Change-Point Detection and Bootstrap for Hilbert Space Valued Random Fields

The problem of testing for the presence of epidemic changes in random fields is investigated. In order to be able to deal with general changes in the marginal distribution, a Cram\'er-von Mises type test is introduced which is based on Hilbert space theory. A functional central limit theorem for $\rho$-mixing Hilbert space valued random fields is proven. In order to avoid the estimation of the long-run variance and obtain critical values, Shao's dependent wild bootstrap method is adapted to this context. For this, a joint functional central limit theorem for the original and the bootstrap sample is shown. Finally, the theoretic results are supplemented by a short simulation study

TRANSPLANTATION OF A SPECIFIC NEURAL STEM CELL SUBPOPULATION AS A THERAPEUTIC APPROACH FOR AMYOTROPHIC LATERAL SCLEROSIS

Amyotrophic Lateral Sclerosis (ALS) is a fatal neuromuscular disorder caused by degeneration of motor neurons (MNs) in the spinal cord, brainstem, and cortex. It belongs to a group of heterogeneous disorders called \u201cmotor neuron diseases\u201d, in which ALS is the most common form in adults. The progressive MN degeneration leads to a gradual muscle atrophy and paralysis. Patients affected by ALS usually die 3-5 years after the onset of symptoms due to respiratory failure. Up to now, no effective cure is available for ALS beyond supportive care and Riluzole, which only modestly prolongs Survival. In the early stage of the disease, MN loss and consequent muscle denervation are compensated by axonal sprouting and reinnervation by the remaining MNs, but this mechanism is insufficient in the long term. Thanks to their multiple beneficial mechanisms, stem cell transplantation represents a promising therapeutic strategy for ALS and other neurodegenerative disorders. In fact, transplanted stem cells can provide therapeutic effect by modulating the micro-environment through the production of neurotrophic factors, eliminating toxic molecules, reducing neuroinflammation and generating auxiliary neural networks. Moreover, stem cells can eventually replace degenerating cells. A novel source for stem cell transplantation consists in the reprogramming of adult somatic cells into induced pluripotent stem cells (iPSCs). Since iPSCs are directly derived from adult tissues, they bypass ethical issue of the embryo manipulation and are patient-specific, potentially reproducing ALS features in vitro. This means that they are a promising tool for stem cells transplantation and to model human pathologies in vitro. In this study, we isolated a specific subpopulation of neural stem cells (NSCs) derived from differentiated iPSCs. Compared to other types of stem cell, NSCs are particularly appropriate for ALS treatment due to their peculiar ability to differentiate into neurons, astrocytes and oligodendrocytes. The rationale of this study consists in the selection of a subpopulation of NSCs able to engraft and migrate through the nervous system parenchyma, to protect degenerating MNs and to improve ALS phenotype. We selected NSCs for the presence of three markers: Lewis X (or LeX), CXCR4 e \u3b21 integrin. Lewis X is a glycoprotein marker of stem cells with a relevant role in cell adhesion and migration. CXCR4 is a chemokine receptor, which increases the sensitivity of the cells to be recruited by the host spinal cord that produces chemoattractant cytokines. \u3b21 integrin is a subunit of VLA4, a receptor that allows cells to cross the blood-brain barrier, particularly in the presence of inflammation as in ALS animal models and human patients. In order to evaluate the ability of LeX+CXCR4+\u3b21+ NSCs to engraft into the nervous system and to improve ALS phenotype, we performed intrathecal injection of these cells in the SOD1G93A mouse model. Transplantation resulted in an efficient engraftment of the cells, which reached central nervous system bypassing blood brain barrier, and in the protection of MNs and their axons from degeneration. This determined a preservation of neuromuscular junction (NMJ) innervations by maintaining their integrity and inducing axonal sprouting. These beneficial effects on neuropathological phenotype correlated with a significant increased survival and improved neuromuscular function of transplanted SOD1G93A mice. We also demonstrated the beneficial effects of LeX+CXCR4+\u3b21+ NSCs in a human in vitro model of ALS. When co-cultured with these cells, iPSC-derived MNs from ALS patients showed an improvement in terms of survival and axonal growth. We then analyzed the molecular mechanisms underlying NSC protection demonstrating that our NSC subpopulation exerted positive effects through neurotrophic factors production, inhibition of the GSK3\u3b2 activity, and limiting astrocytes proliferation through activation of vanilloid receptor. The results of this study suggest that effective protection of MNs and NMJs can be achieved targeting multiple deregulated cellular and molecular mechanisms in both MNs and glial cells in ALS models. This is particularly relevant for ALS because different pathological mechanisms likely contribute to its onset, making NSC transplantation a promising therapeutic approach for ALS

Asymptotic Procedures for a Change-Point Analysis of Random Field

The aim of this thesis is to extend some methods of change-point analysis, where classically, measurements in time are examined for structural breaks, to random field data which is observed over a grid of points in multidimensional space. The thesis is concerned with the a posteriori detection and estimation of changes in the marginal distribution of such random field data. In particular, the focus lies on constructing nonparametric asymptotic procedures which take the possible stochastic dependence into account. In order to avoid having to restrict the results to specific distributional assumptions, the tests and estimators considered here use a nonparametric approach where the inference is justified by the asymptotic behavior of the considered procedures (i.e. their behavior as the sample size goes towards infinity). This behavior can often be derived from functional central limit theorems which make it possible to write the limit variables of the statistics as functionals of Wiener processes, independent of the distribution of the original data. A large part of this thesis is concerned with constructing viable asymptotic tests for an epidemic change. For a change in the mean, an asymptotic test is derived under the assumption of a functional central limit theorem. The asymptotic critical values of the test are estimated using the special form of the limit of the statistic. Estimators for the long-run variance, which influences the asymptotic distribution, are discussed. These need to be consistent under the null hypothesis, while staying stochastically bounded under the alternative hypothesis. A special focus there lies on taking a possible change in the mean into account. For a general change in the marginal distribution of the random field under mixing assumptions, the dependent wild bootstrap is introduced to construct an asymptotic test. This is achieved by constructing a test for a change in the mean of Hilbert space valued random fields and translating the change in the marginal distribution of a vector-valued random field into this setting. %a change in mean problem for Hilbert space valued observations. Under the assumption that a change has taken place, one is interested in determining the location of the change-set. For a change in the mean over a rectangular index set, consistent estimators for the edge points of the rectangle are presented and the rate of convergence is derived. Finally, for changes in the mean over more general sets, the consistency and rate of convergence of an argmax-type estimator of the change-set are obtained under the assumption of maximal inequalities. The latter general results are illustrated by examples for classes of sets which fulfill the assumptions

Is spinal muscular atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications?

Spinal muscular atrophy (SMA) is a genetic neurological disease that causes infant mortality; no effective therapies are currently available. SMA is due to homozygous mutations and/or deletions in the survival motor neuron 1 gene and subsequent reduction of the SMN protein, leading to the death of motor neurons. However, there is increasing evidence that in addition to motor neurons, other cell types are contributing to SMA pathology. In this review, we will discuss the involvement of non-motor neuronal cells, located both inside and outside the central nervous system, in disease onset and progression. Even if SMN restoration in motor neurons is needed, it has been shown that optimal phenotypic amelioration in animal models of SMA requires a more widespread SMN correction. It has been demonstrated that non-motor neuronal cells are also involved in disease pathogenesis and could have important therapeutic implications. For these reasons it will be crucial to take this evidence into account for the clinical translation of the novel therapeutic approaches

IPSC-derived neural stem cells act via kinase inhibition to exert neuroprotective effects in spinal muscular atrophy with respiratory distress type 1

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a motor neuron disease caused by mutations in the IGHMBP2 gene, without a cure. Here, we demonstrate that neural stem cells (NSCs) from human-induced pluripotent stem cells (iPSCs) have therapeutic potential in the context of SMARD1. We show that upon transplantation NSCs can appropriately engraft and differentiate in the spinal cord of SMARD1 animals, ameliorating their phenotype, by protecting their endogenous motor neurons. To evaluate the effect of NSCs in the context of human disease, we generated human SMARD1-iPSCs motor neurons that had a significantly reduced survival and axon length. Notably, the coculture with NSCs ameliorate these disease features, an effect attributable to the production of neurotrophic factors and their dual inhibition of GSK-3 and HGK kinases. Our data support the role of iPSC as SMARD1 disease model and their translational potential for therapies in motor neuron disorders

Key role of SMN/SYNCRIP and RNA-Motif 7 in spinal muscular atrophy: RNA-Seq and motif analysis of human motor neurons

Spinal muscular atrophy is a motor neuron disorder caused by mutations in SMN1. The reasons for the selective vulnerability of motor neurons linked to SMN (encoded by SMN1) reduction remain unclear. Therefore, we performed deep RNA sequencing on human spinal muscular atrophy motor neurons to detect specific altered gene splicing/expression and to identify the presence of a common sequence motif in these genes. Many deregulated genes, such as the neurexin and synaptotagmin families, are implicated in critical motor neuron functions. Motif-enrichment analyses of differentially expressed/spliced genes, including neurexin2 (NRXN2), revealed a common motif, motif 7, which is a target of SYNCRIP. Interestingly, SYNCRIP interacts only with full-length SMN, binding and modulating several motor neuron transcripts, including SMN itself. SYNCRIP overexpression rescued spinal muscular atrophy motor neurons, due to the subsequent increase in SMN and their downstream target NRXN2 through a positive loop mechanism and ameliorated SMN-loss-related pathological phenotypes in Caenorhabditis elegans and mouse models. SMN/SYNCRIP complex through motif 7 may account for selective motor neuron degeneration and represent a potential therapeutic target

Extremes of locally stationary chi-square processes with trend

Chi-square processes with trend appear naturally as limiting processes in various statistical models. In this paper we are concerned with the exact tail asymptotics of the supremum taken over (0,1) of a class of locally stationary chi-square processes with particular admissible trends. An important tool for establishing our results is a weak version of Slepian’s lemma for chi-square processes. Some special cases including squared Brownian bridge and Bessel process are discussed

Organic contaminants in western pond turtles in remote habitat in California

Remote aquatic ecosystems are exposed to an assortment of semivolatile organic compounds (SOCs) originating from current and historic uses, of local and global origin. Here, a representative suite of 57 current- and historic-use pesticides, polychlorinated biphenyls, and polycyclic aromatic hydrocarbons were surveyed in the plasma of the western pond turtle (Emys marmorata) and their potential prey items and habitat. California study sites included Sequoia National Park, Whiskeytown National Recreation Area, and Six Rivers National Forest. Each was downstream of undeveloped watersheds and varied in distance from agricultural and urban pollution sources. SOCs were detected frequently in all sites with more found in turtle plasma and aquatic macroinvertebrates in the two sites closest to agricultural and urban sources. Summed PCBs were highest in Whiskeytown National Recreation Area turtle plasma (mean; 1.56 ng/g ww) compared to plasma from Sequoia National Park (0.16 ng/g ww; p = 0.002) and Six Rivers National Forest (0.07 ng/g ww; p = 0.001). While no current-use pesticides were detected in turtle plasma at any site, both current- and historic-use pesticides were found prominently in sediment and macroinvertebrates at the Sequoia National Park site, which is immediately downwind of Central Valley agriculture. SOC classes associated with urban and industrial pollution were found more often and at higher concentrations at Whiskeytown National Recreation Area. These findings demonstrate a range of SOC exposure in a turtle species with current and proposed conservation status and shed additional light on the fate of environmental contaminants in remote watersheds