Biphasic Phenomenon Research Articles

Nb-Based Oxides As High Power Negative Electrode Materials

Today, one of the main challenges of lithium-ion batteries is to have the ability to charge faster and to provide high power during longer periods, thus allowing a larger development of intermittent electric power sources [1]. The actual negative electrode materials (graphite and silicon mainly) cannot sustain such high rate capabilities. In this work, we are therefore investigated some materials of the plentiful family of niobium-based oxides. A presentation of old and interesting structures will be briefly reviewed. As an example, the case of KTiNbO5 will be discussed and proposed as efficient negative electrode materials for next generation of lithium ion batteries.The layered KTiNbO5 with a two-dimensional framework represents a playground to produce a large range of closely related phases.[2] The protonated HTiNbO5 analogue is obtained by ion exchange in acidic solution and it preserves a layered structure with a smaller interlayer distance. After dehydration of HTiNbO5 at 400°C, the so-obtained Ti2Nb2O9 phase displays a 2D arrangement with empty channels unlike tunnels of H(K)TiNbO5.In this work, all the synthesized phases were studied as negative electrode materials in lithium-ion batteries. Tested in 1M LiPF6 in EC/DMC between 1.0V and 3.0V vs Li/Li+, these phases have shown different electrochemical behaviors. When HTiNbO5 exhibits a typical plateau during the charge/discharge experiment corresponding to a biphasic phenomenon, lithiation of Ti2Nb2O9 is governed by a solid—solution mechanism. For a better understanding of the charge storage mechanism, we have combined electrochemical experiments with in situ XRD measurements. We have shown that multielectron redox and corner/edge sharing system of Ti/Nb octaedra are at the origin of an interesting capacity of more than 100 mAh.g-1 at a rate of 0.2 A.g-1. A good observed cyclability (< 500 cycles) is in accordance with in situ XRD results showing a reversible behavior of the structure during cycling. Another synthesis method, using Chimie Douce techniques, leads to nanoparticules for both HTiNbO5 and Ti2Nb2O9 and allows an increase of the electrochemical performance of these materials. References : [1] Choi, C. et al, Nature Rev. Mat. 5, 5-19 (2020).[2] A. D. Wadsley, Acta Cryst. 623, 17-41 (1964).

Uninterrupted embryonic growth leading to viviparous propagule formation in woody mangrove.

Vivipary is a rare sexual reproduction phenomenon where embryos germinate directly on the maternal plants. However, it is a common genetic event of woody mangroves in the Rhizophoraceae family. The ecological benefits of vivipary in mangroves include the nurturing of seedlings in harsh coastal and saline environments, but the genetic and molecular mechanisms of vivipary remain unclear. Here we investigate the viviparous embryo development and germination processes in mangrove Kandelia obovata by a transcriptomic approach. Many key biological pathways and functional genes were enriched in different tissues and stages, contributing to vivipary. Reduced production of abscisic acid set a non-dormant condition for the embryo to germinate directly. Genes involved in the metabolism of and response to other phytohormones (gibberellic acid, brassinosteroids, cytokinin, and auxin) are expressed precociously in the axis of non-vivipary stages, thus promoting the embryo to grow through the seed coat. Network analysis of these genes identified the central regulatory roles of LEC1 and FUS3, which maintain embryo identity in Arabidopsis. Moreover, photosynthesis related pathways were significantly up-regulated in viviparous embryos, and substance transporter genes were highly expressed in the seed coat, suggesting a partial self-provision and maternal nursing. We conclude that the viviparous phenomenon is a combinatorial result of precocious loss of dormancy and enhanced germination potential during viviparous seed development. These results shed light on the relationship between seed development and germination, where the continual growth of the embryo replaces a biphasic phenomenon until a mature propagule is established.

Flupyradifurone induces transgenerational hormesis effects in the cowpea aphid, Aphis craccivora.

With low-dose stimulation and high-dose inhibition, insecticide-induced hormesis, a biphasic phenomenon, can contribute to pest resurgence. The cowpea aphid, Aphis craccivora (Koch) (Homoptera: Aphididae), is a vital insect that infests legume crops. Its hormesis of flupyradifurone has not been previously established. Age-stage two-sex life analysis is used to investigate the sublethal and transgenerational effects of flupyradifurone on two successive generations of A. craccivora. A leaf-dip bioassay method revealed high toxicity of flupyradifurone against A. craccivora, with lethal concentration 50% value (LC50) of 1.82 mg L-1 after 48 h exposure. Treatment of parent generation (F0) with LC10 and LC25 of flupyradifurone significantly increased the longevity and fecundity of the directly exposed adults. The results of transgenerational effects showed that the treatment of (F0) with LC25 induced significant hormetic effects in progeny generation (F1). Furthermore, flupyradifurone at LC25 significantly enhanced the biological traits, such as intrinsic rate of increase (r), finite rate of increase (λ), and net reproductive rate (R0) compared with the control. Similarly, both LC10 and LC25 induced a significant increase in the mean generation time T (d). Conversely, both treatments caused a significant decrease in the doubling time (DT). Data in the present study demonstrate that the exposure of (F0) to flupyradifurone at LC10 and LC25 enhanced longevity and fecundity in the directly exposed adults of A. craccivora, and induced transgenerational hormesis across the subsequent (F1) generation. These results should be taken into consideration when using flupyradifurone for controlling cowpea aphid.

The biphasic phenomenon of cytokine storm in COVID pneumonia

COVID-19 is a viral disease that commonly presents with mild symptoms with predominant respiratory system involvement. However, it can cause serious complications such as acute respiratory disease, multi-organ dysfunction, especially in patients with comorbidities. As it is a new disease, the full picture of the disease and its complications are not yet fully understood. Moreover, the patients at risk of complications are not well identified, and the data about the biphasic pattern of cytokine storm syndrome are limited. Here, we report the case of a 64-year-old male having diabetes mellitus, hypertension, ischemic heart disease with triple-vessel coronary artery disease tested positive for severe acute respiratory syndrome coronavirus 2, then complicated with acute respiratory distress syndrome and two waves of cytokine storm in 28 days.

Photocatalytic dye degradation and photoexcited anti-microbial activities of green zinc oxide nanoparticles synthesized via Sargassum muticum extracts.

Drug-resistant superbugs (DRS) were isolated from hospital sewage waste and confirmed by a 16S rDNA molecular technique as B. filamentosus, B. flexus, P. stutzeri, and A. baumannii. Green nanotechnologies provide a new promising alternative pathway that was found to be much safer, eco-friendly, and has economic benefits over physical/chemical methods. Sargassum muticum (SM) mediated zinc oxide nanoparticles (ZnO-NPs) were proved to be photocatalytic and anti-microbial agents. Anti-microbial action was demonstrated by a maximal growth inhibition activity of 18 mm against A. baumannii and a minimal of 12 mm against B. flexus at 80 μg mL−1 concentrations. The anti-microbial mechanism of SMZnO-NPs employed a biphasic phenomenon persuaded by an osmotic shock that can attack the DRS bacterial cells directly and lead to death. In addition, photocatalytic activity was investigated by SMZnO-NPs for the degradation of methylene blue (MB) dye under different light conditions. Natural sunlight irradiation shows effective enhancement with the highest efficiencies of 96% being achieved within 60 min compared to UV-light and visible-light. The reusability of SMZnO-NPs provides up to 6 consecutive cycles towards MB decolorization for environmental water cleansing.

Reconceptualization of Hormetic Responses in the Frame of Redox Toxicology.

Cellular adaptive mechanisms emerging after exposure to low levels of toxic agents or stressful stimuli comprise an important biological feature that has gained considerable scientific interest. Investigations of low-dose exposures to diverse chemical compounds signify the non-linear mode of action in the exposed cell or organism at such dose levels in contrast to the classic detrimental effects induced at higher ones, a phenomenon usually referred to as hormesis. The resulting phenotype is a beneficial effect that tests our physiology within the limits of our homeostatic adaptations. Therefore, doses below the region of adverse responses are of particular interest and are specified as the hormetic gain zone. The manifestation of redox adaptations aiming to prevent from disturbances of redox homeostasis represent an area of particular interest in hormetic responses, observed after exposure not only to stressors but also to compounds of natural origin, such as phytochemicals. Findings from previous studies on several agents demonstrate the heterogeneity of the specific zone in terms of the molecular events occurring. Major factors deeply involved in these biphasic phenomena are the bioactive compound per se, the dose level, the duration of exposure, the cell, tissue or even organ exposed to and, of course, the biomarker examined. In the end, the molecular fate is a complex toxicological event, based on beneficial and detrimental effects, which, however, are poorly understood to date.

Niobium Oxides: A New Path to Achieving High-Power Batteries? the Case of H-Ti-Nb Oxide System

Today, one of the main challenges of lithium-ion batteries is to have the ability to charge faster and to provide high power during longer periods, thus allowing a larger development of intermittent electric power sources [1]. The actual negative electrode materials (graphite and silicon mainly) cannot sustain such high rate capabilities. We are therefore investigating a family of titanoniobate oxides, such as KTiNbO5, HTiNbO5, and Ti2Nb2O9, and proposing them as efficient negative electrode materials for next generation lithium ion batteries.The layered KTiNbO5 with a two-dimensional framework represents a playground to produce a large range of closely related phases [2]. The protonated HTiNbO5 analogue is obtained by ion exchange in acidic solution and it preserves a layered structure with a smaller interlayer distance. After dehydration of HTiNbO5 at 400°C, the so-obtained Ti2Nb2O9 phase displays a 2D arrangement with empty channels unlike tunnels of H(K)TiNbO5 [3]. Afterwards, by acido/basic reduction, exfoliation of HTiNbO5 into TiNbO5 - single nanosheets (NS) followed by their restacking, results in a material with smaller particles size and higher specific surface area as shown in Figure 1.a.In this work, all the synthesized phases were studied as negative electrode materials in lithium-ion batteries. Tested in 1M LiPF6 in ED/DMC between 1.0V and 3.0V vs Li/Li+, these phases have shown different electrochemical behaviors (Figure 1.b). When HTiNbO5 exhibits a typical plateau during the charge/discharge experiment corresponding to a biphasic phenomenon, Ti2Nb2O9 show a solid—solution mecanism. For a better understanding of the charge storage mechanism, we have combined electrochemical experiments with in situ XRD measurements. We have shown that multielectron redox and corner/edge sharing system of Ti/Nb octaedra are at the origin of an interesting capacity of more than 100 mAh.g-1 at a rate of 0.2 A.g-1. A good observed cyclability (< 1000 cycles) is in accordance with in situ XRD results showing a reversible behavior of the structure during cycling. Another synthesis method, using Chimie Douce techniques, leads to nanoparticules for both HTiNbO5 SG and Ti2Nb2O9 SG and allows an increase of the electrochemical performance of these materials, will also be discussed in this presentation. Figure 1

A Bayesian semi-parametric model for thermal proteome profiling

The thermal stability of proteins can be altered when they interact with small molecules, other biomolecules or are subject to post-translation modifications. Thus monitoring the thermal stability of proteins under various cellular perturbations can provide insights into protein function, as well as potentially determine drug targets and off-targets. Thermal proteome profiling is a highly multiplexed mass-spectrommetry method for monitoring the melting behaviour of thousands of proteins in a single experiment. In essence, thermal proteome profiling assumes that proteins denature upon heating and hence become insoluble. Thus, by tracking the relative solubility of proteins at sequentially increasing temperatures, one can report on the thermal stability of a protein. Standard thermodynamics predicts a sigmoidal relationship between temperature and relative solubility and this is the basis of current robust statistical procedures. However, current methods do not model deviations from this behaviour and they do not quantify uncertainty in the melting profiles. To overcome these challenges, we propose the application of Bayesian functional data analysis tools which allow complex temperature-solubility behaviours. Our methods have improved sensitivity over the state-of-the art, identify new drug-protein associations and have less restrictive assumptions than current approaches. Our methods allows for comprehensive analysis of proteins that deviate from the predicted sigmoid behaviour and we uncover potentially biphasic phenomena with a series of published datasets.

Model-Based Prediction to Evaluate Residence Time of Hyaluronic Acid Based Dermal Fillers

Dermal fillers are gel-type substances for nonsurgical medical-device use to achieve facial rejuvenation. Currently, the most widely used skin fillers are hyaluronic-acid-based dermal fillers. This study aimed to explain the change in the volume of injected dermal fillers by developing a mathematical kinetic model for various dermal fillers. The kinetics of the injected fillers were separated by a biphasic phenomenon. We attributed an increase in filler volume to the hydration of hyaluronic acid molecules and injection-site reaction and a decrease in volume to enzyme-mediated degradation. To explain these in vivo characteristics of dermal fillers, we proposed a two-compartment model, divided into a depot compartment (where the filler was injected) and a subcutaneous compartment (an observation compartment where the fillers swell and degrade), assuming that the swelling and degradation occurred in accordance with the swelling and degradation rate constants, respectively. The model was developed using five hyaluronic-acid-based dermal fillers and NONMEM. We determined that the rate-limiting step for the complete degradation of the dermal fillers in vivo was the swelling phase, as described by the swelling rate constant (Kswell). This study could enable scientists developing novel dermal fillers to predict the in vivo behavior of fillers.

Thiamethoxam induces transgenerational hormesis effects and alteration of genes expression in Aphis gossypii

Insecticide induced-hormesis, a bi-phasic phenomenon characterized by low dose stimulation and high dose inhibition following exposure to insecticide, is crucial to insect pest resurgence. In this study, the effects of low or sublethal concentrations of thiamethoxam on biological traits and genes expression were investigated for Aphis gossypii Glover following 72 h exposures. Leaf-Dip bioassay results showed that thiamethoxam was very toxic against adult A. gossypii with an LC50 of 1.175 mg L−1. The low lethal (LC15) and sublethal (LC5) concentrations of thiamethoxam significantly reduced longevity and fecundity of the directly exposed aphids. However, stimulatory effects on pre-adult stage, longevity, and fertility were observed in the progeny generation (F1) of A. gossypii, when parental aphids (F0) were exposed to LC15 of thiamethoxam. Subsequently, biological traits such as intrinsic rate of increase (r), finite rate of increase (λ), and net reproductive rate (R0) increased significantly to F1 individuals due to LC15 treatment. No significant responses were observed for LC5 of thiamethoxam. The LC15 of thiamethoxam significantly increased the expression level of vitellogenin and ecdysone receptors genes in progeny generation, while no effects were observed for treatment with LC5. Additionally, the expression levels of P450 genes including CYP6CY14, CYP6CZ1, CYP6DC1, CYP6CY9, and CYP6DD1 were up-regulated in the exposed aphids. Taken together, our results show the hormetic effects of thiamethoxam on F1 individuals, which might be due to the intermittent changes in expression of genes involved in fertility, growth and insecticide detoxification in A. gossypii.

Biocompatible nanoparticles with enhanced photocatalytic and anti-microfouling potential

Biocompatible green synthesized nanoparticles (NPs) were investigated for their use in improving the photocatalytic efficacy of methylene blue (MB) dye and anti-microfouling activity. Silver nanoparticles (AgNPs) synthesized using seaweed extract of Sargassum muticum (SM) as reducing agent and their structural, textural features were characterized by various analytical techniques. SM-AgNPs under UV-light irradiation attained a photocatalytic activity of MB dye up to 94.6% for 60 min in addition to anti-microfouling performance of MBF bacteria achieved 96% inhibition within 20 min. Kinetics study of MB removal followed a pseudo first order kinetics and the apparent constant rate value was calculated as 0.0365 min−1 showing higher catalytic activity under UV-light irradiation. Anti-microbial screening against 16S rDNA confirmed MBF (n = 3) strains such as Gram Positive - Bacillus flexus (NCBI Accession No: MBF1 AB894825), Bacillus megaterium (NCBI Accession No: AB894828) and Gram Negative - Pseudomonas sp., (NCBI Accession No: AB894829) were studied. SM-AgNPs showed a maximum inhibition zone (18 mm) in Pseudomonas sp., and minimal inhibition zone (12 mm) in Bacillus flexus. These results signified that SM-AgNPs employed a biphasic phenomenon persuading by osmotic shock and thymine-dimer formation on microbial cells that cause microbial destruction.

Evaluation of Insecticides induced hormesis on the demographic parameters of Myzus persicae and expression changes of metabolic resistance detoxification genes

Insecticide induced-hormesis is a bi-phasic phenomenon generally characterized by low-dose induction and high-dose inhibition. It has been linked to insect pest outbreaks and insecticide resistance, which have importance in the integrated pest management (IPM). In this paper, hormesis effects of four insecticides on demographic parameters and expression of genes associated with metabolic resistance were evaluated in a field collected population of the green peach aphid, Myzus persicae Sulzer. The bioassay results showed that imidacloprid was more toxic than acetamiprid, deltamethrin and lambda-cyhalothrin. After exposure to sublethal doses of acetamiprid and imidacloprid for four generations, significant prolonged nymphal duration and increased fecundity were observed. Subsequently, mean generation time (T) and gross reproductive rate (GRR) was significantly increased. Moreover, expression of CYP6CY3 gene associated with resistance to neonicotinoids was increased significantly compared to the control. For pyrethriods, across generation exposure to sublethal doses of lambda cyhalothrin and deltamethrin prolonged the immature development duration. However, the expression of E4 gene in M. persicase was decreased by deltamethrin exposure but increased by lambda cyhalothrin. Based on results, demographic fitness parameters were effected by hormetic dose and accompanied with detoxifying genes alteration, hence, which would be evaluated in developing optimized insect pest management strategies.

Wnt/β-Catenin/TCF Pathway Is a Phase-Dependent Promoter of Colony Formation and Mesendodermal Differentiation During Human Somatic Cell Reprogramming.

Somatic cell reprogramming is a biphasic phenomenon that goes through a mesenchymal-to-epithelial transition, called initiation phase, followed by a maturation phase wherein reprogramming cells acquire pluripotency. Here, we show that these phases display a differential response to Wnt signaling activation. Wnt signaling increases colony formation by promoting cellular epithelialization during the initiation phase in a TCF7-dependent manner. However, during maturation phase, it is also responsible for inducing mesendodermal differentiation, which is negatively regulated by TCF7L1. Thus, Wnt signaling inhibition or TCF7L1 overexpression downregulates mesendodermal gene expression without perturbing pluripotency. Together, our results demonstrate that a phase-specific modulation of Wnt signaling leads to an improved reprogramming efficiency in terms of colony output and pluripotency acquisition. This work provides new insights into the cell context-dependent roles of Wnt signaling during human somatic cell reprogramming. Stem Cells 2018;36:683-695.

Supraphysiologic Testosterone Therapy in the Treatment of Prostate Cancer: Models, Mechanisms and Questions.

Since Huggins defined the androgen-sensitive nature of prostate cancer (PCa), suppression of systemic testosterone (T) has remained the most effective initial therapy for advanced disease although progression inevitably occurs. From the inception of clinical efforts to suppress androgen receptor (AR) signaling by reducing AR ligands, it was also recognized that administration of T in men with castration-resistant prostate cancer (CRPC) could result in substantial clinical responses. Data from preclinical models have reproducibly shown biphasic responses to T administration, with proliferation at low androgen concentrations and growth inhibition at supraphysiological T concentrations. Many questions regarding the biphasic response of PCa to androgen treatment remain, primarily regarding the mechanisms driving these responses and how best to exploit the biphasic phenomenon clinically. Here we review the preclinical and clinical data on high dose androgen growth repression and discuss cellular pathways and mechanisms likely to be involved in mediating this response. Although meaningful clinical responses have now been observed in men with PCa treated with high dose T, not all men respond, leading to questions regarding which tumor characteristics promote response or resistance, and highlighting the need for studies designed to determine the molecular mechanism(s) driving these responses and identify predictive biomarkers.

Development and in vitro evaluation of oxytetracycline-loaded PMMA nanoparticles for oral delivery against anaplasmosis.

Poly-methyl methacrylate (PMMA) polymer with remarkable properties and merits are being preferred in various biomedical applications due to its biocompatibility, non-toxicity and cost effectiveness. In this investigation, oxytetracycline-loaded PMMA nanoparticles were prepared using nano-precipitation method for the treatment of anaplasmosis. The prepared nanoparticles were characterised using dynamic light scattering (DLS), atomic force microscopy (AFM), differential scanning calorimetry (DSC) and Fourier transform infrared (FTIR) spectroscopy. The mean average diameter of the nanoparticles ranged between 190-240 nm and zeta potential was found to be -19 mV. The drug loading capacity and entrapment efficiency of nanoparticles was found varied between 33.7-62.2% and 40.5-60.0%. The in vitro drug release profile exhibited a biphasic phenomenon indicating controlled drug release. The uptake of coumarin-6(C-6)-loaded PMMA nanoparticles in Plasmodium falciparum (Pf3D7) culture model was studied. The preferential uptake of C-6-loaded nanoparticles by the Plasmodium infected erythrocytes in comparison with the uninfected erythrocytes was observed under fluorescence microscopy. These findings suggest that oxytetracycline-loaded PMMA nanoparticles were found to be an effective oral delivery vehicle and an alternative pharmaceutical formulation in anaplasmosis treatment, too.

Elimination of the biphasic pharmacodynamics of 15d-PGJ2 by controlling its release from a nanoemulsion.

15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) has a dual action of stimulating anti-inflammation and anti-proliferation when exogenously administered at high doses. However, at lower doses, it can be toxic inducing opposite actions, ie, stimulation of both inflammation and cell proliferation. This biphasic phenomenon of 15d-PGJ2 is believed to be due to its multitarget behavior. In this study, we provide a strategy for controlling such biphasic pharmacodynamics by separating its dual actions while retaining the beneficial one by using a nanoemulsion (NE). The 15d-PGJ2 was encapsulated in the NE composed of triolein/distearoyl phosphatidylcholine/Tween 80 at a high encapsulation ratio (>83%). Furthermore, NE enhanced drug retention by slowing down its release rate, which was, unconventionally, inversely dependent on the total surface area of the NE system. Next, focusing on the biphasic effect on cell proliferation, we found that the 15d-PGJ2-loaded slow-release NE showed only a dose-dependent inhibition of the viability of a mouse macrophage cell line, RAW264.7, although a fast-release NE as well as free 15d-PGJ2 exerted a biphasic effect. The observed slow-release kinetics are believed to be responsible for elimination of the biphasic pharmacodynamics of 15d-PGJ2 mainly for two reasons: 1) a high proportion of 15d-PGJ2 that is retained in the NE was delivered to the cytosol, where proapoptotic targets are located and 2) 15d-PGJ2 was able to bypass cell membrane-associated targets that lead to the induction of cellular proliferation. Collectively, our strategy of eliminating the 15d-PGJ2-induced biphasic pharmacodynamics was based on the delivery of 15d-PGJ2 to its desired site of action, excluding undesired sites, on a subcellular level.

Biphasic effect of hypercapnia on myocardial contractility.

AbstractThe effects of hypercapnia were studied in cat papillary muscles driven at a frequency of 12 beats/min. The Pco2 of the medium was changed from ⋍ 25 mm to 95 mmHg. Developed tension (DT) and maximal rate of tension development (dT/dt max) were recorded during a 30-minute period. Under isometric conditions and at 30 °C, increasing Pco2 resulted in a biphasic phenomenon Characterized by a decrease in DT and dT/dt max, followed by a partial recovery. Similar results were obtained under isotonic conditions, reserpine pretreatment or addition of propranolol. In the latter experiments, however, values of maximum depression and after 30 minutes of hypercapnia, were significantly lower than without the β-blocking agent.At 22 °C and 22 °C plus reserpine, maximum contractility depression was greater and occurred later during the hypercapnic period than at 30 °C. In addition, at 22 °C plus reserpine, the degree and rate of recovery were significantly lower than at 30 °C.High calcium concentration diminished ...

Sublethal concentrations of imidacloprid increase reproduction, alter expression of detoxification genes, and prime Myzus persicae for subsequent stress

Hormesis, a biphasic phenomenon characterized by low-dose stimulation and high-dose inhibition following exposure to stress, has been reported in many different insects exposed to low doses of pesticide. Using green peach aphid, Myzus persicae (Sulzer) (Hemiptera: Aphididae), and the insecticide imidacloprid as a model, we tested whether or not there were changes in expression of genes involved in insecticide detoxification and general stress when aphids were exposed over multiple generations in a greenhouse setting to imidacloprid concentrations that induced hormetic responses. We also wanted to know whether exposure to insecticide concentrations that induce reproductive hormesis impacted the insect’s ability to cope with a subsequent stressor. The instantaneous rate of increase and total reproductive output of aphids developing on potato plants treated with 0.25 µg imidacloprid L−1 was significantly greater than that on control plants. Treatments of 0.25 and 2.5 µg imidacloprid L−1 significantly increased or decreased expression of genes for E4-esterase, cytochrome P450-CYP6CY3, and Hsp60 in aphids, with variation within and across generations. Third-generation aphids from plants treated with 0.25 µg imidacloprid L−1 survived longer than control aphids when subsequently subjected to food/water stress, but not when subsequently exposed to a LC20 of another insecticide. Our results indicate insecticide-induced reproduction hormesis in M. persicae is accompanied by intermittent changes in expression of detoxification and stress-coping genes, and that it can prime the insect to cope with subsequent stress.

Abstract B55: Chemokine biased agonists regulate pancreatic cancer migration and metastasis through bioenergetic signaling

Abstract Across all stages of initial diagnosis, the majority of patients with pancreatic ductal adenocarcinoma (PDAC) eventually succumb to metastatic disease. Yet, there are no drugs approved for disruption of the specific mechanisms behind PDAC metastasis. As soluble/secreted proteins, chemokines provide a unique opportunity to manipulate cancer cell movement and metastasis. Our prior reports show that chemokines such as CXCL12 regulate movement in a biphasic concentration dependent fashion, wherein low doses drive migration and higher doses are cytostatic. This biphasic migration response reflects the dose dependent oligomerization of the ligand, with monomeric CXCL12 as pro-migratory and dimeric CXCL12 as anti-migratory. Previously, we demonstrated that the CXCL12 gene is silenced in human PDAC tumor cells and, when re-expressed, is a tumor suppressor decreasing growth and metastasis. Herein, we examine how CXCL12 inhibits PDAC malignancy and explore CXCL12 use as a biologic therapy for PDAC metastasis. Established and patient-derived PDAC cells along with tumor cells derived from the B6-KRasLSL.G12D/+-p53R172H/+-PdxCretg/+ (KPC) model were used to test the hypothesis that CXCL12 biphasic chemotactic signaling reflects biased agonist regulation of bioenergetic signaling. In transwell assays, human PDAC cells responded to recombinant wild type CXCL12 (L12WT) in a biphasic manner, with 10 nM L12WT as pro-migratory and concentrations ≥ 100 nM as cytostatic. As predicted by the biased agonist model, migratory and cytostatic doses of L12WT stimulated equivalent intracellular calcium mobilization. Though calcium signaling has previously been associated with activity of AMP-Kinase (AMPK), a known regulator of metabolic stress, no prior studies have established a link between bioenergetics and chemotactic migration. Given CXCL12 dual regulation of growth and migration, we next tested the hypothesis that CXCL12 alters bioenergetic metabolism using a Seahorse XF analyzer. In MiaPaCa2 cells, while cell bioenergetics were unchanged by migratory doses, cytostatic doses of L12WT significantly decreased both ATP-linked oxidative phosphorylation and reserve glycolysis capacity. In parallel, cytostatic doses of L12WT significantly increased levels of phosphorylated AMPK in human and murine PDAC cells. L12WT-induced AMPK activity was calcium/calmodulin-kinase II dependent. Anti-motile effects of CXCL12 were dependent on AMPK signaling as the specific inhibitor Compound C completely prevented the cytostasis induced by L12WT. Subsequent experiments established that cytostatic doses of L12WT drove inhibitory phosphorylation of MYPT1, preventing dephosphorylation of myosin light chain (MLC). Thus, use of the AMPK inhibitor reversed the CXCL12 biphasic phenomenon by restoring balance to MLC dephosphorylation-phosphorylation cycling, allowing PDAC cells to once again migrate. CXCL12 biphasic migration was mimicked with locked mutants of CXCL12, with monomer (L121) as pro-migratory but equal levels of dimer (L122) as anti-migratory. Stimulation of PDAC cells with L122 lead to more sustained AMPK activity when compared with L121. Finally, in mouse orthotopic xenografts of two different PDAC cell lines, intraperitoneal administration of 5 μM L12WT significantly decreased PDAC metastasis to the liver and lung. Together, these data demonstrate for the first time that the cytostatic component of CXCL12 function is AMPK dependent. Given the ability of CXCL12 to regulate bioenergetic migratory signaling, our data show the promise of recombinant CXCL12 and biased agonist variants, as a biologic therapy for abrogating PDAC metastasis. Citation Format: Ishan Roy, Donna McAllister, Egal Gorse, Kate Dixon, Gang Cheng, Anthony Getschman, Dannielle Engle, Susan Tsai, David Tuveson, Douglas Evans, Brian Volkman, Balaraman Kalyanaraman, Michael Dwinell. Chemokine biased agonists regulate pancreatic cancer migration and metastasis through bioenergetic signaling. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B55.

Biphasic Alterations in Expression and Subcellular Localization of MUC1 in Pancreatic Ductal Carcinogenesis in Syrian Hamsters.

The aim of the present study was to characterize molecular targets for the prevention/diagnosis of pancreatic cancer using a chemically induced hamster pancreatic carcinogenesis model, in which background injuries to the parenchyma, for example, chronic pancreatitis or acinar atrophy, are limited. Gene expression profiles in atypical hyperplasias were first investigated using a microarray technique. Immunohistochemical analyses of early lesions and invasive ductal carcinoma (IDC) were then conducted for MUC1, of which mRNA levels were prominent among the up-regulated genes, in contrast with the coexpression of epithelial-mesenchymal transition (EMT)-related proteins. Immunohistochemistry for MUC1 cytoplasmic domain (MUC1-CD), which was not detected in normal-like pancreatic ducts, was positive in the apical surfaces of the epithelia of hyperplasias with and without atypia and IDC areas with distinct tubular patterns. In contrast, cytoplasmic/nuclear positivity for MUC1-CD was observed in the invasive front of IDCs. The coexpression of EMT-related proteins, such as slug and vimentin, with cytoplasmic/nuclear MUC1-CD was also detected. Alterations in the expression and subcellular localization of MUC1 represent a biphasic phenomenon, and the latter may be associated with EMT in pancreatic carcinogenesis in hamsters, which indicates that changes in MUC1 are important targets for pancreatic cancer prevention and chemotherapy.