Xilin Zhao | Rutgers, The State University of New Jersey (original) (raw)

Papers by Xilin Zhao

Yi chuan = Hereditas, Oct 20, 2016

Misuse and overuse of antibiotics have led to serious resistance problems that pose a grave threa... more Misuse and overuse of antibiotics have led to serious resistance problems that pose a grave threat to human health. How to solve the increasing antibiotic resistance problem is a huge challenge. Besides the traditional strategy of developing novel antimicrobial agents, exploring ways to enhance the lethal activity of antibiotics currently available is another feasible approach to fight against resistance. Recent studies showed that ROS plays an important role in regulating both antibiotic resistance and antimicrobial lethality. ROS produced by sublethal levels of antibiotic induces antibiotic resistance through activating drug efflux pumps via MarR(Multiple antibiotic resistance repressor)-MarA(Multiple antibiotic resistance activator), triggers the protective function against stress via SoxR (Superoxide response transcriptional regulator)-SoxS (Superoxide response transcription factor), and promotes mutagenesis by induction of SOS system. On the contrary, ROS triggered by lethal le...

Frontiers in Cellular and Infection Microbiology

Multidrug-resistant (MDR) bacteria pose a significant clinical threat to human health, but the de... more Multidrug-resistant (MDR) bacteria pose a significant clinical threat to human health, but the development of antibiotics cannot meet the urgent need for effective agents, especially those that can kill persisters and biofilms. Here, we reported that nigericin showed potent bactericidal activity against various clinical MDR Gram-positive bacteria, persisters and biofilms, with low frequencies of resistance development. Moreover, nigericin exhibited favorable in vivo efficacy in deep-seated mouse biofilm, murine skin and bloodstream infection models. With Staphylococcus aureus, nigericin disrupted ATP production and electron transport chain; cell death was associated with altered membrane structure and permeability. Obtaining nigericin-resistant/tolerant mutants required multiple rounds of challenge, and, cross-resistance to members of several antimicrobial classes was absent, probably due to distinct nigericin action with the GraSR two-component regulatory system. Thus, our work rev...

Antimicrobial Resistance in the 21st Century

One way to restrict the emergence of new antibiotic resistance is to make antimicrobials more let... more One way to restrict the emergence of new antibiotic resistance is to make antimicrobials more lethal. To achieve that, a better understanding of how antimicrobials kill pathogens is needed. In the last decade, the idea emerged that reactive oxygen species (ROS) play a role in the lethal action of diverse antimicrobials. Experimental support was obtained (1) by measuring the effects of antimicrobials on intracellular ROS accumulation using dyes that become fluorescent in the presence of ROS and (2) by altering antimicrobial lethality using mutations in genes known to protect from oxidative damage and by using chemicals expected to alter ROS levels. Moreover, an ROS-mediated death process, which is blocked by treatment with an ROS-mitigating agent, continues after removal of the original lethal stress that triggers the ROS cascade. Challenges to the idea that ROS contribute to antimicrobial lethality led to refinements and additional support. For example, a drop in ROS explains the paradoxical loss of killing seen at very high concentrations of quinolone antibacterials, and an increase in ROS accounts for most of thymineless death. A potential consequence of ROS-mediated antimicrobial action is reduced antimicrobial effectiveness when antioxidants are consumed as nutritional supplements during antimicrobial therapy. Another is novel cross-tolerance that has not been previously considered with combination therapies. Overall, the experimental observations fit well with the concept that bacteria respond to severe stress by building up ROS levels and self-destructing.

Antimicrobial Resistance in the 21st Century, 2018

During infection, bacterial populations often contain subpopulations that exhibit reduced antimic... more During infection, bacterial populations often contain subpopulations that exhibit reduced antimicrobial susceptibility. The resulting population heterogeneity is called heteroresistance. Since a heteroresistant population can evolve into a resistant one, a heteroresistant infection is a risk factor for the development of complete resistance. We describe heteroresistant tuberculosis as an example of a chronic infection in which enrichment of resistant subpopulations readily progresses in individual patients and threatens successful treatment. Heteroresistance provides such a clear warning that improved DNA-based tests are being designed to identify isolates containing resistant subpopulations while they are still small. We also examine heteroresistance with Staphylococcus aureus as an example of how resistant subpopulations affect treatment of an opportunistic pathogen. Heteroresistance to methicillin resistance emerged via a horizontal gene transfer event that produced methicillin-resistant S. aureus (MRSA), which spread worldwide. Now heteroresistance to vancomycin-intermediate Staphylococcus aureus (VISA) is appearing among MRSA strains. Many other pathogens are also displaying heteroresistance that is often undetected by routine, automated susceptibility testing. Refinement of assays is likely to reveal that antimicrobial heteroresistance is much more prevalent than we realize and that treatment strategies need to be refined now to slow the emergence of new resistance.

International Journal of Antimicrobial Agents, 2019

Highlights  B. fragilis clinical isolates from China have antimicrobial pan-resistance.  Chromo... more Highlights  B. fragilis clinical isolates from China have antimicrobial pan-resistance.  Chromosome-born cfiA causes carbapenem resistance in B. fragilis isolates.  Upstream insertion sequences regulate cfiA.

Nucleic Acids Research, 1991

The recombinant plasmid pGEM4Z-ras DNA which was methylated on dam and dcm sites outside the Pvul... more The recombinant plasmid pGEM4Z-ras DNA which was methylated on dam and dcm sites outside the Pvull recognition sequence was digested with restriction endonuclease Pvull, and one of the three Pvull sites was about 16-fold less efficient to cleave than either of the other two. On the contrary, the three Pvull sites were cleaved at about the same rate on the unmethylated DNA molecule.The results show that the cleavage inhibition of the methylated DNA on the certain Pvull site was caused by methylation outside the Pvull recognition sequence. Maybe a adjacent methylated dam site *A was responsible for the less efficient cleavage. This observation suggests that methylation outside the recognition sequence may be considered a new factor in the kinetic experiment of restriction endonuclease.

Reference Module in Biomedical Sciences, 2014

ABSTRACT One of the main clinical problems with quinolones is the development of bacterial resist... more ABSTRACT One of the main clinical problems with quinolones is the development of bacterial resistance. Resistance genes are now being disseminated by plasmids, and the compounds themselves induce resistance through the mutagenic SOS response. Moreover, resistance arises spontaneously, producing mutant subpopulations that can be selectively amplified by traditional treatment strategies. Since many different resistance alleles exist and since resistance develops in a gradual, step-wise manner, many paths can be taken to reach clinical resistance. It is possible to adjust drug concentrations to force bacteria to acquire two or more mutations concurrently for growth. Such mutant-restricting concentrations are likely to be lower for compounds that kill resistant mutants. Thus, new quinolones, and indeed all new antimicrobials, should be developed to be highly lethal with resistant mutants. Although it is possible to define doses that will restrict the emergence of resistance, changing treatment protocols to protect existing quinolones is difficult. Part of the problem is that mutant-restricting doses are higher than usually needed to cure disease, and they may increase the frequency of toxic side-effects. Consequently, the mutant selection window hypothesis will not be applied until medical philosophy changes from seeking cure to restricting resistance.

Ore Geology Reviews, 2021

Abstract The Wuyi metallogenic belt can be divided into the South and the North Wuyi metallogenic... more Abstract The Wuyi metallogenic belt can be divided into the South and the North Wuyi metallogenic belt by the ENE-trending Nanping–Ninghua–Ganzhou Tectonic Belt. In the Wuyi metallogenic belt, Paleozoic mineralization, which has caused typical deposits such as the Yongping, Fenglin, and Yushui Cu deposits and the Makeng Fe deposit, exhibits notable variations. However, systematic research on the controlling factors of these mineralization episodes is lacking. In order to understand the Paleozoic minerlization in the Wuyi metallogenic belt, we study the genesis of typical deposits in Wuyi metallogenic belt. The phenomenon of “basal ore control” was observed as different basement units control different ore types in the Wuyi metallogenic belt. We believed that Paleozoic mineralization in the Wuyi metallogenic belt includes siliceous–carbonate Jingshe, Lindi, and Chuanshan Formations, which are related to the Fe–Mn deposits such as the Makeng Fe deposit, Dapai Fe–Pb–Zn deposit, and Luoyang Fe deposit in the Southwest Fujian Province, carbonate formations of the Hutian Group related to Cu deposits such as the Yushui Cu deposit in the North Guangdong Province of the southern Wuyi region, and the Carboniferous Outangdi Formation related to the Yongping and Fenglin Cu deposits in the Northeast Jiangxi Province of the northern Wuyi region. Based on a systematic analysis on typical metallogenic deposits and basement characteristics in the Wuyi metallogenic belt, we proposed that the Paleozoic mineralization is not only controlled by Paleozoic strata and Mesozoic magmatism, but also by the basement. The basement controls Paleozoic Cu mineralizations in the southern and northern Wuyi regions. However, Fe–Mn mineralization is mostly related to Late Paleozoic sedimentation. The superposition and transformation of Mesozoic magmatism to the basement and Paleozoic strata is an indispensable factor in the Cu and Fe–Mn mineralizations in the Wuyi metallogenic belt.

Journal of Asian Earth Sciences, 2019

Abstract The geodynamic transformation of the Cathaysia Block and its relationship with the Creta... more Abstract The geodynamic transformation of the Cathaysia Block and its relationship with the Cretaceous granitic intrusions have been controversial in recent decades. In this study, petrology, zircon U–Pb ages, Lu–Hf isotopic composition, whole-rock geochemistry and Sr–Nd isotopes were carried on Cretaceous granites that were collected from the Fujian province, SE China. Combining previously published ages with the new ages obtained in this study indicates that the magmatism in the study area occurred in three distinct stages at 145–137 Ma, 136–118 Ma and 107–86 Ma. The first stage I-type granites were intruded at 137 ± 1 Ma and 145 ± 1 Ma, which are characterized by low eNd(t) values of −7.3 to −6.8 and eHf(t) values of −12.5 to −2.5. It was formed by partial melting of Mesoproterozoic medium-to-high K basaltic rocks in the thickened crust of ~40 km without significant hybridization of mantle-derived magmas and fractional crystallization. The second stage highly differentiated I-type granites yield zircon U-Pb ages of 125 ± 1 Ma and 128 ± 1 Ma, which contain slightly negative eNd(t) values of −5.4 to −5.3 and eHf(t) values of −8.4 to −3.2. It was generated by partial melting of the Mesoproterozoic basement at the depth of 30–40 km triggered by underplating of a small amount of mantle-derived magma, with primary crustal melts undergoing plagioclase-dominated fractionation crystallization. The third stage I-type granites yield zircon U-Pb ages of 104 ± 1 Ma and 105 ± 1 Ma, which contain eNd(t) values of −1.7 to −7.3 and eHf(t) values of −6.0 to −0.5. It was derived from partial melting of Mesoproterozoic basaltic source at a depth of ~30 km. Besides, a mass of mantle-derived magma was mixed into the crustal melts, accompanied with plagioclase-dominated fractionation crystallization. Combining previously published data and those obtained in this study provides significant information for the tectonic evolution of Paleo-Pacific. In stage 1 (145–137 Ma), the existence of I-type granites and adakitic rocks suggests that the dip-angle subduction of the Paleo-Pacific Plate led to the partial melting of the thickened lower crust under the compressional environment. In stage 2 (136–118 Ma), the generation of I-type and A-type granitic magmas imply the thinning of the lithospheric crust under the extensional environment and the upwelling of the asthenospheric mantle, which are caused by slab rollback of Paleo-Pacific. In stage 3 (107–86 Ma), the appearance of much more I-type and A-type granites indicates that the break-off of the Paleo-Pacific plate led to much stronger crust–mantle interactions under the extensional environment.

Geological Journal, 2019

This thesis utilizes a theoretical and methodological approach that explores subjectivity as the ... more This thesis utilizes a theoretical and methodological approach that explores subjectivity as the relational, complex, fluid, multidimensional, recursive and intersectional modes in which social subjects are animated (Ortner 2005, 31). I discuss these different aspects of subjectivity construction through a contemporary example from urban Australia and by employing frameworks that underscore the agency of Aboriginal and Torres Strait Islander Peoples (Aboriginal or Aboriginal Australians) in constructing and maintaining their own subjectivities through discourses that challenge settler colonialism. I work to intertwine related theoretical approaches such as practice theory as defined by Sherry Ortner, and Pierre Bourdieu's discussion of the distinction of taste and its ties to unequal power relations in contemporary societies (Ortner 1984, 146; Bourdieu 1984, 57). Specifically, my study questions and problematizes the processes that constitute, perpetuate, and hinder the subjectivity formation of Aboriginal and Torres Strait Islander People (Aboriginal Australians) in an inner city suburb of Sydney, New South Wales called Redfern. My case study examines the intersection of Aboriginality (as both an ethnicity and as a facet of subjectivity), agency in contemporary urban Australia, and to a lesser extent the role of bureaucracy. I analyze these concepts in terms of their historical and cultural contexts, which complicate and inform contemporary lived experiences of members of Aboriginal communities in Redfern. Specifically, I argue that initiatives aimed at lowering inequality between Aboriginal and non-Aboriginal Australians as well as attempts at incorporating Aboriginal Sydneysiders into an Anglo-Australian society ultimately perpetuate longstanding tensions involving Aboriginality, agency, and subjectivity. This paper also argues that the adoption, contestation, maintenance, rejection, and construction of Aboriginality are inextricably tied with bureaucratic processes and the agency of Aboriginal Australians in Sydney, which can be seen through examples of initiatives such as this housing development that are aimed at combatting inequality between Aboriginal Australians and Anglo-Australians.

Geological Magazine, 2016

The Honggong pluton is the largest ferroan alkalic (A-type) granite intrusion emplaced along the ... more The Honggong pluton is the largest ferroan alkalic (A-type) granite intrusion emplaced along the Jiangshan–Shaoxing fault zone in southwestern Zhejiang Province, and has important implications for understanding the Late Mesozoic tectonic evolution of SE China. U–Pb ages of 138.7 ± 0.8, 134.2 ± 1.1, 128.5 ± 1.5 and 126.1 ± 0.9 Ma were obtained from zircon by laser ablation–inductively coupled plasma–mass spectrometry, indicating that the Honggong pluton formed in the Early Cretaceous. The Honggong pluton has a clear ferroan alkalic (A-type) granite geochemical signature with, for example, high total alkali contents and FeOt/(FeOt + MgO) values. The Sr–Nd–Hf isotopic compositions suggest that there was juvenile material in the magma source. Geochemical evidence indicates that the pluton was derived through extensive fractionation of melts that contained both asthenospheric mantle and Mesoproterozoic crustal components. These rare granites in southern China were emplaced during five ep...

Nature microbiology, 2017

Nutrient starvation usually halts cell growth rather than causing death. Thymine starvation is ex... more Nutrient starvation usually halts cell growth rather than causing death. Thymine starvation is exceptional, because it kills cells rapidly. This phenomenon, called thymineless death (TLD), underlies the action of several antibacterial, antimalarial, anticancer, and immunomodulatory agents. Many explanations for TLD have been advanced, with recent efforts focused on recombination proteins and replication origin (oriC) degradation. Because current proposals account for only part of TLD and because reactive oxygen species (ROS) are implicated in bacterial death due to other forms of harsh stress, we investigated the possible involvement of ROS in TLD. Here, we show that thymine starvation leads to accumulation of both single-stranded DNA regions and intracellular ROS, and interference with either event protects bacteria from double-stranded DNA breakage and TLD. Elevated levels of single-stranded DNA were necessary but insufficient for TLD, whereas reduction of ROS to background levels...

Island Arc, 2015

ABSTRACT Zircons from two samples of the Sukeng pluton in the southwest Fujian Province, China, w... more ABSTRACT Zircons from two samples of the Sukeng pluton in the southwest Fujian Province, China, were analyzed by LA–ICP–MS with the aim of determining the timing of formation. The zircons from the two samples yield similar U–Pb ages of 100.47 ± 0.42 and 102.46 ± 0.69 Ma, indicating that the Sufeng pluton is contemporaneous with the Sifang and Luoboling plutons, all of which are also related to Cu–Au–Pb–Zn–Mo mineralization within the study area. All three plutons have geochemical features of I-type granites, are high- to mid-K calc-alkaline metaluminous rocks, and have average molar Al2O3/ (CaO+Na2O+K2O) values of 0.95, initial 87Sr/86Sr ratios of 0.70465–0.70841, εNd(t) values at 101 Ma from –1.72 to –7.26, and two-stage Nd model ages (T2DM) from 1.16 to 1.60 Ga. Zircons within these plutons have εHf(t) values at 101 Ma from –3.5 to 6.25 and T2DM ages from 0.74 to 1.46 Ga, suggesting these I-type granites formed from magmas generated by partial melting of Mesoproterozoic to Neoproterozoic continental crust that mixed with mantle-derived magmas. The magmatism was associated with thickening of the lower crust caused by collisions between microcontinents in the Cathaysian Block, which were driven by Early Cretaceous subduction of the Pacific Plate.

mBio, Jan 9, 2014

Ribosomal elongation factor 4 (EF4) is highly conserved among bacteria, mitochondria, and chlorop... more Ribosomal elongation factor 4 (EF4) is highly conserved among bacteria, mitochondria, and chloroplasts. However, the EF4-encoding gene, lepA, is nonessential and its deficiency shows no growth or fitness defect. In purified systems, EF4 back-translocates stalled, posttranslational ribosomes for efficient protein synthesis; consequently, EF4 has a protective role during moderate stress. We were surprised to find that EF4 also has a detrimental role during severe stress: deletion of lepA increased Escherichia coli survival following treatment with several antimicrobials. EF4 contributed to stress-mediated lethality through reactive oxygen species (ROS) because (i) the protective effect of a ΔlepA mutation against lethal antimicrobials was eliminated by anaerobic growth or by agents that block hydroxyl radical accumulation and (ii) the ΔlepA mutation decreased ROS levels stimulated by antimicrobial stress. Epistasis experiments showed that EF4 functions in the same genetic pathway as t...

Reviews in Medical Microbiology, 2004

ABSTRACT In vitro studies have defined antimicrobial concentration ranges within which resistant ... more ABSTRACT In vitro studies have defined antimicrobial concentration ranges within which resistant bacterial mutants are enriched. Each pathogen-antimicrobial combination has a characteristic range called the mutant selection window. Traditional antimicrobial dosing strategies, which are designed to cure disease, tend to place drug concentrations inside selection windows. Removal of resistant mutant subpopulations then relies on the action of host defences rather than antimicrobial treatment. Such strategies will lead increasingly to antimicrobial resistance because immunosuppression is becoming more widespread. Alternative approaches for closing the selection window and for keeping antimicrobial concentrations outside the window are discussed.

Journal of Molecular Biology, 2001

The B subunit of DNA gyrase (GyrB) consists of a 43 kDa N-terminal domain, containing the site of... more The B subunit of DNA gyrase (GyrB) consists of a 43 kDa N-terminal domain, containing the site of ATP binding and hydrolysis, and a 47 kDa C-terminal domain that is thought to play a role in interactions with GyrA and DNA. In cells containing a deletion of topA (the gene encoding DNA topoisomerase I) a compensatory mutation is found in gyrB. This mutation (gyrB-225) results in a two amino acid insertion in the N-terminal domain of GyrB. We found that cells containing this mutation are more sensitive than wild-type cells to quinolone drugs with respect to bacteriostatic and lethal action. We have characterised the mutant GyrB protein in vitro and found it to have reduced DNA supercoiling, relaxation, ATPase, and cleavage activities. The mutant enzyme is up to threefold more sensitive to quinolones than wild-type. The mutation also increases the affinity of GyrB for GyrA and DNA, while the affinity of quinolone for the enzyme-DNA complex is unaffected. We propose that the loss in activity is due to misfolding of the GyrB-225 protein, providing an example in which misfolding of one protein, DNA gyrase, suppresses a deficiency of another, topoisomerase I. The increased quinolone sensitivity is proposed to be a consequence of an altered conformation of the protein that renders quinolones better able to disrupt, rather than generate, gyrase-drug-DNA complexes.

Journal of Asian Earth Sciences, 2013