This paper studies the impact of climate change-imposed constraints on the recoverability of airline networks. We first use models that capture the modified payload-range curves for different aircraft types under multiple climate change scenarios, and the associated (reduced) aircraft capacities. We next construct a modeling and algorithmic framework that allows for simultaneous and integrated aircraft and passenger recovery that explicitly capture the above-mentioned capacity changes in aircraft at different times of day. The results, based on the RCP8.5 climate change scenario, suggest that daily total airline recovery costs increase on average by 15.7% to 49.4%; and by 10.6% to 165.0% over individual disrupted days - depending on the original source of disruption, the climate change case of interest and year of interest. Aircraft-related costs are driven by a huge increase in aircraft swaps and cancellations; and passenger-related costs are driven by increases in disrupted (misconnected) passengers who need to be rebooked on the same or a different airline. This work motivates the critical need for airlines to systematically incorporate climate change as a factor in the design of aircraft as well as in the design and operations of airline networks.

Air traffic disruptions result in flight delays, cancellations, passenger misconnections, and ultimately high costs to aviation stakeholders. This paper proposes a jointly reactive and proactive approach to airline disruption management, which optimizes recovery decisions in response to realized disruptions and in anticipation of future disruptions. The approach forecasts future disruptions partially and probabilistically by estimating systemic delays at hub airports (and the uncertainty thereof) and ignoring other contingent disruptions. It formulates a dynamic stochastic integer programming framework to minimize network-wide expected disruption recovery costs. Specifically, our Stochastic Reactive and Proactive Disruption Management (SRPDM) model combines a stochastic queuing model of airport congestion, a flight planning tool from Boeing/Jeppesen and an integer programming model of airline disruption recovery. We develop a solution procedure based on look-ahead approximation and sample average approximation, which enables the model’s implementation in short computational times. Experimental results show that leveraging even partial and probabilistic estimates of future disruptions can reduce expected recovery costs by 1%–2%, as compared with a myopic baseline approach based on realized disruptions alone. These benefits are mainly driven by the deliberate introduction of departure holds to reduce expected fuel costs, flight cancellations, and aircraft swaps.

BACKGROUND: Lipoprotein subspecies containing apoCIII adversely affect cardiovascular disease (CVD) risk; for example, low density lipoprotein (LDL) with apoCIII is a stronger CVD predictor than LDL without apoCIII. The Epanova for Lowering Very High Triglycerides (EVOLVE) trial showed that Epanova (omega-3 carboxylic acids [0M3-CA]) significantly lowered TG and apoCIII but raised LDL-C. However, it is unknown what subspecies of LDL were affected by treatment.OBJECTIVE: To determine how lipoprotein subspecies are affected by omega-3 fatty acid treatment, we studied the effect of 0M3-CA on apoCIII concentrations in high density lipoprotein (HDL), LDL, and very low density lipoprotein (VLDL) and on the concentrations of subspecies of HDL, LDL, and VLDL that contain or do not contain apoCIII.METHODS: We analyzed plasma from a subset of subjects from the EVOLVE trial, a 12-week double-blind study of 399 subjects with fasting TG of 500 to 2000 mg/dL who were randomized to 0M3-CA 2, 3, or 4 g/d or olive oil (placebo).RESULTS: 0M3-CA significantly reduced plasma apoCIII relative to placebo, as well as apOCIII in HDL, and apoCIII in LDL. Treatment did not significantly affect the concentration of LDL with apoCIII, a subspecies highly associated with CVD risk. 0M3-CA increased selectively the concentration of LDL that does not contain apoCill, a subspecies with a weak relation to coronary heart disease. The reduction in apoCIII was associated with plasma increases in eicosapentaenoic acid, docosahexaenoic acid, and arachidonic acid and decreases in linoleic, palmitic, and oleic acids.CONCLUSION: Reduction in apoCIII may be a mechanism for the TG-lowering effects of 0M3-CA. The increase in LDL-C seen in the EVOLVE trial may not be associated with increased risk of CVD. (C) 2016 National Lipid Association. All rights reserved.

In this study, the Escherichia coli strain MG1655 with fadD mutant (named as ML103), and MG1655 with fadD and ptsG double mutant (named as ML190) carrying the plasmid with the acyl-ACP thioesterase (TE) from Ricinus communis (pXZ18) or the plasmid with the combination of the TE and the native (3R)-hydroxyacyl-ACP dehydrase (fabZ) (pXZ18Z), produced free fatty acids (FFAs) efficiently using mannose as the sole carbon source. Due to the carbon catabolite repression (CCR) regulation, ML103(pXZ18) utilized glucose and mannose sequentially in the mixed sugar culture, while ML190(pXZ18) and ML190(pXZ18Z), with ptsG mutation, used glucose and mannose simultaneously. The highest total FFA concentration from the mixed sugar culture reached 2.96g/L by ML190(pXZ18Z). Furthermore, the strain ML190(pXZ18Z) can produce 2.86g/L FFAs with a high yield of 0.23g/g using hydrolysate mainly contained glucose and mannose from a commercial plant.

Our mechanistic understanding of damage formation in DNA by the direct effect relies heavily on what is known of free radical intermediates studied by EPR spectroscopy. Bridging this information to stable product formation requires methods with comparable sensitivities, a criterion met by the P-32-post-labeling assay developed by Weinfeld and Soderlind, [Weinfeld,M. and Soderlind,K.-J.M. (1991) P-32-Postlabeling detection of radiation-induced DNA damage: identification and estimation of thymine glycols and phosphoglycolate termini. Biochemistry, 30, 1091-1097] which when applied to the indirect effect, detected phosphoglycolate (pg) and thymine glycol (Tg). Here we applied this assay to the direct effect, measuring product yields in pUC18 films with hydration levels (Gamma) of 2.5, 16 or 23 waters per nucleotide and X-irradiated at either 4 K or room temperature (RT). The yields of pg [G(pg)] for Gamma similar to 2.5 were 2.8 +/- 0.2 nmol/J (RT) and 0.2 +/- 0.3 nmol/J (4 K), which is evidence that the C4' radical contributes little to the total deoxyribose damage via the direct effect. The yield of detectable base damage [G(B*)] at Gamma similar to 2.5 was found to be 30.2 +/- 1.0 nmol/J (RT) and 12.9 +/- 0.7 nmol/J (4 K). While the base damage called B*, could be due to either oxidation or reduction, we argue that two reduction products, 5,6-dihydrouracil and 5,6-dihydrothymine, are the most likely candidates.

The human bladder is one of the primary target organs for arsenic-induced carcinogenicity, and arsenic metabolites in urine have been suspected to be directly involved in carcinogenesis. Thioarsenicals are commonly found in human and animal urine and are also considered to be highly toxic arsenic metabolites. The present study was performed to gain insight into the toxicity and accumulation of arsenic species found in urine, including arsenate (iAs(V)), arsenite (iAs(III)), monomethylarsonic acid (MMA(V)), monomethylmonothioarsonic acid (MMMTA(V)), dimethylarsinic acid (DMA(V)), dimethylarsinous acid (DMA(III)), dimethylmonothioarsinic acid, (DMMTA(V)), and dimethyldithioarsinic acid (DMDTA(V)) in human bladder cancer EJ-1 cells. The order of cytotoxicity of these arsenic compounds in EJ-1 human bladder cancer cells was DMA(III), DMMTA(V) > iAs(III) ≫ iAs(V) > MMMTA(V) > MMA(V), DMA(V), and DMDTA(V), indicating that the sulfur-containing DMMTA(V) was among the most toxic arsenic compounds similar to trivalent DMA(III). We further characterized the DNA damage, generation of highly reactive oxygen species (hROS), and expression of proteins p21 and p53 in cells after exposure to iAs(III), DMA(III), and DMMTA(V). Cellular exposure to DMMTA(V) resulted in reduced protein expression of p53 and p21, increased DNA damage, and increased intracellular hROS (hydroxyl radical). In contrast, iAs(III) significantly increased the protein expression of p21 and p53 and did not increase the hROS at the IC(50). Intracellular glutathione (GSH) was reduced by 60% after exposure to DMA(III) or DMMTA(V), suggesting that DMMTA(V) causes cell death through oxidative stress. In contrast, GSH levels increased in cells exposed to iAs(III), and hROS only increased after a long exposure to iAs(III). Our findings demonstrate that DMMTA(V) may be one of the most toxicologically potent arsenic species, relevant to arsenic-induced carcinogenicity in the urinary bladder.

OBJECTIVE:This study tested the effects of bisphosphonates (BPs) on the suppressor of cytokine signaling 3 (SOCS3) protein in macrophages. SOCS3 has been shown to regulate cell differentiation and survival; however, its potential role in mediating the effects of BPs has not been explored. STUDY DESIGN:The cell viability of murine RAW 267.4 macrophages was assessed after culturing with control medium or media containing increasing concentrations of 2 BPs (ibandronate or clodronate) for 24, 48, and 72 hours. The phosphorylation status of signal transducer and activator of transcription 3 (STAT3) and the expression of SOCS3 protein levels were determined by Western blot analysis. RESULTS:In control cultures, STAT3 phosphorylation and STAT3 and SOCS3 protein levels increased within 5 minutes after the addition of fresh medium. This increase was inhibited in cultures treated with both BPs. Macrophage cell viability also decreased after BP treatment. CONCLUSIONS:These data demonstrate that, in addition to their effects on macrophage viability, BPs can decrease STAT3 and SOCS3 expression, which are important modulators of immune responses and bone homeostasis.

This article investigates secondary school teachers' conceptions of mathematics and their teaching practices in the use of graphing calculators in their mathematics classrooms. Case studies on three teacher participants were developed using quantitative and qualitative data that consisted of self-assessments on beliefs in mathematics, observations, surveys on professional and personal technology use and semi-structured interviews. All three teachers had a similar goal of attempting to use the graphing calculators to eliminate mechanical processing time and enhance their students' ability to construct their own learning. The major findings of this article relate to: (1) proficiency with the graphing calculator; (2) a common starting point and (3) integration into the curriculum. This article concludes that factors such as teachers' personal experiences and teaching practices, together with the level of proficiency of the students with the technology, influence how the graphing calculators are used in the mathematics classroom. When graphing calculators are effectively used in the mathematics classroom, they are a powerful tool to assist teachers in providing their students with an environment to help them construct their mathematical knowledge and understanding.

Arsenic toxicity is dependent on its chemical species. In humans, the bladder is one of the primary target organs for arsenic-induced carcinogenicity. However, little is known about the mechanisms underlying arsenic-induced carcinogenicity, and what arsenic species are responsible for this carcinogenicity. The present study aimed at comparing the toxic effect of DMMTA(V) with that of inorganic arsenite (iAs(III)) on cell viability, uptake efficiency and production of reactive oxygen species (ROS) toward human bladder cancer EJ-1 cells. The results were compared with those of a previous study using human epidermoid carcinoma A431 cells. Although iAs(III) was known to be toxic to most cells, here we show that iAs(III) (LC50 = 112 mu M) was much less cytotoxic than DMMTA(V) (LC50 = 16.7 mu M) in human bladder EJ-1 cells. Interestingly, pentavalent sulfur-containing DMMTA(V) generated a high level of intracellular ROS in EJ-1 cells. However, this was not observed in the cells exposed to trivalent inorganic iAs(III) at their respective LC50 dose. Furthermore, the presence of N-acetyl-cysteine completely inhibited the cytotoxicity of DMMTA(V) but not iAs(III), suggesting that production of ROS was the main cause of cell death from exposure to DMMTA(V), but not iAs(III). Because the cellular uptake of iAs(III) is mediated by aquaporin proteins, and because the resistance of cells to arsenite can be influenced by lower arsenic uptake due to lower expression of aquaporin proteins (AQP 3, 7 and 9), the expression of several members of the aquaporin family was also examined. In human bladder EJ-1 cells, mRNA/proteins of AQP3, 7 and 9 were not detected by reverse transcription polymerase chain reaction (RT-PCR)/western blotting. In A431 cells, only mRNA and protein of AQP3 were detected. The large difference in toxicity between the two cell lines could be related to their differences in uptake of arsenic species. (C) 2009 Elsevier Inc. All rights reserved.

The objective of this study was to evaluate the efficacy and safety of fluticasone furoate (FF) nasal spray 55 and 110 μg once daily in children with seasonal allergic rhinitis (SAR). Patients (n = 554) received placebo nasal spray or FF, administered using a unique side‐actuated device, in a 2‐wk, randomized, double‐blind study. Symptoms were evaluated by patients using a 4‐point categorical scale. Efficacy assessments included reflective and instantaneous total nasal symptom scores (r/iTNSS). Primary analyses were conducted in patients aged 6–11 yr in the intent‐to‐treat population (ITT); the 2–11 yr group provided supportive analyses. In patients aged 6–11 yr, FF 110 μg once daily significantly improved the daily rTNSS compared with placebo. FF 55 μg once daily was only numerically better for rTNSS and iTNSS. Secondary pre‐dose iTNSS and overall response to therapy were significant with FF 110 μg. The significant findings for FF 110 μg were supported by analyses in the entire ITT population of 2–11 yr olds. Both doses of FF were well tolerated. These study results suggest that FF nasal spray administered once daily for 2 wk is well tolerated and effective for the treatment of SAR symptoms in children aged 2–11 yr.

Recently, inorganic arsenite (iAs(III)) and its mono- and dimethylated metabolites have been examined for their interference with the formation and repair of benzo[a]pyrene diol epoxide (BPDE)-induced DNA adducts in human cells (Schwerdtle, ., Walter, I., and Hartwig, A. (2003) DNA Repair 2, 1449 - 1463). iAs(III) and monomethylarsonous acid (MMA(III)) were found to be able to enhance the formation of BPDE-DNA adducts, whereas dimethylarsinous acid (DMA(III)) had no enhancing effect at all. The anomaly manifested by DMA(III) prompted us to further investigate the effects of the three trivalent arsenic species on the formation of BPDE-DNA adducts. Use of a nucleotide excision repair (NER)-deficient Xeroderma pigmentosum complementation group A cell line (GM04312C) allowed us to dissect DNA damage induction from DNA repair and to examine the effects of arsenic on the formation of BPDE-DNA adducts only. At concentrations comparable to those used in the study by Schwerdtle et al., we found that each of the three trivalent arsenic species was able to enhance the formation of BPDE-DNA adducts with the potency in a descending order of MMA(III) > DMA(III) > iAs(III), which correlates well with their cytotoxicities. Similar to iAs(III), DMA(III) modulation of reduced glutathione (GSH) or total glutathione S-transferase (GST) activity could not account for its enhancing effect on DNA adduct formation. Additionally, the enhancing effects elicited by the trivalent arsenic species were demonstrated to be highly time-dependent. Thus, although our study made use of short-term assays with relatively high doses, our data may have meaningful implications for carcinogenesis induced by chronic exposure to arsenic at low doses encountered environmentally.

Multimodal interfaces are the emerging technology that offers expressive, transparent, efficient, robust, and mobile human-computer interaction. In this paper, we described the speech/gesture based multimodal interface systematically from the human factors point of view. To design more practical and efficient multimodal interface, human factors issues such as user modeling, usability studies, speech and gesture interaction/integration, and redundancy are discussed. This paper can be helpful to the researchers in the field of study that enhances the performance of multimodal interaction.

Inhibition of DNA repair processes has been suggested as one predominant mechanism in arsenic co-genotoxicity. However, the underlying mode of action responsible for DNA repair inhibition by arsenic remains elusive. To further elucidate the mechanism of repair inhibition by arsenic, we examined the effect of trivalent inorganic and methylated arsenic metabolites on the repair of benzo(a)pyrene diol epoxide (BPDE)-DNA adducts in normal human primary fibroblasts and their effect on repair-related protein expression. We observed that monomethylarsonous acid (MMA(III)) was the most potent inhibitor of the DNA repair. MMA(III) did not change the expression levels of some key repair proteins involved upstream of the dual incision in the global nucleotide excision repair (NER) pathway, including p48, XPC, xeroderma pigmentosum complementation group A (XPA), and p62-TFIIH. However, it led to a marked impairment of p53 induction in response to BPDE treatment. The abrogated p53 expression translated into reduced p53 DNA-binding activity, suggesting a possibility of downregulating downstream repair genes by p53. A p53-null cell line failed to exhibit the inhibitory effect of MMA(III) on NER, implicating a role for p53 in the NER inhibition by MMA(III). Further investigation revealed that MMA(III) dramatically inhibited p53 phosphorylation at serine 15, implying that MMA(III) destabilized p53 by inhibiting its phosphorylation. Because p53 is required for proficient global NER, our data suggest that arsenic inhibits NER through suppressing p53 induction in response to DNA damage in cells with normal p53 gene expression.

Purpose: To evaluate the preoperative characteristics and postoperative outcomes of presbyopic and prepresbyopic patients selecting monovision correction by LASKDesign: Retrospective observational case series.Participants: One hundred seventy-two sequentially treated myopic and hyperopic patients, 45 years or older, who sought LASIK vision correction with the goal of monovision.Methods: Patients treated with monovision correction by LASIK were measured and categorized. All treatments were conducted using conventional (nonwavefront) technology.Main Outcome Measures: Acuity, refractive and functional success of monovision correction based on postoperative manifest refraction relative to target correction, and patient enhancement rate.Results: Of 284 consecutively treated LASIK patients 45 years or older, 188 (67%) chose to be corrected for monovision and 96 (34%) chose bilateral distance correction. Of the patients seeking laser vision correction, women (60%) outnumbered men (40%), and women selected monovision slightly more often than men (66.9% vs. 60.5%, P = 0.14). A majority of patients (85%) chose their dominant eye to be corrected for distance. Patients who selected their dominant eye for near vision correction had similar acceptance and refractive success rates. Hyperopic patients achieved results comparable to those of myopic patients. Of the 172 patients treated with monovision correction, only 7% chose to forego monovision and subsequently enhance the near eye to distance vision. However, 27.9% of monovision patients underwent subsequent enhancement of their distance vision eye.Conclusions: LASIK monovision correction represents a viable and increasingly popular method of correcting presbyopic and prepresbyopic patients considering refractive surgery. Crossed monovision may be applied successfully to appropriately chosen patients. The distance vision eye in the monovision patient may have a lower tolerance for residual refractive error and require a higher rate of enhancements than a standard laser vision correction patient.

BackgroundArsenite (iAsIII) can promote mutagenicity and carcinogenicity of other carcinogens. Considerable attention has focused on interference with DNA repair by inorganic arsenic, especially the nucleotide excision repair (NER) pathway, whereas less is known about the effect of arsenic on the induction of DNA damage by other agents.ObjectivesWe examined how arsenic modulates DNA damage by other chemicals.MethodsWe used an NER-deficient cell line to dissect DNA damage induction from DNA repair and to examine the effects of iAsIII on the formation of benzo[a]pyrene diol epoxide (BPDE)–DNA adducts.ResultsWe found that pretreatment with iAsIII at subtoxic concentrations (10 μM) led to enhanced formation of BPDE–DNA adducts. Reduced glutathione levels, glutathione S-transferase activity and chromatin accessibility were also measured after iAsIII treatment, but none of these factors appeared to account for the enhanced formation of DNA adducts. However, we found that pretreatment with iAsIII increased the cellular uptake of BPDE in a dose-dependent manner.ConclusionsOur results suggest that iAsIII enhanced the formation of BPDE–DNA adducts by increasing the cellular uptake of BPDE. Therefore, the ability of arsenic to increase the bioavailability of other carcinogens may contribute to arsenic co-carcinogenicity.

Previous findings from our laboratory demonstrated that some clonally expanded cerebrospinal fluid (CSF) B cells from MS patients exhibit diminished mutation targeting patterns in comparison to typical B cells selected in the context of germinal centers (GCs). In order to determine whether the overall CSF B cell repertoires adhered to mutation patterns typical of GC-selected B cells, we analyzed the immunoglobulin repertoires from CSF B cells of 8 MS patients for mutation characteristics typical of GC-derived B cells. Mutation targeting was preserved. Thus, clonal expansion of some CSF B cells may occur independently of GC, but the CSF B cell pool is governed by typical GC selection. Interestingly, the heavy chain CDR3's of CSF B cells from MS patients had a net acidic charge, similar to GC-derived B cells, but a tendency towards longer CDR3's, consistent with autoreactive B cells. How these findings may support current hypotheses regarding the origin of CSF B cells is discussed.

Arsenic is a pervasive cytotoxin and carcinogen in the environment. Although its mode of action has yet to be fully elucidated, oxidative DNA damage has been suggested. A series of DNA repair-defective human and hamster cell lines associated with sensitivity to oxidative agents were examined for their response to arsenic-induced cytotoxicity. Only the Ataxia telangiectasia (AT) cells displayed a marked hypersensitive response (greater than twofold). The protective role of the ATM protein was confirmed by the normal response to arsenic displayed by AT cells expressing wild-type ATM. Although the ATM protein plays a pivotal role in response to DNA double-strand breakage, none of the other cell lines with defects in double-strand break repair displayed a similar hypersensitivity. Further examination indicated that concentrations of sodium arsenite as high as 1 mg/l do not generate significant levels of double-strand breaks. Our data suggest that the ATM protein functions in an important but different capacity in the cellular response to arsenic toxicity than it does in response to agents that generate double-strand breaks, such as ionizing radiation. Furthermore, the lack of hypersensitivity to arsenic displayed by the other cell lines calls into question the hypothesis that DNA damage is a significant factor in arsenic cytotoxicity.

Human DNA is exposed to a variety of endogenous and environmental agents that may induce a wide range of damage. The critical role of DNA damage in cancer development makes it essential to develop highly sensitive and specific assays for DNA lesions. We describe here ultrasensitive assays for DNA damage, which incorporate immuno-affinity with capillary electrophoresis (CE) separation and laser induced fluorescence (LIF) detection. Both competitive and non-competitive assays using CE/LIF were developed for the determination of DNA adducts of benzo[a]pyrene diol epoxide (BPDE). A fluorescently labeled oligonucleotide containing a single BPDE adduct was synthesized and used as a fluorescent probe for competitive assay. Binding between this synthetic oligonucleotide and a monoclonal antibody (MAb) showed both 1:1 and 1:2 complexes between the MAb and the oligonucleotide. The 1:1 and 1:2 complexes were separated by CE and detected with LIF, revealing binding stoichiometry information consistent with the bidentate nature of the immunoglobulin G antibody. For non-competitive assay, a fluorescently labeled secondary antibody fragment F(ab′)2 was used as an affinity probe to recognize a primary antibody that was specific for the BPDE-DNA adducts. The ternary complex of BPDE-DNA adducts with the bound antibodies was separated from the unbound antibodies using CE and detected with LIF for quantitation of the DNA adducts. The assay was used for the determination of trace levels of BPDE-DNA adducts in human cells. Analysis of cellular DNA from A549 human lung carcinoma cells that were incubated with low doses of BPDE (32nM–1μM) showed a clear dose–response relationship. BPDE is a potent environmental carcinogen, and the ultrasensitive assays for BPDE-DNA adducts are potentially useful for monitoring human exposure to this carcinogen and for studying cellular repair of DNA damage.

The effects of acute administration of nicotine on target biting (defensive) and resident-intruder (offensive) attack of male mice were assessed. In the target biting procedure confined mice received tail shock on a fixed time, 2-min schedule. Under baseline conditions, biting attack directed toward an inanimate target occurred at three distinct rates. A high target biting rate (13.5 ± 3.8 bites/15 sec) followed shock delivery, an intermediate biting rate (9.6 ± 4.1 bites/15 sec) occurred during the inter-shock interval, and a low biting rate (1.0 ± 0.5 bites/15 sec) occurred during a tone stimulus which signalled the impending shock. Nicotine (administered IP, 15 min presession) reduced post-shock and inter-shock interval target biting in a dose-dependent manner (ED50 values estimated at 0.13 and 0.14 mg/kg, respectively) but exerted more variable effects on target biting during the tone. In the resident-intruder paradigm the same mice were exposed to an intruder introduced into its home cage for a 10-min test session. Under baseline conditions, residents directed 20 ± 3.2 biting attacks toward the intruder during the session with an average latency of 89 ± 40 sec to the first attack. Nicotine caused a dose-dependent decrease in this attack behavior (ED50 values estimated to be 0.48 and 0.49 mg/kg, respectively). These observations are interpreted to indicate that nicotine has an increased potency at reducing "defensive" aggression.