Statistical metamodeling of dynamic network loading

Dynamic traffic assignment models rely on a network performance module known as dynamic network loading (DNL), which expresses flow propagation, flow conservation, and travel delay at a network level. The DNL defines the so-called network delay operator, which maps a set of path departure rates to a set of path travel times (or costs). It is widely known that the delay operator is not available in closed form, and has undesirable properties that severely complicate DTA analysis and computation, such as discontinuity, non-differentiability, non-monotonicity, and computational inefficiency. This paper proposes a fresh take on this important and difficult issue, by providing a class of surrogate DNL models based on a statistical learning method known as Kriging. We present a metamodeling framework that systematically approximates DNL models and is flexible in the sense of allowing the modeler to make trade-offs among model granularity, complexity, and accuracy. It is shown that such surrogate DNL models yield highly accurate approximations (with errors below 8%) and superior computational efficiency (9 to 455 times faster than conventional DNL procedures such as those based on the link transmission model). Moreover, these approximate DNL models admit closed-form and analytical delay operators, which are Lipschitz continuous and infinitely differentiable, with closed-form Jacobians. We provide in-depth discussions on the implications of these properties to DTA research and model applications

Nearly Monodispersion CoSm Alloy Nanoparticles Formed by an In-situ Rapid Cooling and Passivating Microfluidic Process

An in siturapid cooling and passivating microfluidic processhas been developed for the synthesis of nearly monodispersed cobalt samarium nanoparticles (NPs) with tunable crystal structures and surface properties. This process involves promoting the nucleation and growth of NPs at an elevated temperature and rapidly quenching the NP colloids in a solution containing a passivating reagent at a reduced temperature. We have shown that Cobalt samarium NPs having amorphous crystal structures and a thin passivating layer can be synthesized with uniform nonspherical shapes and size of about 4.8 nm. The amorphous CoSm NPs in our study have blocking temperature near 40 K and average coercivity of 225 Oe at 10 K. The NPs also exhibit high anisotropic magnetic properties with a wasp-waist hysteresis loop and a bias shift of coercivity due to the shape anisotropy and the exchange coupling between the core and the thin oxidized surface layer

Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer

Cancer cells are known to execute reprogramed metabolism of glucose, amino acids and lipids. Here, we report a significant role of cholesterol metabolism in cancer metastasis. By using label-free Raman spectromicroscopy, we found an aberrant accumulation of cholesteryl ester in human pancreatic cancer specimens and cell lines, mediated by acyl-CoA cholesterol acyltransferase-1 (ACAT-1) enzyme. Expression of ACAT-1 showed a correlation with poor patient survival. Abrogation of cholesterol esterification, either by an ACAT-1 inhibitor or by shRNA knockdown, significantly suppressed tumor growth and metastasis in an orthotopic mouse model of pancreatic cancer. Mechanically, ACAT-1 inhibition increased intracellular free cholesterol level, which was associated with elevated endoplasmic reticulum stress and caused apoptosis. Collectively, our results demonstrate a new strategy for treating metastatic pancreatic cancer by inhibiting cholesterol esterification

ChIP-PaM: an algorithm to identify protein-DNA interaction using ChIP-Seq data

<p>Abstract</p> <p>Background</p> <p>ChIP-Seq is a powerful tool for identifying the interaction between genomic regulators and their bound DNAs, especially for locating transcription factor binding sites. However, high cost and high rate of false discovery of transcription factor binding sites identified from ChIP-Seq data significantly limit its application.</p> <p>Results</p> <p>Here we report a new algorithm, ChIP-PaM, for identifying transcription factor target regions in ChIP-Seq datasets. This algorithm makes full use of a protein-DNA binding pattern by capitalizing on three lines of evidence: 1) the tag count modelling at the peak position, 2) pattern matching of a specific tag count distribution, and 3) motif searching along the genome. A novel data-based two-step eFDR procedure is proposed to integrate the three lines of evidence to determine significantly enriched regions. Our algorithm requires no technical controls and efficiently discriminates falsely enriched regions from regions enriched by true transcription factor (TF) binding on the basis of ChIP-Seq data only. An analysis of real genomic data is presented to demonstrate our method.</p> <p>Conclusions</p> <p>In a comparison with other existing methods, we found that our algorithm provides more accurate binding site discovery while maintaining comparable statistical power.</p

Mycolactone-dependent depletion of endothelial cell thrombomodulin is strongly associated with fibrin deposition in Buruli ulcer lesions

A well-known histopathological feature of diseased skin in Buruli ulcer (BU) is coagulative necrosis caused by the Mycobacterium ulcerans macrolide exotoxin mycolactone. Since the underlying mechanism is not known, we have investigated the effect of mycolactone on endothelial cells, focussing on the expression of surface anticoagulant molecules involved in the protein C anticoagulant pathway. Congenital deficiencies in this natural anticoagulant pathway are known to induce thrombotic complications such as purpura fulimans and spontaneous necrosis. Mycolactone profoundly decreased thrombomodulin (TM) expression on the surface of human dermal microvascular endothelial cells (HDMVEC) at doses as low as 2ng/ml and as early as 8hrs after exposure. TM activates protein C by altering thrombin's substrate specificity, and exposure of HDMVEC to mycolactone for 24 hours resulted in an almost complete loss of the cells' ability to produce activated protein C. Loss of TM was shown to be due to a previously described mechanism involving mycolactone-dependent blockade of Sec61 translocation that results in proteasome-dependent degradation of newly synthesised ER-transiting proteins. Indeed, depletion from cells determined by live-cell imaging of cells stably expressing a recombinant TM-GFP fusion protein occurred at the known turnover rate. In order to determine the relevance of these findings to BU disease, immunohistochemistry of punch biopsies from 40 BU lesions (31 ulcers, nine plaques) was performed. TM abundance was profoundly reduced in the subcutis of 78% of biopsies. Furthermore, it was confirmed that fibrin deposition is a common feature of BU lesions, particularly in the necrotic areas. These findings indicate that there is decreased ability to control thrombin generation in BU skin. Mycolactone's effects on normal endothelial cell function, including its ability to activate the protein C anticoagulant pathway are strongly associated with this. Fibrin-driven tisischemia could contribute to the development of the tissue necrosis seen in BU lesions

Cystic hygroma and potential airway obstruction in a newborn: a case report and review of the literature

BACKGROUND: Cervical cystic hygroma is a benign congenital malformation of the lymphatic system. Incidence of cystic hygroma is 1/6000 live births. We present a case of right neck mass with potential respiratory compromise in a newborn. CASE PRESENTATION: The patient was a full term baby girl with an incidental finding of right neck mass which was described on ultrasound and magnetic resonance imaging as a cystic lesion in the nasopharynx and right neck which inferiorly followed the course of the right carotid artery, consistent with cystic hygroma. She started with respiratory compromise, and a follow-up magnetic resonance imaging showed increased size of the cystic hygroma. Dexamethasone was started to reduce fluid build up in the mass. When the cystic hygroma was found to be inseparable from the right half of the thyroid gland, the otolaryngologist performed hemithyroidectomy. CONCLUSION: The patient had neuropraxia involving the marginal mandibular branch of the facial nerve, which was expected to correct with time. Large cervical cystic hygromas may surround or displace neurovascular structures making their identification quite challenging intraoperatively. A team of experienced surgeons will help to ensure a successful surgical outcome

The use of thermographic imaging to evaluate therapeutic response in human tumour xenograft models

YesNon-invasive methods to monitor tumour growth are an important goal in cancer drug development. Thermographic imaging systems offer potential in this area, since a change in temperature is known to be induced due to changes within the tumour microenvironment. This study demonstrates that this imaging modality can be applied to a broad range of tumour xenografts and also, for the first time, the methodology’s suitability to assess anti-cancer agent efficacy. Mice bearing subcutaneously implanted H460 lung cancer xenografts were treated with a novel vascular disrupting agent, ICT-2552, and the cytotoxin doxorubicin. The effects on tumour temperature were assessed using thermographic imaging over the first 6 hours post-administration and subsequently a further 7 days. For ICT-2552 a significant initial temperature drop was observed, whilst for both agents a significant temperature drop was seen compared to controls over the longer time period. Thus thermographic imaging can detect functional differences (manifesting as temperature reductions) in the tumour response to these anti-cancer agents compared to controls. Importantly, these effects can be detected in the first few hours following treatment and therefore the tumour is observable non-invasively. As discussed, this technique will have considerable 3Rs benefits in terms of reduction and refinement of animal use.University of Bradfor

Novel technologies and emerging biomarkers for personalized cancer immunotherapy

The culmination of over a century's work to understand the role of the immune system in tumor control has led to the recent advances in cancer immunotherapies that have resulted in durable clinical responses in patients with a variety of malignancies. Cancer immunotherapies are rapidly changing traditional treatment paradigms and expanding the therapeutic landscape for cancer patients. However, despite the current success of these therapies, not all patients respond to immunotherapy and even those that do often experience toxicities. Thus, there is a growing need to identify predictive and prognostic biomarkers that enhance our understanding of the mechanisms underlying the complex interactions between the immune system and cancer. Therefore, the Society for Immunotherapy of Cancer (SITC) reconvened an Immune Biomarkers Task Force to review state of the art technologies, identify current hurdlers, and make recommendations for the field. As a product of this task force, Working Group 2 (WG2), consisting of international experts from academia and industry, assembled to identify and discuss promising technologies for biomarker discovery and validation. Thus, this WG2 consensus paper will focus on the current status of emerging biomarkers for immune checkpoint blockade therapy and discuss novel technologies as well as high dimensional data analysis platforms that will be pivotal for future biomarker research. In addition, this paper will include a brief overview of the current challenges with recommendations for future biomarker discovery

Timed inhibition of CDC7 increases CRISPR-Cas9 mediated templated repair.

Repair of double strand DNA breaks (DSBs) can result in gene disruption or gene modification via homology directed repair (HDR) from donor DNA. Altering cellular responses to DSBs may rebalance editing outcomes towards HDR and away from other repair outcomes. Here, we utilize a pooled CRISPR screen to define host cell involvement in HDR between a Cas9 DSB and a plasmid double stranded donor DNA (dsDonor). We find that the Fanconi Anemia (FA) pathway is required for dsDonor HDR and that other genes act to repress HDR. Small molecule inhibition of one of these repressors, CDC7, by XL413 and other inhibitors increases the efficiency of HDR by up to 3.5 fold in many contexts, including primary T cells. XL413 stimulates HDR during a reversible slowing of S-phase that is unexplored for Cas9-induced HDR. We anticipate that XL413 and other such rationally developed inhibitors will be useful tools for gene modification

Voluntary exercise can strengthen the circadian system in aged mice

Consistent daily rhythms are important to healthy aging according to studies linking disrupted circadian rhythms with negative health impacts. We studied the effects of age and exercise on baseline circadian rhythms and on the circadian system's ability to respond to the perturbation induced by an 8 h advance of the light:dark (LD) cycle as a test of the system's robustness. Mice (male, mPer2luc/C57BL/6) were studied at one of two ages: 3.5 months (n = 39) and &gt;18 months (n = 72). We examined activity records of these mice under entrained and shifted conditions as well as mPER2::LUC measures ex vivo to assess circadian function in the suprachiasmatic nuclei (SCN) and important target organs. Age was associated with reduced running wheel use, fragmentation of activity, and slowed resetting in both behavioral and molecular measures. Furthermore, we observed that for aged mice, the presence of a running wheel altered the amplitude of the spontaneous firing rate rhythm in the SCN in vitro. Following a shift of the LD cycle, both young and aged mice showed a change in rhythmicity properties of the mPER2::LUC oscillation of the SCN in vitro, and aged mice exhibited longer lasting internal desynchrony. Access to a running wheel alleviated some age-related changes in the circadian system. In an additional experiment, we replicated the effect of the running wheel, comparing behavioral and in vitro results from aged mice housed with or without a running wheel (&gt;21 months, n = 8 per group, all examined 4 days after the shift). The impact of voluntary exercise on circadian rhythm properties in an aged animal is a novel finding and has implications for the health of older people living with environmentally induced circadian disruption