The impact of uncorrected mild aortic insufficiency at the time of left ventricular assist device implantation

OBJECTIVE: The study objective was to investigate the progression of uncorrected mild aortic insufficiency and its impact on survival and functional status after left ventricular assist device implantation. METHODS: We retrospectively reviewed 694 consecutive patients who underwent implantation of a continuous-flow left ventricular assist device between January 2006 and March 2018. Pre-left ventricular assist device transthoracic echocardiography identified 111 patients with mild aortic insufficiency and 493 patients with trace or no aortic insufficiency. To adjust for differences in preoperative factors, propensity score matching was used, resulting in 101 matched patients in each of the mild aortic insufficiency and no aortic insufficiency groups. RESULTS: Although both groups showed similar survival (P = .58), the mild aortic insufficiency group experienced higher incidence of readmission caused by heart failure (hazard ratio, 2.62; 95% confidence interval, 1.42-4.69; P \u3c .01). By using the mixed effect model, pre-left ventricular assist device mild aortic insufficiency was a significant risk factor for both moderate or greater aortic insufficiency and worsening New York Heart Association functional status (P \u3c .01). CONCLUSIONS: Patients with uncorrected mild aortic insufficiency had a higher risk of progression to moderate or greater aortic insufficiency after left ventricular assist device implantation with worse functional status and higher incidence of readmission caused by heart failure compared with patients without aortic insufficiency. Further investigations into the safety and efficacy of concomitant aortic valve procedures for mild aortic insufficiency at the time of left ventricular assist device implant are warranted to improve patients\u27 quality of life, considering the longer left ventricular assist device use as destination therapy and bridge to transplant with the new US heart allocation system

Discovery of chemerin as the new chemoattractant of human mesenchymal stem cells

Background The homing capacity of human mesenchymal stem cells (hMSCs) to the injured sites enables systemic administration of hMSCs in clinical practice. In reality, only a small proportion of MSCs are detected in the target tissue, which is a major bottleneck for MSC-based therapies. We still dont know the mechanism how MSCs are chemo-attracted to certain target organ and engrafted through trans-endothelial migration. In this study, we aimed to determine the mechanism how the circulating hMSCs home to the injured liver. Methods and results When we compare the cytokine array between normal and injured mouse liver at 1-day thioacetamide (TAA)-treatment, we found that chemerin, CXCL2, and CXCL10 were higher in the injured liver than normal one. Among three, only chemerin was the chemoattractant of hMSCs in 2D- and 3D-migration assay. Analysis of the signal transduction pathways in hMSCs showed that chemerin activated the phosphorylation of JNK1/2, ERK1/2 and p38, and finally upregulated CD44, ITGA4, and MMP-2 that are involved in the transendothelial migration and extravasation of MSCs. Upstream transcription regulators of CD44, ITGA4, and MMP-2 after chemerin treatment were MZF1, GATA3, STAT3, and STAT5A. To develop chemerin as a chemoattractant tool, we cloned gene encoding the active chemerin under the CMV promoter (CMV-aChemerin). We analyzed the migration of hMSCs in the 3D model for space of the Disse, which mimics transmigration of hMSCs in the liver. CMV-aChemerin-transfected hepatocytes were more effective to attract hMSC than control hepatocytes, leading to the enhanced transendothelial migration and homing of hMSCs to liver. The homing efficiency of the intravascularly-delivered hMSCs to liver was evaluated after systemic introduction of the CMV-aChemerin plasmid packed in liposome-vitamin A conjugates which target liver. CMV-aChemerin plasmid targeting liver significantly enhanced homing efficiency of hMSCs to liver compared with control plasmid vector. Conclusions Chemerin is the newly found chemoattractant of hMSCs and may be a useful tool to manipulate the homing of the intravascularly-administered hMSC to the specific target organ.This work was supported by the Korea Health Technology R&D Project Strategic Center of Cell and Bio Therapy [Grant number HI17C2085] and Korea Research-Driven Hospital [Grant number HI14C1277] through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare (MHW), Republic of Korea. The funders had no role in the study design, data collection and analysis, deci‑sion to publish, or preparation of the manuscript

A novel application of pattern recognition for accurate SNP and indel discovery from high-throughput data: Targeted resequencing of the glucocorticoid receptor co-chaperone FKBP5 in a Caucasian population

The detection of single nucleotide polymorphisms (SNPs) and insertion/deletions (indels) with precision from high-throughput data remains a significant bioinformatics challenge. Accurate detection is necessary before next-generation sequencing can routinely be used in the clinic. In research, scientific advances are inhibited by gaps in data, exemplified by the underrepresented discovery of rare variants, variants in non-coding regions and indels. The continued presence of false positives and false negatives prevents full automation and requires additional manual verification steps. Our methodology presents applications of both pattern recognition and sensitivity analysis to eliminate false positives and aid in the detection of SNP/indel loci and genotypes from high-throughput data. We chose FK506-binding protein 51(FKBP5) (6p21.31) for our clinical target because of its role in modulating pharmacological responses to physiological and synthetic glucocorticoids and because of the complexity of the genomic region. We detected genetic variation across a160 kb region encompassing FKBP5. 613 SNPs and 57 indels, including a 3.3 kb deletion were discovered. We validated our method using three independent data sets and, with Sanger sequencing and Affymetrix and Illumina microarrays, achieved 99% concordance. Furthermore we were able to detect 267 novel rare variants and assess linkage disequilibrium. Our results showed both a sensitivity and specificity of 98%, indicating near perfect classification between true and false variants. The process is scalable and amenable to automation, with the downstream filters taking only 1.5 hours to analyze 96 individuals simultaneously. We provide examples of how our level of precision uncovered the interactions of multiple loci, their predicted influences on mRNA stability, perturbations of the hsp90 binding site, and individual variation in FKBP5 expression. Finally we show how our discovery of rare variants may change current conceptions of evolution at this locus

Advances in Production Management Systems: Issues, Trends, and Vision Towards 2030

Since its inception in 1978, the IFIP Working Group (WG) 5.7 on Advances in Production Management Systems (APMS) has played an active role in the fields of production and production management. The Working Group has focused on the conception, development, strategies, frameworks, architectures, processes, methods, and tools needed for the advancement of both fields. The associated standards created by the IFIP WG5.7 have always been impacted by the latest developments of scientific rigour, academic research, and industrial practices. The most recent of those developments involves the Fourth Industrial Revolution, which is having remarkable (r)evolutionary and disruptive changes in both the fields and the standards. These changes are triggered by the fusion of advanced operational and informational technologies, innovative operating and business models, as well as social and environmental pressures for more sustainable production systems. This chapter reviews past, current, and future issues and trends to establish a coherent vision and research agenda for the IFIP WG5.7 and its international community. The chapter covers a wide range of production aspects and resources required to design, engineer, and manage the next generation of sustainable and smart production systems.acceptedVersio

The MOSDEF Survey: Neon as a Probe of ISM Physical Conditions at High Redshift

We present results on the properties of neon emission in $z\sim2$ star-forming galaxies drawn from the MOSFIRE Deep Evolution Field (MOSDEF) survey. Doubly-ionized neon ([NeIII]3869) is detected at $\geq3\sigma$ in 61 galaxies, representing $\sim$25% of the MOSDEF sample with H$\alpha$, H$\beta$, and [OIII]$5007$ detections at similar redshifts. We consider the neon emission-line properties of both individual galaxies with [NeIII]3869 detections and composite $z\sim2$ spectra binned by stellar mass. With no requirement of [NeIII]3869 detection, the latter provide a more representative picture of neon emission-line properties in the MOSDEF sample. The [NeIII]3869/[OII]3727 ratio (Ne3O2) is anti-correlated with stellar mass in $z\sim2$ galaxies, as expected based on the mass-metallicity relation. It is also positively correlated with the [OIII]$5007$/[OII]$3727$ ratio (O32), but $z\sim2$ line ratios are offset towards higher Ne3O2 at fixed O32, compared with both local star-forming galaxies and individual H~II regions. Despite the offset towards higher Ne3O2 at fixed O32 at $z\sim2$, biases in inferred Ne3O2-based metallicity are small. Accordingly, Ne3O2 may serve as an important metallicity indicator deep into the reionization epoch. Analyzing additional rest-optical line ratios including [NeIII]$3869$/[OIII]$5007$ (Ne3O3) and [OIII]$5007$/H$\beta$ (O3H$\beta$), we conclude that the nebular emission-line ratios of $z\sim2$ star-forming galaxies suggest a harder ionizing spectrum (lower stellar metallicity, i.e., Fe/H) at fixed gas-phase oxygen abundance, compared to systems at $z\sim0$. These new results based on neon lend support to the physical picture painted by oxygen, nitrogen, hydrogen, and sulfur emission, of an ionized ISM in high-redshift star-forming galaxies irradiated by chemically young, $\alpha$-enhanced massive stars.Comment: 7 pages, 5 figures, accepted to ApJ Letter

Upregulation of the Wnt Co-Receptor LRP6 Promotes Hepatocarcinogenesis and Enhances Cell Invasion

Background: Activation of the Wnt/b-catenin signaling pathway plays a crucial role in hepatocellular carcinoma (HCC). Lowdensity lipoprotein (LDL) receptor-related protein-6 (LRP6) is one of the co-receptors of the Wnt/b-catenin pathway and forms a signaling complex with Wnt ligand and Frizzled receptor to activate downstream signaling. However, the role of LRP6 in hepatocarcinogenesis is unclear. In this study, we examined its expression and roles in human HCC. Methodology/Principal Findings: Using real-time quantitative RT-PCR, we found that LRP6 was frequently (45%) overexpressed in human HCCs (P = 0.003). In vitro studies showed that ectopic expression of LRP6 increased the protein level of b-catenin. Moreover, overexpression of the full-length and constitutively active LRP6, respectively, activated the WNT/b-catenin signaling pathway, as shown by the TCF/b-catenin reporter assay. With regard to the effects of LRP6 overexpression in HCC cells, stable overexpression of the constitutively active LRP6 in BEL-7402 HCC cells enhanced cell proliferation, cell migration, and invasion in vitro as well as tumorigenicity in nude mice. Conclusions/Significance: Our findings indicate that overexpression of LRP6 contributes to the hyperactivation of the Wnt

Human Milk Secretory Antibodies against Attaching and Effacing Escherichia coli Antigens

Secretory immunoglobulin A (sIgA) is a primary factor responsible for preventing attachment of enteropathogens to gut epithelium in breastfeeding infants. We compared the frequency of sIgA to major surface antigens of enterohemorrhagic Escherichia coli (EHEC) in milk of 123 women from the United States and Mexico to determine whether regional differences existed in the frequency of antibodies to these surface antigens. In both groups of women, milk commonly has sIgA against various EHEC lipopolysaccharides, EspA, EspB, intimin, and less frequently against Shiga toxin. The study suggests that persons living in the U.S. are exposed to attaching/effacing enteropathogens more frequently than is generally assumed. The low frequency of antibodies to Stx1 (in 12% of Mexican and in 22% of U.S. samples) suggests that the rare appearance of hemolytic uremic syndrome in adults is not due to neutralization of toxin at the gut level. Only anti-EspA is found in most milk samples from both populations of women. EspA may represent a useful target for an immunization strategy to prevent EHEC disease in humans

Inference of financial networks using the normalised mutual information rate

In this paper we study data from financial markets using an information theory tool that we call the normalised Mutual Information Rate and show how to use it to infer the underlying network structure of interrelations in foreign currency exchange rates and stock indices of 14 countries world-wide and the European Union. We first present the mathematical method and discuss about its computational aspects, and then apply it to artificial data from chaotic dynamics and to correlated random variates. Next, we apply the method to infer the network structure of the financial data. Particularly, we study and reveal the interrelations among the various foreign currency exchange rates and stock indices in two separate networks for which we also perform an analysis to identify their structural properties. Our results show that both are small-world networks sharing similar properties but also having distinct differences in terms of assortativity. Finally, the consistent relationships depicted among the 15 economies are further supported by a discussion from the economics view point

ENU Mutagenesis Identifies Mice with Morbid Obesity and Severe Hyperinsulinemia Caused by a Novel Mutation in Leptin

BACKGROUND: Obesity is a multifactorial disease that arises from complex interactions between genetic predisposition and environmental factors. Leptin is central to the regulation of energy metabolism and control of body weight in mammals. METHODOLOGY/PRINCIPAL FINDINGS: To better recapitulate the complexity of human obesity syndrome, we applied N-ethyl-N-nitrosourea (ENU) mutagenesis in combination with a set of metabolic assays in screening mice for obesity. Mapping revealed linkage to the chromosome 6 within a region containing mouse Leptin gene. Sequencing on the candidate genes identified a novel T-to-A mutation in the third exon of Leptin gene, which translates to a V145E amino acid exchange in the leptin propeptide. Homozygous Leptin(145E/145E) mutant mice exhibited morbid obesity, accompanied by adipose hypertrophy, energy imbalance, and liver steatosis. This was further associated with severe insulin resistance, hyperinsulinemia, dyslipidemia, and hyperleptinemia, characteristics of human obesity syndrome. Hypothalamic leptin actions in inhibition of orexigenic peptides NPY and AgRP and induction of SOCS1 and SOCS3 were attenuated in Leptin(145E/145E) mice. Administration of exogenous wild-type leptin attenuated hyperphagia and body weight increase in Leptin(145E/145E) mice. However, mutant V145E leptin coimmunoprecipitated with leptin receptor, suggesting that the V145E mutation does not affect the binding of leptin to its receptor. Molecular modeling predicted that the mutated residue would form hydrogen bond with the adjacent residues, potentially affecting the structure and formation of an active complex with leptin receptor within that region. CONCLUSIONS/SIGNIFICANCE: Thus, our evolutionary, structural, and in vivo metabolic information suggests the residue 145 as of special function significance. The mouse model harboring leptin V145E mutation will provide new information on the current understanding of leptin biology and novel mouse model for the study of human obesity syndrome