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

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

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

The AIDS and Cancer Specimen Resource: Role in HIV/AIDS scientific discovery

The AIDS Cancer and Specimen Resource (ACSR) supports scientific discovery in the area of HIV/AIDS-associated malignancies. The ACSR was established as a cooperative agreement between the NCI (Office of the Director, Division of Cancer Treatment and Diagnosis) and regional consortia, University of California, San Francisco (West Coast), George Washington University (East Coast) and Ohio State University (Mid-Region) to collect, preserve and disperse HIV-related tissues and biologic fluids and controls along with clinical data to qualified investigators. The available biological samples with clinical data and the application process are described on the ACSR web site. The ACSR tissue bank has more than 100,000 human HIV positive specimens that represent different processing (43), specimen (15), and anatomical site (50) types. The ACSR provides special biospecimen collections and prepares speciality items, e.g., tissue microarrays (TMA), DNA libraries. Requests have been greatest for Kaposi's sarcoma (32%) and non-Hodgkin's lymphoma (26%). Dispersed requests include 83% tissue (frozen and paraffin embedded), 18% plasma/serum and 9% other. ACSR also provides tissue microarrays of, e.g., Kaposi's sarcoma and non-Hodgkin's lymphoma, for biomarker assays and has developed collaborations with other groups that provide access to additional AIDS-related malignancy specimens. ACSR members and associates have completed 63 podium and poster presentations. Investigators have submitted 125 letters of intent requests. Discoveries using ACSR have been reported in 61 scientific publications in notable journals with an average impact factor of 7. The ACSR promotes the scientific exploration of the relationship between HIV/AIDS and malignancy by participation at national and international scientific meetings, contact with investigators who have productive research in this area and identifying, collecting, preserving, enhancing, and dispersing HIV/AIDS-related malignancy specimens to funded, approved researchers at no fee. Scientific discovery has been advanced by this unique biorepository. Investigators are encouraged to browse the ACSR Internet site for materials to enhance their own scientific initiatives

"As soon as you’ve had the baby that’s it…” a qualitative study of 24 postnatal women on their experience of maternal obesity care pathways

Abstract Background Maternal obesity is associated with risks to mother and infant, and has implications for healthcare costs. United Kingdom (UK) levels of maternal obesity are rising, with higher prevalence in North East (NE) England, where this study was set. Pregnancy is often seen as an opportune time for intervention – a ‘teachable moment’ - which is ripe for promoting behaviour change. In response to rising obesity levels, a National Health Service (NHS) Foundation Trust in NE England implemented three maternal obesity care pathways contingent on Body Mass Index (BMI) at time of booking: pathway 1 for those with BMI ≥30 kg/m2; pathway 2 for BMI ≥35 kg/m2; and pathway 3 for BMI ≥40 kg/m2. These incorporated relevant antenatal, intrapartum and postnatal clinical requirements, and included a focus on weight management intervention. This evaluation explored the accounts of postnatal women who had been through one of these pathways in pregnancy. Methods The study used a generic qualitative approach. Semi-structured interviews were carried out to explore the views and experiences of 24 recent mothers (aged 20–42), living in NE England, who had commenced on one of the pathways during pregnancy. Interviews explored experiences of weight management support during and after pregnancy, and perceived gaps in this support. Data were analysed using thematic content analysis. Results Three main themes emerged reflecting women’s views and experiences of the pathways: communication about the pathways; treating obese pregnant women with sensitivity and respect; and appropriate and accessible lifestyle services and information for women during and after pregnancy. An overarching theme: differences in care, support and advice, was evident when comparing the experiences of women on pathways 1 or 2 with those on pathway 3. Conclusions This study indicated that women were not averse to risk management and weight management intervention during and after pregnancy. However, in order to improve reach and effectiveness, such interventions need to be well communicated and offer constructive, individualised advice and support. The postnatal phase may also offer an opportune moment for intervention, suggesting that the simple notion of seeing pregnancy alone as a window of opportunity or a ‘teachable moment’ should be reconsidered

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

Disruption of TLR3 Signaling Due to Cleavage of TRIF by the Hepatitis A Virus Protease-Polymerase Processing Intermediate, 3CD

Toll-like receptor 3 (TLR3) and cytosolic RIG-I-like helicases (RIG-I and MDA5) sense viral RNAs and activate innate immune signaling pathways that induce expression of interferon (IFN) through specific adaptor proteins, TIR domain-containing adaptor inducing interferon-β (TRIF), and mitochondrial antiviral signaling protein (MAVS), respectively. Previously, we demonstrated that hepatitis A virus (HAV), a unique hepatotropic human picornavirus, disrupts RIG-I/MDA5 signaling by targeting MAVS for cleavage by 3ABC, a precursor of the sole HAV protease, 3Cpro, that is derived by auto-processing of the P3 (3ABCD) segment of the viral polyprotein. Here, we show that HAV also disrupts TLR3 signaling, inhibiting poly(I:C)-stimulated dimerization of IFN regulatory factor 3 (IRF-3), IRF-3 translocation to the nucleus, and IFN-β promoter activation, by targeting TRIF for degradation by a distinct 3ABCD processing intermediate, the 3CD protease-polymerase precursor. TRIF is proteolytically cleaved by 3CD, but not by the mature 3Cpro protease or the 3ABC precursor that degrades MAVS. 3CD-mediated degradation of TRIF depends on both the cysteine protease activity of 3Cpro and downstream 3Dpol sequence, but not 3Dpol polymerase activity. Cleavage occurs at two non-canonical 3Cpro recognition sequences in TRIF, and involves a hierarchical process in which primary cleavage at Gln-554 is a prerequisite for scission at Gln-190. The results of mutational studies indicate that 3Dpol sequence modulates the substrate specificity of the upstream 3Cpro protease when fused to it in cis in 3CD, allowing 3CD to target cleavage sites not normally recognized by 3Cpro. HAV thus disrupts both RIG-I/MDA5 and TLR3 signaling pathways through cleavage of essential adaptor proteins by two distinct protease precursors derived from the common 3ABCD polyprotein processing intermediate