Neuromagnetic studies on cortical somatosensory functions in infants and children : Normal development and effect of early brain lesions

Until recently, objective investigation of the functional development of the human brain in vivo was challenged by the lack of noninvasive research methods. Consequently, fairly little is known about cortical processing of sensory information even in healthy infants and children. Furthermore, mechanisms by which early brain insults affect brain development and function are poorly understood. In this thesis, we used magnetoencephalography (MEG) to investigate development of cortical somatosensory functions in healthy infants, very premature infants at risk for neurological disorders, and adolescents with hemiplegic cerebral palsy (CP). In newborns, stimulation of the hand activated both the contralateral primary (SIc) and secondary somatosensory cortices (SIIc). The activation patterns differed from those of adults, however. Some of the earliest SIc responses, constantly present in adults, were completely lacking in newborns and the effect of sleep stage on SIIc responses differed. These discrepancies between newborns and adults reflect the still developmental stage of the newborns’ somatosensory system. Its further maturation was demonstrated by a systematic transformation of the SIc response pattern with age. The main early adult­like components were present by age two. In very preterm infants, at term age, the SIc and SIIc were activated at similar latencies as in healthy fullterm newborns, but the SIc activity was weaker in the preterm group. The SIIc response was absent in four out of the six infants with brain lesions of the underlying hemisphere. Determining the prognostic value of this finding remains a subject for future studies, however. In the CP adolescents with pure subcortical lesions, contrasting their unilateral symptoms, the SIc responses of both hemispheres differed from those of controls: For example the distance between SIc representation areas for digits II and V was shorter bilaterally. In four of the five CP patients with cortico­subcortical brain lesions, no normal early SIc responses were evoked by stimulation of the palsied hand. The varying differences in neuronal functions, underlying the common clinical symptoms, call for investigation of more precisely designed rehabilitation strategies resting on knowledge about individual functional alterations in the sensorimotor networks.

Tumour necrosis factor receptor-associated periodic syndrome (TRAPS) : Identification of novel TNFRSF1A mutations and intracellular signalling defects

The systemic autoinflammatory disorders are a group of rare diseases characterized by periodically recurring episodes of acute inflammation and a rise in serum acute phase proteins, but with no signs of autoimmunity. At present eight hereditary syndromes are categorized as autoinflammatory, although the definition has also occasionally been extended to other inflammatory disorders, such as Crohn s disease. One of the autoinflammatory disorders is the autosomally dominantly inherited tumour necrosis factor receptor-associated periodic syndrome (TRAPS), which is caused by mutations in the gene encoding the tumour necrosis factor type 1 receptor (TNFRSF1A). In patients of Nordic descent, cases of TRAPS and of three other hereditary fevers, hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), chronic infantile neurologic, cutaneous and articular syndrome (CINCA) and familial cold autoinflammatory syndrome (FCAS), have been reported, TRAPS being the most common of the four. Clinical characteristics of TRAPS are recurrent attacks of high spiking fever, associated with inflammation of serosal membranes and joints, myalgia, migratory rash and conjunctivitis or periorbital cellulitis. Systemic AA amyloidosis may occur as a sequel of the systemic inflammation. The aim of this study was to investigate the genetic background of hereditary periodically occurring fever syndromes in Finnish patients, to explore the reliability of determining serum concentrations of soluble TNFRSF1A and metalloproteinase-induced TNFRSF1A shedding as helpful tools in differential diagnostics, as well as to study intracellular NF-κB signalling in an attempt to widen the knowledge of the pathomechanisms underlying TRAPS. Genomic sequencing revealed two novel TNFRSF1A mutations, F112I and C73R, in two Finnish families. F112I was the first TNFRSF1A mutation to be reported in the third extracellular cysteine-rich domain of the gene and C73R was the third novel mutation to be reported in a Finnish family, with only one other TNFRSF1A mutation having been reported in the Nordic countries. We also presented a differential diagnostic problem in a TRAPS patient, emphasizing for the clinician the importance of differential diagnostic vigiliance in dealing with rare hereditary disorders. The underlying genetic disease of the patient both served as a misleading factor, which possibly postponed arrival at the correct diagnosis, but may also have predisposed to the pathologic condition, which led to a critical state of the patient. Using a method of flow cytometric analysis modified for the use on fresh whole blood, we studied intracellular signalling pathways in three Finnish TRAPS families with the F112I, C73R and the previously reported C88Y mutations. Evaluation of TNF-induced phosphorylation of NF-κB and p38, revealed low phosphorylation profiles in nine out of ten TRAPS patients in comparison to healthy control subjects. This study shows that TRAPS is a diagnostic possibility in patients of Nordic descent, with symptoms of periodically recurring fever and inflammation of the serosa and joints. In particular in the case of a family history of febrile episodes, the possibility of TRAPS should be considered, if an etiology of autoimmune or infectious nature is excluded. The discovery of three different mutations in a population as small as the Finnish, reinforces the notion that the extracellular domain of TNFRSF1A is prone to be mutated at the entire stretch of its cysteine-rich domains and not only at a limited number of sites, suggesting the absence of a founder effect in TRAPS. This study also demonstrates the challenges of clinical work in differentiating the symptoms of rare genetic disorders from those of other pathologic conditions and presents the possibility of an autoinflammatory disorder as being the underlying cause of severe clinical complications. Furthermore, functional studies of fresh blood leukocytes show that TRAPS is often associated with a low NF-κB and p38 phosphorylation profile, although low phosphorylation levels are not a requirement for the development of TRAPS. The aberrant signalling would suggest that the hyperinflammatory phenotype of TRAPS is the result of compensatory NF-κB-mediated regulatory mechanisms triggered by a deficiency of the innate immune response.

Quasi-periodic, global oscillations in sea level pressure on intraseasonal timescales

The sea level pressure (SLP) variability in 30-60 day intraseasonal timescales is investigated using 25 years of reanalysis data addressing two issues. The first concerns the non-zero zonal mean component of SLP near the equator and its meridional connections, and the second concerns the fast eastward propagation (EP) speed of SLP compared to that of zonal wind. It is shown that the entire globe resonates with high amplitude wave activity during some periods which may last for few to several months, followed by lull periods of varying duration. SLP variations in the tropical belt are highly coherent from 25A degrees S to 25A degrees N, uncorrelated with variations in mid latitudes and again significantly correlated but with opposite phase around 60A degrees S and 65A degrees N. Near the equator (8A degrees S-8A degrees N), the zonal mean contributes significantly to the total variance in SLP, and after its removal, SLP shows a dominant zonal wavenumber one structure having a periodicity of 40 days and EP speeds comparable to that of zonal winds in the Indian Ocean. SLP from many of the atmospheric and coupled general circulation models show similar behaviour in the meridional direction although their propagation characteristics in the tropical belt differ widely.

Characterization of LRRTM and NGR gene families: Expression and functions

Some leucine-rich repeat (LRR) -containing membrane proteins are known regulators of neuronal growth and synapse formation. In this work I characterize two gene families encoding neuronal LRR membrane proteins, namely the LRRTM (leucine-rich repeat, transmembrane neuronal) and NGR (Nogo-66 receptor) families. I studied LRRTM and NGR family member's mRNA tissue distribution by RT-PCR and by in situ hybridization. Subcellular localization of LRRTM1 protein was studied in neurons and in non-neuronal cells. I discovered that LRRTM and NGR family mRNAs are predominantly expressed in the nervous system, and that each gene possesses a specific expression pattern. I also established that LRRTM and NGR family mRNAs are expressed by neurons, and not by glial cells. Within neurons, LRRTM1 protein is not transported to the plasma membrane; rather it localizes to endoplasmic reticulum. Nogo-A (RTN4), MAG, and OMgp are myelin-associated proteins that bind to NgR1 to limit axonal regeneration after central nervous system injury. To better understand the functions of NgR2 and NgR3, and to explore the possible redundancy in the signaling of myelin inhibitors of neurite growth, I mapped the interactions between NgR family and the known and candidate NgR1 ligands. I identified high-affinity interactions between RTN2-66, RTN3-66 and NgR1. I also demonstrate that Rtn3 mRNA is expressed in the same glial cell population of mouse spinal cord white matter as Nogo-A mRNA, and thus it could have a role in myelin inhibition of axonal growth. To understand how NgR1 interacts with multiple structurally divergent ligands, I aimed first to map in more detail the nature of Nogo-A:NgR1 interactions, and then to systematically map the binding sites of multiple myelin ligands in NgR1 by using a library of NgR1 expression constructs encoding proteins with one or multiple surface residues mutated to alanine. My analysis of the Nogo-A:NgR1 -interactions revealed a novel interaction site between the proteins, suggesting a trivalent Nogo-A:NgR1-interaction. Our analysis also defined a central binding region on the concave side of NgR1's LRR domain that is required for the binding of all known ligands, and a surrounding region critical for binding MAG and OMgp. To better understand the biological role of LRRTMs, I generated Lrrtm1 and Lrrtm3 knock out mice. I show here that reporter genes expressed from the targeted loci can be used for maping the neuronal connections of Lrrtm1 and Lrrtm3 expressing neurons in finer detail. With regard to LRRTM1's role in humans, we found a strong association between a 70 kb-spanning haplotype in the proposed promoter region of LRRTM1 gene and two possibly related phenotypes: left-handedness and schizophrenia. Interestingly, the responsible haplotype was linked to phenotypic variability only when paternally inherited. In summary, I identified two families of neuronal receptor-like proteins, and mapped their expression and certain protein-protein interactions. The identification of a central binding region in NgR1 shared by multiple ligands may facilitate the design and development of small molecule therapeutics blocking binding of all NgR1 ligands. Additionally, the genetic association data suggests that allelic variation upstream of LRRTM1 may play a role in the development of left-right brain asymmetry in humans. Lrrtm1 and Lrrtm3 knock out mice developed as a part of this study will likely be useful for schizophrenia and Alzheimer s disease research.

Exploring the post-genomic world: Differing explanatory and manipulatory functions of post-genomic sciences

Richard Lewontin proposed that the ability of a scientific field to create a narrative for public understanding garners it social relevance. This article applies Lewontin's conceptual framework of the functions of science (manipulatory and explanatory) to compare and explain the current differences in perceived societal relevance of genetics/genomics and proteomics. We provide three examples to illustrate the social relevance and strong cultural narrative of genetics/genomics for which no counterpart exists for proteomics. We argue that the major difference between genetics/genomics and proteomics is that genomics has a strong explanatory function, due to the strong cultural narrative of heredity. Based on qualitative interviews and observations of proteomics conferences, we suggest that the nature of proteins, lack of public understanding, and theoretical complexity exacerbates this difference for proteomics. Lewontin's framework suggests that social scientists may find that omics sciences affect social relations in different ways than past analyses of genetics.

Guessing based on length functions

Close relationships between guessing functions and length functions are established. Good length functions lead to good guessing functions. In particular, guessing in the increasing order of Lempel-Ziv lengths has certain universality properties for finite-state sources. As an application, these results show that hiding the parameters of the key-stream generating source in a private key crypto-system may not enhance the privacy of the system, the privacy level being measured by the difficulty in brute-force guessing of the key stream.

Turbulence-induced melting of a nonequilibrium vortex crystal in a forced thin fluid film

To gain a better understanding of recent experiments on the turbulence-induced melting of a periodic array of vortices in a thin fluid film, we perform a direct numerical simulation of the two-dimensional Navier-Stokes equations forced such that, at low Reynolds numbers, the steady state of the film is a square lattice of vortices. We find that as we increase the Reynolds number, this lattice undergoes a series of nonequilibrium phase transitions, first to a crystal with a different reciprocal lattice and then to a sequence of crystals that oscillate in time. Initially, the temporal oscillations are periodic; this periodic behaviour becoming more and more complicated with increasing Reynolds number until the film enters a spatially disordered nonequilibrium statistical steady state that is turbulent. We study this sequence of transitions using fluid-dynamics measures, such as the Okubo-Weiss parameter that distinguishes between vortical and extensional regions in the flow, ideas from nonlinear dynamics, e.g. Poincare maps, and theoretical methods that have been developed to study the melting of an equilibrium crystal or the freezing of a liquid and that lead to a natural set of order parameters for the crystalline phases and spatial autocorrelation functions that characterize short- and long-range order in the turbulent and crystalline phases, respectively.

New rational interpolation functions for finite element analysis of rotating beams

A rotating beam finite element in which the interpolating shape functions are obtained by satisfying the governing static homogenous differential equation of Euler–Bernoulli rotating beams is developed in this work. The shape functions turn out to be rational functions which also depend on rotation speed and element position along the beam and account for the centrifugal stiffening effect. These rational functions yield the Hermite cubic when rotation speed becomes zero. The new element is applied for static and dynamic analysis of rotating beams. In the static case, a cantilever beam having a tip load is considered, with a radially varying axial force. It is found that this new element gives a very good approximation of the tip deflection to the analytical series solution value, as compared to the classical finite element given by the Hermite cubic shape functions. In the dynamic analysis, the new element is applied for uniform, and tapered rotating beams with cantilever and hinged boundary conditions to determine the natural frequencies, and the results compare very well with the published results given in the literature.

Novel window functions for digital filters

Window technique is one of the simplest methods to design Finite Impulse Response (FIR) filters. It uses special functions to truncate an infinite sequence to a finite one. In this paper, we propose window techniques based on integer sequences. The striking feature of the proposed work is that it overcomes all the problems posed by floating point numbers and inaccuracy, as the sequences are made of only integers. Some of these integer window sequences, yield sharp transition, while some of them result in zero ripple in passband and stopband.

Stiff-String Basis Functions for Vibration Analysis of High Speed Rotating Beams

A new rotating beam finite element is developed in which the basis functions are obtained by the exact solution of the governing static homogenous differential equation of a stiff string, which results from an approximation in the rotating beam equation. These shape functions depend on rotation speed and element position along the beam and account for the centrifugal stiffening effect. Using this new element and the Hermite cubic finite element, a convergence study of natural frequencies is performed, and it is found that the new element converges much more rapidly than the conventional Hermite cubic element for the first two modes at higher rotation speeds. The new element is also applied for uniform and tapered rotating beams to determine the natural frequencies, and the results compare very well with the published results given in the literature.

Time and Energy Complexity of Distributed Computation of a Class of Functions in Wireless Sensor Networks

We consider a scenario in which a wireless sensor network is formed by randomly deploying n sensors to measure some spatial function over a field, with the objective of computing a function of the measurements and communicating it to an operator station. We restrict ourselves to the class of type-threshold functions (as defined in the work of Giridhar and Kumar, 2005), of which max, min, and indicator functions are important examples: our discussions are couched in terms of the max function. We view the problem as one of message-passing distributed computation over a geometric random graph. The network is assumed to be synchronous, and the sensors synchronously measure values and then collaborate to compute and deliver the function computed with these values to the operator station. Computation algorithms differ in (1) the communication topology assumed and (2) the messages that the nodes need to exchange in order to carry out the computation. The focus of our paper is to establish (in probability) scaling laws for the time and energy complexity of the distributed function computation over random wireless networks, under the assumption of centralized contention-free scheduling of packet transmissions. First, without any constraint on the computation algorithm, we establish scaling laws for the computation time and energy expenditure for one-time maximum computation. We show that for an optimal algorithm, the computation time and energy expenditure scale, respectively, as Theta(radicn/log n) and Theta(n) asymptotically as the number of sensors n rarr infin. Second, we analyze the performance of three specific computation algorithms that may be used in specific practical situations, namely, the tree algorithm, multihop transmission, and the Ripple algorithm (a type of gossip algorithm), and obtain scaling laws for the computation time and energy expenditure as n rarr infin. In particular, we show that the computation time for these algorithms scales as Theta(radicn/lo- g n), Theta(n), and Theta(radicn log n), respectively, whereas the energy expended scales as , Theta(n), Theta(radicn/log n), and Theta(radicn log n), respectively. Finally, simulation results are provided to show that our analysis indeed captures the correct scaling. The simulations also yield estimates of the constant multipliers in the scaling laws. Our analyses throughout assume a centralized optimal scheduler, and hence, our results can be viewed as providing bounds for the performance with practical distributed schedulers.