Evolution and Mutations Predisposing to Daptomycin Resistance in Vancomycin-Resistant Enterococcus faecium ST736 Strains

We recently identified a novel vancomycin-resistant Enterococcus faecium (VREfm) clone ST736 with reduced daptomycin susceptibility. The objectives of this study were to assess the population dynamics of local VREfm strains and genetic alterations predisposing to daptomycin resistance in VREfm ST736 strains. Multilocus sequence typing and single nucleotide variant data were derived from whole-genome sequencing of 250 E. faecium isolates from 1994-1995 (n = 43), 2009-2012 (n = 115) and 2013 (n = 92). A remarkable change was noticed in the clonality and antimicrobial resistance profiles of E. faecium strains between 1994-1995 and 2013. VREfm sequence type 17 (ST17), the prototype strain of clade A1, was the dominant clone (76.7%) recognized in 1994-1995. By contrast, clone ST736 accounted for 46.7% of VREfm isolates, followed by ST18 (26.1%) and ST412 (20.7%) in 2013. Bayesian evolutionary analysis suggested that clone ST736 emerged between 1996 and 2009. Co-mutations (liaR.W73C and liaS.T120A) of the liaFSR system were identified in all ST736 isolates (n = 111, 100%) examined. Thirty-eight (34.2%) ST736 isolates exhibited daptomycin-resistant phenotype, of which 13 isolates had mutations in both the liaFSR and cardiolipin synthase (cls) genes and showed high level of resistance with a daptomycin MIC50 of 32 mug/mL. The emergence of ST736 strains with mutations predisposing to daptomycin resistance and subsequent clonal spread among inpatients contributed to the observed high occurrence of daptomycin resistance in VREfm at our institution. The expanding geographic distribution of ST736 strains in other states and countries raises concerns about its global dissemination

Enterovirus D68 subclade B3 Strain Circulating and Causing an Outbreak in the United States in 2016

In 2014 the United States experienced a nationwide outbreak of Enterovirus D68 (EV-D68) infection. There were no confirmed cases of EV-D68 in 2015 and CDC was only aware of limited sporadic EV-D68 detection in the US in 2016. In this report, we analyzed 749 nasopharyngeal (NP) specimens collected in 2015 and 2016 from patients in the Lower Hudson Valley, New York using a previously validated EV-D68-specific rRT-PCR assay. EV-D68 was detected in none of 199 NP specimens collected in 2015, and in one of 108 (0.9%) samples from January to May and 159 of 442 (36.0%) samples from July to October 2016. Complete EV-D68 genome sequences from 22 patients in 2016 were obtained using a metagenomic next-generation sequencing assay. Comparative genome analysis confirmed that a new EV-D68 strain belonging to subclade B3, with 3.2-4.8% divergence in nucleotide from subclade B1 strains identified during the 2014 US outbreak, was circulating in the US in 2016 and caused an outbreak in the Lower Hudson Valley, New York with 160 laboratory-confirmed cases. Our data highlight the genetic variability and capacity in causing outbreak by diverse EV-D68 strains, and the necessity of awareness and more surveillance on their active circulation worldwide

Ruxolitinib Significantly Enhances in Vitro Apoptosis in Hodgkin Lymphoma and Primary Mediastinal B-Cell Lymphoma and Survival in a Lymphoma Xenograft Murine Model

Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBL) share similar molecular features by gene expression profiling. Frequent gains of chromosome 9p exhibit higher Janus Kinase 2 (JAK2) transcript levels with increased JAK2 activity, suggesting aberrant activity of JAK2 and STAT pathways. This signaling pathway alteration may in part play an important role in the pathogenesis and/or chemoradiotherapy resistance in HL and PMBL. Ruxolitinib is a potent and selective JAK1/JAK2 inhibitor, with activity against myeloproliferative neoplasms (MPNs) including those harboring the JAK2V617F mutation. We investigated the in vitro and in vivo efficacy of ruxolitinib and changes in downstream signaling pathways in HL and PMBL. We demonstrated that ruxolitinib significantly inhibited STAT signaling in both HL and PMBL with constitutively active JAK2 signaling. We also observed that ruxolitinib significantly induced in vitro anti-proliferative effects (p \u3c 0.05) and increased programmed cell death (p \u3c 0.05) against both HL and PMBL cells. Importantly, ruxolitinib significantly inhibited tumor progression by bioluminescence (p \u3c 0.05) and significantly improved survival in HL (p = 0.0001) and PMBL (p \u3c 0.0001) xenograft NSG mice. Taken altogether, these studies suggest that ruxolitinib may be a potential adjuvant targeted agent in the therapeutic approach in patients with high risk HL and PMBL

Complete Genome Sequences of Four Toxigenic ;Clostridium difficile Clinical Isolates from Patients of the Lower Hudson Valley, New York, USA

Complete genome sequences of four toxigenic Clostridium difficile isolates from patients in the lower Hudson Valley, New York, USA, were achieved. These isolates represent four common sequence types (ST1, ST2, ST8, and ST42) belonging to two distinct phylogenetic clades. All isolates have a 4.0- to 4.2-Mb circular chromosome, and one carries a phage

Emergence and Evolution of Multidrug-Resistant Klebsiella pneumoniae with both blaKPC and blaCTX-M Integrated in the Chromosome

The extended-spectrum-β-lactamase (ESBL)- and Klebsiella pneumoniaecarbapenemase (KPC)-producing Enterobacteriaceae represent serious and urgent threats to public health. In a retrospective study of multidrug-resistant K. pneumoniae, we identified three clinical isolates, CN1, CR14, and NY9, carrying both blaCTX-M and blaKPC genes. The complete genomes of these three K. pneumoniae isolates were de novo assembled by using both short- and long-read whole-genome sequencing. In CR14 and NY9, blaCTX-M and blaKPC were carried on two different plasmids. In contrast, CN1 had one copy of blaKPC-2 and three copies of blaCTX-M-15 integrated in the chromosome, for which the blaCTX-M-15 genes were linked to an insertion sequence, ISEcp1, whereas the blaKPC-2 gene was in the context of a Tn4401a transposition unit conjugated with a PsP3-like prophage. Intriguingly, downstream of the Tn4401a-blaKPC-2-prophage genomic island, CN1 also carried a clustered regularly interspaced short palindromic repeat (CRISPR)-cas array with four spacers targeting a variety of K. pneumoniae plasmids harboring antimicrobial resistance genes. Comparative genomic analysis revealed that there were two subtypes of type I-E CRISPR-cas in K. pneumoniae strains and suggested that the evolving CRISPR-cas, with its acquired novel spacer, induced the mobilization of antimicrobial resistance genes from plasmids into the chromosome. The integration and dissemination of multiple copies of blaCTX-Mand blaKPC from plasmids to chromosome depicts the complex pandemic scenario of multidrug-resistant K. pneumoniae. Additionally, the implications from this study also raise concerns for the application of a CRISPR-cas strategy against antimicrobial resistance

Complete Genome Sequence of a Colistin-resistant Escherichia coli Strain Harboring mcr-1 on an InchI2 Plasmid in the United States

We report here the incidental detection and complete genome sequence of a urinary Escherichia coli strain harboring mcr-1 and resistant to colistin in a New York patient returning from Portugal in 2016. This strain, with sequence type 1485 (ST1485), was a non-extended-spectrum beta-lactamase (ESBL) and non-carbapenemase producer and carried the mcr-1 gene on an IncHI2 plasmid

The Effects of DLEU1 Gene Expression in Burkitt Lymphoma (BL): Potential Mechanism of Chemoimmunotherapy Resistance in BL

Following a multivariant analysis we demonstrated that children and adolescents with Burkitt lymphoma (BL) and a 13q14.3 deletion have a significant decrease in event free survival (EFS) despite identical short intensive multi-agent chemotherapy. However, how this deletion in the 13q14.3 region is associated with a significant decrease in EFS in children and adolescents with BL is largely unknown. The gene Deleted in Lymphocytic Leukemia 1 (DLEU1) is located in the region of 13q14.3. Here, we report that DLEU1 expression is implicated in the regulation of BL programmed cell death, cell proliferation, and expression of apoptotic genes in transcription activator-like effector nuclease (TALEN)s-induced DLEU1 knockdown and DLEU1 overexpressing BL cell lines. Furthermore, NSG mice xenografted with DLEU1 knockdown BL cells had significantly shortened survival (p \u3c 0.05 and p \u3c 0.005), whereas those xenografted with DLEU1 overexpressing BL cells had significantly improved survival (p \u3c 0.05 and p \u3c 0.0001), following treatment with rituximab and/or cyclophosphamide. These data suggest that DLEU1 may in part function as a tumor suppressor gene and confer chemoimmunotherapy resistance in children and adolescents with BL

City-level meteorological conditions modify the relationships between exposure to multiple air pollutants and the risk of pediatric hand, foot, and mouth disease in the Sichuan Basin, China

BackgroundSeveral studies have examined the effects of city-level meteorological conditions on the associations between meteorological factors and hand, foot, and mouth disease (HFMD) risk. However, evidence that city-level meteorological conditions modify air pollutant-HFMD associations is lacking.MethodsFor each of the 17 cities in the Sichuan Basin, we obtained estimates of the relationship between exposures to multiple air pollutants and childhood HFMD risk by using a unified distributed lag nonlinear model (DLNM). Multivariate meta-regression models were used to identify the effects of city-level meteorological conditions as effect modifiers. Finally, we conducted subgroup analyses of age and sex to explore whether the modification effects varied in different subgroups.ResultsThe associations between PM2.5/CO/O3 and HFMD risk showed moderate or substantial heterogeneity among cities (I2 statistics: 48.5%, 53.1%, and 61.1%). Temperature conditions significantly modified the PM2.5-HFMD association, while relative humidity and rainfall modified the O3-HFMD association. Low temperatures enhanced the protective effect of PM2.5 exposure against HFMD risk [PM2.5 <32.7  μg/m3 or PM2.5 >100  μg/m3, at the 99th percentile: relative risk (RR) = 0.14, 95% CI: 0.03–0.60]. Low relative humidity increased the adverse effect of O3 exposure on HFMD risk (O3 >128.7 μg/m3, at the 99th percentile: RR = 2.58, 95% CI: 1.48–4.50). However, high rainfall decreased the risk of HFMD due to O3 exposure (O3: 14.1–41.4  μg/m3). In addition, the modification effects of temperature and relative humidity differed in the female and 3–5  years-old subgroups.ConclusionOur findings revealed moderate or substantial heterogeneity in multiple air pollutant-HFMD relationships. Temperature, relative humidity, and rainfall modified the relationships between PM2.5 or O3 exposure and HFMD risk

Dysregulated protocadherin-pathway activity as an intrinsic defect in induced pluripotent stem cell-derived cortical interneurons from subjects with schizophrenia.

We generated cortical interneurons (cINs) from induced pluripotent stem cells derived from 14 healthy controls and 14 subjects with schizophrenia. Both healthy control cINs and schizophrenia cINs were authentic, fired spontaneously, received functional excitatory inputs from host neurons, and induced GABA-mediated inhibition in host neurons in vivo. However, schizophrenia cINs had dysregulated expression of protocadherin genes, which lie within documented schizophrenia loci. Mice lacking protocadherin-α showed defective arborization and synaptic density of prefrontal cortex cINs and behavioral abnormalities. Schizophrenia cINs similarly showed defects in synaptic density and arborization that were reversed by inhibitors of protein kinase C, a downstream kinase in the protocadherin pathway. These findings reveal an intrinsic abnormality in schizophrenia cINs in the absence of any circuit-driven pathology. They also demonstrate the utility of homogenous and functional populations of a relevant neuronal subtype for probing pathogenesis mechanisms during development