Altered Responses to Endoplasmic Reticulum Stress in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) represents the fourth most common cause of cancer-associated death in the United States. Little progress has been made in understanding how proteotoxic stress affects rapidly proliferating pancreatic tumor cells. Endoplasmic reticulum (ER) stress occurs when protein homeostasis in the ER lumen is perturbed. ER stress activates the unfolded protein response (UPR) to reduce the protein load in the ER. Under conditions of moderate ER stress, the UPR promotes cell cycle arrest which allows time for successful protein load reduction and enables cell survival. However, under conditions of high levels of ER stress the UPR induces cellular apoptosis. In this dissertation, I investigated the role of endoplasmic reticulum (ER) stress and its effects on the cell cycle in pancreatic cancer cells. Activation of the unfolded protein response after ER stress induction was determined by comparing expression of key UPR mediators in non-tumorigenic pancreatic ductal cells to pancreatic cancer cells. Two arms of the UPR were assessed: eIF2α/ATF4/CHOP and IRE1α/XBP1s. Pancreatic cancer cells exhibited altered UPR activation characterized by a delay in both phosphorylation of eIF2α and induction of spliced XBP1. Further evaluation of the UPR-mediated effects on cell cycle progression revealed that pancreatic cancer cells showed a compromised ability to inhibit G1 to S phase progression after ER stress. This reduced ability to arrest proliferation was found to be due to an impaired ability to downregulate cyclin D1, a key gatekeeper of the G1/S checkpoint. Abrogation of cyclin D1 repression was mediated through a slow induction of phosphorylation of eIF2α, a critical mediator of translational attenuation in response to ER stress. In conclusion, pancreatic cancer cells demonstrate a globally compromised ability to regulate the unfolded protein response. This deficiency results in reduced cyclin D1 repression through an eIF2α-mediated mechanism. These findings indicate that pancreatic cancer cells have increased tolerance for elevated ER stress compared to normal cells, and this tolerance results in continued tumor cell proliferation under proteotoxic conditions.

Disentangling human tolerance and resistance against HIV.

In ecology, "disease tolerance" is defined as an evolutionary strategy of hosts against pathogens, characterized by reduced or absent pathogenesis despite high pathogen load. To our knowledge, tolerance has to date not been quantified and disentangled from host resistance to disease in any clinically relevant human infection. Using data from the Swiss HIV Cohort Study, we investigated if there is variation in tolerance to HIV in humans and if this variation is associated with polymorphisms in the human genome. In particular, we tested for associations between tolerance and alleles of the Human Leukocyte Antigen (HLA) genes, the CC chemokine receptor 5 (CCR5), the age at which individuals were infected, and their sex. We found that HLA-B alleles associated with better HIV control do not confer tolerance. The slower disease progression associated with these alleles can be fully attributed to the extent of viral load reduction in carriers. However, we observed that tolerance significantly varies across HLA-B genotypes with a relative standard deviation of 34%. Furthermore, we found that HLA-B homozygotes are less tolerant than heterozygotes. Lastly, tolerance was observed to decrease with age, resulting in a 1.7-fold difference in disease progression between 20 and 60-y-old individuals with the same viral load. Thus, disease tolerance is a feature of infection with HIV, and the identification of the mechanisms involved may pave the way to a better understanding of pathogenesis.

Ultrasound-assisted versus conventional catheter-directed thrombolysis for acute iliofemoral deep vein thrombosis

BACKGROUND For patients with acute iliofemoral deep vein thrombosis, it remains unclear whether the addition of intravascular high-frequency, low-power ultrasound energy facilitates the resolution of thrombosis during catheter-directed thrombolysis. METHODS AND RESULTS In a controlled clinical trial, 48 patients (mean age 50±21 years, 52% women) with acute iliofemoral deep vein thrombosis were randomized to receive ultrasound-assisted catheter-directed thrombolysis (N=24) or conventional catheter-directed thrombolysis (N=24). Thrombolysis regimen (20 mg r-tPA over 15 hours) was identical in all patients. The primary efficacy end point was the percentage of thrombus load reduction from baseline to 15 hours according to the length-adjusted thrombus score, obtained from standardized venograms and evaluated by a core laboratory blinded to group assignment. The percentage of thrombus load reduction was 55%±27% in the ultrasound-assisted catheter-directed thrombolysis group and 54%±27% in the conventional catheter-directed thrombolysis group (P=0.91). Adjunctive angioplasty and stenting was performed in 19 (80%) patients and in 20 (83%) patients, respectively (P>0.99). Treatment-related complications occurred in 3 (12%) and 2 (8%) patients, respectively (P>0.99). At 3-month follow-up, primary venous patency was 100% in the ultrasound-assisted catheter-directed thrombolysis group and 96% in the conventional catheter-directed thrombolysis group (P=0.33), and there was no difference in the severity of the post-thrombotic syndrome (mean Villalta score: 3.0±3.9 [range 0-15] versus 1.9±1.9 [range 0-7]; P=0.21), respectively. CONCLUSIONS In this randomized controlled clinical trial of patients with acute iliofemoral deep vein thrombosis treated with a fixed-dose catheter thrombolysis regimen, the addition of intravascular ultrasound did not facilitate thrombus resolution. CLINICAL TRIAL REGISTRATION URL http://www.clinicaltrials.gov. Unique identifier: NCT01482273.

Investigation of knot nests on Ellesmere Island

Knots arrive on Ellesmere Island in late May or early June. At Hazen Camp small flocks were present on 3 June 1966, but the main influx occurred 5 June when many flocks were seen ranging in size from 6 to 60 individuals. The sexes appeared to arrive together, but the manner of pair-formation was not determined. By 7 June pairs were distributed over the tundra with large feeding flocks forming at snowfree wet marshy areas. Most nests were on Dryas-hummocked slopes and tundra, either dry or moist, with some on clay plains and summits in a mixed Dryas and Salix vegetation. A census area of 240 ha supported at least 3 breeding pairs, and possibly 5; the total number of pairs breeding in the Hazen Camp study area was estimated to be about 25 (1.09 pairs/km**2). Egg-laying (4 nests) extended from 15 to 28 June, with 3 of the 4 sets completed between 20 and 23 June. Both sexes incubated, one of the pair more regularly than the other. The song-flight display of the male was performed most frequently during egglaying and incubation. The incubation period of the last egg in one clutch was established as being between 21.5 and 22.4 days. Four nests hatched between 12 and 20 July, and the hatching period of the entire clutch was less than 24 hours. Four of 7 nests (57 %) survived and egg survival (53 %) was low. Families left the nesting area so on after hatching, concentrating at ponds where food was readily available for the young. Both adults attended the young during the pre-fledging period, but the females apparently departed before the young had hedged. Males left once the young could fly and the adult fall migration was complete by early August. Most 01 the young departed belore mid-August. Fall migration is complete by late August or early September. The breeding season appears to be timed to peak load supply for the young. Adult Chironomidae emergence was highest between 3 and 17 July, the period during which most successful nests hatched. The increasing scarcity of adult insects for the young after mid-July was offset by family movements over the tundra and the early departure of half the adult population. Food also seemed to influence the distribution of breeding pairs aver the tundra, restricting them to the general vicinity of marshes, streams, and ponds where food is most available when the young hatch. Territoriality in the Knot appears to be closely associated with the protection of the nest against predators and has at least a local effect in regulating the number of breeding pairs. Plant material was important in the diet of adult Knots throughout the summer and the primary food from the time of arrival until mid-June. After mid-June the percentage of animal matter increased as dipterous insects became available (especially adult Chironomidae), but plant materials continued to constitute a large part of the diet, usually more than 50 %. The food of the young before fledging consisted principally of adult chironomids.

Mechanical behavior and deformation micromechanisms of polypropylene nonwoven fabrics as a function of temperature and strain rate

The mechanical behavior and the deformation and failure micromechanisms of a thermally-bonded polypropylene nonwoven fabric were studied as a function of temperature and strain rate. Mechanical tests were carried out from 248 K (below the glass transition temperature) up to 383 K at strain rates in the range ≈10−3 s−1 to 10−1 s−1. In addition, individual fibers extracted from the nonwoven fabric were tested under the same conditions. Micromechanisms of deformation and failure at the fiber level were ascertained by means of mechanical tests within the scanning electron microscope while the strain distribution at the macroscopic level upon loading was determined by means of digital image correlation. It was found that the nonwoven behavior was mainly controlled by the properties of the fibers and of the interfiber bonds. Fiber properties determined the nonlinear behavior before the peak load while the interfiber bonds controlled the localization of damage after the peak load. The influence of these properties on the strength, ductility and energy absorbed during deformation is discussed from the experimental observations.

Effects of phosphorus on the growth and nitrogen fixation rates of Lyngbya majuscula: implications for management in Moreton Bay, Queensland

Significant acetylene reduction and therefore N-2 fixation was observed for Lyngbya majuscula only during dark periods, which suggests that oxygenic photosynthesis and N-2 fixation are incompatible processes for this species. Results from a series of batch and continuous-flow-culture reactor studies showed that the specific growth rate and N-2 fixation rate of L, majuscula increased with phosphate (P-PO4) concentration up to a maximum value and thereafter remained constant. The P-PO4 concentrations corresponding to the maximum N-2 fixation and maximum growth rates were -0.27 and -0.18 muM respectively and these values are denoted as the saturation values for N-2 fixation and growth respectively. Regular monitoring studies in Moreton Bay, Queensland, show that concentrations Of P-PO4 generally exceed these saturation values over a large portion of the Bay and therefore, the growth of the bloom-forming L, majuscula is potentially maximised throughout much of the Bay by the elevated P-PO4 concentrations. Results from other studies suggest that the elevated P-PO4 concentrations in the Bay can be largely attributed to discharges from waste-water treatment plants (WWTPs), and thus it is proposed that the control of the growth of L. majuscula in Moreton Bay will require a significant reduction in the P load from the WWTP discharges. If the current strategy of N load reduction for these discharges is maintained in the absence of substantial P load reduction, it is hypothesised that the growth of L, majuscula and other diazotrophs in Moreton Bay will increase in the future.

A techno-economic comparison of power production by biomass fast pyrolysis with gasification and combustion

This paper presents an assessment of the technical and economic performance of thermal processes to generate electricity from a wood chip feedstock by combustion, gasification and fast pyrolysis. The scope of the work begins with the delivery of a wood chip feedstock at a conversion plant and ends with the supply of electricity to the grid, incorporating wood chip preparation, thermal conversion, and electricity generation in dual fuel diesel engines. Net generating capacities of 1–20 MWe are evaluated. The techno-economic assessment is achieved through the development of a suite of models that are combined to give cost and performance data for the integrated system. The models include feed pretreatment, combustion, atmospheric and pressure gasification, fast pyrolysis with pyrolysis liquid storage and transport (an optional step in de-coupled systems) and diesel engine or turbine power generation. The models calculate system efficiencies, capital costs and production costs. An identical methodology is applied in the development of all the models so that all of the results are directly comparable. The electricity production costs have been calculated for 10th plant systems, indicating the costs that are achievable in the medium term after the high initial costs associated with novel technologies have reduced. The costs converge at the larger scale with the mean electricity price paid in the EU by a large consumer, and there is therefore potential for fast pyrolysis and diesel engine systems to sell electricity directly to large consumers or for on-site generation. However, competition will be fierce at all capacities since electricity production costs vary only slightly between the four biomass to electricity systems that are evaluated. Systems de-coupling is one way that the fast pyrolysis and diesel engine system can distinguish itself from the other conversion technologies. Evaluations in this work show that situations requiring several remote generators are much better served by a large fast pyrolysis plant that supplies fuel to de-coupled diesel engines than by constructing an entire close-coupled system at each generating site. Another advantage of de-coupling is that the fast pyrolysis conversion step and the diesel engine generation step can operate independently, with intermediate storage of the fast pyrolysis liquid fuel, increasing overall reliability. Peak load or seasonal power requirements would also benefit from de-coupling since a small fast pyrolysis plant could operate continuously to produce fuel that is stored for use in the engine on demand. Current electricity production costs for a fast pyrolysis and diesel engine system are 0.091/kWh at 1 MWe when learning effects are included. These systems are handicapped by the typical characteristics of a novel technology: high capital cost, high labour, and low reliability. As such the more established combustion and steam cycle produces lower cost electricity under current conditions. The fast pyrolysis and diesel engine system is a low capital cost option but it also suffers from relatively low system efficiency particularly at high capacities. This low efficiency is the result of a low conversion efficiency of feed energy into the pyrolysis liquid, because of the energy in the char by-product. A sensitivity analysis has highlighted the high impact on electricity production costs of the fast pyrolysis liquids yield. The liquids yield should be set realistically during design, and it should be maintained in practice by careful attention to plant operation and feed quality. Another problem is the high power consumption during feedstock grinding. Efficiencies may be enhanced in ablative fast pyrolysis which can tolerate a chipped feedstock. This has yet to be demonstrated at commercial scale. In summary, the fast pyrolysis and diesel engine system has great potential to generate electricity at a profit in the long term, and at a lower cost than any other biomass to electricity system at small scale. This future viability can only be achieved through the construction of early plant that could, in the short term, be more expensive than the combustion alternative. Profitability in the short term can best be achieved by exploiting niches in the market place and specific features of fast pyrolysis. These include: •countries or regions with fiscal incentives for renewable energy such as premium electricity prices or capital grants; •locations with high electricity prices so that electricity can be sold direct to large consumers or generated on-site by companies who wish to reduce their consumption from the grid; •waste disposal opportunities where feedstocks can attract a gate fee rather than incur a cost; •the ability to store fast pyrolysis liquids as a buffer against shutdowns or as a fuel for peak-load generating plant; •de-coupling opportunities where a large, single pyrolysis plant supplies fuel to several small and remote generators; •small-scale combined heat and power opportunities; •sales of the excess char, although a market has yet to be established for this by-product; and •potential co-production of speciality chemicals and fuel for power generation in fast pyrolysis systems.

Modular ESS with second life batteries operating in grid independent mode

This work is part of a bigger project which aims to research the potential development of commercial opportunities for the re-use of batteries after their use in low carbon vehicles on an electricity grid or microgrid system. There are three main revenue streams (peak load lopping on the distribution Network to allow for network re-enforcement deferral, National Grid primary/ secondary/ high frequency response, customer energy management optimization). These incomes streams are dependent on the grid system being present. However, there is additional opportunity to be gained from also using these batteries to provide UPS backup when the grid is no longer present. Most UPS or ESS on the market use new batteries in conjunction with a two level converter interface. This produces a reliable backup solution in the case of loss of mains power, but may be expensive to implement. This paper introduces a modular multilevel cascade converter (MMCC) based ESS using second-life batteries for use on a grid independent industrial plant without any additional onsite generator as a potentially cheaper alternative. The number of modules has been designed for a given reliability target and these modules could be used to minimize/eliminate the output filter. An appropriate strategy to provide voltage and frequency control in a grid independent system is described and simulated under different disturbance conditions such as load switching, fault conditions or a large motor starting. A comparison of the results from the modular topology against a traditional two level converter is provided to prove similar performance criteria. The proposed ESS and control strategy is an acceptable way of providing backup power in the event of loss of grid. Additional financial benefit to the customer may be obtained by using a second life battery in this way.

Sizing energy storage on the 11kV distribution network

The cost and limited flexibility of traditional approaches to 11kV network reinforcement threatens to constrain the uptake of low carbon technologies. Ofgem has released £500m of funding for DNOs to trial innovative techniques and share the learning with the rest of the industry. One of the techniques under study is the addition of Energy Storage at key substations to the network to help with peak load lopping. This paper looks in detail at the sizing algorithm for use in the assessment of alternatives to traditional reinforcement and investigates a method of sizing a battery for use on a Network taking into account load growth, capacity fade and battery lifecycle issues. A further complication to the analysis is the method of operation of the battery system and how this affects the Depth of Discharge (DoD). The proposed method is being trialled on an area of 11kV network in Milton Keynes Central area and the simulation results are presented in this paper.

Estratégias de enfrentamento de pessoas vivendo com AIDS frente à situação da doença

The Acquired Immune Deficiency Syndrome (AIDS), considered today one chronic nature of the disease due to the advent of antiretroviral therapy (TARV), brings to individuals living with this disease, difficulties related to social interaction and adaptation to new physical condition and the routines imposed by the treatment. This reality has a strong impact on the lives of these people in order of overcoming them use coping strategies, Coping. In this context, the aim of this study was to characterize the epidemiological, clinical and life habits of people living with AIDS and analyze the coping strategies used with the situation of the disease, according to sociodemographic, clinical and life habits. This is a cross-sectional study with a quantitative approach. The sample consisted of 331 people registered at the clinic of the Hospital Giselda Trigueiro (HGT), located in Natal / RN, who had scheduling for outpatient medical consultation from January to August 2014. The study was approved by the Ethics Committee the Federal University of Rio Grande do Norte with the Presentation of Certificate for Ethics Assessment (CAAE), paragraph 16578613.0.0000.5537. The data of social characterization showed predominance of men (52%), young people (42%) coming from the capital (58%), mulatto (53%), single (56%), heterosexual (79%), poor (68 %). With regard to clinical aspects it has been found that most held the first HIV testing for less than five years (60%) had signs and symptoms of AIDS before the examination (90%) were hospitalized (90%) started ART for less than five years (60%) believe they have good knowledge of the disease (75%) and believe that their health has improved (92%). For lifestyle, it became clear that most do not consume alcohol (71%), do not smoke (88%) and do not use illicit drugs (92%) and never used condoms before diagnosis (62%) and only 192 (58%) use the currently codon. With regard to the reference was higher coping focused modes of emotion, although the problem solving has been the second most common. The mean scores of women, workers, religious and never abandoned the treatment were higher for all factors. Having a partner, living with family members and support in the treatment had higher average scores for various factors, coinciding in the confrontation, withdrawal and social support. As for the leisure and physical exercise also dominated the modes focused on emotion as was seen in the correlation between the time of treatment, education and family income and IEEFL factors, although with low intensity. The profile of the study population confers with national characteristics, suggesting feminization, internalization, pauperization, heterosexual, increased CD4 cell count and viral load reduction during treatment and maintaining healthy lifestyle habits. Coping strategies used were more focused on emotion. In this context, it is understood that the identification of these strategies can facilitate care planning, encouraging such persons to adapt to stressors with the situation of the disease

The Effect of Foam Core Density on the Flexural and Axial Behaviour of Sandwich Panels of Varying Slenderness with Natural Flax-FRP and Glass-FRP Composite Skins

This study investigates the effect of foam core density and skin type on the behaviour of sandwich panels as structural beams tested in four-point bending and axially compressed columns of varying slenderness and skin thickness. Bio-composite unidirectional flax fibre-reinforced polymer (FFRP) is compared to conventional glass-FRP (GFRP) as the skin material used in conjunction with three polyisocyanurate (PIR) foam cores with densities of 32, 64 and 96 kg/m3. Eighteen 1000 mm long flexural specimens were fabricated and tested to failure comparing the effects of foam core density between three-layer FFRP skinned and single-layer GFRP skinned panels. A total of 132 columns with slenderness ratios (kLe/r) ranging from 22 to 62 were fabricated with single-layer GFRP skins, and one-, three-, and five-layer FFRP skins for each of the three foam core densities. The columns were tested to failure in concentric axial compression using pinned-end conditions to compare the effects of each material type and panel height. All specimens had a foam core cross-section of 100x50 mm with 100 mm wide skins of equal thickness. In both flexural and axial loading, panels with skins comprised of three FFRP layers showed equivalent strength to those with a single GFRP layer for all slenderness ratios and core densities examined. Doubling the core density from 32 to 64 kg/m3 and tripling the density to 96 kg/m3 led to flexural strength increases of 82 and 213%, respectively. Both FFRP and GFRP columns showed a similar variety of failure modes related to slenderness. Low slenderness of 22-25 failed largely due to localized single skin buckling, while those with high slenderness of 51-61 failed primarily by global buckling followed by secondary skin buckling. Columns with intermediate slenderness experienced both localized and global failure modes. High density foam cores more commonly exhibited core shear failure. Doubling the core density of the columns resulted in peak axial load increases, across all slenderness ratios, of 73, 56, 72 and 71% for skins with one, three and five FFRP layers, and one GFRP layer, respectively. Tripling the core density resulted in respective peak load increases of 116, 130, 176 and 170%.

Geospatial Data Indexing Analysis and Visualization via Web Services with Autonomic Resource Management

With the exponential growth of the usage of web-based map services, the web GIS application has become more and more popular. Spatial data index, search, analysis, visualization and the resource management of such services are becoming increasingly important to deliver user-desired Quality of Service. First, spatial indexing is typically time-consuming and is not available to end-users. To address this, we introduce TerraFly sksOpen, an open-sourced an Online Indexing and Querying System for Big Geospatial Data. Integrated with the TerraFly Geospatial database [1-9], sksOpen is an efficient indexing and query engine for processing Top-k Spatial Boolean Queries. Further, we provide ergonomic visualization of query results on interactive maps to facilitate the user’s data analysis. Second, due to the highly complex and dynamic nature of GIS systems, it is quite challenging for the end users to quickly understand and analyze the spatial data, and to efficiently share their own data and analysis results with others. Built on the TerraFly Geo spatial database, TerraFly GeoCloud is an extra layer running upon the TerraFly map and can efficiently support many different visualization functions and spatial data analysis models. Furthermore, users can create unique URLs to visualize and share the analysis results. TerraFly GeoCloud also enables the MapQL technology to customize map visualization using SQL-like statements [10]. Third, map systems often serve dynamic web workloads and involve multiple CPU and I/O intensive tiers, which make it challenging to meet the response time targets of map requests while using the resources efficiently. Virtualization facilitates the deployment of web map services and improves their resource utilization through encapsulation and consolidation. Autonomic resource management allows resources to be automatically provisioned to a map service and its internal tiers on demand. v-TerraFly are techniques to predict the demand of map workloads online and optimize resource allocations, considering both response time and data freshness as the QoS target. The proposed v-TerraFly system is prototyped on TerraFly, a production web map service, and evaluated using real TerraFly workloads. The results show that v-TerraFly can accurately predict the workload demands: 18.91% more accurate; and efficiently allocate resources to meet the QoS target: improves the QoS by 26.19% and saves resource usages by 20.83% compared to traditional peak load-based resource allocation.

Peak power demand reduction under moving block signalling using an expert system

The concept of moving block signallings (MBS) has been adopted in a few mass transit railway systems. When a dense queue of trains begins to move from a complete stop, the trains can re-start in very close succession under MBS. The feeding substations nearby are likely to be overloaded and the service will inevitably be disturbed unless substations of higher power rating are used. By introducing starting time delays among the trains or limiting the trains’ acceleration rate to a certain extent, the peak energy demand can be contained. However, delay is introduced and quality of service is degraded. An expert system approach is presented to provide a supervisory tool for the operators. As the knowledge base is vital for the quality of decisions to be made, the study focuses on its formulation with a balance between delay and peak power demand.