959 research outputs found
Activity of the Lactate Dehydrogenase Inhibitor Oxamic Acid against the Fermentative Bacterium \u3ci\u3eStreptococcus mitis/oralis\u3c/i\u3e: Bactericidal Effects and Prevention of Daptomycin Resistance In Vitro and in an Ex Vivo Model
Streptococcus mitis/oralis is a fermentative bacterium that relies on lactate dehydrogenase to balance its redox poise and keep glycolysis active. Metabolomic analysis of an in vitro– derived daptomycin-resistant (DAP-R) S. mitis/oralis strain (351-D10) revealed differences in glucose catabolism relative to its DAP-susceptible (DAP-S) parental strain, 351. Metabolic changes associated with the transition to this DAP-R phenotype suggested that inhibiting glycolysis could alter DAP susceptibility. In addition, the strong reliance of S. mitis/oralis on glycolysis for energy and biosynthetic intermediates suggested that inhibiting glycolysis would adversely affect growth and biomass accumulation. To test these hypotheses, we used the lactate dehydrogenase inhibitor oxamic acid (OXA) to assess its efficacy against DAP-S S. mitis/oralis strain 351 during DAP exposures in vitro and ex vivo. As expected, OXA was growth inhibitory to S. mitis/oralis in a dose-dependent manner in vitro; however, it did not alter in vitro DAP susceptibility profiles. In contrast, OXA did prevent the emergence of DAP-R in an ex vivo model of simulated endocardial vegetations. These data suggest that metabolic inhibitors directed against this fermentative bacterium with limited metabolic capabilities could enhance killing and potentially forestall the emergence of DAP resistance
Proteomic and Membrane Lipid Correlates of Reduced Host Defense Peptide
We previously described a transposon mutant in Staphylococcus aureus strain SH1000 that exhibited reduced susceptibility to cationic thrombin-induced platelet microbicidal proteins (tPMPs). The transposon insertion site was mapped to the gene snoD, the staphylococcal nuo orthologue. Hence, further studies have been performed to understand how this mutation impacts susceptibility to tPMP, by comparing proteomics profiling and membrane lipid analyses of the parent vs. mutant strains. Surprisingly, the mutant showed differential regulation of only a single protein when cultivated aerobically (FadB), and only a small number of proteins under anaerobic growth conditions (AdhE, DapE, Ddh, Ald1, IlvA1, AgrA, Rot, SA2366, and SA2367). Corresponding to FadB impact on lipid remodeling, membrane fatty acid analyses showed that the snoD mutant contained more short chain anteiso-, but fewer short chain iso-branched chain fatty acids under both aerobic and anaerobic conditions vs. the parental strain. Based upon these proteomic and membrane compositional data, a hypothetical "network" model was developed to explain the impact of the snoD mutation upon tPMP susceptibility
Lattice-Boltzmann hydrodynamics of anisotropic active matter
A plethora of active matter models exist that describe the behavior of
self-propelled particles (or swimmers), both with and without hydrodynamics.
However, there are few studies that consider shape-anisotropic swimmers and
include hydrodynamic interactions. Here, we introduce a simple method to
simulate self-propelled colloids interacting hydrodynamically in a viscous
medium using the lattice-Boltzmann technique. Our model is based on
raspberry-type viscous coupling and a force/counter-force formalism which
ensures that the system is force free. We consider several anisotropic shapes
and characterize their hydrodynamic multipolar flow field. We demonstrate that
shape-anisotropy can lead to the presence of a strong quadrupole and octupole
moments, in addition to the principle dipole moment. The ability to simulate
and characterize these higher-order moments will prove crucial for
understanding the behavior of model swimmers in confining geometries.Comment: 11 pages, 3 figures, 3 table
The Electromagnetic Background Environment for the Interaction-point Beam Feedback System at the ILC
A mathematical framework for critical transitions: normal forms, variance and applications
Critical transitions occur in a wide variety of applications including
mathematical biology, climate change, human physiology and economics. Therefore
it is highly desirable to find early-warning signs. We show that it is possible
to classify critical transitions by using bifurcation theory and normal forms
in the singular limit. Based on this elementary classification, we analyze
stochastic fluctuations and calculate scaling laws of the variance of
stochastic sample paths near critical transitions for fast subsystem
bifurcations up to codimension two. The theory is applied to several models:
the Stommel-Cessi box model for the thermohaline circulation from geoscience,
an epidemic-spreading model on an adaptive network, an activator-inhibitor
switch from systems biology, a predator-prey system from ecology and to the
Euler buckling problem from classical mechanics. For the Stommel-Cessi model we
compare different detrending techniques to calculate early-warning signs. In
the epidemics model we show that link densities could be better variables for
prediction than population densities. The activator-inhibitor switch
demonstrates effects in three time-scale systems and points out that excitable
cells and molecular units have information for subthreshold prediction. In the
predator-prey model explosive population growth near a codimension two
bifurcation is investigated and we show that early-warnings from normal forms
can be misleading in this context. In the biomechanical model we demonstrate
that early-warning signs for buckling depend crucially on the control strategy
near the instability which illustrates the effect of multiplicative noise.Comment: minor corrections to previous versio
Numerical Methods for the QCD Overlap Operator IV: Hybrid Monte Carlo
The extreme computational costs of calculating the sign of the Wilson matrix
within the overlap operator have so far prevented four dimensional dynamical
overlap simulations on realistic lattice sizes, because the computational power
required to invert the overlap operator, the time consuming part of the Hybrid
Monte Carlo algorithm, is too high. In this series of papers we introduced the
optimal approximation of the sign function and have been developing
preconditioning and relaxation techniques which reduce the time needed for the
inversion of the overlap operator by over a factor of four, bringing the
simulation of dynamical overlap fermions on medium-size lattices within the
range of Teraflop-computers.
In this paper we adapt the HMC algorithm to overlap fermions. We approximate
the matrix sign function using the Zolotarev rational approximation, treating
the smallest eigenvalues of the Wilson operator exactly within the fermionic
force. We then derive the fermionic force for the overlap operator, elaborating
on the problem of Dirac delta-function terms from zero crossings of eigenvalues
of the Wilson operator. The crossing scheme proposed shows energy violations
which are better than O() and thus are comparable with the
violations of the standard leapfrog algorithm over the course of a trajectory.
We explicitly prove that our algorithm satisfies reversibility and area
conservation. Finally, we test our algorithm on small , , and
lattices at large masses.Comment: v2 60 pages; substantial changes to all parts of the article; v3
minor revsion
The CpG Island Methylator Phenotype and Chromosomal Instability Are Inversely Correlated in Sporadic Colorectal Cancer
BACKGROUND & AIMS: The CpG island methylator phenotype (CIMP) is one of the mechanisms involved in colorectal carcinogenesis (CRC). Although CIMP is probably the cause of high-frequency microsatellite instability (MSI-H) sporadic CRCs, its role in microsatellite stable (MSS) tumors is debated. The majority of MSS CRCs demonstrate chromosomal instability (CIN) with frequent loss of heterozygosity (LOH) at key tumor suppressor genes. We hypothesized that the majority of sporadic CRCs without CIN would be associated with CIMP.
METHODS: We tested 126 sporadic CRCs for MSI and LOH and categorized tumors into MSI, LOH, or MSI-/LOH- subgroups. Methylation status was evaluated using 6 CIMP-related markers (MINT1, MINT2, MINT31, p16(INK4alpha), p14(ARF), and hMLH1) and 6 tumor suppressor genes (PTEN, TIMP3, RUNX3, HIC1, APC, and RARbeta2). BRAF V600E mutation analysis was performed using allele-specific polymerase chain reaction and DNA sequencing.
RESULTS: We observed frequent methylation at all 12 loci in all CRCs. BRAF V600E mutations correlated with the MSI (P < .0001) and MSI-/LOH- (P = .03) subgroups. MSI and MSI-/LOH- tumors exhibited more promoter methylation than CRCs with LOH (P < .0001). We also found an inverse correlation between the frequencies of methylation and LOH (rho = -0.36; P < .0001).
CONCLUSIONS: The associations between methylation frequencies at CIMP-related markers and MSI or MSI-/LOH- sporadic CRCs suggest that the majority of these tumors evolve through CIMP. These findings suggest that CIN and CIMP represent 2 independent and inversely related mechanisms of genetic and epigenetic instability in sporadic CRCs and confirm that MSI cancers arise as a consequence of CIMP
CMB-S4 Science Book, First Edition
This book lays out the scientific goals to be addressed by the
next-generation ground-based cosmic microwave background experiment, CMB-S4,
envisioned to consist of dedicated telescopes at the South Pole, the high
Chilean Atacama plateau and possibly a northern hemisphere site, all equipped
with new superconducting cameras. CMB-S4 will dramatically advance cosmological
studies by crossing critical thresholds in the search for the B-mode
polarization signature of primordial gravitational waves, in the determination
of the number and masses of the neutrinos, in the search for evidence of new
light relics, in constraining the nature of dark energy, and in testing general
relativity on large scales
Chylothorax after surgery on congenital heart disease in newborns and infants -risk factors and efficacy of MCT-diet
<p>Abstract</p> <p>Objectives</p> <p>To analyze risk factors for chylothorax in infants after congenital heart surgery and the efficacy of median chain triglyceride diet (MCT). To develop our therapeutic pathway for the management of chylothorax.</p> <p>Patients and methods</p> <p>Retrospective review of the institutional surgical database and patient charts including detailed perioperative informations between 1/2000 and 10/2006. Data analyzing with an elimination regression analysis.</p> <p>Results</p> <p>Twenty six out of 282 patients had chylothorax (=9.2%). Secondary chest closure, low body weight, small size, longer cardiopulmonary bypass (242 ± 30 versus 129 ± 5 min) and x-clamp times (111 ± 15 versus 62 ± 3 min) were significantly associated with chylothorax (p < 0.05). One patient was cured with total parenteral nutrition (TPN) and one without any treatment. 24 patients received MCT-diet alone, which was successful in 17 patients within 10 days. After conversion to regular alimentation within one week only one chylothorax relapsed. Out of 7 patients primarily not responsive to MCT-diet, 2 were successfully treated by lysis of a caval vein thrombosis, 2 by TPN + pleurodesis + supradiaphragmatic thoracic duct ligation, one by octreotide treatment, and two patients finally died.</p> <p>Conclusions</p> <p>Chylothorax may appear due to injury of the thoracic duct, due to venous or lymphatic congestion, central vein thrombosis, or diffuse injury of mediastinal lymphatic tissue in association with secondary chest closure. Application of MCT alone was effective in 71%, and more invasive treatments like TPN should not be used in primary routine. After resolution of chylothorax, MCT-diet can be converted to regular milk formula within one week and with very low risk of relapse.</p
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