Kalman Filters for Time Delay of Arrival-based Source Localization

In this work, we propose an algorithm for acoustic source localization based on time delay of arrival (TDOA) estimation. In earlier work by other authors, an initial closed-form approximation was first used to estimate the true position of the speaker followed by a Kalman filtering stage to smooth the time series of estimates. In the proposed algorithm, this closed-form approximation is eliminated by employing a Kalman filter to directly update the speaker\u27s position estimate based on the observed TDOAs. In particular, the TDOAs comprise the observation associated with an extended Kalman filter whose state corresponds to the speaker\u27s position. We tested our algorithm on a data set consisting of seminars held by actual speakers. Our experiments revealed that the proposed algorithm provides source localization accuracy superior to the standard spherical and linear intersection techniques. Moreover, the proposed algorithm, although relying on an iterative optimization scheme, proved efficient enough for real-time operation

The role of the transcription factor Tcf-1 for the development and the function of NK cells

Natural Killer (NK) cells are innate immune cells that can eliminate malignant and foreign cells and that play an important role for the early control of viral and fungal infections. Further, they are important regulators of the adaptive and innate immune responses. During their development in the bone marrow (BM) NK cells undergo several maturation steps that directly establish an effector program. The transcriptional network that controls NK cell development and maturation is still incompletely understood. Based on earlier findings that NK cell numbers are reduced in the absence of the transcription factor T cell factor-1 (Tcf-1), my thesis has addressed the precise role of this transcription factor for NK cell development, maturation and function and whether Tcf-1 acts as a nuclear effector of the canonical Wnt signaling pathway to mediate its effects. It is shown that Tcf-1 is selectively required for the emergence of mature BM NK cells. Surprisingly, the emergence of BM NK cells depends on the repressor function of Tcf-1 and is independent of the Wnt pathway. In BM and peripheral NK cells Tcf-1 is found to suppress Granzyme B (GzmB) expression, a key cytotoxic effector molecule required to kill target cells. We provide evidence that GzmB over-expression in the absence of Tcf-1 results in accelerated spontaneous death of bone marrow NK cells and of cytokine stimulated peripheral NK cells. Moreover, Tcf-1 deficient NK cells show reduced target cell killing, which is due to enhanced GzmB-dependent NK cell death induced by the recognition of tumour target cells. Collectively, these data provide significant new insights into the transcriptional regulation of NK cell development and function and suggest a novel mechanism that protects NK cells from the deleterious effects of highly cytotoxic effector molecules. - Les cellules NK (de l'anglais Natural Killer) font partie du système immunitaire inné et sont capables d'éliminer à elles seules les cellules cancéreuses ou infectées. Ces cellules participent dans la régulation et la coordination des réponses innée et adaptative. Lors de leur développement dans la moelle osseuse, les cellules NK vont acquérir leurs fonctions effectrices, un processus contrôlé par des facteurs de transcription mais encore peu connu. Des précédentes travaux ont montré qu'une diminution du nombre de cellules NK corrélait avec l'absence du facteur de transcription Tcf-1 (T cell factor-1), suggérant un rôle important de Tcf-1 dans le développement de cellules NK. Cette thèse a pour but de mieux comprendre le rôle du facteur de transcription Tcf-1 lors du développement et la maturation des cellules NK, ainsi que son interaction avec la voie de signalisation Wnt. Nous avons montré que Tcf-1 est essentiel pour la transition des cellules immatures NK (iNK) à des cellules matures NK (mNK) dans la moelle osseuse, et cela de manière indépendamment de la voie de signalisation Wnt. De manière intéressante, nous avons observé qu'en absence du facteur de transcription Tcf-1, les cellules NK augmentaient l'expression de la protéine Granzyme B (GzmB), une protéine essentielle pour l'élimination des cellules cancéreuses ou infectées. Ceci a pour conséquence, une augmentation de la mort des cellules mNK dans la moelle osseuse ainsi qu'une diminution de leur fonction «tueuses». Ces résultats montrent pour la première fois, le rôle répresseur du facteur de transcription Tcf-1 dans l'expression de la protéine GzmB. L'ensemble de ces résultats apporte de nouveaux éléments concernant le rôle de Tcf-1 dans la régulation du développement et de la fonction des cellules NK et suggèrent un nouveau mécanisme cellulaire de protection contre les effets délétères d'une dérégulation de l'expression des molécules cytotoxique

Adaptations of Natural Killer Cells to Self-MHC Class I.

Natural Killer (NK) cells use germ line encoded receptors to detect diseased host cells. Despite the invariant recognition structures, NK cells have a significant ability to adapt to their surroundings, such as the presence or absence of MHC class I molecules. It has been assumed that this adaptation occurs during NK cell development, but recent findings show that mature NK cells can also adapt to the presence or absence of MHC class I molecules. Here, we summarize how NK cells adjust to changes in the expression of MHC class I molecules. We propose an extension of existing models, in which MHC class I recognition during NK cell development sequentially instructs and maintains NK cell function. The elucidation of the molecular basis of the two effects may identify ways to improve the fitness of NK cells and to prevent the loss of NK cell function due to persistent alterations in their environment

Quacks, Lemons, and Self-Regulation: A Welfare Analysis

The paper provides a framework in which suppliers of experience goods find it in their best interest to provide and enforce quality standards. This self-regulatory outcome is compared to various forms of statutory regulation, such as price regulation and quality regulation. The comparision is attractive, since the suppliers can observe each others' product qulity at lower cost than customers or policy maker. As long as quality is the only variable unknown to consumers and policy makers, any self-regulatory outcome can be replicated by an appropriate statutory policy. However, when additional variables (such as cost parameters) are private information of the suppliers, self-regulation may be strictly socially desirable.

Information sharing and credit : firm-level evidence from transition countries

We investigate whether information sharing among banks has affected credit market performance in the transition countries of Eastern Europe and the former Soviet Union, using a large sample of firm-level data. Our estimates show that information sharing is associated with improved availability and lower cost of credit to firms. This correlation is stronger for opaque firms than transparent ones and stronger in countries with weak legal environments than in those with strong legal environments. In cross-sectional estimates, we control for variation in country-level aggregate variables that may affect credit, by examining the differential impact of information sharing across firm types. In panel estimates, we also control for the presence of unobserved heterogeneity at the firm level, as well as for changes in macroeconomic variables and the legal environment

Prevalence of pelvic floor disorders in women with suspected gynecological malignancy: a survey-based study

Understanding of pelvic floor disorders among women with gynecological cancer is limited. The objective of this study was to describe the prevalence of pelvic floor disorders in women with suspected gynecological malignancy before surgery

Detection of Genomic Variation by Selection of a 9 Mb DNA Region and High Throughput Sequencing

Detection of the rare polymorphisms and causative mutations of genetic diseases in a targeted genomic area has become a major goal in order to understand genomic and phenotypic variability. We have interrogated repeat-masked regions of 8.9 Mb on human chromosomes 21 (7.8 Mb) and 7 (1.1 Mb) from an individual from the International HapMap Project (NA12872). We have optimized a method of genomic selection for high throughput sequencing. Microarray-based selection and sequencing resulted in 260-fold enrichment, with 41% of reads mapping to the target region. 83% of SNPs in the targeted region had at least 4-fold sequence coverage and 54% at least 15-fold. When assaying HapMap SNPs in NA12872, our sequence genotypes are 91.3% concordant in regions with coverage≥4-fold, and 97.9% concordant in regions with coverage≥15-fold. About 81% of the SNPs recovered with both thresholds are listed in dbSNP. We observed that regions with low sequence coverage occur in close proximity to low-complexity DNA. Validation experiments using Sanger sequencing were performed for 46 SNPs with 15-20 fold coverage, with a confirmation rate of 96%, suggesting that DNA selection provides an accurate and cost-effective method for identifying rare genomic variants

FHL1 reduces dystrophy in transgenic mice overexpressing FSHD muscular dystrophy region gene 1 (FRG1)

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disease with no effective treatment. The genetic cause of FSHD is complex and the primary pathogenic insult underlying the muscle disease is unknown. Several disease candidate genes have been proposed including DUX4 and FRG1. Expression analysis studies of FSHD report the deregulation of genes which mediate myoblast differentiation and fusion. Transgenic mice overexpressing FRG1 recapitulate the FSHD muscular dystrophy phenotype. Our current study selectively examines how increased expression of FRG1 may contribute to myoblast differentiation defects. We generated stable C2C12 cell lines overexpressing FRG1, which exhibited a myoblast fusion defect upon differentiation. To determine if myoblast fusion defects contribute to the FRG1 mouse dystrophic phenotype, this strain was crossed with skeletal muscle specific FHL1-transgenic mice. We previously reported that FHL1 promotes myoblast fusion in vitro and FHL1-transgenic mice develop skeletal muscle hypertrophy. In the current study, FRG1 mice overexpressing FHL1 showed an improvement in the dystrophic phenotype, including a reduced spinal kyphosis, increased muscle mass and myofiber size, and decreased muscle fibrosis. FHL1 expression in FRG1 mice, did not alter satellite cell number or activation, but enhanced myoblast fusion. Primary myoblasts isolated from FRG1 mice showed a myoblast fusion defect that was rescued by FHL1 expression. Therefore, increased FRG1 expression may contribute to a muscular dystrophy phenotype resembling FSHD by impairing myoblast fusion, a defect that can be rescued by enhanced myoblast fusion via expression of FHL1

Malt1 protease inactivation efficiently dampens immune responses but causes spontaneous autoimmunity.

The protease activity of the paracaspase Malt1 has recently gained interest as a drug target for immunomodulation and the treatment of diffuse large B-cell lymphomas. To address the consequences of Malt1 protease inactivation on the immune response in vivo, we generated knock-in mice expressing a catalytically inactive C472A mutant of Malt1 that conserves its scaffold function. Like Malt1-deficient mice, knock-in mice had strong defects in the activation of lymphocytes, NK and dendritic cells, and the development of B1 and marginal zone B cells and were completely protected against the induction of autoimmune encephalomyelitis. Malt1 inactivation also protected the mice from experimental induction of colitis. However, Malt1 knock-in mice but not Malt1-deficient mice spontaneously developed signs of autoimmune gastritis that correlated with an absence of Treg cells, an accumulation of T cells with an activated phenotype and high serum levels of IgE and IgG1. Thus, removal of the enzymatic activity of Malt1 efficiently dampens the immune response, but favors autoimmunity through impaired Treg development, which could be relevant for therapeutic Malt1-targeting strategies

Selectivity and functional diversity in arbuscular mycorrhizas of co-occurring fungi and plants from a temperate deciduous woodland

1 The arbuscular mycorrhizal (AM) fungi colonizing plants at a woodland site in North Yorkshire (UK) have been characterized from the roots of five plant species (Rubus fruticosus agg. L., Epilobium angustifolium L., Acer pseudoplatanus L., Ajuga reptans L. and Glechoma hederacea L.), and identified using small-subunit rRNA (SSUrRNA) gene amplification and sequencing. 2 Interactions between five plant species from the site and four co-occurring glomalean fungi were investigated in artificial one-to-one AM symbioses. Three of the fungi were isolated from the site; the fourth was a culture genetically similar to a taxon found at the site. Phosphorus uptake and growth responses were compared with non-mycorrhizal controls. 3 Individual fungi colonized each plant with different spatial distribution and intensity. Some did not colonize at all, indicating incompatibility under the conditions used in the experiments. 4 Glomus hoi consistently occupied a large proportion of root systems and outperformed the other fungi, improving P uptake and enhancing the growth of four out of the five plant species. Only G. hoi colonized and increased P uptake in Acer pseudoplatanus, the host plant with which it associates almost exclusively under field conditions. Colonization of all plant species by Scutellospora dipurpurescens was sparse, and beneficial to only one of the host plants (Teucrium scorodonia). Archaeospora trappei and Glomus sp. UY1225 had variable effects on the host plants, conferring a range of P uptake and growth benefits on Lysimachia nummularia and T. scorodonia, increasing P uptake whilst not affecting biomass in Ajuga reptans and Glechoma hederacea, and failing to form mycorrhizas with A. pseudoplatanus. 5 These experimental mycorrhizas show that root colonization, symbiont compatibility and plant performance vary with each fungus-plant combination, even when the plants and fungi naturally co-exist. 6 We provide evidence of physical and functional selectivity in AM. The small number of described AM fungal species (154) has been ascribed to their supposed lack of host specificity, but if the selectivity we have observed is the general rule, then we may predict that many more, probably hard-to-culture glomalean species await discovery, or that members of species as currently perceived may be physiologically or functionally distinct