Biology subjects

Zheng, X.

Publications and source records attributed to Zheng, X..

At least 19 recordsLinked to original sources

bioRxiv2026

Mycoplasmal endosymbionts of Trichomonas vaginalis are associated with reduced risk for Chlamydia trachomatis endometrial infection in asymptomatic, coinfected, women.

Trichomonas vaginalis is a protozoan parasite that causes trichomoniasis, the most common curable non-viral sexually transmitted infection, and Chlamydia trachomatis is a bacterial pathogen that can ascend to the upper genital tract and cause pelvic inflammatory disease, infertility, and ectopic pregnancy. T. vaginalis harbors bacterial endosymbionts, including Candidatus Malacoplasma girerdii, an obligate symbiont, and Metamycoplasma hominis, which can live freely or symbiotically. In a 16S rRNA sequencing study of the cervicovaginal microbiome of women at high risk for chlamydial infection, Ca. M. girerdii abundance was one of 13 features predicting lack of chlamydial spread to the endometrium, despite no direct association between T. vaginalis infection and reduced chlamydial ascension. Investigating the relationship between these microorganisms further, we found that T. vaginalis vaginal abundance correlated positively with chlamydial burden in women whose infection was confined to the cervix, while a nonsignificant inverse relationship was seen in women with endometrial spread. Among participants with high chlamydial burden, Ca. M. girerdii was detected exclusively in women without endometrial infection. Both endosymbionts trended toward more frequent detection, and higher abundance, in coinfected women without endometrial spread, while M. hominis abundance correlated strongly with T. vaginalis burden in this group. These findings suggest that mycoplasmal endosymbionts of T. vaginalis, rather than T. vaginalis itself, are microbial factors limiting chlamydial ascension, and point to a three-way interaction between parasite, endosymbiont, and bacterial pathogen that shapes upper genital tract C. trachomatis infection risk.

microbiology↗

bioRxiv2018

Bacterial T6SS Effector EvpP Inhibits Neutrophil Recruitment via Jnk-Caspy Inflammasome Signaling In vivo

The type VI secretion system (T6SS) comprises dynamic complex bacterial contractile nanomachines and is used by many bacteria to inhibit or kill other prokaryotic or eukaryotic cells. Previous studies have revealed that T6SS is constitutively active in response to various stimuli, or fires effectors into host cells during infection. It has been proposed that the T6SS effector EvpP in Edwardsiella piscicida can inhibit NLRP3 inflammasome activation via the Ca2+-dependent JNK pathways. Here, we developed an in vivo infection model by microinjecting bacteria into the tail vein muscle of 3-day-post-fertilized zebrafish larvae, and found that both macrophages and neutrophils are essential for bacterial clearance. Further study revealed that EvpP plays a critical role in promoting the pathogenesis of E. piscicida via inhibiting the phosphorylation of Jnk signaling to reduce the expression of cxcl8a, mmp13 and IL-1{beta} in vivo. Subsequently, by utilizing Tg (mpo:eGFP+/+) zebrafish larvae for E. piscicida infection, we found that the EvpP-inhibited Jnk-caspy inflammasome signaling axis significantly suppressed the recruitment of neutrophils to infection sites, and the caspy- or IL-1{beta}-MO knockdown larvae were more susceptible to infection and failed to restrict bacterial colonization in vivo.\n\nIMPORTANCEInnate immunity is regulated by phagocytic cells and is critical for host control of bacterial infection. In many bacteria, T6SSs can affect bacterial virulence in certain environments, but little is known about the mechanisms underlying T6SS regulation of innate immune responses during infection in vivo. Here, we investigated the role of an E. piscicida T6SS effector EvpP in manipulating the reaction of neutrophils in vivo. We show that EvpP inhibits the activation of Jnk-caspy inflammasome pathway in zebrafish larvae, and reveal that macrophages are essential for neutrophil recruitment in vivo. This interaction improves our understanding about the complex and contextual role of a bacterial T6SS effector in modulating the action of myeloid cells during infection, and offers new insights into the warfare between bacterial weapons and host immunological surveillance.

microbiology↗

bioRxiv2018

Cell type-specific role of lamin-B1 and its inflammation-driven reduction in organ building and aging

Cellular architectural proteins often participate in organ development and maintenance. Although functional decay of some of these proteins during aging is known, the cell-type specific developmental role and the cause and consequence of their subsequent decay remain to be established especially in mammals. By studying lamins, the nuclear structural proteins, we demonstrate that lamin-B1 functions specifically in the thymic epithelial cells (TECs) for proper thymus organogenesis. An upregulation of proinflammatory cytokines in the intra-thymic myeloid immune cells during aging accompanies a gradual reduction of adult TEC lamins-B1. These cytokines cause adult TEC senescence and lamin-B1 reduction. We identify 17 adult TEC subsets and show that TEC lamin-B1 maintains the composition of these TECs. Lamin-B1 supports the expression of TEC genes needed for maintaining adult thymic architecture and function. Thus, structural proteins involved in organ building and maintenance can undergo inflammation-driven decay which can in turn contribute to age-associated organ degeneration.

immunology↗

bioRxiv2018

Flavor compounds in fermented Chinese alcoholic beverage alter gut microbiota and attenuate ethanol-induced liver

Alcoholic beverages which are consumed widely in most parts of the world have long been identified as a major risk factor for all liver diseases, particularly alcohol-induced liver disease (ALD). Recent compositional analyses suggest that Chinese Baijiu (CB), a clear alcoholic liquid distilled from fermented grains, contains large amounts of small molecule bioactive compounds in addition to a significant amount of ethanol. Here, in an experimental mouse model, we show that CB caused lower degrees of liver injury than pure ethanol by protecting against the decrease of the relative abundance of Akkermansia and increased relative abundance of Prevotella in the gut thereby preventing the destruction of the intestinal barrier. Furthermore, we demonstrated that ethanol-induced alteration of the gut microbiota profoundly affected the host metabolome. Compared with ethanol feeding, CB feeding resulted in higher concentrations of functional saturated LCFAs and SCFAs. Our results provide supporting evidence that ALD was profoundly influenced by host-gut microbiota metabolic interactions and that small molecule organic compounds in CB could attenuate ALD.

microbiology↗

bioRxiv2018

The seven transmembrane domain protein MoRgs7 functions in surface perception and undergoes coronin MoCrn1-dependent endocytosis in complex with Gα subunit MoMagA to promote cAMP signaling and appressorium formation in Magnaporthe oryzae

Regulator of G-protein signaling (RGS) proteins primarily function as GTPase-accelerating proteins (GAPs) to promote GTP hydrolysis of G subunits, thereby regulating G-protein mediated signaling. RGS proteins could also contain additional domains such as GoLoco to inhibit GDP dissociation. The rice blast fungus Magnaporthe oryzae encodes eight RGS and RGS-like proteins (MoRgs1 to MoRgs8) that have shared and distinct functions in growth, appressorium formation and pathogenicity. Interestingly, MoRgs7 and MoRgs8 contain a C-terminal seven-transmembrane domain (7-TM) motif typical of G-protein coupled receptor (GPCR) proteins, in addition to the conserved RGS domain. We found that MoRgs7, together with G MoMagA but not MoRgs8, undergoes endocytic transport from the plasma membrane to the endosome upon sensing of surface hydrophobicity. We also found that MoRgs7 can interact with hydrophobic surfaces via a hydrophobic interaction, leading to the perception of environmental hydrophobic cues. Moreover, we found that MoRgs7-MoMagA endocytosis is regulated by actin patch-associated protein MoCrn1, linking it to cAMP signaling. Our studies provided evidence suggesting that MoRgs7 could also function in a GPCR-like manner to sense environmental signals and it, together with additional proteins of diverse functions, promotes cAMP signaling required for developmental processes underlying appressorium function and pathogenicity.\n\nAuthor summaryThe 7-TM domain is considered the hallmark of GPCR proteins, which activate G proteins upon ligand binding and undergo endocytosis for regeneration or recycling. Among eight RGS and RGS-like proteins of M. oryzae, MoRgs7 and MoRgs8 contain the 7-TM domain in addition to the RGS domain. We found that MoRgs7 can form hydrophobic interactions with the hydrophobic surface. This interaction is important in sensing hydrophobic cues by the fungus. We also found that, in response to surface hydrophobicity, MoRgs7 couples with G subunit MoMagA to undergo endocytosis leading to the activation of cAMP signaling. Moreover, we found that such an endocytic event requires functions of the actin-binding protein MoCrn1. Our results revealed MoRgs7 functions as a GPCR-like receptor protein to sense surface cues and activate signaling required for pathogenesis, providing new insights into G-protein regulatory mechanisms in this and other pathogenic fungi.

microbiology↗

bioRxiv2018

Common and dissociable contributions of alexithymia and autism to domain-specific interoceptive dysregulations - a dimensional neuroimaging approach

Alexithymia represents a transdiagnostic marker across psychiatric entities associated with emotional impairments, including autism spectrum disorders (ASD). Accumulating evidence suggests that interoceptive dysfunctions that underpin the core symptomatic emotion recognition and empathy deficits in ASD may be contributed to by high levels of alexithymia rather than autistic symptoms per se. However, previous findings are hampered by generally elevated alexithymia in ASD patients, and thus were not able to differentiate common and distinct contributions across the entire spectrum of variations of autism and alexithymia. Moreover, the multi-factorial nature of the domains affected, such as distinct neural reactivity towards perceiving physical and affective pain, has not been accounted for. Against this background the present fMRI study employed a dimensional trait approach in n = 242 healthy subjects to determine common and distinct associations between both traits and pain empathic responses towards physical and affective pain. Higher levels of alexithymia associated with increased left anterior insula pain empathic reactivity. Disentangling these effects revealed a positive association during perceived physical pain, but a negative one during affective pain. No significant associations with trait autism were found, but an interaction effect between the trait dimensions was observed in the mid-cingulate cortex. Moderation analysis demonstrated that trait autism only impacted mid-cingulate reactivity towards physical pain in high alexithymia subjects, whereas reactivity towards affective pain was specifically associated with trait autism in low alexithymia subjects. Findings confirm previous patient studies suggesting that alexithymia rather than autism per se may drive altered insula pain empathic reactivity. Importantly, the present approach allowed for the first time to demonstrate that the impact of alexithymia on insula reactivity varies as a function of the pain empathic domain and that effects on other core empathy nodes evolve in interaction with trait autism.

neuroscience↗

bioRxiv2018

The Clinical and Molecular Epidemiology of CTX-M-9 Group Producing Enterobacteriaceae infections in children

BackgroundThe pandemic of extended-spectrum-beta-lactamase (ESBL)-producing-Enterobacteriaceae (Ent) is strongly linked to the dissemination of CTX-M-type-ESBL-Ent. We sought to define the epidemiology of infections in children due to an emerging resistance type, CTX-M-9-group-producing-Ent (CTX-M-9-grp-Ent).\n\nMethodsA multi-centered case-control analysis of Chicago children with CTX-M-9-grp-Ent infections was performed. Cases were defined as children possessing extended-spectrum-cephalosporin-resistant (ESC-R) infections. PCR and DNA analysis assessed beta-lactamase (bla) genes, multi-locus sequence types (MLST) and phylogenetic grouping of E. coli. Controls were children with ESC-susceptible (ESC-S)-Ent infections matched 3:1 by age, source, and hospital. The clinical-epidemiologic predictors of CTX-M-9-grp-Ent infection were assessed.\n\nResultsOf 356 ESC-R-Ent isolates from children (median age 4.1 years), CTX-M-9-group was the solely detected bla gene in 44(12.4%). The predominant species was E. coli (91%) of virulent phylogroups D(60%) and B2(40%). MLST revealed multiple strain types. On multivariable analysis, CTX-M-9-grp-Ent occurred more often in E. coli (OR 7.0), children of non-black-white-Hispanic race (OR 6.5), and outpatients (OR 4.5) which was a very unexpected finding for infections due to antibiotic-resistant bacteria. Residents of South Chicago were 6.7 times more likely to have CTX-M-9-grp-Ent infections than those in the reference region (West), while residence in Northwestern Chicago was associated with an 81% decreased risk. Other demographic, comorbidity, invasive-device, and antibiotic use differences were not found.\n\nConclusionsCTX-M-9-grp-Ent infection is strikingly associated with patient residence and is occurring in children without traditional in-patient exposure risk factors. This suggests that among children, the community environment may be a key contributor in the spread of these resistant pathogens.

epidemiology↗

bioRxiv2018

Oxytocin amplifies sex differences in human mate choice

Infidelity is the major cause of breakups and individuals with a history of infidelity are more likely to repeat it, but may also present a greater opportunity for short-term sexual relationships. Here in a pre-registered, double-blind study involving 160 subjects we report that while both sexes valued faithful individuals most for long-term relationships, both single men and those in a relationship were more interested in having short-term relationships with previously unfaithful individuals than women. Oxytocin administration resulted in men rating the faces of unfaithful women as more attractive but in women rating those of unfaithful men as less attractive and also finding them less memorable. Oxytocin also increased mens interest in having short-term relationships with previously unfaithful women whereas it increased womens interest in having long-term relationships with faithful men. Thus, oxytocin release during courtship may first act to amplify sex-dependent priorities in attraction and mate choice before subsequently promoting romantic bonds.

neuroscience↗

bioRxiv2018

Direct observation of rotation-coupled protein diffusion along DNA on the microsecond timescale

Many proteins that bind specific DNA sequences search the genome by combining three dimensional (3D) diffusion in the cytoplasm with one dimensional (1D) sliding on non-specific regions of the DNA1-5. It is however not known how sliding proteins are oriented with respect to DNA in order to recognize specific sequences. Here we measure the polarization of fluorescence emission from single fluorescently labeled lac repressor (LacI) molecules sliding on stretched DNA. Real-time feedback-coupled confocal single-particle tracking allows us to measure fluorescence correlation of the sliding molecules. We find that the fluctuations in the fluorescence signal on the s timescale are accurately described by rotation-coupled sliding on DNA. On average, LacI moves [~]50 base pairs per revolution, which is significantly longer than the 10.5 bp helical periodicity of DNA. Our data support a facilitated diffusion model1 where the transcription factor (TF) scans the DNA grooves for hydrogen bonding opportunities in a pre-aligned orientation with occasional slippage out of the groove.

biophysics↗

bioRxiv2018

Mining unknown porcine protein isoforms by tissue-based map of proteome enhances the pig genome annotation

A lack of the complete pig proteome has left a gap in our knowledge of the pig genome and has restricted the feasibility of using pigs as a biomedical model. We developed the tissue-based proteome maps using 34 major normal pig tissues. A total of 7,319 unknown protein isoforms were identified and systematically characterized, including 3,703 novel protein isoforms, 669 protein isoforms from 460 genes symbolized beginning with LOC, and 2,947 protein isoforms without clear NCBI annotation in current pig reference genome. These newly identified protein isoforms were functionally annotated through profiling the pig transcriptome with high-throughput RNA sequencing (RNA-seq) of the same pig tissues, further improving the genome annotation of corresponding protein coding genes. Combining the well-annotated genes that having parallel expression pattern and subcellular witness, we predicted the tissue related subcellular components and potential function for these unknown proteins. Finally, we mined 3,656 orthologous genes for 49.95% of unknown protein isoforms across multiple species, referring to 65 KEGG pathways and 25 disease signaling pathways. These findings provided valuable insights and a rich resource for enhancing studies of pig genomics and biology as well as biomedical model application to human medicine.

genomics↗

bioRxiv2018

UBE2G1 Governs the Destruction of Cereblon Neomorphic Substrates

The immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide as well as the novel cereblon modulating agents (CMs) including CC-122, CC-220 and cereblon-based proteolysis-targeting chimaeras (PROTACs) repurpose the Cul4-RBX1-DDB1-CRBN (CRL4CRBN) E3 ubiquitin ligase complex to induce the degradation of specific neomorphic substrates via polyubiquitination in conjunction with an E1 ubiquitin-activating enzyme and E2 ubiquitin-conjugating enzymes, which have until now remained elusive. Here we show that the ubiquitin-conjugating enzymes UBE2G1 and UBE2D3 cooperatively promote the polyubiquitination of CRL4CRBN neomorphic substrates in a cereblon- and CM-dependent manner via a sequential ubiquitination mechanism: UBE2D3 transforms the neomorphic substrates into mono-ubiquitinated forms, upon which UBE2G1 catalyzes K48-linked polyubiquitin chain extension. Blockade of UBE2G1 diminishes the ubiquitination and degradation of neomorphic substrates, and consequent antitumor activities elicited by all tested CMs. For example, UBE2G1 inactivation significantly attenuated the degradation of myeloma survival factors IKZF1 and IKZF3 induced by lenalidomide and pomalidomide, hence conferring drug resistance. UBE2G1-deficient myeloma cells, however, remained sensitive to a more potent IKZF1/3 degrader CC-220. Collectively, these findings suggest that loss of UBE2G1 activity might be a resistance mechanism to drugs that hijack the CRL4CRBN to eliminate disease-driving proteins, and that this resistance mechanism can be overcome by next-generation CMs that destroy the same targeted protein more effectively.

molecular biology↗

bioRxiv2018

Progression of chronic kidney disease in African American with type 2 diabetes mellitus using topology learning in electronic medical records

BackgroundChronic kidney disease (CKD) is a common, complex, and heterogeneous disease impacting aging populations. Determining the landscape of disease progression trajectories from midlife to senior age in a \"real-world\" context allows us to better understand the progression of CKD, the heterogeneity of progression patterns among the risk population, and the interactions with other clinical conditions. Genetics also plays an important role. In previous work, we and others have demonstrated that African Americans with high-risk APOL1 genotypes are more likely to develop CKD, tend to develop CKD earlier, and the disease progresses faster. Diabetes, which is more common in African Americans, also significantly increases risk for CKD.\n\nData and MethodElectronic medical records (EMRs) were used to outline the first CKD progression trajectory roadmap for an African American population with type 2 diabetes. By linking participants in 5 genome-wide association study (GWAS) to their clinical records at Wake Forest Baptist Medical Center (WFBMC), an EMR-GWAS cohort was established (n = 1,581). Patients health status was described by 18 Essential Clinical Indices across 84,009 clinical encounters. A novel graph learning algorithm, Discriminative Dimensionality Reduction Tree (DDRTree) was implemented, to establish the trajectories of declines in health. Moreover, a prediction model for new patients was proposed along the learned graph structure. We annotated these trajectories with clinical and genomic features including kidney function, other major risk indices of CKD, APOL1 genotypes, and age. The prediction power of the learned disease progression trajectories was further examined using the k-nearest neighbor model.\n\nResultsThe CKD progression trajectory roadmap revealed diverse kidney failure pathways associated with different clinical conditions. Specifically, we identified one high-risk trajectory and two low-risk trajectories. Switching pathways from low-risk trajectories to the high-risk one was associated with accelerated decline in kidney function. On this roadmap, patients with APOL1 high-risk genotypes were enriched in the high-risk trajectory, suggesting fundamentally different disease progression mechanisms from those without APOL1 risk genotypes. The k-nearest neighbor-based prediction showed effective prediction rate of 87%.\n\nConclusionThe CKD progression trajectory roadmap revealed novel diverse renal failure pathways in African Americans with type 2 diabetes mellitus and highlights disease progression patterns that associate with APOL1 renal-risk genotypes.

bioinformatics↗

bioRxiv2018

Monitoring of language selection errors in switching: Not all about conflict

Although bilingual speakers are very good at selectively using one language rather than another, sometimes language selection errors occur. To investigate how bilinguals monitor their speech errors and control their languages in use, we recorded event-related potentials (ERPs) in unbalanced Dutch-English bilingual speakers in a cued language-switching task. We tested the conflict-based monitoring model by investigating the error-related negativity (ERN) and comparing the effects of the two switching directions (i.e., to the first language, L1 vs. to the second language, L2). Results show that the speakers made more language selection errors when switching from their L2 to the L1 than vice versa. In the EEG, we observed a robust ERN effect following language selection errors compared to correct responses, reflecting monitoring of speech errors. Most interestingly, the ERN effect was enlarged when the speakers were switching to their L2 (less conflict) compared to switching to the L1 (more conflict). Our findings do not support the conflict-based monitoring model. We discuss an alternative account in terms of error prediction and reinforcement learning.

neuroscience↗

bioRxiv2018

Cell boundary confinement sets the size and position of the E. coli chromosome

While the spatiotemporal structure of the genome is crucial to its biological function, many basic questions remain unanswered on the morphology and segregation of chromosomes. Here, we experimentally show in Escherichia coli that spatial confinement plays a dominant role in determining both the chromosome size and position. In non-dividing cells with lengths up to 10 times normal, single chromosomes are observed to expand more than 4 fold in size, an effect only modestly influenced by deletions of various nucleoid-associated proteins. Chromosomes show pronounced internal dynamics but exhibit a robust positioning where single nucleoids reside strictly at mid-cell, while two nucleoids self-organize at [1/4] and [3/4] cell positions. Molecular dynamics simulations of model chromosomes recapitulate these phenomena and indicate that these observations can be attributed to depletion effects induced by cytosolic crowders. These findings highlight boundary confinement as a key causal factor that needs to be considered for understanding chromosome organization.

biophysics↗

bioRxiv2018

A Fully-Adjusted Two-Stage Procedure for Rank Normalization in Genetic Association Studies

When testing genotype-phenotype associations using linear regression, departure of the trait distribution from normality can impact both Type I error rate control and statistical power, with worse consequences for rarer variants. While it has been shown that applying a rank-normalization transformation to trait values before testing may improve these statistical properties, the factor driving them is not the trait distribution itself, but its residual distribution after regression on both covariates and genotype. Because genotype is expected to have a small effect (if any) investigators now routinely use a two-stage method, in which they first regress the trait on covariates, obtain residuals, rank-normalize them, and then secondly use the rank-normalized residuals in association analysis with the genotypes. Potential confounding signals are assumed to be removed at the first stage, so in practice no further adjustment is done in the second stage. Here, we show that this widely-used approach can lead to tests with undesirable statistical properties, due to both a combination of a mis-specified mean-variance relationship, and remaining covariate associations between the rank-normalized residuals and genotypes. We demonstrate these properties theoretically, and also in applications to genome-wide and whole-genome sequencing association studies. We further propose and evaluate an alternative fully-adjusted two-stage approach that adjusts for covariates both when residuals are obtained, and in the subsequent association test. This method can reduce excess Type I errors and improve statistical power.

genetics↗

bioRxiv2018

Distinctive types of postzygotic single-nucleotide mosaicisms in healthy individuals revealed by genome-wide profiling of multiple organs

Postzygotic single-nucleotide mosaicisms (pSNMs) have been extensively studied in tumors and are known to play critical roles in tumorigenesis. However, the patterns and origin of pSNMs in normal organs of healthy humans remain largely unknown. Using whole-genome sequencing and ultra-deep amplicon re-sequencing, we identified and validated 164 pSNMs from 27 postmortem organ samples obtained from five healthy donors. The mutant allele fractions ranged from 1.0% to 29.7%. Inter- and intra-organ comparison revealed two distinctive types of pSNMs, with about half originating during early embryogenesis (embryonic pSNMs) and the remaining more likely to result from clonal expansion events that had occurred more recently (clonal expansion pSNMs). Compared to clonal expansion pSNMs, embryonic pSNMs had higher proportion of C>T mutations with elevated mutation rate at CpG sites. We observed differences in replication timing between these two types of pSNMs, with embryonic and clonal expansion pSNMs enriched in early- and late-replicating regions, respectively. An increased number of embryonic pSNMs were located in open chromatin states and topologically associating domains that transcribed embryonically. Our findings provide new insights into the origin and spatial distribution of postzygotic mosaicism during normal human development.\n\nAuthor SummaryGenomic mosaicism led by postzygotic mutation is the major cause of cancers and many non-cancer developmental disorders. Theoretically, postzygotic mutations should be accumulated during the developmental process of healthy individuals, but the genome-wide characterization of postzygotic mosaicisms across many organ types of the same individual remained limited. In this study, we identified and validated two types of postzygotic mosaicism from the whole-genomes of 27 organs obtained from five healthy donors. We further found that the postzygotic mosaicisms arising during early embryogenesis and later clonal expansion events show distinct genomic patterns in mutation spectrum, replication timing, and chromatin status.

genomics↗

bioRxiv2018

Endothelial cells secreted ET-1 augments DN via inducing EM accumulation of MCs in ETBR-/- mice

ETBR deficiency may contribute to the progression of DN in a STZ model, but the underlying mechanism is not fully revealed. In this study, STZ-diabetic ETBR-/- mice was characterized by increased serum creatinine, urinary albumin and ET-1 expression, and enhanced glomerulosclerosis compared with STZ-diabetic WT mice. HG conditioned media of ETBR-/- endothelial cells promoted MC proliferation and upregulated ECM-related proteins, and ET-1 knockout in endothelial cells or inhibition of ET-1/ETAR in MC suppressed MC proliferation. ET-1 was over-expressed in ETBR-/- endothelial cells and was regulated by NF-kapapB pathway. And ET-1/ETBR suppressed NF-kappaB via eNOS to modulate ET-1 in endothelial cells. Furthermore, ET-1/ETAR promoted RhoA/ROCK pathway in MC, and accelerated MC proliferation and ECM accumulation. In vivo experiments proved ETBR-/- mice inhibited NF-kappaB pathway to ameliorate DN and eNOS mice had similar results. Hence, in HG-exposed ETBR-/- endothelial cells, suppression of ET-1/ETBR activated NF-kappaB pathway via inhibiting eNOS to secrete large amount of ET-1. Due to the communication between endothelial cells and MCs, ET-1/ETAR in MC promoted RhoA/ROCK pathway to accelerate MC proliferation and ECM accumulation.

biochemistry↗

bioRxiv2018

Community origins and regional differences in plasmid-mediated fluoroquinolone resistant Enterobacteriaceae infections in children

BackgroundFluoroquinolones (FQs) are uncommonly prescribed in children, yet pediatric multidrug-resistant (MDR)-Enterobacteriaceae (Ent) infections often reveal FQ resistance (FQR). We sought to define the molecular epidemiology of FQR and MDR-Ent in children.\n\nMethodsA case-control analysis of children with MDR-Ent infections at 3 Chicago hospitals was performed. Cases were children with third-generation-cephalosporin-resistant (3GCR) and/or carbapenem-resistant (CR)-Ent infections. PCR and DNA analysis assessed bla and plasmid-mediated FQR (PMFQR) genes. Controls were children with 3GC and carbapenem susceptible-Ent infections matched by age, source and hospital. We assessed clinical-epidemiologic predictors of PMFQR Ent infection.\n\nResultsOf 169 3GCR and/or CR Ent isolates from children (median age 4.8 years), 85 were FQR; 56 (66%) contained PMFQR genes. The predominant organism was E. coli and most common bla gene bla CTX-M-1 group. In FQR isolates, PMFQR gene mutations included aac61b-cr, oqxA/B, qepA, and qnrA/B/D/S in 83%, 15%, 13% and 11% of isolates, respectively. FQR E. coli was often associated with phylogroup B2, ST43/ST131. On multivariable analysis, PMFQR Ent infections occurred mostly in outpatients (OR 33.1) of non-black-white-Hispanic race (OR 6.5). Residents of Southwest Chicago were >5 times more likely to have PMFQR-Ent infections than those in the reference region, while residence in Central Chicago was associated with a 97% decreased risk. Other demographic, comorbidity, invasive-device, antibiotic use, or healthcare differences were not found.\n\nConclusionsThe strong association of infection with MDROs showing FQR with patient residence rather than with traditional risk factors suggests that the community environment is a major contributor to spread of these pathogens in children.

epidemiology↗