facilitate the evolution of resistance, and here we describe a previously unknown mechanism of collective antibiotic tolerance in Pseudomonas aeruginosa. In particular, P. aeruginosa treated with sublethal concentrations of antibiotics covering all major classes promotes accumulation of pyocyanin (PYO), an important virulence factor. In turn, PYO confers general tolerance against diverse antibiotics for both P. aeruginosa and other bacteria. Our discovery is a perfect example of what Nietzsche once said: That which does not kill me makes me stronger.

microbiology↗

bioRxiv2018

Infection-generated electric field in gut epithelium drives bidirectional migration of macrophages

Many bacterial pathogens hijack macrophages to egress from the port of entry to the lymphatic/blood-stream, causing dissemination of life-threatening infections. However, the underlying mechanisms are not well understood. Here, we report that Salmonella infection generates directional electric fields (EF) in the follicle-associated epithelium of mouse cecum. In vitro application of an EF, mimicking the infection-generated electric field (IGEF), induces directional migration of primary mouse macrophages to the anode, which is reversed to the cathode upon Salmonella infection. This infection-dependent directional switch is independent of the Salmonella pathogenicity island 1 (SPI-1) type III secretion system. The switch is accompanied by a reduction of sialic acids on glycosylated surface components during phagocytosis of bacteria, which is absent in macrophages challenged by microspheres. Moreover, enzymatic cleavage of terminally exposed sialic acids reduces macrophage surface negativity and severely impairs directional migration of macrophages in response to EF. Based on these findings, we propose that macrophages are attracted to the site of infection by a combination of chemotaxis and galvanotaxis; after phagocytosis of bacteria, surface electrical properties of the macrophage change, and galvanotaxis directs the cells away from the site of infection.\n\nAbbreviationsCFU, colony-forming unit; Con A, Concanavalin A; EF, electric field; FAE, follicle-associated epithelium; GNL, Galanthus Nivalis lectin; IGEF, infection-generated electric field; Ji, electric current density; MAL-2, Maackia Amurensis lectin II; MLN, mesenteric lymph node; MOI, multiplicity of infection; nMFI, normalized mean fluorescence intensity; RCA-1, Ricinus Communis Agglutinin I; SNA, Sambucus Nigra lectin; S. Typhimurium, Salmonella enterica serotype Typhimurium; SPI-1, Salmonella pathogenicity island 1; PDMS, polydimethylsiloxane; TEP, trans-epithelial potential difference; TLR, Toll-like receptors; WGEF, wound-generated electric field

cell biology↗

bioRxiv2018

Combinatorial Detection of Conserved Alteration Patterns for Identifying Cancer Subnetworks

BackgroundAdvances in large scale tumor sequencing have lead to an understanding that there are combinations of genomic and transcriptomic alterations speciflc to tumor types, shared across many patients. Unfortunately, computational identiflcation of functionally meaningful shared alteration patterns, impacting gene/protein interaction subnetworks, has proven to be challenging. FindingsWe introduce a novel combinatorial method, cd-CAP, for simultaneous detection of connected subnetworks of an interaction network where genes exhibit conserved alteration patterns across tumor samples. Our method differentiates distinct alteration types associated with each gene (rather than relying on binary information of a gene being altered or not), and simultaneously detects multiple alteration proflle conserved subnetworks. ConclusionsIn a number of The Cancer Genome Atlas (TCGA) data sets, cd-CAP identifled large biologically signiflcant subnetworks with conserved alteration patterns, shared across many tumor samples.

systems biology↗

bioRxiv2018

Creating Standards for Evaluating Tumour Subclonal Reconstruction

Tumours evolve through time and space. Computational techniques have been developed to infer their evolutionary dynamics from DNA sequencing data. A growing number of studies have used these approaches to link molecular cancer evolution to clinical progression and response to therapy. There has not yet been a systematic evaluation of methods for reconstructing tumour subclonality, in part due to the underlying mathematical and biological complexity and to difficulties in creating gold-standards. To fill this gap, we systematically elucidated the key algorithmic problems in subclonal reconstruction and developed mathematically valid quantitative metrics for evaluating them. We then created approaches to simulate realistic tumour genomes, harbouring all known mutation types and processes both clonally and subclonally. We then simulated 580 tumour genomes for reconstruction, varying tumour read-depth and benchmarking somatic variant detection and subclonal reconstruction strategies. The inference of tumour phylogenies is rapidly becoming standard practice in cancer genome analysis; this study creates a baseline for its evaluation.

bioinformatics↗

bioRxiv2017

Cell cycle repression and DNA repair defects follow constricted migration

Cancer cell invasion into tissue or narrow capillaries often elongates the nucleus and sometimes damages it, but cell cycle effects are unknown and highly relevant to tumorigenesis. Here, nuclear rupture and DNA breaks caused by constricted migration are quantified in different phases of cell cycle - which is effectively repressed. Cancer lines with varying levels of contact inhibition and lamina proteins exhibit diverse frequencies of nuclear lamina rupture after migration, with prerupture dilation of gene-edited RFP-Lamin-B1 preceding DNA repair factor leakage in pressure-controlled distension. Post-migration rupture indeed associates with mis-localized DNA repair factors and increased DNA breaks as quantified by pan-nucleoplasmic foci of {gamma}H2AX, with foci counts always suppressed in late cell cycle. When contact-inhibited cells migrate through large pores into sparse microenvironments, cells re-enter cell cycle consistent with release from contact inhibition. In contrast, constricting pores effectively delay re-entry, but the excess DNA damage nonetheless exceeds any cell cycle dependence. Partial depletion of topoisomerase does not strongly affect cell cycle or the excess DNA damage, consistent with weak dependencies on replication stress. Constricted migration thus impacts cell cycle as well as DNA damage.

biophysics↗