Statistical dialog management for health interventions

Research endeavors on spoken dialogue systems in the 1990s and 2000s have led to the deployment of commercial spoken dialogue systems (SDS) in microdomains such as customer service automation, reservation/booking and question answering systems. Recent research in SDS has been focused on the development of applications in different domains (e.g. virtual counseling, personal coaches, social companions) which requires more sophistication than the previous generation of commercial SDS. The focus of this research project is the delivery of behavior change interventions based on the brief intervention counseling style via spoken dialogue systems. ^ Brief interventions (BI) are evidence-based, short, well structured, one-on-one counseling sessions. Many challenges are involved in delivering BIs to people in need, such as finding the time to administer them in busy doctors' offices, obtaining the extra training that helps staff become comfortable providing these interventions, and managing the cost of delivering the interventions. Fortunately, recent developments in spoken dialogue systems make the development of systems that can deliver brief interventions possible. ^ The overall objective of this research is to develop a data-driven, adaptable dialogue system for brief interventions for problematic drinking behavior, based on reinforcement learning methods. The implications of this research project includes, but are not limited to, assessing the feasibility of delivering structured brief health interventions with a data-driven spoken dialogue system. Furthermore, while the experimental system focuses on harmful alcohol drinking as a target behavior in this project, the produced knowledge and experience may also lead to implementation of similarly structured health interventions and assessments other than the alcohol domain (e.g. obesity, drug use, lack of exercise), using statistical machine learning approaches. ^ In addition to designing a dialog system, the semantic and emotional meanings of user utterances have high impact on interaction. To perform domain specific reasoning and recognize concepts in user utterances, a named-entity recognizer and an ontology are designed and evaluated. To understand affective information conveyed through text, lexicons and sentiment analysis module are developed and tested.^

Materiais bionanocompósitos a base de argilominerais e hidróxidos duplos lamelares como sistemas de liberação de fármacos

Bionanocomposites systems clay base (montmorillonite and sepiolite), layered double hidroxides and biopolymers (carboxymethylcellulose and zein) were evaluated as topical delivery systems with antibacterial activity and as oral delivery systems. For this study, neomycin, a topical antibiotic, indicated mainly for open wound infections. The drug amoxicillin, an antibiotic indicated mainly for throat infections, were also used in this study. Both antibiotics were used as model drugs. Initially, drugs were incorporated directly into the biopolymer matrix, comprising the combination of carboxymethylcellulos and zein, being conformed as movies and balls and evaluated for their antibacterial activity and controlled release simulating gastrointestinal fluids. Moreover, hybrids materials have been prepared where the neomycin drug was incorporated into the lamellar inorganic solids, such as montmorillonite by ion exchange reaction, and the fibrous type, such as sepiolite by adsorption in aqueous solution. But the drug amoxicillin was incorporated into layered double hydroxides by anion exchange and montmorillonite by cation exchange. The resulting hybrids were in turn combined with the biopolymer matrix yielding bionanocomposites shaped materials such as films were tested for their antibacterial activity, and the shaped materials beads were tested for their release in the gastrointestinal fluids. Through the analysis of various physico-chemical techniques, we observed the interactions between the studied materials, the formation of hybrids materials, obtaining the bionanocomposites materials and material efficiency when applied in controlled release of drugs both topical and use oral mainly influenced by the presence of zein, are promising as topical delivery systems and oral drugs.

Peptide-induced coalescence of bicellar lipid assemblies: sensitivity to anionic lipid and peptide properties

Bicellar lipid mixture dispersions progressively coalesce to larger structures on warming. This phase behaviour is particularly sensitive to interactions that perturb bilayer properties. In this study, ²H NMR was used to study the perturbation of bicellar lipid mixtures by two peptides (SP-B₆₃₋₇₈, a lung surfactant protein fragment and Magainin 2, an antimicrobial peptide) which are structurally similar. Particular attention was paid to the relation between peptide-induced perturbation and lipid composition. In bicellar dispersions containing only zwitterionic lipids (DMPC-d₅₄/DMPC/DHPC (3:1:1)) both peptides had little to no effect on the temperature at which coalescence to larger structures occurred. Conversely, in mixtures containing anionic lipids (DMPC-d₅₄/DMPG/DHPC (3:1:1)), both peptides modified bicellar phase behaviour. In mixtures containing SP-B₆₃₋₇₈, the presence of peptide decreased the temperature of the ribbon-like to extended lamellar phase transition. The addition of Magainin 2 to DMPCd₅₄/ DMPG/DHPC (3:1:1) mixtures, in contrast, increased the temperature of this transition and yielded a series of spectra resembling DMPC/DHPC (4:1) mixtures. Additional studies of lipid dispersions containing deuterated anionic lipids were done to determine whether the observed perturbation involved a peptide-induced separation of zwitterionic and anionic lipids. Comparison of DMPC/DMPG-d₅₄/DHPC (3:1:1) and DMPC-d₅₄/DMPG/DHPC (3:1:1) mixtures showed that DMPC and DMPG occupy similar environments in the presence of SP-B₆₃₋₇₈, but different lipid environments in the presence of Magainin 2. This might reflect the promotion of anionic lipid clustering by Magainin 2. These results demonstrate the variability of mechanisms of peptide-induced perturbation and suggest that lipid composition is an important factor in the peptide-induced perturbation of lipid structures.

Investigação da rota biohidrometalúrgica com Acidithiobacillus ferrooxidans/thiooxidans para recuperação do cobalto de baterias de íons lítio descartadas

The recycling of metals from secondary sources can be advantageous. Among the metals of interest, we have cobalt, a metal used for various purposes. As regards the secondary sources of cobalt, the lithium-ion batteries can be considered, since they contain cobalt oxide in their composition (LiCoO2). This way, the objective of this work was to use the microorganism strains (Acidithiobacillus ferrooxidans and Acidithiobacillus thiooxidans) to bioleach the LiCoO2 extracted from discarded lithium ion batteries with emphasis on the recovery of cobalt for synthesis of new materials of interest. The lineage growth occurred in T&K medium and the growth investigation was made by observing the media, by platelet growth and microscope analysis. Then, the inoculum was standardized on 5 x 106 cells mL-1 and used in bioleaching tests. The bioleaching was investigated: the microorganism nature: separate strains and A. ferrooxidans and A. thiooxidans consortium, bioleaching time (0 to 40 days), inoculum proportion (5 to 50% v/v), energy source (iron and sulfur) and residue concentration (1063 to 8500 mg L-1 of cobalt). The cobalt concentration in the media was found by atomic absorption spectrometry and the medium pH was monitored during the bioleaching. The results show that the amount of bioleached cobalt increases with time and the iron concentration. The bioleaching with A. thiooxidans was not influenced by the addition of sulfur. The use of the two lineages together did not improve the bioleaching rates. Among the lineages, the A. thiooxidans presented better results and was able to bioleach cobalt amounts above 50% in most of the experiments. A. thiooxidans presented lower bioleaching rates, with a maximum of 50% after 24 days of experiment. After reprocessing by bioleaching, the cobalt in solution was used for synthesis of new materials: such as LiCoO2 cathode and as adsorbent pesticide double lamellar hydroxide (HDL Co-Al-Cl) by the Pechini and co-precipitation methods. The reprocessed LiCoO2 presented a unique stoichiometric phase relative to the HT-LiCoO2 structure similar to the JCPDS 44-0145, presenting electrochemical activity when tested as a cathode material. The double lamellar hydroxide Co-Al-Cl was tested as pesticide adsorbent, being possible to adsorb around 100% of the pesticide. The bioleaching was efficient in the recovery of cobalt present in lithium-ion batteries and microorganisms presented high tolerance to the residue, being able to bioleach even at higher LiCoO2 concentrations. The cobalt bioleaching medium did not impair the synthesis phases and the obtained materials presented structure and activity similar to the sintered materials from the reagents containing cobalt.

Human rhinovirus-induced inflammatory responses are inhibited by phosphatidylserine containing liposomes

Human rhinovirus (HRV) infections are major contributors to the healthcare burden associated with acute exacerbations of chronic airway disease, such as chronic obstructive pulmonary disease and asthma. Cellular responses to HRV are mediated through pattern recognition receptors that may in part signal from membrane microdomains. We previously found Toll-like receptor signaling is reduced, by targeting membrane microdomains with a specific liposomal phosphatidylserine species, 1-stearoyl-2-arachidonoyl-sn-glycero-3-phospho-L-serine (SAPS). Here we explored the ability of this approach to target a clinically important pathogen. We determined the biochemical and biophysical properties and stability of SAPS liposomes and studied their ability to modulate rhinovirus-induced inflammation, measured by cytokine production, and rhinovirus replication in both immortalized and normal primary bronchial epithelial cells. SAPS liposomes rapidly partitioned throughout the plasma membrane and internal cellular membranes of epithelial cells. Uptake of liposomes did not cause cell death, but was associated with markedly reduced inflammatory responses to rhinovirus, at the expense of only modest non-significant increases in viral replication, and without impairment of interferon receptor signaling. Thus using liposomes of phosphatidylserine to target membrane microdomains is a feasible mechanism for modulating rhinovirus-induced signaling, and potentially a prototypic new therapy for viral-mediated inflammation.

AuxAg1-x alloy seeds: A way to control growth, morphology and defect formation in Ge nanowires

Germanium (Ge) nanowires are of current research interest for high speed nanoelectronic devices due to the lower band gap and high carrier mobility compatible with high K-dielectrics and larger excitonic Bohr radius ensuing a more pronounced quantum confinement effect [1-6]. A general way for the growth of Ge nanowires is to use liquid or a solid growth promoters in a bottom-up approach which allow control of the aspect ratio, diameter, and structure of 1D crystals via external parameters, such as precursor feedstock, temperature, operating pressure, precursor flow rate etc [3, 7-11]. The Solid-phase seeding is preferred for more control processing of the nanomaterials and potential suppression of the unintentional incorporation of high dopant concentrations in semiconductor nanowires and unrequired compositional tailing of the seed-nanowire interface [2, 5, 9, 12]. There are therefore distinct features of the solid phase seeding mechanism that potentially offer opportunities for the controlled processing of nanomaterials with new physical properties. A superior control over the growth kinetics of nanowires could be achieved by controlling the inherent growth constraints instead of external parameters which always account for instrumental inaccuracy. The high dopant concentrations in semiconductor nanowires can result from unintentional incorporation of atoms from the metal seed material, as described for the Al catalyzed VLS growth of Si nanowires [13] which can in turn be depressed by solid-phase seeding. In addition, the creation of very sharp interfaces between group IV semiconductor segments has been achieved by solid seeds [14], whereas the traditionally used liquid Au particles often leads to compositional tailing of the interface [15] . Korgel et al. also described the superior size retention of metal seeds in a SFSS nanowire growth process, when compared to a SFLS process using Au colloids [12]. Here in this work we have used silver and alloy seed particle with different compositions to manipulate the growth of nanowires in sub-eutectic regime. The solid seeding approach also gives an opportunity to influence the crystallinity of the nanowires independent of the substrate. Taking advantage of the readily formation of stacking faults in metal nanoparticles, lamellar twins in nanowires could be formed.

Study of the kinetics and mechanism of rapid self-assembly in block copolymer thin films during solvo-microwave annealing

Microwave annealing is an emerging technique for achieving ordered patterns of block copolymer films on substrates. Little is understood about the mechanisms of microphase separation during the microwave annealing process and how it promotes the microphase separation of the blocks. Here, we use controlled power microwave irradiation in the presence of tetrahydrofuran (THF) solvent, to achieve lateral microphase separation in high- lamellar-forming poly(styrene-b-lactic acid) PS-b-PLA. A highly ordered line pattern was formed within seconds on silicon, germanium and silicon on insulator (SOI) substrates. In-situ temperature measurement of the silicon substrate coupled to condition changes during "solvo-microwave" annealing allowed understanding of the processes to be attained. Our results suggest that the substrate has little effect on the ordering process and is essentially microwave transparent but rather, it is direct heating of the polar THF molecules that causes microphase separation. It is postulated that the rapid interaction of THF with microwaves and the resultant temperature increase to 55 degrees C within seconds causes an increase of the vapor pressure of the solvent from 19.8 to 70 kPa. This enriched vapor environment increases the plasticity of both PS and PLA chains and leads to the fast self-assembly kinetics. Comparing the patterns formed on silicon, germanium and silicon on insulator (SOI) and also an in situ temperature measurement of silicon in the oven confirms the significance of the solvent over the role of substrate heating during "solvo-microwave" annealing. Besides the short annealing time which has technological importance, the coherence length is on a micron scale and dewetting is not observed after annealing. The etched pattern (PLA was removed by an Ar/O-2 reactive ion etch) was transferred to the underlying silicon substrate fabricating sub-20 nm silicon nanowires over large areas demonstrating that the morphology is consistent both across and through the film.

The morphology of ordered block copolymer patterns as probed by high resolution imaging

The microphase separation of block copolymer (BCP) thin films can afford a simple and cost-effective means to studying nanopattern surfaces, and especially the fabrication of nanocircuitry. However, because of complex interface effects and other complications, their 3D morphology, which is often critical for application, can be more complex than first thought. Here, we describe how emerging microscopic methods may be used to study complex BCP patterns and reveal their rich detail. These methods include helium ion microscopy (HIM) and high resolution x-section transmission electron microscopy (XTEM), and complement conventional secondary electron and atomic force microscopies (SEM and TEM). These techniques reveal that these structures are quite different to what might be expected. We illustrate the advances in the understanding of BCP thin film morphology in several systems, which result from this characterization. The systems described include symmetric, lamellar forming polystyrene-b-polymethylmethacrylate (PS-b-PMMA), cylinder forming polystyrene-b-polydimethylsiloxane (PS-b-PDMS), as well as lamellar and cylinder forming patterns of polystyrene-b-polyethylene oxide (PS-b-PEO) and polystyrene-b-poly-4-vinylpyridine (PS-b-P4VP). Each of these systems exhibits more complex arrangements than might be first thought. Finding and developing techniques whereby complex morphologies, particularly at very small dimensions, can be determined is critical to the practical use of these materials in many applications. The importance of quantifying these complex morphologies has implications for their use in integrated circuit manufacture, where they are being explored as alternative pattern forming methods to conventional UV lithography.

Statistical Dialog Management for Health Interventions

Research endeavors on spoken dialogue systems in the 1990s and 2000s have led to the deployment of commercial spoken dialogue systems (SDS) in microdomains such as customer service automation, reservation/booking and question answering systems. Recent research in SDS has been focused on the development of applications in different domains (e.g. virtual counseling, personal coaches, social companions) which requires more sophistication than the previous generation of commercial SDS. The focus of this research project is the delivery of behavior change interventions based on the brief intervention counseling style via spoken dialogue systems. Brief interventions (BI) are evidence-based, short, well structured, one-on-one counseling sessions. Many challenges are involved in delivering BIs to people in need, such as finding the time to administer them in busy doctors' offices, obtaining the extra training that helps staff become comfortable providing these interventions, and managing the cost of delivering the interventions. Fortunately, recent developments in spoken dialogue systems make the development of systems that can deliver brief interventions possible. The overall objective of this research is to develop a data-driven, adaptable dialogue system for brief interventions for problematic drinking behavior, based on reinforcement learning methods. The implications of this research project includes, but are not limited to, assessing the feasibility of delivering structured brief health interventions with a data-driven spoken dialogue system. Furthermore, while the experimental system focuses on harmful alcohol drinking as a target behavior in this project, the produced knowledge and experience may also lead to implementation of similarly structured health interventions and assessments other than the alcohol domain (e.g. obesity, drug use, lack of exercise), using statistical machine learning approaches. In addition to designing a dialog system, the semantic and emotional meanings of user utterances have high impact on interaction. To perform domain specific reasoning and recognize concepts in user utterances, a named-entity recognizer and an ontology are designed and evaluated. To understand affective information conveyed through text, lexicons and sentiment analysis module are developed and tested.

A new genus Abyssogena from deep-water vents and seeps

A new genus Abyssogena is established for A. phaseoliformis (Métivier, Okutani & Ohta, 1986) and A. kaikoi (Okutani & Métivier, 1986), which were previously assigned to the genus Calyptogena Dall, 1891, and also for two new species, A. southwardae and A. novacula. The most characteristic features of Abyssogena are an elongate shell up to about 280 mm in length; a pallial line starting from the ventral margin of the anterior adductor scar; secondary pallial attachment scars developed dorsal to the pallial line; radially arranged hinge teeth with a reduced anterior cardinal tooth in the right valve; and presence of an inner ctenidial demibranch only. Abyssogena occurs in deep water from 2,985 to 6,400 m and is distributed in the Pacific and Atlantic Oceans at cold seeps along continental margins and hydrothermal vents at mid-oceanic ridges. Some species have a remarkably wide geographic distribution; A. southwardae is present throughout the Atlantic and A. phaseoliformis is present in Japan, Kuril-Kamchatka, as well as Aleutian Trenches. No fossils of Abyssogena are known.

(Figure 2) Stratigraphic distribution of Schizosphaerella in DSDP Hole 79-547B

The Jurassic (hemi)pelagic continental margin deposits drilled at Hole 547B, off the Moroccan coast, reveal striking Tethyan affinity. Analogies concern not only types and gross vertical evolution of facies, but also composition and textures of the fine sediment and the pattern of diagenetic alteration. In this context, the occurrence of the nanno-organism Schizosphaerella Deflandre and Dangeard (sometimes as a conspicuous portion of the fine-grained carbonate fraction) is of particular interest. Schizosphaerella, an incertae sedis taxon, has been widely recorded as a sediment contributor from Tethyan Jurassic deeper-water carbonate facies exposed on land. Because of its extremely long range (Hettangian to early Kimmeridgian), the genus Schizosphaerella (two species currently described, S. punctulata Deflandre and Dangeard and S. astrea Moshkovitz) is obviously not of great biostratigraphic interest. However, it is of interest in sedimentology and petrology. Specifically, Schizosphaerella was often the only component of the initial fine-grained fraction of a sediment that was able to resist diagenetic obliteration. However, alteration of the original skeletal structure did occur to various degrees. Crystal habit and mineralogy of the fundamental skeletal elements, as well as their mode of mutual arrangement in the test wall with the implied high initial porosity of the skeleton (60-70%), appear to be responsible for this outstanding resistance. Moreover, the ability to concentrate within and, in the case of the species S. punctulata, around the skeleton, large amounts of diagenetic calcite also contributed to the resistance. In both species of Schizosphaerella, occlusion of the original skeletal void space during diagenesis appears to have proceeded in an analogous manner, with an initial slight uniform syntaxial enlargement of the basic lamellar skeletal crystallites followed, upon mutual impingement, by uneven accretion of overgrowth cement in the remaining skeletal voids. However, distinctive fabrics are evident according to the different primary test wall architecture. In S. punctulata, intraskeletal cementation is usually followed by the growth of a radially structured crust of bladed to fibrous calcite around the valves. These crusts are interpreted as a product of aggrading neomorphism, associated with mineralogic stabilization of the original, presumably polyphase, sediment. Data from Hole 547B, along with inferences, drawn from the fabric relationships, suggest that the crusts formed and (inferentially) mineralogic stabilization occurred at a relatively early time in the diagenetic history in the shallow burial realm. An enhanced rate of lithification at relatively shallow burial depths and thus the chance for neomorphism to significantly influence the textural evolution of the buried sediment may be related to a lower Mg/Ca concentration ratio in the oceanic system and, hence, in marine pore waters in pre-Late Jurassic times.

Size effects on self-assembly and melting of silver-alkanethiolate on inert surfaces

Self-assembled materials produced in the reaction between alkanethiol and Ag are characterized and compared. It is revealed that the size of the Ag substrate has a significant role in the self-assembly process and determines the reaction products. Alkanethiol adsorbs on the surface of Ag continuous planar thin films and only forms self-assembled monolayers (SAMs), while the reaction between alkanethiol and Ag clusters on inert surfaces is more aggressive and generates a significantly larger amount of alkanethiolate. Two dissimilar products are yielded depending on the size of the clusters. Small Ag clusters are more likely to be converted into multilayer silver-alkanethiolate (AgSR, R = CnH2n+1) crystals, while larger Ag clusters form monolayer-protected clusters (MPCs). The AgSR crystals are initially small and can ripen into large lamellae during thermal annealing. The crystals have facets and flat terraces with extended area, and have a strong preferred orientation in parallel with the substrate surface. The MPCs move laterally upon annealing and reorganize into a single-layer network with their separation distance approximately equal to the length of an extended alkyl chain. AgSR lamellar crystals grown on inert surfaces provide an excellent platform to study the melting characteristics of crystalline lamellae of polymeric materials with the thickness in the nanometer scale. This system is also unique in that each crystal has integer number of layers – magic-number size (thickness). The size of the crystals is controlled by adjusting the amount of Ag and the annealing temperature. X-ray diffraction (XRD) and atomic force microscopy (AFM) are combined to accurately determine the size (number of layers) of the lamellar crystals. The melting characteristics are measured with nanocalorimetry and show discrete melting transitions which are attributed to the magic-number sizes of the lamellar crystals. The discrete melting temperatures are intrinsic properties of the crystals with particular sizes. Smaller lamellar crystals with less number of layers melt at lower temperatures. The melting point depression is inversely proportional to the total thickness of the lamellae – the product of the number of layers and the layer thickness.

Persistent localized states for a chaotically mixed bistable reaction

We describe the evolution of a bistable chemical reaction in a closed two-dimensional chaotic laminar flow, from a localized initial disturbance. When the fluid mixing is sufficiently slow, the disturbance may spread and eventually occupy the entire fluid domain. By contrast, rapid mixing tends to dilute the initial state and so extinguish the disturbance. Such a dichotomy is well known. However, we report here a hitherto apparently unremarked intermediate case, a persistent highly localized disturbance. Such a localized state arises when the Damkoehler number is great enough to sustain a "hot spot," but not so great as to lead to global spread. We show that such a disturbance is located in the neighborhood of an unstable periodic orbit of the flow, and we describe some limited aspects of its behavior using a reduced, lamellar model. Copyright American Physical Society (APS) 2006.

Comparison of the modes of action of Apremilast and Roflumilast

The phosphodiesterase 4 (PDE4) family are cAMP specific phosphodiesterases that play an important role in the inflammatory response and is the major PDE type found in inflammatory cells. A significant number of PDE4 specific inhibitors have been developed and are currently being investigated for use as therapeutic agents. Apremilast, a small molecule inhibitor of PDE 4 is in development for chronic inflammatory disorders and has shown promise for the treatment of psoriasis, psoriatic arthritis as well as other inflammatory diseases. It has been found to be safe and well tolerated in humans and in March 2014 it was approved by the US food and drug administration for the treatment of adult patients with active psoriatic arthritis. The only other PDE4 inhibitor on the market is Roflumilast and it is used for treatment of respiratory disease. Roflumilast is approved in the EU for the treatment of COPD and was recently approved in the US for treatment to reduce the risk of COPD exacerbations. Roflumilast is also a selective PDE4 inhibitor, administered as an oral tablet once daily, and is thought to act by increasing cAMP within lung cells. As both (Apremilast and Roflumilast) compounds selectively inhibit PDE4 but are targeted at different diseases, there is a need for a clear understanding of their mechanism of action (MOA). Differences and similarity of MOA should be defined for the purposes of labelling, for communication to the scientific community, physicians, and patients, and for an extension of utility to other diseases and therapeutic areas. In order to obtain a complete comparative picture of the MOA of both inhibitors, additional molecular and cellular biology studies are required to more fully elucidate the signalling mediators downstream of PDE4 inhibition which result in alterations in pro- and anti-inflammatory gene expression. My studies were conducted to directly compare Apremilast with Roflumilast, in order to substantiate the differences observed in the molecular and cellular effects of these compounds, and to search for other possible differentiating effects. Therefore the main aim of this thesis was to utilise cutting-edge biochemical techniques to discover whether Apremilast and Roflumilast work with different modes of action. In the first part of my thesis I used novel genetically encoded FRET based cAMP sensors targeted to different intracellular compartments, in order to monitor cAMP levels within specific microdomains of cells as a consequence of challenge with Apremilast and Roflumilast, which revealed that Apremilast and Roflumilast do regulate different pools of cAMP in cells. In the second part of my thesis I focussed on assessing whether Apremilast and Roflumilast cause differential effects on the PKA phosphorylation state of proteins in cells. I used various biochemical techniques (Western blotting, Substrate kinase arrays and Reverse Phase Protein array and found that Apremilast and Roflumilast do lead to differential PKA substrate phosphorylation. For example I found that Apremilast increases the phosphorylation of Ribosomal Protein S6 at Ser240/244 and Fyn Y530 in the S6 Ribosomal pathway of Rheumatoid Arthritis Synovial fibroblast and HEK293 cells, whereas Roflumilast does not. This data suggests that Apremilast has distinct biological effects from that of Roflumilast and could represent a new therapeutic role for Apremilast in other diseases. In the final part of my thesis, Phage display technology was employed in order to identify any novel binding motifs that associate with PDE4 and to identify sequences that were differentially regulated by the inhibitors in an attempt to find binding motifs that may exist in previously characterised signalling proteins. Petide array technology was then used to confirm binding of specific peptide sequences or motifs. Results showed that Apremilast and Roflumilast can either enhance or decrease the binding of PDE4A4 to specific peptide sequences or motifs that are found in a variety of proteins in the human proteome, most interestingly Ubiquitin-related proteins. The data from this chapter is preliminary but may be used in the discovery of novel binding partners for PDE4 or to provide a new role for PDE inhibition in disease. Therefore the work in this thesis provides a unique snapshot of the complexity of the cAMP signalling system and is the first to directly compare action of the two approved PDE4 inhibitors in a detailed way.