Nagrinėjami sistemos sprendiniai, kai eilės išsigimimas reguliarus (p=0) ir pirmasis sistemos koeficientų dėstinio laipsnine eilute narys nepriklauso nuo kintamųjų y ir z, reiškiami laipsnine x laipsnių eilute.Nereguliaraus arba stipraus išsigimimo atveju formalūs sprendiniai laipsninėmis eilutėmis neegzistuoja.Čia sukonstruotos nagrinėjamos sistemos atskirųjų sprendinių šeimos priklauso nuo laisvai parenkamos kintamųjų y ir z funkcijos, t.y. ta funkcija priklauso nuo kintamųjų, pagal kuriuos nėra jokio išsigimimo. Paprastųjų diferencialinių lygčių teorijoje sprendiniai yra vienparametrinės kreivių šeimos.Visais atvejais sukonstruotos apskritai 4 (4 pirmos eilės dalinių išvestinių diferencialinių lygčių sistema) atskirųjų sprendinių šeimos. / Under consideration solutions of the system, when the malformation of the system’s queue is regular and first member of the system’s coefficients power queue opt out variable y and z, stands for power x power queue.Under consideration here was designed discrete’s solutions families of the system without restraint selecting variables y and z function, i.e., that function depends from variables whereby none malformation. In theory of the regular differentials equations the solutions are family’s of one-parameter curve’s.Generally, in all senses there are designed 4 (4 partial’s derived diferencials equations of the first queue’s system) families of the discrete solutions.

Occurrences of carbonate-cemented nodules and concretions exposed on the seafloor that contain cements with light carbon isotopes, indicating a contribution of methane-derived carbon, are commonly interpreted to be indicators of seafloor fluid venting. Thus, their presence is commonly used as an indicator of the possible occurrence of methane gas hydrate within the near subsurface. While some of these carbonates exhibit facies that require formation on the seafloor, the dominant fine-grained lithology associated with these carbonates indicates they were formed as sedimenthosted nodules within the subsurface and are similar to nodules that are obtained from the subsurface in Deep Sea Drilling Project, Ocean Drilling Project, and Integrated Ocean Drilling Project boreholes. Here we present the hypothesis that the occurrence of these carbonates on the seafloor may instead indicate areas of persistent seafloor erosion.

Despite the increasing clinical demand in reconstructive, cosmetic and correctional surgery there remains no optimal strategy for the regeneration or replacement of adipose tissue. Previous approaches to adipose tissue engineering have failed to create an adipose tissue depot that maintains implant volume in vivo long-term (>3 months). This is due to inadequate mechanical properties of the biomaterial and insufficient vascularization upon implantation. Modular tissue engineering is a means to produce large volume functional tissues from small sub-mm sized tissues with an intrinsic vascularization. We first explored the potential of a semi-synthetic collagen/poloxamine hydrogel with improved mechanical properties to be used as the module biomaterial. We found this biomaterial to not be suitable for adipose tissue engineering because it did not support embedded adipose-derived stem cell (ASC) viability, differentiation and human microvascular endothelial cell (HMEC) attachment. ASC-embedded collagen gel modules coated with HMEC were then implanted subcutaneously in SCID mice to study its revascularization potential. ASC cotransplantation was shown to drive HMEC vascularization in vivo: HMEC were seen to detach from the surface of the modules to form vessels containing erythrocytes as early as day 3; vessels decreased in number but increased in size over 14 days; and persisted for up to 3 months. Early vascularization promoted fat development. Only in the case of ASC-HMEC cotransplantation was progressive fat accumulation observed in the module implants. Although implant volume was not maintained, likely due rapid collagen degradation, the key result here is that ASC-HMEC cotransplantation in the modular approach was successful in creating vascularized adipose tissue in vivo that persisted for 3 months. The modular system was then studied in vitro to further understand ASC-EC interaction. Coculture with ASC was shown to promote an angiogenic phenotype (e.g. sprouting, migration) from HUVEC on modules. RT-PCR analysis revealed that VEGF, PAI-1 and TNFα was involved in ASC-EC paracrine signalling. In summary, ASC-HMEC cotransplantation in modules was effective in rapidly forming a vascular network that supported fat development. Future work should focus on further elucidating ASC-EC interactions and developing a suitable biomaterial to improve adipose tissue development and volume maintenance of engineered constructs.

The world’s appetite for energy is producing growing quantities of CO2, a pollutant that contributes to the warming of the planet and which currently cannot be removed or stored in any significant way. Other natural reserves are also being devoured at alarming rates and current assessments suggest that we will need to identify alternative sources in the near future. With the aid of materials chemistry it should be possible to create a world in which energy use needs not be limited and where usable energy can be produced and stored wherever it is needed, where we can minimize and remediate emissions as new consumer products are created, whilst healing the planet and preventing further disruptive and harmful depletion of valuable mineral assets. In achieving these aims, the creation of new and very importantly greener industries and new sustainable pathways are crucial. In all of the aforementioned applications, new materials based on carbon, ideally produced via inexpensive, low energy consumption methods, using renewable resources as precursors, with flexible morphologies, pore structures and functionalities, are increasingly viewed as ideal candidates to fulfill these goals. The resulting materials should be a feasible solution for the efficient storage of energy and gases. At the end of life, such materials ideally must act to improve soil quality and to act as potential CO2 storage sinks. This is exactly the subject of this habilitation thesis: an alternative technology to produce carbon materials from biomass in water using low carbonisation temperatures and self-generated pressures. This technology is called hydrothermal carbonisation. It has been developed during the past five years by a group of young and talented researchers working under the supervision of Dr. Titirici at the Max-Planck Institute of Colloids and Interfaces and it is now a well-recognised methodology to produce carbon materials with important application in our daily lives. These applications include electrodes for portable electronic devices, filters for water purification, catalysts for the production of important chemicals as well as drug delivery systems and sensors. / Der stets wachsende globale Energiebedarf führt zu immer weiter zunehmenden Emissionen von Kohlenstoffdioxid, einem umweltschädlichen Gas, das als eines der Hauptprobleme im weltweiten Klimawandel darstellt. Bislang ist es jedoch nicht möglich, dieses Kohlenstoffdioxid in sinnvoller Weise zu verwerten oder einzulagern. Zudem existieren weitere Probleme in der globalen Energieversorgung, da viele natürlich vorkommende Rohstoffe sehr schnell ausgebeutet werden, so dass in naher Zukunft dringend alternative Energiequellen gefunden werden müssen, um den aktuellen Problemen zu begegnen. Der Wissenschaftszweig der Materialchemie zielt in diesem Zusammenhang darauf ab, dazu beizutragen, die bestehende Energieinfrastruktur nachhaltig zu verändern. Dabei stehen verschiedene Aspekte im Vordergrund: Energie sollte in allen gewünschten Mengen jederzeit verfügbar und auch speicherbar sein. Zudem sollte ihre Erzeugung ohne umweltschädliche Abfallprodukte ablaufen. Tiefgreifende Eingriffe in die Umwelt, v.a. durch den übermäßigen Abbau von Rohstoffen, sollte nicht mehr erforderlich sein. Auf diese Weise können die Folgen des bisherigen Klimawandels eingedämmt werden und neue Schäden an der Umwelt vermieden werden. Neue, grüne Industrie- und Energieprozesse schützen hier also nachhaltig den Planeten. Bei der Forschung an nachhaltigen Formen der Energieversorgung beschäftigen sich Materialchemiker in mannigfaltiger Weise mit Kohlenstoffmaterialien. Diese sollten idealerweise kostengünstig und ohne hohen Energiebedarf produziert werden können. Am vielversprechendsten sind Materialien, die eine flexibel gestaltbare Morphologie besitzen, d.h. die besondere strukturelle Eigenschaften besitzen, wie z.B. Porosität oder chemisch veränderte und damit funktionale Oberflächen. Idealerweise sollten solche neu entwickelten Materialien nicht nur als Speicher von Energie oder Energieträgern dienen, sondern auch nach ihrer Lebensdauer als funktionales Material zur Verbesserung der Bodenqualität eingesetzt werden können und dort noch weiter als potentielle Senke für Kohlenstoffdioxid dienen können. Die zuvor beschriebenen Themen und Probleme stellen den Gegenstand der vorliegenden Habilitationsschrift dar: die Entwicklung einer alternativen Methode zur Herstellung von Kohlenstoffmaterialien aus Biomasse in Wasser bei geringen Temperaturen. Dabei handelt es sich um die sogenannte hydrothermale Karbonisierung, die in den letzten fünf Jahren von einer Gruppe junger, talentierter Wissenschaftler unter der Anleitung von Frau Dr. Titirici am Max-Planck-Institut für Kolloid- und Grenzflächenforschung erarbeitet und weiterentwickelt wurde zu einer heutzutage anerkannten und verbreiteten Methode. Zudem wurden die über diesen Weg gewonnenen Materialien erfolgreich in zahlreichen, für den Alltag wichtigen Anwendungen eingesetzt, so z.B. als Elektroden in tragbaren elektronischen Geräten, als Filtermaterialien für die Aufreinigung kontaminierten Wassers, als Katalysatoren für wichtige chemische Reaktionen, als Trägermaterial für Arzneimittel und als Sensoren.

Co-delivery of the embedded growth factor-loaded microspheres and adult stem cells in a hydrogel matrix was studied for its potential as a cell-based therapeutic strategy for cartilage regeneration in partial thickness chondral defects. A photopolymerizable N-methacrylate glycol chitosan (MGC) was employed to form an in situ gel that was embedded with two formulations of growth factor-loaded microspheres and human adipose-derived stem cells (ASC). The polymeric microspheres were used as a delivery vehicle for the controlled release of growth factors to stimulate differentiation of the ASC towards the chondrocyte lineage. The microspheres were made of amphiphilic low molecular weight (Mn < 10,000 Da) poly(1,3-trimethylene carbonate-co--caprolactone)-b-poly(ethylene glycol)-b-poly(1,3-trimethylene carbonate-co--caprolactone) (P(TMC-CL)2-PEG)). This triblock copolymer is solid below 100C, but liquid with a low degree of crystallinity at physiological temperature and degrades slowly, and so acidic degradation products do not accumulate locally. Bone morphogenetic protein-6 (BMP-6) and transforming growth factor-3 (TGF-3) were delivered at 5 ng/day with initial bursts of 14.3 and 23.6%, respectively. Both growth factors were highly bioactive when released, retaining greater than 95% bioactivity for 33 days as measured by cell-based assays. To improve ASC viability within the MGC vehicle, an RGD-containing ligand was grafted to the MGC backbone. Prior to chondrogenic induction within the MGC gel, ASC viability was assessed and greater than 90% of ASC were viable in the gel grafted with cell-adhesive RGD peptides as compared to that in non-RGD grafted gels. For ASC chondrogenesis induced by the sustained release of BMP-6 and TGF-3 in MGC gels, the ASC cellularity and glycosaminosglycan production were similar for 28 days. The ratio of collagen type II to I per cell (normalized to deoxyribonucleic acid content) in the microsphere delivery group was significantly higher than that of non-induced ASC or with soluble growth factor administration in the culture media, and increased with time. Thus, the co-delivery of growth factor-loaded microspheres and ASC in MGC gels successfully induced ASC chondrogenesis and is a promising strategy for cartilage repair. / Thesis (Ph.D, Chemical Engineering) -- Queen's University, 2011-06-07 19:32:50.94

Recent paleolimnological research in the eastern Canadian high Arctic on the ecological impact of the Thule c.1000-1500 AD has documented the influence of prehistoric anthropogenic activities. Six lake and pond sites (three pairs) on the south-western coast of Baffin Island, Nunavut, were used to compare impacted and non-impacted sites in the southern-most region of Thule occupation, as well as to compare Thule occupation sites with sites occupied by another early Arctic population group, the Dorset. Tanfield 1 and Tanfield 2 (impacted and control, respectively) are adjacent to several multiple-occupation Dorset sites on Cape Tanfield; Juet 1 and 2 (impacted and control, respectively) are adjacent to a short-term occupation Dorset site on Juet Island; McKellar 1 is adjacent to a multiple-occupation Thule site near McKellar Bay. A nearby site (McKellar 2) was also studied, but it was clearly an anomalous, eutrophic site, rather than a control for McKellar 1. Diatom assemblages and sedimentary 15N profiles were analyzed in sediment cores from all study sites. Selected paired sediment intervals were AMS radiocarbon dated using both humic acids and terrestrial macrofossils in an attempt to establish basal dates for each core. Significant differences between several of the paired AMS radiocarbon dates serve as a cautionary note for dating Arctic sediments using either humic acids or terrestrial macrofossils. Paleolimnological analyses revealed that at both multiple-occupation sites (Tanfield 1 and McKellar 1), the activities of the Dorset and the Thule influenced lake ecology, while at the short-term occupation site (Juet 1), the Dorset occupation was not sufficiently large to have a discernible impact. McKellar 1 showed a greater impact compared to Tanfield 1, consistent with the intense marine mammal hunting by Thule at the former, compared to the moderate marine mammal hunting by Dorset at Tanfield 1. The origin of marine-derived nutrients at McKellar 2 could not be ascertained with certainty. The influence of early Arctic population groups remains obvious in present-day nutrient- and production-related water chemistry variables. This research points to the value of collaborations between paleolimnologists and archaeologists and may provide insight into the future implications of current anthropogenic activities in the Arctic. / Thesis (Master, Biology) -- Queen's University, 2011-10-04 15:52:18.29

Despite the increasing clinical demand in reconstructive, cosmetic and correctional surgery there remains no optimal strategy for the regeneration or replacement of adipose tissue. Previous approaches to adipose tissue engineering have failed to create an adipose tissue depot that maintains implant volume in vivo long-term (>3 months). This is due to inadequate mechanical properties of the biomaterial and insufficient vascularization upon implantation. Modular tissue engineering is a means to produce large volume functional tissues from small sub-mm sized tissues with an intrinsic vascularization. We first explored the potential of a semi-synthetic collagen/poloxamine hydrogel with improved mechanical properties to be used as the module biomaterial. We found this biomaterial to not be suitable for adipose tissue engineering because it did not support embedded adipose-derived stem cell (ASC) viability, differentiation and human microvascular endothelial cell (HMEC) attachment. ASC-embedded collagen gel modules coated with HMEC were then implanted subcutaneously in SCID mice to study its revascularization potential. ASC cotransplantation was shown to drive HMEC vascularization in vivo: HMEC were seen to detach from the surface of the modules to form vessels containing erythrocytes as early as day 3; vessels decreased in number but increased in size over 14 days; and persisted for up to 3 months. Early vascularization promoted fat development. Only in the case of ASC-HMEC cotransplantation was progressive fat accumulation observed in the module implants. Although implant volume was not maintained, likely due rapid collagen degradation, the key result here is that ASC-HMEC cotransplantation in the modular approach was successful in creating vascularized adipose tissue in vivo that persisted for 3 months. The modular system was then studied in vitro to further understand ASC-EC interaction. Coculture with ASC was shown to promote an angiogenic phenotype (e.g. sprouting, migration) from HUVEC on modules. RT-PCR analysis revealed that VEGF, PAI-1 and TNFα was involved in ASC-EC paracrine signalling. In summary, ASC-HMEC cotransplantation in modules was effective in rapidly forming a vascular network that supported fat development. Future work should focus on further elucidating ASC-EC interactions and developing a suitable biomaterial to improve adipose tissue development and volume maintenance of engineered constructs.

Hypochlorous acid (HOCl) is a powerful oxidant produced by activated phagocytes at sites of inflammation to kill a wide range of pathogens. Yet, it may also damage and kill the neighbouring host cells. The abundance of dead macrophages in atherosclerotic plaques and their colocalization with HOCl-modified proteins implicate HOCl may play a role in killing macrophages, contributing to disease progression. The first part of this research was to investigate the cytotoxic effect and cell death mechanism(s) of HOCl on macrophages. Macrophages require efficient defense mechanism(s) against HOCl to function properly at inflammatory sites. The second part of the thesis was to examine the antioxidative effects of glutathione (GSH) and 7,8-dihydroneopterin (7,8-NP) on HOCl-induced cellular damage in macrophages. GSH is an efficient scavenger of HOCl and a major intracellular antioxidant against oxidative stress, whereas 7,8-NP is secreted by human macrophages upon interferon-γ (IFN-γ) induction during inflammation and can also scavenge HOCl. HOCl caused concentration-dependent cell viability loss in human monocyte derived macrophage (HMDM) cells above a specific concentration threshold. HOCl reacted with HMDMs to cause viability loss within the first 10 minutes of treatment, and it posed no latent effect on the cells afterwards regardless of the HOCl concentrations. The lack of caspase-3 activation, rapid influx of propidium iodide (PI) dye, rapid loss of intracellular ATP and cell morphological changes (cell swelling, cell membrane integrity loss and rupture) were observed in HMDM cells treated with HOCl. These results indicate that HOCl caused HMDM cells to undergo necrotic cell death. In addition to the loss of intracellular ATP, HOCl also caused rapid loss of GAPDH enzymatic activity and mitochondrial membrane potential, indicating impairment of the metabolic energy production. Loss of the mitochondrial membrane potential was mediated by mitochondrial permeability transition (MPT), as blocking MPT pore formation using cyclosporin A (CSA) prevented mitochondrial membrane potential loss. HOCl caused an increase in cytosolic calcium ion (Ca2+) level, which was due to both intra- and extra-cellular sources. However, extracellular sources only contributed significantly above a certain HOCl concentration. Preventing cytosolic Ca2+ increase significantly inhibited HOCl-induced cell viability loss. This suggests that cytosolic Ca2+ increase was associated with HOCl-induced necrotic cell death in HMDM cells, possibly via the activation of Ca2+-dependent calpain cysteine proteases. Calpain inhibitors prevented HOCl-induced lysosomal destabilisation and cell viability loss in HMDM cells. Calpains induced HOCl-induced necrotic cell death possibly by degrading cytoskeletal and other cellular proteins, or causing the release of cathepsin proteases from ruptured lysosomes that also degraded cellular components. The HOCl-induced cytosolic Ca2+ increase also caused mitochondrial Ca2+ accumulation and MPT activation-mediated mitochondrial membrane potential loss. MPT activation, like calpain activation, was also associated with the HOCl-induced necrotic cell death, as preventing MPT activation completely inhibited HOCl-induced cell viability loss. The involvement of both calpain activation and MPT activation in HOCl-induced necrotic cell death in HMDM cells implies a cause and effect relationship between these two events. HMDM cells depleted of intracellular GSH using diethyl maleate showed increased susceptibility towards HOCl insult compared to HMDM cells with intact intracellular GSH levels, indicating that intracellular GSH played an important role in protecting HMDM cells against HOCl exposure. Intracellular GSH level in each HMDM cell preparation directly correlated with HOCl concentration required to kill 50% of population for each cell preparation, indicating intracellular GSH concentrations determine the efficiency of GSH in preventing HOCl-induced damage to HMDM cells. Intracellular GSH and cell viability loss induced by 400 μM HOCl were significantly prevented by 300 μM extracellular 7,8-NP, indicating that added 7,8-NP is an efficient scavenger of HOCl and out-competed intracellular GSH for HOCl. The amount of 7,8-NP synthesized by HMDM cells upon IFN-γ induction was too low to efficiently prevent HOCl-mediated intracellular GSH and cell viability loss. HOCl clearly causes HMDM cells to undergo necrosis when the concentration exceeds the intracellular GSH concentrations. Above this concentration HOCl causes oxidative damage to the Ca2+ ion channels on cell and ER membranes, resulting in an influx of Ca2+ ions into the cytosol and possibly the mitochondria. The rise in Ca2+ ions triggers calpain activation, resulting in the MPT-mediated loss of mitochondrial membrane potential, lysosomal instability and cellular necrosis.

Although attractive interactions between π systems (π-π interaction) have been known for many years, understanding of its origin is still incomplete. Quantitative measuring of π-stacking is challenging due to the weak nature of the π-π interaction. This dissertation aims at elucidating a quantitative conformational analysis by NMR ring current anisotropy of an organic compound capable of intramolecular π-stacking in solution and studying charge effects on the stacking of π-systems. This dissertation offers four contributions to the area. (1) A general approach to four-state, conformational analysis based on the magnetic anisotropy of molecules undergoing fast dynamic exchange is described. (2) Study unveiled the importance of charges in the conformation of a dication in the solution. (3) Novel aromatic salt pairs of triangulene derivatives with the delocalized cation-anion interaction were synthesized and studied. (4) Study unveiled ionic π-systems preferred face-to-face stacking due to strong cation-π and anion-cation attractions. A general protocol for the application of magnetic anisotropy to quantitative multi-state conformational analysis of molecules undergoing fast conformational exchange was suggested in the current study. The reliability of this method of conformational analysis was checked by the mass balance. VT-NMR was also conducted to study the enthalpic parameters. This technique can be further used to study canonical interactions such as ion pairing, hydrogen boning, and molecular recognition. In the current study, dependence of the probe conformations on the dispersive interactions at the aromatic edges between solvent and probes was tested by conformational distributions of the fluorinated derivatives (2b and 2c) of the probe molecule (1a). Solution and solid studies of these molecules put the previous conclusion drawn by the Cammers group in question. Current studies show that the dispersive interaction at the aromatic edge could not be the predominant force on the conformational changes in the probe molecule 1a during the fluoroalkanol perturbation. This study indicated that charges might be important in the formation of the folding conformations in the solution and solid state of 1a, 2b, and 2c. A contribution of this thesis was to prepare and study a conformational model that lacked charges. The previous molecules were charged. The solid-state structures of pyridinium-derived aromatic rings from the CSD (Cambridge Structural Database) were studied to investigate the π-π interaction between cationic π-systems in solid state. Novel aromatic salt pairs of triangulene derivatives with the delocalized cation-anion interaction were synthesized to study the π-π interaction between two aromatic rings that carried opposite charges. This study showed that the interaction between ionic π-systems can be enhanced by cation-π and anion-cation attractions. The stackings of these π-systems introduce more overlap, closer packing and stronger atomic contact than that of the solid states of comparable neutral species. Cation-π and anion-cation attractions are synergistic in aromatic salts.

In the absence of ligand, certain growth factor receptors can be activated via G protein-coupled receptor (GPCR) activation in a process termed transactivation. Serotonin (5-HT) receptors can transactivate the receptor tyrosine kinase (RTK) platelet-derived growth factor (PDGF) ?? receptors in smooth muscle cells, but it is not known if similar pathways occur in neuronal cells. Here, it is shown that 5-HT can transiently increase the phosphorylation of PDGF?? receptors in a time- and concentration-dependent manner in SH-SY5Y neuroblastoma cells. This transactivation pathway was pertussis-toxin sensitive, and was dependent on phospholipase C activity, intracellular calcium signaling and subsequent protein kinase C activation. Exogenous application of non-lethal concentrations of H2O2 induced the phosphorylation of PDGF?? receptors in a concentration-dependent fashion, similar to that observed with 5-HT. Further investigation revealed reactive oxygen species (ROS) production as a necessary component in the transactivation pathway, as scavenging ROS eliminated PDGF?? receptor phosphorylation. NADPH oxidase was determined to be the likely source of ROS given that the NADPH oxidase inhibitors diphenyleneiodonium chloride and apocynin abrogated PDGF?? receptor transactivation. The role of Src tyrosine kinase was also investigated, and its location in this signaling cascade was determined to be downstream of calcium signaling, but upstream of NADPH oxidase activity. In addition, the activation of ERK1/2 in this system was elucidated to be independent of PDGF?? receptor transactivation. Interestingly, 5-HT also transactivated TrkB receptors, another RTK whose function is implicated in clinical depression. Expectedly, the enzymes in this mechanism were consistent with those revealed in 5-HT-to-PDGF?? receptor signaling. This cross-talk between 5-HT and RTKs such as TrkB and PDGF?? receptors identifies a potentially important signaling link between the serotonergic system and neurotrophic factor signaling in neurons that could have implications in mental health disorders including depression. Furthermore, although transactivation pathways are commonly initiated by a GPCR, recent reports have demonstrated that selective serotonin reuptake inhibitors (SSRIs) were able to block 5-HT-induced transactivation of PDGF?? receptors, suggesting that in addition to GPCRs, monoamine transporters may also be involved in RTK transactivation. SH-SY5Y cells pretreated with the SSRI fluoxetine blocked 5-HT-induced transactivation of the PDGF?? receptors, but not PDGF-induced PDGF?? receptor activation. Upon further examination, it was discovered that during the pretreatment period, fluoxetine itself was transiently transactivating the PDGF?? receptor via 5-HT2 receptors. By the end of the pretreatment period, the effects of fluoxetine on PDGF?? receptor phosphorylation had returned to baseline, and a subsequent transactivating stimulus (5-HT) failed to ???re-transactivate??? the PDGF?? receptor. Additional investigations demonstrated that 5-HT pretreatment can block dopamine-induced PDGF?? receptor transactivation, but not PDGF-induced PDGF?? receptor activation. This is the first demonstration of the heterologous desensitization of an RTK via a transactivation pathway, and this phenomenon is specific for transactivation pathways because in all cases the PDGF?? receptor ligand PDGF-BB was able to directly stimulate receptor activity in spite of GPCR agonist pretreatment. Heterologous desensitization in transactivation signaling reveals a previously unknown short-term ???blackout??? period wherein no further transactivation signaling can occur to potentially exploit the mitogenic effects of RTK activation.