Acquired and Hereditary Hypercoagulable States in Patients with Continuous Flow Left Ventricular Assist Devices: Prevalence and Thrombotic Complications.

BACKGROUND: Thrombotic events in patients with continuous flow left ventricular assist devices (CF-LVADs) are associated with significant morbidity and mortality. The objective of this study was to delineate the frequency, clinical characteristics, and outcomes of patients with hypercoagulable states who undergo CF-LVAD implantation. METHODS: We performed a retrospective review of 168 consecutive patients who underwent CF-LVAD implantation between 2010 and 2013. Chart and laboratory data were reviewed for the presence of a hereditary and/or acquired hypercoagulable state. Adverse outcomes were defined as death, confirmed pump thrombosis, aortic root clot, stroke, deep vein thrombosis, and pulmonary embolism. Fisher's exact test and Kaplan-Meier estimate were used to analyze frequency of adverse outcomes and event free survival, respectively. RESULTS: A hypercoagulable state was identified in 20 patients (11.9%). There were 18 patients with acquired, 1 with a congenital, and 1 with both congenital and acquired hypercoagulable states. The median follow-up was 429 days and 475 days in patients with and without hypercoagulable states, respectively. During the study period, 15% (3/20) of the patients with a hypercoagulable state had a diagnosis of deep vein thrombosis vs 3% (4/148) of the patients without a hypercoagulable state (P = .030). Only patients with a hypercoagulable state had a subarachnoid hemorrhage (3/20 vs 0/148; P < .01). The event-free survival was lower in the patients with hypercoagulable states (P = .005). CONCLUSION: Hypercoagulable states are not uncommon in patients with CF-LVADs and may be associated with increased morbidity. Prospective studies are needed to more accurately identify the incidence, prevalence, and significance of hypercoagulable states in patients being considered for CF-LVAD.

Hydrogen peroxide modulates the expression of the target of rapamycin (TOR) and cell division in Arabidopsis thaliana.

Hydrogen peroxide (H2O2) is naturally produced by plant cells during normal development and serves as a messenger that regulates cell metabolism. Despite its importance, the relationship between hydrogen peroxide and the target of rapamycin (TOR) pathway, as well as its impact on cell division, has been poorly analyzed. In this study, we explore the interaction of H2O2 with TOR, a serine/threonine protein kinase that plays a central role in controlling cell growth, size, and metabolism in Arabidopsis thaliana. By applying two concentrations of H2O2 exogenously (0.5 and 1 mM), we could correlate developmental traits, such as primary root growth, lateral root formation, and fresh weight, with the expression of the cell cycle gene CYCB1;1, as well as TOR expression. When assessing the expression of the ribosome biogenesis-related gene RPS27B, an increase of 94.34% was noted following exposure to 1 mM H2O2 treatment. This increase was suppressed by the TOR inhibitor torin 2. The elimination of H2O2 accumulation with ascorbic acid (AA) resulted in decreased cell division as well as TOR expression. The potential molecular mechanisms associated with the effects of H2O2 on the cell cycle and TOR expression in roots are discussed in the context of the results.

On Acceleration of Gradient-Based Empirical Risk Minimization using Local Polynomial Regression.

We study the acceleration of the Local Polynomial Interpolation-based Gradient Descent method (LPI-GD) recently proposed for the approximate solution of empirical risk minimization problems (ERM). We focus on loss functions that are strongly convex and smooth with condition number σ. We additionally assume the loss function is η-Hölder continuous with respect to the data. The oracle complexity of LPI-GD is O ˜ ( σ m d log ( 1 / ε ) ) for a desired accuracy ε, where d is the dimension of the parameter space, and m is the cardinality of an approximation grid. The factor m d can be shown to scale as O((1/ε) d/2η ). LPI-GD has been shown to have better oracle complexity than gradient descent (GD) and stochastic gradient descent (SGD) for certain parameter regimes. We propose two accelerated methods for the ERM problem based on LPI-GD and show an oracle complexity of O ˜ ( σ m d log ( 1 / ε ) ) . Moreover, we provide the first empirical study on local polynomial interpolation-based gradient methods and corroborate that LPI-GD has better performance than GD and SGD in some scenarios, and the proposed methods achieve acceleration.

Bacterial cyclodipeptides elicit Arabidopsis thaliana immune responses reducing the pathogenic effects of Pseudomonas aeruginosa PAO1 strains on plant development.

Plants being sessile organisms are exposed to various biotic and abiotic factors, thus causing stress. The Pseudomonas aeruginosa bacterium is an opportunistic pathogen for animals, insects, and plants. Direct exposure of Arabidopsis thaliana to the P. aeruginosa PAO1 strain induces plant death by producing a wide variety of virulence factors, which are regulated mainly by quorum sensing systems. Besides virulence factors, P. aeruginosa PAO1 also produces cyclodipeptides (CDPs), which possess auxin-like activity and promote plant growth through activation of the target of the rapamycin (AtTOR) pathway. On the other hand, plant defense mechanisms are regulated through the production of phytohormones, such as salicylic acid (SA) and jasmonic acid (JA), which are induced in response to pathogen-associated molecular patterns (PAMPs), activating defense genes associated with SA and JA such as PATHOGENESIS-RELATED-1 (PR-1) and LIPOXYGENASE2 (LOX2), respectively. PR proteins are suggested to play critical roles in coordinating the Systemic Acquired Resistance (SAR). In contrast, LOX proteins (LOX2, LOX3, and LOX4) have been associated with the production of JA by producing its precursors, oxylipins. The activation of defense mechanisms involves signaling cascades such as Mitogen-Activated Protein Kinases (MAPKs) or the TOR pathway as a switch for re-directing energy towards defense or growth. In this work, we challenged A. thaliana (wild type, mpk6 or mpk3 mutants, and overexpressing TOR) seedlings with P. aeruginosa PAO1 strains to identify the role of bacterial CDPs in the plant immune response. Results showed that the pre-exposure of these Arabidopsis seedlings to CDPs significantly reduced plant infection of the pathogenic P. aeruginosa PAO1 strains, indicating that plants that over-express AtTOR or lack MPK3/MPK6 protein-kinases are more susceptible to the pathogenic effects. In addition, CDPs induced the GUS activity only in the LOX2::GUS plants, indicative of JA-signaling activation. Our findings indicate that the CDPs are molecules that trigger SA-independent and JA-dependent defense responses in A. thaliana; hence, bacterial CDPs may be considered elicitors of the Arabidopsis immune response to pathogens.

Endothelial Dysfunction-related Neurological Bleeds with Continuous Flow-Left Ventricular Assist Devices Measured by Digital Thermal Monitor.

Endothelial dysfunction has been demonstrated in patients with Continuous Flow-Left Ventricular Assist Devices (CF-LVADs) but association with adverse events has not been shown. We used a noninvasive, operator-independent device called VENDYS® to assess vasodilatory function based on digital thermal measurements postrelease of a brachial artery occlusion in ambulatory patients with CF-LVAD (n = 56). Aortic valve opening and pulse perception were also documented before the test. Median duration of CF-LVAD support was 438 days. The VENDYS® test generates a vascular reactivity index (VRI). Outcomes for the CF-LVAD patients were compared between VRI < 1 and VRI ≥ 1. The bleeding events were driven primarily by a difference in neurologic bleeds. Multivariate analysis showed that VRI < 1 correlated with future bleeding events (HR: 5.56; P = 0.01). The C-statistic with the VRI dichotomized as above was 0.82. There was a trend toward a worse survival in patients with poor endothelial function. Endothelial vasodilatory dysfunction measured by a simple test utilizing digital thermal monitoring can predict adverse bleeding events in patients with CF-LVADs.

Growth promotion in Arabidopsis thaliana by bacterial cyclodipeptides involves the TOR/S6K pathway activation.

Cyclodipeptides (CDPs) are the smallest peptidic molecules that can be produced by diverse organisms such as bacteria, fungi, and animals. They have multiple biological effects. In this paper, we examined the CDPs produced by the bacteria Pseudomonas aeruginosa PAO1, which are known as opportunistic pathogens of humans and plants on TARGET OF RAPAMYCIN (TOR) signaling pathways, and regulation of root system architecture. This bacterium produces the bioactive CDPs: cyclo(L-Pro-L-Leu), cyclo(L-Pro-L-Phe), cyclo(L-Pro-L-Tyr), and cyclo(L-Pro-L-Val). In a previous report, these molecules were found to modulate basic cellular programs not only via auxin mechanisms but also by promoting the phosphorylation of the S6 ribosomal protein kinase (S6K), a downstream substrate of the TOR kinase. In the present work, we found that the inoculation of Arabidopsis plants with P. aeruginosa PAO1, the non-pathogenic P. aeruginosa ΔlasI/Δrhll strain (JM2), or by direct exposure of plants to CDPs influenced growth and promoted root branching depending upon the treatment imposed, while genetic evidence using Arabidopsis lines with enhanced or decreased TOR levels indicated a critical role of this pathway in the bacterial phytostimulation.

Azospirillum brasilense Sp245 lipopolysaccharides induce target of rapamycin signaling and growth in Arabidopsis thaliana.

The Target of Rapamycin (TOR) protein kinase plays a pivotal role in metabolism and gene expression, which enables cell proliferation, growth and development. Lipopolysaccharides (LPS) are a class of complex glycolipids present in the cell surface of Gram-negative bacteria and mediate plant-bacteria interactions. In this study, we examined whether LPS from Azospirillum brasilense Sp245 affect Arabidopsis thaliana growth via a mechanism involving TOR. A. thaliana plants were treated with LPS and plant growth and development were analyzed in mature plants. Morphological and molecular changes as well as TOR expression and activity were analyzed in root tissues. LPS increased total fresh weight, root length and TOR::GUS expression in the root meristem. Phosphorylation of S6k protein, a downstream target of TOR, increased following LPS treatment, which correlated with increased or decreased expression of CycB1;1::GUS protein upon treatment with LPS or TOR inhibitor AZD-8055, respectively. Long term LPS treatment further increased the rosette size as well as the number of stems and siliques per plant, indicating an overall phytostimulant effect for these signaling molecules. Taken together, the results suggest that A. brasilense LPS play probiotic roles in plants influencing TOR-mediated processes.

TARGET OF RAPAMYCIN signaling plays a role in Arabidopsis growth promotion by Azospirillum brasilense Sp245.

Azospirillum brasilense colonizes plant roots and improves productivity, but the molecular mechanisms behind its phytostimulation properties remain mostly unknown. Here, we uncover an important role of TARGET OF RAPAMYCIN (TOR) signaling on the response of Arabidopsis thaliana to A. brasilense Sp245. The effect of the bacterium on TOR expression was analyzed in the transgenic line TOR/tor-1, which carries a translational fusion with the GUS reporter protein, and the activity of TOR was assayed thought the phosphorylation of its downstream signaling target S6K protein. Besides, the role of TOR on plant growth in inoculated plants was assessed using the ATP-competitive inhibitor AZD-8055. A decrease in growth of the primary root correlates with an improved branching and absorptive capacity via lateral root and root hair proliferation 6 days after transplant to different concentrations of the bacterium (103 or 105 CFU/mL). Bacterization increased the expression of TOR in shoot and root apexes and promoted phosphorylation of S6K 3 days after transplant. The TOR inhibitor AZD-8055 (1 µM) inhibited plant growth and cell division in root meristems and in lateral root primordia, interfering with the phytostimulation by A. brasilense. In addition, the role of auxin produced by the bacterium to stimulate TOR expression was explored. Noteworthy, the A. brasilense mutant FAJ009, impaired in auxin production, was unable to elicit TOR signaling to the level observed for the wild-type strain, showing the importance of this phyhormone to stimulate TOR signaling. Together, our findings establish an important role of TOR signaling for the probiotic traits elicited by A. brasilense in A. thaliana.

ALTERED MERISTEM PROGRAM 1 promotes growth and biomass accumulation influencing guard cell aperture and photosynthetic efficiency in Arabidopsis.

ALTERED MERISTEM PROGRAM 1 (AMP1) encodes a putative glutamate-carboxypeptidase important for plant growth and development. In this study, by comparing the growth of Arabidopsis wild-type, amp1-10 and amp1-13 mutants, and AMP1-GFP/OX2- and AMP1-GFP/OX7-overexpressing seedlings in vitro and in soil, we uncover the role of AMP1 in biomass accumulation in Arabidopsis. AMP1-overexpressing plants had longer primary roots and increased lateral root number and density than the WT, which correlated with improved root, shoot, and total biomass accumulation. AMP1-overexpressing seedlings had an enhanced rate of growth of primary roots, and accordingly, sucrose supplementation restored primary root growth and promoted lateral root formation in amp1 mutants, while reproductive development, fruit size, and seed content were also modified according to disruption or overexpression of AMP1. We further found that AMP1 plays an important role for stomatal development, guard cell functioning, and carbon assimilation. These data help explain the pleiotropic functions of AMP1 in both root and shoot system development, possibly acting in a sugar-dependent manner for regulation of root architecture, biomass accumulation, and seed production.

Graph-Theoretic Analysis of Belief System Dynamics under Logic Constraints.

Opinion formation cannot be modeled solely as an ideological deduction from a set of principles; rather, repeated social interactions and logic constraints among statements are consequential in the construct of belief systems. We address three basic questions in the analysis of social opinion dynamics: (i) Will a belief system converge? (ii) How long does it take to converge? (iii) Where does it converge? We provide graph-theoretic answers to these questions for a model of opinion dynamics of a belief system with logic constraints. Our results make plain the implicit dependence of the convergence properties of a belief system on the underlying social network and on the set of logic constraints that relate beliefs on different statements. Moreover, we provide an explicit analysis of a variety of commonly used large-scale network models.

Cyclodipeptides from Pseudomonas aeruginosa modulate the maize (Zea mays L.) root system and promote S6 ribosomal protein kinase activation.

BACKGROUND: Pseudomonas aeruginosa is an opportunistic and pathogenic bacterium with the ability to produce cyclodipeptides (CDPs), which belong to a large family of molecules with important biological activities. Excessive amounts of CDPs produced by Pseudomonas strains can activate an auxin response in Arabidopsis thaliana and promote plant growth. Target of rapamycin (TOR) is an evolutionarily conserved eukaryotic protein kinase that coordinates cell growth and metabolic processes in response to environmental and nutritional signals. Target of rapamycin kinase phosphorylates various substrates, of which S6 ribosomal protein kinase (S6K) is particularly well known. The PI3K/Akt/mTOR/S6K signaling pathway has been studied extensively in mammals because of its association with fundamental biological processes including cell differentiation. However, evidences suggest that this pathway also has specific and conserved functions in plants and may thus be conserved, as are several of its components like TOR complex 1 and S6K proteins. In plants, TOR-S6K signaling has been shown to be modulated in response to plant growth promoters or stressors. METHODS: In this study, we evaluated the effects of P. aeruginosa CDPs on the growth and root development of maize plants (Zea mays L.) by adding different CDPs concentrations on culture plant media, as well as the effect on the phosphorylation of the maize S6K protein (ZmS6K) by protein electrophoresis and western blot. RESULTS: Our results showed that P. aeruginosa CDPs promoted maize growth and development, including modifications in the root system architecture, correlating with the increased ZmS6K phosphorylation and changes induced in electrophoretic mobility, suggesting post-translational modifications on ZmS6K. These findings suggest that the plant growth-promoting effect of the Pseudomonas genus, associated with the CDPs production, involves the TOR/S6K signaling pathway as a mechanism of plant growth and root development in plant-microorganism interaction.

Physiological impact of continuous flow on end-organ function: clinical implications in the current era of left ventricular assist devices.

The clinical era of continuous-flow left ventricular assist devices has debunked many myths about the dire need of a pulse for human existence. While this therapy has been documented to provide a clear survival benefit in end-stage heart failure patients, we are now faced with certain morbidity challenges that as of yet have no easy mechanistic physiological explanation. The effect of physiological changes on end-organ function in patients supported by continuous-flow ventricular assist devices may offer insight into some of these morbidities. We therefore present a review of current evidence documenting the impact of continuous flow on end-organ function.

Enhanced Cardiac Regenerative Ability of Stem Cells After Ischemia-Reperfusion Injury: Role of Human CD34+ Cells Deficient in MicroRNA-377.

BACKGROUND: MicroRNA (miR) dysregulation in the myocardium has been implicated in cardiac remodeling after injury or stress. OBJECTIVES: The aim of this study was to explore the role of miR in human CD34(+) cell (hCD34(+)) dysfunction in vivo after transplantation into the myocardium under ischemia-reperfusion (I-R) conditions. METHODS: In response to inflammatory stimuli, the miR array profile of endothelial progenitor cells was analyzed using a polymerase chain reaction-based miR microarray. miR-377 expression was assessed in myocardial tissue from human patients with heart failure (HF). We investigated the effect of miR-377 inhibition on an hCD34(+) cell angiogenic proteome profile in vitro and on cardiac repair and function after I-R injury in immunodeficient mice. RESULTS: The miR array data from endothelial progenitor cells in response to inflammatory stimuli indicated changes in numerous miR, with a robust decrease in the levels of miR-377. Human cardiac biopsies from patients with HF showed significant increases in miR-377 expression compared with nonfailing control hearts. The proteome profile of hCD34(+) cells transfected with miR-377 mimics showed significant decrease in the levels of proangiogenic proteins versus nonspecific control-transfected cells. We also validated that serine/threonine kinase 35 is a target of miR-377 using a dual luciferase reporter assay. In a mouse model of myocardial I-R, intramyocardial transplantation of miR-377 silenced hCD34(+) cells in immunodeficient mice, promoting neovascularization (at 28 days, post-I-R) and lower interstitial fibrosis, leading to improved left ventricular function. CONCLUSIONS: These findings indicate that HF increased miR-377 expression in the myocardium, which is detrimental to stem cell function, and transplantation of miR-377 knockdown hCD34(+) cells into ischemic myocardium promoted their angiogenic ability, attenuating left ventricular remodeling and cardiac fibrosis.