Smoothed Analysis of the Minimum-Mean Cycle Canceling Algorithm and the Network Simplex Algorithm

The minimum-cost flow (MCF) problem is a fundamental optimization problem with many applications and seems to be well understood. Over the last half century many algorithms have been developed to solve the MCF problem and these algorithms have varying worst-case bounds on their running time. However, these worst-case bounds are not always a good indication of the algorithms' performance in practice. The Network Simplex (NS) algorithm needs an exponential number of iterations for some instances, but it is considered the best algorithm in practice and performs best in experimental studies. On the other hand, the Minimum-Mean Cycle Canceling (MMCC) algorithm is strongly polynomial, but performs badly in experimental studies. To explain these differences in performance in practice we apply the framework of smoothed analysis. We show an upper bound of $O(mn^2\log(n)\log(\phi))$ for the number of iterations of the MMCC algorithm. Here $n$ is the number of nodes, $m$ is the number of edges, and $\phi$ is a parameter limiting the degree to which the edge costs are perturbed. We also show a lower bound of $\Omega(m\log(\phi))$ for the number of iterations of the MMCC algorithm, which can be strengthened to $\Omega(mn)$ when $\phi=\Theta(n^2)$. For the number of iterations of the NS algorithm we show a smoothed lower bound of $\Omega(m \cdot \min \{ n, \phi \} \cdot \phi)$.Comment: Extended abstract to appear in the proceedings of COCOON 201

Gold Nanoparticle Delivery of Modified CpG Stimulates Macrophages and Inhibits Tumor Growth for Enhanced Immunotherapy

Gold nanoparticle accumulation in immune cells has commonly been viewed as a side effect for cancer therapeutic delivery; however, this phenomenon can be utilized for developing gold nanoparticle mediated immunotherapy. Here, we conjugated a modified CpG oligodeoxynucleotide immune stimulant to gold nanoparticles using a simple and scalable selfassembled monolayer scheme that enhanced the functionality of CpG in vitro and in vivo. Nanoparticles can attenuate systemic side effects by enhancing CpG delivery passively to innate effector cells. The use of a triethylene glycol (TEG) spacer on top of the traditional poly-thymidine spacer increased CpG macrophage stimulatory effects without sacrificing DNA content on the nanoparticle, which directly correlates to particle uptake. In addition, the immune effects of modified CpGAuNPs were altered by the core particle size, with smaller 15 nm AuNPs generating maximum immune response. These TEG modified CpG-AuNP complexes induced macrophage and dendritic cell tumor infiltration, significantly inhibited tumor growth, and promoted survival in mice when compared to treatments with free CpG

The Aminopeptidase CD13 Induces Homotypic Aggregation in Neutrophils and Impairs Collagen Invasion.

Aminopeptidase N (CD13) is a widely expressed cell surface metallopeptidase involved in the migration of cancer and endothelial cells. Apart from our demonstration that CD13 modulates the efficacy of tumor necrosis factor-α-induced apoptosis in neutrophils, no other function for CD13 has been ascribed in this cell. We hypothesized that CD13 may be involved in neutrophil migration and/or homotypic aggregation. Using purified human blood neutrophils we confirmed the expression of CD13 on neutrophils and its up-regulation by pro-inflammatory agonists. However, using the anti-CD13 monoclonal antibody WM-15 and the aminopeptidase enzymatic inhibitor bestatin we were unable to demonstrate any direct involvement of CD13 in neutrophil polarisation or chemotaxis. In contrast, IL-8-mediated neutrophil migration in type I collagen gels was significantly impaired by the anti-CD13 monoclonal antibodies WM-15 and MY7. Notably, these antibodies also induced significant homotypic aggregation of neutrophils, which was dependent on CD13 cross-linking and was attenuated by phosphoinositide 3-kinase and extracellular signal-related kinase 1/2 inhibition. Live imaging demonstrated that in WM-15-treated neutrophils, where homotypic aggregation was evident, the number of cells entering IL-8 impregnated collagen I gels was significantly reduced. These data reveal a novel role for CD13 in inducing homotypic aggregation in neutrophils, which results in a transmigration deficiency; this mechanism may be relevant to neutrophil micro-aggregation in vivo.This work was funded by a Medical Research Council Research Training Fellowship to CAF (G0900329), Addenbrooke’s Charitable Trust (ACT), CUHNHSFT, Papworth Hospital NHS Foundation Trust and the NIHR Cambridge Biomedical Research Centre. CAF received a Raymond and Beverly Sackler Studentship.This is the final version of the article. It first appeared from the Public Library of Science via http://dx.doi.org/10.1371/journal.pone.016010

The importance of sedimenting organic matter, relative to oxygen and temperature, in structuring lake profundal macroinvertebrate assemblages

We quantified the role of a main food resource, sedimenting organic matter (SOM), relative to oxygen (DO) and temperature (TEMP) in structuring profundal macroinvertebrate assemblages in boreal lakes. SOM from 26 basins of 11 Finnish lakes was analysed for quantity (sedimentation rates), quality (C:N:P stoichiometry) and origin (carbon stable isotopes, d13C). Hypolimnetic oxygen and temperature were measured from each site during summer stratification. Partial canonical correspondence analysis (CCA) and partial regression analyses were used to quantify contributions of SOM, DO and TEMP to community composition and three macroinvertebrate metrics. The results suggested a major contribution of SOM in regulating the community composition and total biomass. Oxygen best explained the Shannon diversity, whereas TEMP had largest contribution to the variation of Benthic Quality Index. Community composition was most strongly related to d13C of SOM. Based on additional d13C and stoichiometric analyses of chironomid taxa, marked differences were apparent in their utilization of SOM and body stoichiometry; taxa characteristic of oligotrophic conditions exhibited higher C:N ratios and lower C:P and N:P ratios compared to the species typical of eutrophic lakes. The results highlight the role of SOM in regulating benthic communities and the distributions of individual species, particularly in oligotrophic systems

Thermal control of long delay lines in a high-resolution astrophotonic spectrograph

High-resolution astronomical spectroscopy carried out with a photonic Fourier transform spectrograph (FTS) requires long asymmetrical optical delay lines that can be dynamically tuned. For example, to achieve a spectral resolution of R = 30,000, a delay line as long as 1.5 cm would be required. Such delays are inherently prone to phase errors caused by temperature fluctuations. This is due to the relatively large thermo-optic coefficient and long lengths of the waveguides, in this case composed of SiN, resulting in thermally dependent changes to the optical path length. To minimize phase error to the order of 0.05 radians, thermal stability of the order of 0.05{\deg} C is necessary. A thermal control system capable of stability such as this would require a fast thermal response and minimal overshoot/undershoot. With a PID temperature control loop driven by a Peltier cooler and thermistor, we minimized interference fringe phase error to +/- 0.025 radians and achieved temperature stability on the order of 0.05{\deg} C. We present a practical system for precision temperature control of a foundry-fabricated and packaged FTS device on a SiN platform with delay lines ranging from 0.5 to 1.5 cm in length using inexpensive off-the-shelf components, including design details, control loop optimization, and considerations for thermal control of integrated photonics

Health state utilities associated with attributes of treatments for hepatitis C

BACKGROUND: Cost-utility analyses are frequently conducted to compare treatments for hepatitis C, which are often associated with complex regimens and serious adverse events. Thus, the purpose of this study was to estimate the utility associated with treatment administration and adverse events of hepatitis C treatments. DESIGN: Health states were drafted based on literature review and clinician interviews. General population participants in the UK valued the health states in time trade-off (TTO) interviews with 10- and 1-year time horizons. The 14 health states described hepatitis C with variations in treatment regimen and adverse events. RESULTS: A total of 182 participants completed interviews (50 % female; mean age = 39.3 years). Utilities for health states describing treatment regimens without injections ranged from 0.80 (1 tablet) to 0.79 (7 tablets). Utilities for health states describing oral plus injectable regimens were 0.77 (7 tablets), 0.75 (12 tablets), and 0.71 (18 tablets). Addition of a weekly injection had a disutility of −0.02. A requirement to take medication with fatty food had a disutility of −0.04. Adverse events were associated with substantial disutilities: mild anemia, −0.12; severe anemia, −0.32; flu-like symptoms, −0.21; mild rash, −0.13; severe rash, −0.48; depression, −0.47. One-year TTO scores were similar to these 10-year values. CONCLUSIONS: Adverse events and greater treatment regimen complexity were associated with lower utility scores, suggesting a perceived decrease in quality of life beyond the impact of hepatitis C. The resulting utilities may be used in models estimating and comparing the value of treatments for hepatitis C. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10198-014-0649-6) contains supplementary material, which is available to authorized users

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Association of in Utero Organophosphate Pesticide Exposure and Fetal Growth and Length of Gestation in an Agricultural Population

Although pesticide use is widespread, little is known about potential adverse health effects of in utero exposure. We investigated the effects of organophosphate pesticide exposure during pregnancy on fetal growth and gestational duration in a cohort of low-income, Latina women living in an agricultural community in the Salinas Valley, California. We measured nonspecific metabolites of organophosphate pesticides (dimethyl and diethyl phosphates) and metabolites specific to malathion (malathion dicarboxylic acid), chlorpyrifos [O,O-diethyl O-(3,5,6-trichloro-2-pyridinyl) phosphoro-thioate], and parathion (4-nitrophenol) in maternal urine collected twice during pregnancy. We also measured levels of cholinesterase in whole blood and butyryl cholinesterase in plasma in maternal and umbilical cord blood. We failed to demonstrate an adverse relationship between fetal growth and any measure of in utero organophosphate pesticide exposure. In fact, we found increases in body length and head circumference associated with some exposure measures. However, we did find decreases in gestational duration associated with two measures of in utero pesticide exposure: urinary dimethyl phosphate metabolites [β(adjusted) = −0.41 weeks per log(10) unit increase; 95% confidence interval (CI), (−)0.75–(−)0.02; p = 0.02], which reflect exposure to dimethyl organophosphate compounds such as malathion, and umbilical cord cholinesterase (β(adjusted) = 0.34 weeks per unit increase; 95% CI, 0.13–0.55; p = 0.001). Shortened gestational duration was most clearly related to increasing exposure levels in the latter part of pregnancy. These associations with gestational age may be biologically plausible given that organophosphate pesticides depress cholinesterase and acetylcholine stimulates contraction of the uterus. However, despite these observed associations, the rate of preterm delivery in this population (6.4%) was lower than in a U.S. reference population

Sex and size influence the spatiotemporal distribution of white sharks, with implications for interactions with fisheries and spatial management in the southwest Indian Ocean

The study was made possible through generous funding by Fischer Productions for fieldwork and equipment costs. TP was supported by a postdoctoral fellowship funded by the Nelson Mandela University Research Career Development Office (2016-2018) and funding from the South African Research Chairs Initiative awarded to Prof AT Lombard by the National Research Foundation, and by a Royal Society Newton International Fellowship (2018-2020, NF170682).Human activities in the oceans increase the extinction risk of marine megafauna. Interventions require an understanding of movement patterns and the spatiotemporal overlap with threats. We analysed the movement patterns of 33 white sharks (Carcharodon carcharias) satellite-tagged in South Africa between 2012 and 2014 to investigate the influence of size, sex and season on movement patterns and the spatial and temporal overlap with longline and gillnet fisheries and marine protected areas (MPAs). We used a hidden Markov model to identify ‘resident’ and ‘transient’ movement states and investigate the effect of covariates on the transition probabilities between states. A model with sex, total length and season had the most support. Tagged sharks were more likely to be in a resident state near the coast and a transient state away from the coast, while the probability of finding a shark in the transient state increased with size. White sharks moved across vast areas of the southwest Indian Ocean, emphasising the need for a regional management plan. White sharks overlapped with longline and gillnet fisheries within 25% of South Africa’s Exclusive Economic Zone and spent 15% of their time exposed to these fisheries during the study period. The demersal shark longline fishery had the highest relative spatial and temporal overlap, followed by the pelagic longline fishery and the KwaZulu-Natal (KZN) shark nets and drumlines. However, the KZN shark nets and drumlines reported the highest white shark catches, emphasising the need to combine shark movement and fishing effort with reliable catch records to assess risks to shark populations accurately. White shark exposure to shark nets and drumlines, by movement state, sex and maturity status, corresponded with the catch composition of the fishery, providing support for a meaningful exposure risk estimate. White sharks spent significantly more time in MPAs than expected by chance, likely due to increased prey abundance or less disturbance, suggesting that MPAs can benefit large, mobile marine megafauna. Conservation of white sharks in Southern Africa can be improved by implementing non-lethal solutions to beach safety, increasing the observer coverage in fisheries, and continued monitoring of movement patterns and existing and emerging threats.Publisher PDFPeer reviewe