Genes involved in complex adaptive processes tend to have highly conserved upstream regions in mammalian genomes

BACKGROUND:Recent advances in genome sequencing suggest a remarkable conservation in gene content of mammalian organisms. The similarity in gene repertoire present in different organisms has increased interest in studying regulatory mechanisms of gene expression aimed at elucidating the differences in phenotypes. In particular, a proximal promoter region contains a large number of regulatory elements that control the expression of its downstream gene. Although many studies have focused on identification of these elements, a broader picture on the complexity of transcriptional regulation of different biological processes has not been addressed in mammals. The regulatory complexity may strongly correlate with gene function, as different evolutionary forces must act on the regulatory systems under different biological conditions. We investigate this hypothesis by comparing the conservation of promoters upstream of genes classified in different functional categories.RESULTS:By conducting a rank correlation analysis between functional annotation and upstream sequence alignment scores obtained by human-mouse and human-dog comparison, we found a significantly greater conservation of the upstream sequence of genes involved in development, cell communication, neural functions and signaling processes than those involved in more basic processes shared with unicellular organisms such as metabolism and ribosomal function. This observation persists after controlling for G+C content. Considering conservation as a functional signature, we hypothesize a higher density of cis-regulatory elements upstream of genes participating in complex and adaptive processes.CONCLUSION:We identified a class of functions that are associated with either high or low promoter conservation in mammals. We detected a significant tendency that points to complex and adaptive processes were associated with higher promoter conservation, despite the fact that they have emerged relatively recently during evolution. We described and contrasted several hypotheses that provide a deeper insight into how transcriptional complexity might have been emerged during evolution.

X-ray Diffraction Tomographic Imaging and Reconstruction

Material discrimination based on conventional or dual energy X-ray computed tomography (CT) imaging can be ambiguous. X-ray diffraction imaging (XDI) can be used to construct diffraction profiles of objects, providing new molecular signature information that can be used to characterize the presence of specific materials. Combining X-ray CT and diffraction imaging can lead to enhanced detection and identification of explosives in luggage screening. In this work we are investigating techniques for joint reconstruction of CT absorption and X-ray diffraction profile images of objects to achieve improved image quality and enhanced material classification. The initial results have been validated via simulation of X-ray absorption and coherent scattering in 2 dimensions.

Cryptographic Tamper Evidence

We propose a new notion of cryptographic tamper evidence. A tamper-evident signature scheme provides an additional procedure Div which detects tampering: given two signatures, Div can determine whether one of them was generated by the forger. Surprisingly, this is possible even after the adversary has inconspicuously learned (exposed) some-or even all-the secrets in the system. In this case, it might be impossible to tell which signature is generated by the legitimate signer and which by the forger. But at least the fact of the tampering will be made evident. We define several variants of tamper-evidence, differing in their power to detect tampering. In all of these, we assume an equally powerful adversary: she adaptively controls all the inputs to the legitimate signer (i.e., all messages to be signed and their timing), and observes all his outputs; she can also adaptively expose all the secrets at arbitrary times. We provide tamper-evident schemes for all the variants and prove their optimality. Achieving the strongest tamper evidence turns out to be provably expensive. However, we define a somewhat weaker, but still practical, variant: α-synchronous tamper-evidence (α-te) and provide α-te schemes with logarithmic cost. Our α-te schemes use a combinatorial construction of α-separating sets, which might be of independent interest. We stress that our mechanisms are purely cryptographic: the tamper-detection algorithm Div is stateless and takes no inputs except the two signatures (in particular, it keeps no logs), we use no infrastructure (or other ways to conceal additional secrets), and we use no hardware properties (except those implied by the standard cryptographic assumptions, such as random number generators). Our constructions are based on arbitrary ordinary signature schemes and do not require random oracles.

Searching the Sky with CONFIGR-STARS

SyNAPSE program of the Defense Advanced Projects Research Agency (HRL Laboratories LLC, subcontract #801881-BS under DARPA prime contract HR0011-09-C-0001); CELEST, a National Science Foundation Science of Learning Center (SBE-0354378)

Spatial and energetic mode dynamics of cold atomic systems

In this thesis we relate the formal description of various cold atomic systems in the energy eigenbasis, to the observable spatial mode dynamics. Herein the `spatial mode dynamics' refers to the direction of photon emission following the spontaneous emission of an excited fermion in the presence of a same species and spin ideal anisotropic Fermi sea in its internal ground state. Due to the Pauli principle, the presence of the ground state Fermi sea renders the phase space, anisotropic and only partially accessible, thereby a ecting the direction of photon emission following spontaneous emission. The spatial and energetic mode dynamics also refers to the quantum `tunneling' interaction between localised spatial modes, synonymous with double well type potentials. Here we relate the dynamics of the wavefunction in both the energetic and spatial representations. Using this approach we approximate the relationship between the spatial and energetic representations of a wavefunction spanning three spatial and energetic modes. This is extended to a process known as Spatial Adiabatic Passage, which is a technique to transport matter waves between localised spatial modes. This approach allows us to interpret the transport of matter waves as a signature of a geometric phase acquired by the one of the internal energy eigenstates of the system during the cyclical evolution. We further show that this geometric phase may be used to create spatial mode qubit and qutrit states.

Applications of finite element computer modelling and thermal infrared remote sensing to the study of geothermal anomalies

Buried heat sources can be investigated by examining thermal infrared images and comparing these with the results of theoretical models which predict the thermal anomaly a given heat source may generate. Key factors influencing surface temperature include the geometry and temperature of the heat source, the surface meteorological environment, and the thermal conductivity and anisotropy of the rock. In general, a geothermal heat flux of greater than 2% of solar insolation is required to produce a detectable thermal anomaly in a thermal infrared image. A heat source of, for example, 2-300K greater than the average surface temperature must be a t depth shallower than 50m for the detection of the anomaly in a thermal infrared image, for typical terrestrial conditions. Atmospheric factors are of critical importance. While the mean atmospheric temperature has little significance, the convection is a dominant factor, and can act to swamp the thermal signature entirely. Given a steady state heat source that produces a detectable thermal anomaly, it is possible to loosely constrain the physical properties of the heat source and surrounding rock, using the surface thermal anomaly as a basis. The success of this technique is highly dependent on the degree to which the physical properties of the host rock are known. Important parameters include the surface thermal properties and thermal conductivity of the rock. Modelling of transient thermal situations was carried out, to assess the effect of time dependant thermal fluxes. One-dimensional finite element models can be readily and accurately applied to the investigation of diurnal heat flow, as with thermal inertia models. Diurnal thermal models of environments on Earth, the Moon and Mars were carried out using finite elements and found to be consistent with published measurements. The heat flow from an injection of hot lava into a near surface lava tube was considered. While this approach was useful for study, and long term monitoring in inhospitable areas, it was found to have little hazard warning utility, as the time taken for the thermal energy to propagate to the surface in dry rock (several months) in very long. The resolution of the thermal infrared imaging system is an important factor. Presently available satellite based systems such as Landsat (resolution of 120m) are inadequate for detailed study of geothermal anomalies. Airborne systems, such as TIMS (variable resolution of 3-6m) are much more useful for discriminating small buried heat sources. Planned improvements in the resolution of satellite based systems will broaden the potential for application of the techniques developed in this thesis. It is important to note, however, that adequate spatial resolution is a necessary but not sufficient condition for successful application of these techniques.

Hardware design of cryptographic accelerators

With the rapid growth of the Internet and digital communications, the volume of sensitive electronic transactions being transferred and stored over and on insecure media has increased dramatically in recent years. The growing demand for cryptographic systems to secure this data, across a multitude of platforms, ranging from large servers to small mobile devices and smart cards, has necessitated research into low cost, flexible and secure solutions. As constraints on architectures such as area, speed and power become key factors in choosing a cryptosystem, methods for speeding up the development and evaluation process are necessary. This thesis investigates flexible hardware architectures for the main components of a cryptographic system. Dedicated hardware accelerators can provide significant performance improvements when compared to implementations on general purpose processors. Each of the designs proposed are analysed in terms of speed, area, power, energy and efficiency. Field Programmable Gate Arrays (FPGAs) are chosen as the development platform due to their fast development time and reconfigurable nature. Firstly, a reconfigurable architecture for performing elliptic curve point scalar multiplication on an FPGA is presented. Elliptic curve cryptography is one such method to secure data, offering similar security levels to traditional systems, such as RSA, but with smaller key sizes, translating into lower memory and bandwidth requirements. The architecture is implemented using different underlying algorithms and coordinates for dedicated Double-and-Add algorithms, twisted Edwards algorithms and SPA secure algorithms, and its power consumption and energy on an FPGA measured. Hardware implementation results for these new algorithms are compared against their software counterparts and the best choices for minimum area-time and area-energy circuits are then identified and examined for larger key and field sizes. Secondly, implementation methods for another component of a cryptographic system, namely hash functions, developed in the recently concluded SHA-3 hash competition are presented. Various designs from the three rounds of the NIST run competition are implemented on FPGA along with an interface to allow fair comparison of the different hash functions when operating in a standardised and constrained environment. Different methods of implementation for the designs and their subsequent performance is examined in terms of throughput, area and energy costs using various constraint metrics. Comparing many different implementation methods and algorithms is nontrivial. Another aim of this thesis is the development of generic interfaces used both to reduce implementation and test time and also to enable fair baseline comparisons of different algorithms when operating in a standardised and constrained environment. Finally, a hardware-software co-design cryptographic architecture is presented. This architecture is capable of supporting multiple types of cryptographic algorithms and is described through an application for performing public key cryptography, namely the Elliptic Curve Digital Signature Algorithm (ECDSA). This architecture makes use of the elliptic curve architecture and the hash functions described previously. These components, along with a random number generator, provide hardware acceleration for a Microblaze based cryptographic system. The trade-off in terms of performance for flexibility is discussed using dedicated software, and hardware-software co-design implementations of the elliptic curve point scalar multiplication block. Results are then presented in terms of the overall cryptographic system.

Secure architectures for pairing based public key cryptography

Along with the growing demand for cryptosystems in systems ranging from large servers to mobile devices, suitable cryptogrophic protocols for use under certain constraints are becoming more and more important. Constraints such as calculation time, area, efficiency and security, must be considered by the designer. Elliptic curves, since their introduction to public key cryptography in 1985 have challenged established public key and signature generation schemes such as RSA, offering more security per bit. Amongst Elliptic curve based systems, pairing based cryptographies are thoroughly researched and can be used in many public key protocols such as identity based schemes. For hardware implementions of pairing based protocols, all components which calculate operations over Elliptic curves can be considered. Designers of the pairing algorithms must choose calculation blocks and arrange the basic operations carefully so that the implementation can meet the constraints of time and hardware resource area. This thesis deals with different hardware architectures to accelerate the pairing based cryptosystems in the field of characteristic two. Using different top-level architectures the hardware efficiency of operations that run at different times is first considered in this thesis. Security is another important aspect of pairing based cryptography to be considered in practically Side Channel Analysis (SCA) attacks. The naively implemented hardware accelerators for pairing based cryptographies can be vulnerable when taking the physical analysis attacks into consideration. This thesis considered the weaknesses in pairing based public key cryptography and addresses the particular calculations in the systems that are insecure. In this case, countermeasures should be applied to protect the weak link of the implementation to improve and perfect the pairing based algorithms. Some important rules that the designers must obey to improve the security of the cryptosystems are proposed. According to these rules, three countermeasures that protect the pairing based cryptosystems against SCA attacks are applied. The implementations of the countermeasures are presented and their performances are investigated.

Acoustic behaviour, ecology and social structure of bottlenose dolphins (Tursiops truncatus, Montagu 1821) in the North Atlantic

Communication is important for social and other behavioural interactions in most marine mammal species. The bottlenose dolphin (Tursiops truncatus, Montagu, 1821) is a highly social species that use whistles as communication calls to express identity and to initiate and maintain contact between socially interactive individuals. In this thesis, the degree of variability in whistle behaviour and whistle characteristics was examined between different habitats on a range of spatial scales. The whistle characteristics that best discriminated between different communities were investigated, along with exploration of whistle variation in relation to habitat type, levels of social interaction and relatedness. Finally, the use and variability of individually distinctive calls (signature whistles) within and between Irish and US waters were also examined. Relatively high levels of whistle variation were found within a genetically and socially isolated population of dolphins in the Shannon Estuary, reflecting the need for individual identification and distinctive whistles in a population with long term site fidelity and high levels of social cohesion. Variation between reproductively separate communities in Irish waters was relatively small except between animals in inshore compared with continental shelf waters. The greatest differences in whistle structure overall were evident between dolphins using inshore and offshore US waters, likely reflecting social isolation of the two distinct ecotypes that occur in these waters but also variation in behaviour or habitat conditions. Variation found among inshore communities in US waters reflected similarities in habitat use and levels of social interaction. These findings suggest that vocal variation is socially mediated, behaviourally maintained and dependent on levels of social contact between individuals. The findings contribute to our understanding of the interaction of factors influencing vocalisation behaviour in this behaviourally complex and ecologically plastic species.

Cryptographic coprocessors for embedded systems

In the field of embedded systems design, coprocessors play an important role as a component to increase performance. Many embedded systems are built around a small General Purpose Processor (GPP). If the GPP cannot meet the performance requirements for a certain operation, a coprocessor can be included in the design. The GPP can then offload the computationally intensive operation to the coprocessor; thus increasing the performance of the overall system. A common application of coprocessors is the acceleration of cryptographic algorithms. The work presented in this thesis discusses coprocessor architectures for various cryptographic algorithms that are found in many cryptographic protocols. Their performance is then analysed on a Field Programmable Gate Array (FPGA) platform. Firstly, the acceleration of Elliptic Curve Cryptography (ECC) algorithms is investigated through the use of instruction set extension of a GPP. The performance of these algorithms in a full hardware implementation is then investigated, and an architecture for the acceleration the ECC based digital signature algorithm is developed. Hash functions are also an important component of a cryptographic system. The FPGA implementation of recent hash function designs from the SHA-3 competition are discussed and a fair comparison methodology for hash functions presented. Many cryptographic protocols involve the generation of random data, for keys or nonces. This requires a True Random Number Generator (TRNG) to be present in the system. Various TRNG designs are discussed and a secure implementation, including post-processing and failure detection, is introduced. Finally, a coprocessor for the acceleration of operations at the protocol level will be discussed, where, a novel aspect of the design is the secure method in which private-key data is handled

Immunomodulatory effects exerted by Lactobacillus salivarius strains on innate immune cells

Despite increased application of commensal bacteria for attempting to improve the symptoms of a variety of inflammatory conditions, including inflammatory bowel diseases, diarrhoea and irritable bowel syndrome, therapeutic approaches that involve live bacteria are hampered by a limited understanding of bacterium-host interactions. Lactobacilli are natural inhabitants of the mammalian gastrointestinal tract and many lactobacilli are regarded as probiotics meaning that they exert a beneficial influence on the health status of their consumers. Modulation of immune responses is a plausible mechanism underlying these beneficial effects. The aim of this thesis was to investigate the effect of 33 Lactobacillus salivarius strains on the production of inflammatory cytokines from a variety of human and mouse immune cells. Induction of immune responses in vitro was shown to be bacterial- and mouse strain-dependent, cell type-dependent, blood donor-dependent and bacterial cell number-dependent. Collectively, these data suggest the importance of a case-by-case selection of candidate strains for their potential therapeutic application. Toll-like receptors (TLRs) recognize microbe-associated molecular patterns (MAMPs) and play a critical role in shaping microbial-specific innate and adaptive immune responses. Following ligand engagement, TLRs trigger a complex network of signalling that culminate in the production of inflammatory mediators. The investigation of the molecular mechanisms underlying the Lb. salivarius-host interaction resulted in the identification of a novel role for TLR2 in negatively regulating TLR4 signalling originated from subcellular compartments within macrophages. Notably, sustained activation of JAK/STAT cascade and M1-signature genes in TLR2-/- macrophages was ablated by selective TLR4 and JAK inhibitors and by absence of TLR4 in TLR2/4-/- cells. In addition, other negative regulators of TLR signalling triggered by Lb. salivarius strains were found to be the adapter molecules TIRAP and TRIF. Understanding negative regulation of TLR signalling may pave the way for the development of novel therapeutics to limit inflammation in multiple diseases.

A study of the regulation of Trib family members expression in normal and malignant haematopoiesis

The Tribbles family of genes consist of three members; TRIB1, TRIB2 and TRIB3. Trib1 and Trib2 have been identified as oncogenes that can induce AML in mice. However little is known about how the expressions of the Tribbles family genes are controlled in the cell during haematopoiesis or leukaemogenesis. To investigate the Tribbles genes in leukaemia a bioinformatics approach was used. TRIB2 expression was found to be elevated in T-ALL and ALL with t(1;19). TRIB1 was found not to be significantly elevated in any leukaemic subtypes. Analyses of the TRIB1 and TRIB2 gene signatures in both leukaemic and normal haematopoietic cells identified pathways and transcription factors associated with these signatures. Pathways enriched for the TRIB1 signature included TLR signalling pathways and NF-κB pathways. Transcription factors enriched for this signature include C/EBP and SRF. Enriched for the TRIB2 signature includes T cell signalling pathways and Notch signalling pathways. Transcription factors enriched for this signature include E2F and ETS. Further investigation in vitro confirmed the finding that E2F1 was as a potential regulator of TRIB2 expression. E2F1 is able to directly bind to the TRIB2 promoter region and induce TRIB2 expression. C/EBPα p42 was found to inhibit E2F1 and the p30 isoform was found to cooperate with E2F1 induced activation of the TRIB2 promoter. Indicating the potential presence of a regulatory loop involved in the regulation of the TRIB2 gene. In conclusion we have investigated the Tribbles gene signatures in both normal haematopoietic and leukaemic cells. This has led to the identification of a number of pathways and transcription factors associated with these genes. We have also identified a family of transcription factors directly responsible for the regulation of TRIB2 expression. This regulatory pathway has the potential to be targeted in the treatment of leukaemia with a high TRIB2 signature.

On the run

AABA Modal/World Music Fusion piece. A modal piece with the A sections based on the D dorian mode and the B section based on the E flat dorian mode. The time signature moves around in the A section (between 6/8 and 9/8. The melody of the B section is fragmented and contains unorthodox phrase starting and ending points

Molecular mechanisms underpinning IFN-gamma and TNF-alpha synergy in intestinal epithelial cells

Cytokine-driven signalling shapes immune homeostasis and guides inflammatory responses mainly through induction of specific gene expression programmes both within and outside the immune cell compartment. These transcriptional outputs are often amplified via cytokine synergy, which sets a stimulatory threshold that safeguards from exacerbated inflammation and immunopathology. In this study, we investigated the molecular mechanisms underpinning synergy between two pivotal Th1 cytokines, IFN-γ and TNF-α, in human intestinal epithelial cells. These two proinflammatory mediators induce a unique state of signalling and transcriptional synergy implicated in processes such as antiviral and antitumour immunity, intestinal barrier and pancreatic β-cell dysfunction. Since its discovery more than 30 years ago, this biological phenomenon remains, however, only partially defined. Here, using a functional genomics approach including RNAi perturbation screens and small-molecule inhibitors, we identified two new regulators of IFN-γ/TNF-α-induced chemokine and antiviral gene and protein expression, a Bcl-2 protein BCL-G and a histone demethylase UTX. We also discovered that IFN-γ/TNF-α synergise to trigger a coordinated shutdown of major receptor tyrosine kinases expression in colon cancer cells. Together, these findings extend our current understanding of how IFN-γ/TNF-α synergy elicits qualitatively and quantitatively distinct outputs in the intestinal epithelium. Given the well-documented role of this synergistic state in immunopathology of various disorders, our results may help to inform the identification of high quality and biologically relevant druggable targets for diseases characterised by an IFN-γ/TNF-α high immune signature

Afro-Cuban Bata Drum Aesthetics: Developing Individual and Group Technique, Sound and Identity

The Lucumi religion (also Santeria and Regla de Ocha) developed in 19th-century colonial Cuba, by syncretizing elements of Catholicism with the Yoruba worship of orisha. When fully initiated, santeros (priests) actively participate in religious ceremonies by periodically being possessed or "mounted" by a patron saint or orisha, usually within the context of a drumming ritual, known as a toque de santo, bembe, or tambor. Within these rituals, there is a clearly defined goal of trance possession, though its manifestation is not the sole measure of success or failure. Rather than focusing on the fleeting, exciting moments that immediately precede the arrival of an orisha in the form of a possession trance, this thesis investigates the entire four- to six-hour musical performance that is central to the ceremony. It examines the brief pauses, the moments of reduced intensity, the slow but deliberate build-ups of energy and excitement, and even the periods when novices are invited to perform the sacred bata drums, and places these moments on an equal footing with the more dynamic periods where possession is imminent or in progress. This document approaches Lucumi ritual from the viewpoint of bata drummers, ritual specialists who, during the course of a toque de santo, exercise wide latitude in determining the shape of the event. Known as omo Ana (children of the orisha Ana who is manifest in drums and rhythms), bata drummers comprise a fraternity that is accessible only through ritual initiation. Though they are sensitive to the desires of the many participants during a toque de santo, and indeed make their living by satisfying the expectations of their hosts, many of the drummers' activities are inwardly focused on the cultivation and preservation of this fraternity. Occasionally interfering with spirit possession, and other expectations of the participants, these aberrant activities include teaching and learning, developing group identity or signature sound, and achieving a state of intimacy among the musicians known as "communitas."