<p>Improved methods are needed to interrogate the genome and the proteome. Methods with high selectivity, wide dynamic range, and excellent precision, capable of simultaneously analyzing many biomolecules are required to decipher cellular function. This thesis describes a molecular and microfluidic toolbox designed with those criteria in mind. It also presents a tool for graphical representation of nucleic acid sequences.</p><p>Proximity ligation is a novel protein detection method that requires dual and proximate binding of two oligonucleotide-tagged affinity reagents to a protein or protein complex in order to elicit a signal. The responses from such recognition reactions are the formation of specific nucleic acid reporter molecules that are subsequently amplified and quantitatively detected. </p><p>A scalable microfluidic platform suitable for fluorescence detection, cell culture, and actuation is also described. The platform uses rapid injection molding to produce microstructures in thermoplastic materials. By applying a thin layer of silica to the structures, a lid made of silicone rubber coated onto a thermoplastic support can be covalently bonded to generate enclosed channels.</p><p>A method is presented for precise biomolecule counting, termed “amplified single-molecule detection”. The method preserves the discrete nature of biomolecules, converting specific molecular recognition events to fluorescence-labeled micrometer-sized objects that are enumerated in microfluidic channels. </p><p>I also present a novel microarray-based detection method. To attain high selectivity and a wide dynamic range, the method is based on dual recognition with enzymatic discrimination and amplification. Upon target recognition in solution, DNA probes are subjected to thousand-fold amplification in solution, followed by selective detection on arrays and another hundred-fold amplification of reporter molecule created from the first amplification reaction. </p><p>Lastly, I describe a novel graphical representation of nucleic acid sequences using TrueType fonts that can be of value for visual inspection of DNA sequences and for teaching purposes</p>

A research synopsis is presented summarizing work with integration of Ge and III-V semiconductors and optical devices with Si. III-V GaAs/AlGaAs quantum well lasers and GaAs/AlGaAs optical circuit structures have been fabricated on Si using Ge/GeSi/Si virtual substrates. The lasers fabricated on bulk GaAs showed similar output characteristics as those on Si. The GaAs/AlGaAs lasers fabricated on Si emitted at 858nm and had room temperature cw lifetimes of ~4hours. Straight optical links integrating an LED emitter, waveguide and detector exhibited losses of approximately 144dB/cm. A process for fabrication of a novel CMOS-compatible platform that integrates III-V or Ge layers with Si is demonstrated. Thin Ge layers have been transferred from Ge/GeSi/Si virtual substrates to bulk Si utilizing wafer bonding and an epitaxial Si CMP layer to facilitate virtual substrate planarization. A unique CMP-less method for removal of Ge exfoliation damage induced by the SmartCut™ process is also presented. / Singapore-MIT Alliance (SMA)

Zum Erhalt vom Aussterben bedrohter Papageienvögel (Psittaciformes) ist die Nachzucht in Menschenobhut neben dem Erhalt freilebender Populationen von großer Bedeutung, die Reproduktion bestimmter Arten gelingt allerdings nur unzureichend. Als Hauptgrund dafür gilt die Zwangsverpaarung im Rahmen von Zuchtprogrammen (Beispiel: Europäisches Erhaltungszuchtprogramm, EEP), hier werden Brutpaare hauptsächlich nach genetischen Aspekten zusammengestellt. Der reproduktive Erfolg ist bei den meisten Papageienarten, die in dauerhaften Paarbindungen leben (perennial monogamy), eng der Paarbindung korreliert. Eine freie Partnerwahl ist demnach von großer Bedeutung für die Zucht in Menschenobhut, im Rahmen von Erhaltungszuchtprogrammen jedoch nur selten möglich. Das Ziel der Untersuchung war, eine wissenschaftlich begründete Methode zu entwickeln, durch die es möglich sein soll, das Fortpflanzungspotential von Brutpaaren der Gattung Ara anhand der Paarbindung zu bestimmen. Dafür wurde die Bedeutung der Qualität der Paarbindung der Brutpaare für den Lebens-Reproduktionserfolg (Lifetime-reproductive success, LRS) untersucht. Die Datenaufnahme erfolgte in dem Zuchtzentrum 'La Vera' der Loro Parque Fundación auf Teneriffa/ Spanien. Hier wurden in den Jahren 2006 und 2007 21 Brutpaare der Gattung Ara untersucht. Die Paarbindung wurde zum Einen durch typisches Paarbindungsverhalten und zum Anderen durch die physiologische Abstimmung der einzelnen Brutpaare anhand der Ausschüttung des Steroidhormons Testosteron dargestellt. Das Paarbindungsverhalten setzte sich aus der ‚Abstimmung der Tagesaktivität’, dem ‚Kontaktverhalten’ und den ‚sozialen Interaktionen’ zusammen. Zur Abstimmung der Tagesaktivität zählten die Verhaltensweisen Ruhen, Sitzen, Nahrungsaufnahme, Gefiederpflege, Beschäftigung und Lokomotion. Unter Kontaktverhalten wurden das Überschreiten der Individualdistanz bei bestimmten Verhaltensweisen und die Rollenverteilung der Geschlechter untersucht. Unter ‚sozialen Interaktionen’ wurden die Dauer und der Häufigkeit der sozialen Gefiederpflege und der Sozialen Index zusammengefasst. Bei der sozialen Gefiederpflege wurde die Dauer und die Häufigkeit der Phasen erhoben, sowie der jeweilige Initiator dieser Interaktion. Zusätzlich wurde untersucht, welches Geschlecht, wie häufig und mit welcher Dauer aktiv an der sozialen Gefiederpflege beteiligt war. Aus den Beobachtungen wurde der soziale Index berechnet, der angibt, wie das Verhältnis sozio-positiver zu agonistischen Interaktionen für jedes Individuum, sowie das Paar an sich ist. Zur Messung der Testosteron-Ausschüttung der Partnertiere wurden von September bis November 2007 über einen Zeitraum von 9 Wochen jede Woche einmal für jedes Individuum Kotproben gesammelt. Mit der Analyse der Proben wurde das Veterinär-Physiologisch-Chemische-Institut der Universität Leipzig unter der Leitung von Prof. Dr. Almuth Einspanier beauftragt. Zur Ermittlung des Hormongehalts in den gewonnenen Kotproben diente ein kompetitiver Doppelantikörper-Enzymimmunoassay (EIA). Das Fortpflanzungspotential wurde über die Anzahl der Eier, Gelege und Jungtiere, sowie über die Gelegegröße dargestellt. Diese Daten geben, bezogen auf die Dauer der Paarbindung, Auskunft über die Produktivität eines Brutpaares, anhand dessen zusätzlich ein Produktivitäts-Koeffizient berechnet wurde. Des weiteren sollte die Anzahl der von einem Brutpaar selbständig großgezogenen Jungtiere Auskunft über die Fähigkeit zur kooperativen Jungenaufzucht geben. Zur Untersuchung der Bedeutung der Paarbindungsqualität wurden Diskriminanzfunktionsanalysen und Regressionsanalysen durchgeführt, wozu die untersuchten Brutpaare anhand ihres Fortpflanzungspotentials in verschiedene Gruppen eingeteilt wurden. Anhand der Ergebnisse der Studie konnte gezeigt werden, dass das Fortpflanzungspotential von Brutpaaren von verschiedenen Kriterien, die die Paarbindungsqualität charakterisieren, abhängt. Dabei ist zwischen der Produktivität und der Fähigkeit zur kooperativen Jungenaufzucht zu unterscheiden. Die Produktivität eines Paares wurde hinsichtlich der abgestimmten Tagesaktivität positiv vom synchronen Ruhen mit dem Partner beeinflusst, sowie von der Häufigkeit und Dauer der vom Weibchen ausgehenden sozialen Gefiederpflege. Brutpaare mit hoher Produktivität waren zudem über eine hohe ‚intra-Paar Fluktuation’ des Steroidhormons Testosteron gekennzeichnet. Die Brutpaare, die in der Lage sind, ihre Jungtiere in Kooperation großzuziehen, zeigten ebenfalls einen hohen Anteil zeitlich mit dem Partner abgestimmter Ruhephasen, zudem häufiges Ruheverhalten in Körperkontakt zum Partner und ein hohes zeitliches Investment der Männchen bei der Initiierung und Durchführung sozialer Gefiederpflege. Darüber hinaus zeigten Männchen, die einen Beitrag zur kooperativen Jungenaufzucht leisten, eine wesentlich geringere durchschnittliche Testosteron-Konzentration – bezogen auf den Untersuchungszeitraum, als Männchen, die Brutpaaren angehören, die nicht zur selbständigen Jungenaufzucht fähig sind. Dieses Ergebnis spiegelt die Bedeutung von Testosteron bei der elterlichen Fürsorge wider und bietet einen Anhaltspunkt für weitere Untersuchungen. Die Untersuchung konnte zeigen, dass es möglich und sinnvoll ist, das individuelle Verhalten von Tieren in Menschenobhut für den Erhalt bedrohter Tierarten einzusetzen. Weitere, auf dieser Studie aufbauende Untersuchungen sollten zum Ziel haben, zuverlässig die Brutpaare erkennbar zu machen, die über ein gutes Fortpflanzungspotential verfügen. Auf diese Weise kann unzureichender Reproduktionserfolg bedrohter Papageienarten in Menschenobhut infolge von Zwangsverpaarung minimiert werden. / In addition to preserve wild populations, captive breeding of certain species is important for the conservation of endangered parrots (Psittaciformes). However, captive breeding of parrot species is rarely successful. The main reason for this failure is that forced pairings are applied under the context of breeding programs such as European Endangered Species Program, EEP, in which breeding pairs are primarily selected under genetic aspects. Bond quality affects the reproductive success of most perennial monogamous parrot species significantly. A free mate selection is therefore important for successful breeding in captivity; however, it is hard to achieve as a part of conservation breeding programs. The aim of this study is to develop a scientific method to determine the reproductive potential of breeding pairs of the genus Ara based on the pair bond. Therefore, the relationship of the pair bond quality in breeding pairs for lifetime reproductive success (LRS) is investigated in this study. The data of 21 breeding pairs was collected in the breeding facility 'La Vera' of the Loro Parque Fundación in Tenerife, Spain between 2006 and 2007. The pair bond was characterized firstly by the typical pair bonding behaviour and secondly by the physiological adaptation of each breeding pair based on the steroid hormone testosterone releases. The pair bonding behaviour consisted in ‘daily activity', ‘contact behaviour' and 'social interactions'. The ‘daily activity' included the behaviours: resting, sitting, eating, preening, activity and movement. Certain individual behaviours and gender roles were examined for the ‘contact behaviour'. The duration and frequency of social preening and the social index were summarized as 'social interactions'. In the social preening the duration and frequency of the phases was recorded, and the respective initiator of this interaction. In addition, gender of the individual, frequency, and duration of the social preening was recorded. Furthermore the social index was calculated, which indicates the relationship between agonistic and socio-positive interactions. To measure the testosterone release in the pair members over 9 weeks (September to November 2007), faecal samples were collected from each individual once a week. The faecal samples were analyzed at the Institute for Physiological Chemistry at the University of Leipzig under supervision of Prof. Dr. Almuth Einspanier. Competitive double-Antibody Enzyme Immunoassay (EIA) was applied to determine the testosteronecontent of the faecal samples. Reproductive success was represented by number of eggs, nests and chicks, and the clutch size. These data provide, based on the duration of the pair bond, information about the productivity of breeding pairs. Furthermore, the number of chicks reared by one breeding pair independently should provide information about the capacity for cooperative breeding. Breeding pairs were classified into different groups depending on their reproductive potential. This classification was verified by discriminant analysis and regression analysis to investigate the importance of the quality of the pair bond for reproductive success. I found that the reproductive potential of breeding pairs is related to various criteria that characterize the quality of a pair bond, but it is essential to distinguish between the productivity itself and the ability to cooperative breeding. The synchronous resting with a partner according to the daily activity, as well as the frequency and duration of social preening initiated by the female positively influenced the productivity of a pair. Breeding pairs with high productivity also showed a high ‚intra-pair fluctuation' of the steroid hormone testosterone level. The breeding pairs which are able to raise their young in cooperation also showed a high percentage of time with coordinated phases of resting, also frequent resting behaviour in physical contact with the partner and a high investment of males in the initiation and implementation of social preening. In addition, males, which actively contribute to cooperative breeding, showed significantly lower testosterone concentrations than males, which were members of breeding pairs not capable of raising chicks on its own. This result emphasizes the importance of testosterone during the parental care, especially in males, and provides a starting point for further investigations. My investigation shows that it is possible and useful to apply the individual behaviour of animals in captivity for the conservation of endangered species. Based on this study, further research should be aimed to expose reliable breeding pairs with good reproductive potential, by behaviour and by measuring hormonal states. In this way, poor reproductive success of endangered parrot species in captivity as a result of forced parings can be minimized.

Direct semiconductor wafer bonding has emerged as a technology to meet the demand foradditional flexibility in materials integration. The applications are found in microelectronics, optoelectronics and micromechanics. For instance, wafer bonding is used to produce silicon-on-insulator (SOI) wafers. Wafer bonding is also interesting to use for combining dissimilar semiconductors, such as Si and InP, with different dictated optical, electronic and mechanicalproperties. This enables a completely new freedom in the design of components and systems, e.g. for high performance optoelectronic integrated circuits (OEIC). Although wafer bonding has proved to be a useful and versatile tool, the high temperature annealing that is needed to achieve reliable properties sometimes hampers its applicability. Therefore, low temperature wafer bonding procedures may further qualify this technology. In the present thesis, low temperature wafer bonding procedures using oxygen plasma surface activation have been studied. A specially designed fixture was adopted enabling in situ oxygen plasma wafer bonding. Oxygen plasma surface activation was seen to indeed yield high Si-Si bonding-strength at low temperatures. Here, the optimisation of the plasma parameters was shown to be the key to improved results. Furthermore, dependence of wafer bonded Si p-n junctions on the annealing temperature was investigated. InP-to-Si wafer bonding is also presented within this thesis. High temperature annealing was seen to induce severe material degradation. However, using oxygen plasma assisted wafer bonding reliable InP-to-Si integration was achieved already at low temperature, thereby circumventing the problems associated with the lattice and thermal mismatch that exist between these materials. As a result, low temperature InP-based epitaxial-layer transferring to Si could be presented. Finally, high-quality SiO2 insulator on InP and Si was realised at low temperatures. It is concluded that low temperature oxygen plasma assisted wafer bonding is an interesting approach to integrate dissimilar materials, for a wide range of applications.

This thesis is based on ten publications (Papers I-X). The phosphodiester backbone makes DNA or RNA to behave as polyelectrolyte, the pentose sugar gives the flexibility, and the aglycones promote the self-assembly or the ligand-binding process. The hydrogen bonding, stacking, stereoelectronics and hydration are few of the important non-covalent forces dictating the self-assembly of DNA/RNA. The pH-dependent thermodynamics clearly show (Papers I and II) that a change of the electronic character of aglycone modulates the conformation of the sugar moiety by the tunable interplay of stereoelectronic anomeric and gauche effects, which are further transmitted to steer the sugar-phosphate backbone conformation in a cooperative manner. 3'-anthraniloyl<b> </b>adenosine<b> </b>(a mimic of 3'-teminal CC<u>A</u>OH of the aminoacyl-tRNAPhe) binds to EF-Tu*GTP in preference over 2'-anthraniloyl<b> </b>adenosine<b>, </b>thereby showing (Paper III) that the 2’-endo sugar conformation is a more suitable mimic of the transition state geometry than the 3’-endo conformation in discriminating between correctly and incorrectly charged aminoacyl-tRNAPhe by EF-Tu during protein synthesis. The presence of 2'-OH in RNA distinguishes it from DNA both functionally as well as structurally. This work (Paper IV) provides straightforward NMR evidence to show that the 2'-OH is intramolecularly hydrogen bonded with the vicinal 3'-oxygen, and the exposure of the 3'-phosphate of the ribonucleotides to the bulk water determines the availability of the bound water around the vicinal 2'-OH, which then can play various functional role through inter- or intramolecular interactions. The pH-dependent 1H NMR study with nicotinamide derivatives demonstrates (Paper V) that the cascade of intramolecular cation (pyridinium)-π(phenyl)-CH(methyl) interaction in edge-to-face geometry is responsible for perturbing the pKa of the pyridine-nitrogen as well as for the modulation of the aromatic character of the neighboring phenyl moiety, which is also supported by the T1 relaxation studies and ab initio calculations. It has been found (Papers VI-IX) that the variable intramolecular electrostatic interaction between electronically coupled nearest neighbor nucleobases (steered by their respective microenvironments) can modulate their respective pseudoaromatic characters. The net result of this pseudoaromatic cross-modulation is the creation of a unique set of aglycones in an oligo or polynucleotide, whose physico-chemical properties are completely dependent upon the propensity and geometry of the nearest neighbor interactions (extended genetic code). The propagation of the interplay of these electrostatic interactions across the hexameric ssDNA chain is considerably less favoured (effectively up to the fourth nucleobase) compared to that of the isosequential ssRNA (up to the sixth nucleobase). The dissection of the relative strength of basepairing and stacking in a duplex shows that stability of DNA-DNA duplex weakens over the corresponding RNA-RNA duplexes with the increasing content of A-T/U base pairs, while the strength of stacking of A-T rich DNA-DNA duplex increases in comparison with A-U rich sequence in RNA-RNA duplexes (Paper X).

Computational methods are combined with synchrotron-based techniques to analyze the structure and bonding of water and water plus hydroxyl at metal surfaces under UHV and at near-ambient conditions. Water-metal interaction plays a crucial role in a multitude of cosmic, atmospheric and biological phenomena as well as heterogeneous catalysis, electrochemistry and corrosion. A spotlight of renewed interest has recently been cast on water-metal systems due to their relevance for surface chemical reactions related to the production and utilization of hydrogen as a clean energy carrier. In particular, H2O and OH are essential reaction intermediates in the renewable production of hydrogen from sunlight and water and in fuel cell electrocatalysis. Fuel cells are considered one of the most promising power generation technologies for a sustainable energy future. A mechanistic understanding of the oxygen reduction reaction (ORR) pathway, including the role of electronic and geometric structure of the catalyst, is essential to the design of more efficient fuel cell catalysts. This is intimately connected to fundamental factors that affect the ability to form water-metal bonds as well as the site occupation and orientation of the adsorbed H2O and OH at active metal surfaces. Key relationships related to critical issues in the fuel cell reaction are illuminated by the synergy of theory and experiment in this thesis. We emerge with a detailed understanding of the structure of the water-metal interface and the factors that rule the wettability of a metal surface, including geometric and electronic structure effects and the influence of coadsorbed species. We show that the preferred microscopic orientation of the water monolayer has consequences for macroscopic properties, and reveal the origin of the hydrophobic water layer. Finally, we identify a cooperativity effect that drives the stability of the mixed water/hydroxyl layer at metal surfaces, an important ORR intermediate.

The purpose of this research is to study the influence of different bonding strategies for customer relationship management on customer loyalty in online shopping. In particular, the research is focused on the mediation effect of relationship quality. ¡@¡@More Specifically, this study examines the following issues¡G(1) the relationship between relationship bonding strategies and relationship quality; (2) whether relationship bonding strategies will influence customer loyalty; and (3) the influence of relationship quality on customer loyalty. An online survey received 311 useful responses. The results include (1) social bondings had a positive effect on customer loyalty, but financial and structural bonding had no direct correlation with customer loyalty, (2) with respect to different dimensions of relationship quality, financial and structural bondings had a positive effect on customer satisfaction, trust and commitment. Social bonding had partial correlation with relationship quality; (3) Customer satisfaction, trust and commitment in relationship quality showed positive connection to customer loyalty. The effect of customer satisfaction was weaker than those of trust and commitment; and (4) Relationship quality is a moderator between bonding strategies and customer loyalty. A complete mediating effect has been observed.

In recent years there has been a huge increase in the growth of communication systems such as mobile phones, wireless local area networks (WLAN), satellite navigation and various other forms of wireless data communication that have made analogue frequency control a key issue. The increase in frequency spectrum crowding and the increase of frequency into microwave region, along with the need for minimisation and capacity improvement, has shown the need for the development of high performance, miniature, on-chip filters operating in the low to medium GHz frequency range. This has hastened the need for alternatives to ceramic resonators due to their limits in device size and performance, which in turn, has led to development of the thin film electro-acoustics industry with surface acoustic wave (SAW) and bulk acoustic wave (BAW) filters now fabricated in their millions. Further, this new technology opens the way for integrating the traditionally incompatible integrated circuit (IC) and electro-acoustic (EA) technologies, bringing about substantial economic and performance benefits. In this thesis the compatibility of aluminium nitride (AlN) to IC fabrication is explored as a means for furthering integration issues. Various issues have been explored where either tailoring thin film bulk acoustic resonator (FBAR) design, such as development of an improved solidly mounted resonator (SMR) technology, and use of IC technology, such as chemical mechanical polishing (CMP) or nickel silicide (NiSi), has made improvements beneficial for resonator fabrication or enabled IC integration. The former has resulted in major improvements to Quality factor, power handling and encapsulation respectively. The later has provided alternative methods to reduce electro- or acoustomigration, reduced device size, for plate waves, supplied novel low acoustic impedance material for high power applications and alternative electrodes for use in high temperature sensors. Another method to enhance integration by using the piezoelectric material, AlN, in the IC side has also been explored. Here methods for analysing AlN film contamination and stoichiometry have been used for analysis of AlN as a high-k dielectric material. This has even brought benefits in knowledge of film composition for use as a passivation material with SiC substrates, investigated in high power high frequency applications. Lastly AlN has been used as a buried insulator material for new silicon-on-insulator substrates (SOI) for increased heat conduction. These new substrates have been analysed with further development for improved performance indicated. / wisenet

Improved methods are needed to interrogate the genome and the proteome. Methods with high selectivity, wide dynamic range, and excellent precision, capable of simultaneously analyzing many biomolecules are required to decipher cellular function. This thesis describes a molecular and microfluidic toolbox designed with those criteria in mind. It also presents a tool for graphical representation of nucleic acid sequences. Proximity ligation is a novel protein detection method that requires dual and proximate binding of two oligonucleotide-tagged affinity reagents to a protein or protein complex in order to elicit a signal. The responses from such recognition reactions are the formation of specific nucleic acid reporter molecules that are subsequently amplified and quantitatively detected. A scalable microfluidic platform suitable for fluorescence detection, cell culture, and actuation is also described. The platform uses rapid injection molding to produce microstructures in thermoplastic materials. By applying a thin layer of silica to the structures, a lid made of silicone rubber coated onto a thermoplastic support can be covalently bonded to generate enclosed channels. A method is presented for precise biomolecule counting, termed “amplified single-molecule detection”. The method preserves the discrete nature of biomolecules, converting specific molecular recognition events to fluorescence-labeled micrometer-sized objects that are enumerated in microfluidic channels. I also present a novel microarray-based detection method. To attain high selectivity and a wide dynamic range, the method is based on dual recognition with enzymatic discrimination and amplification. Upon target recognition in solution, DNA probes are subjected to thousand-fold amplification in solution, followed by selective detection on arrays and another hundred-fold amplification of reporter molecule created from the first amplification reaction. Lastly, I describe a novel graphical representation of nucleic acid sequences using TrueType fonts that can be of value for visual inspection of DNA sequences and for teaching purposes

Halogen bonding (XB), the interaction between electron deficient halogen compounds and electron donors, is an established non-covalent interaction in the solid and gaseous phases. Understanding of XB in the solution phase is limited. This thesis describes experimental studies of XB interactions in solution, and the application of XB interactions in anion recognition. Chapter 1 is a brief review of current understanding of XB interaction: theoretical models, studies of XB in solid and gaseous phases and examples in biological systems are discussed. At the end of this chapter, halogen bonding in the solution phase is discussed, along with applications of halogen bonding in organic syntheses. In chapter 2, linear free energy relationships involving the thermodynamics of halogen bonding of substituted iodoaromatics are studied. The utility of substituent constants and calculated molecular electrostatic potential values as metrics of halogen bond donor ability are discussed. Density Functional Theory (DFT) calculations are shown to have useful predictive values for trends in halogen bond strength for a range of donor-acceptor pairs. Chapter 3 describes the development of new multidentate anion receptors based on halogen bonding. Bidentate and tridentate receptors were found to exhibit significantly higher binding constants than simple monodentate donors. These receptors show selectivity for halide anions over oxyanions. Using 19F NMR spectra at different temperature, the enthalpies and entropies of anion bindings for monodentate and tridentate receptors were determined. The results indicate a positive entropy contribution to anion binding for both mono and tridentate receptors in acetone solvent. Finally in chapter 4, some mesitylene based receptors with 3-halopyridinium and 2-iodobenzimidazolium donors are introduced. The receptors perform halide anion recognition in aqueous solvent system through charge-assisted XB interactions. These findings can allude to utility in organic synthesis, supramolecular chemistry and drug design.