Search

Hearing instruments (HIs) aim at helping people with hearing impairment who often have difficulties to understand speech in noisy environments. This chapter provides an overview of the current technological trends and challenges in the field of HI applications. It covers the state-of-the-art of signal-processing algorithms used in modern digital HIs. Focus is given on the extensions of such algorithms for applications, where microphone signals are employed from both the left and right HIs (binaural case). Furthermore, the chapter refers to the challenges for the optimal parametrization and steering of the HI algorithms. The concepts of environment classification for automatically controlling the settings of an HI in different listening situations are discussed and a brief summary of sound-source-localization methods is given. Finally, this chapter discusses the current trends of adding sensors in HIs that can potentially further enhance the hearing performance of the devices and improve the life of hearing-impaired people.

This research addresses the challenge of incorporating dynamic range limiting of the magnitude response of HRTFs for hearing-impaired listeners who are using binaural hearing aids. In this application, a direct implementation of spatialization using the original HRTFs may pose a problem if some frequency areas are moved above the pain threshold or below the hearing threshold for hearing-impaired listeners. An extensive discrimination experiment was conducted with 38 normal-hearing participants to determine the maximum amount of limitation that could be applied before audible artifacts degraded the sound image. The experiment helped to determine the maximum limitation that can be applied so that at least half of the normal-hearing tested subjects cannot distinguish between the original and limited version of the spatial filters used. Although wide-dynamic range compression (WDRC) at the output of the hearing aids can produce benefits, pre-processing the HRTFs is preferable to limit its effect on the frequency spectrum and loudness. The objective is to optimize the HRTFs to diminish the risk that they are distorted by the WDRC processing in a crucial part of the sound spectrum.

Little is known about the perception of artificial spatial hearing by hearing-impaired subjects. The purpose of this study was to investigate how listeners with hearing disorders perceived the effect of a spatialization feature designed for wireless microphone systems. Forty listeners took part in the experiments. They were arranged in four groups: normal-hearing, moderate, severe, and profound hearing loss. Their performance in terms of speech understanding and speaker localization was assessed with diotic and binaural stimuli. The results of the speech intelligibility experiment revealed that the subjects presenting a moderate or severe hearing impairment better understood speech with the spatialization feature. Thus, it was demonstrated that the conventional diotic binaural summation operated by current wireless systems can be transformed to reproduce the spatial cues required to localize the speaker, without any loss of intelligibility. The speaker localization experiment showed that a majority of the hearing-impaired listeners had similar performance with natural and artificial spatial hearing, contrary to the normal-hearing listeners. This suggests that certain subjects with hearing impairment preserve their localization abilities with approximated generic head-related transfer functions in the frontal horizontal plane.

We prove that complete Riemannian manifolds with polynomial growth and Ricci curvature bounded from below, admit uniform Poincar\'e inequalities. A global, uniform Poincar\'e inequality for horospheres in the universal cover of a closed, $n$-dimensional Riemannian manifold with pinched negative sectional curvature follows as a corollary., Comment: 20 pages, 2 fugures

Cerebral small-vessel diseases (SVD) are a common cause of vascular dementia and disability in the elderly. Apart from risk containment, little can be done to prevent or to treat SVD. Although most cases occur sporadically, hereditary forms of the disease provide the chance to elucidate the molecular and cellular mechanisms leading to microvascular pathology. Along this line, authoritative reviews on SVD have been published.1-3 Here, we would like to extend current concepts of SVD by highlighting a molecular pathway that seems to be involved in several well-defined SVD, some of which are hereditary. As a new piece of evidence, we will focus on incontinentia pigmenti (IP), which has recently been shown to be associated with microvascular pathology of the brain and retina.4,5 As will be elaborated below, IP is a SVD that does not present in the elderly but rather during infancy. The young age of onset and the nonprogressive microvascular pathology lead to a clinical picture that differs from other SVD. We suggest the term developmental SVD for this form of presentation. IP is caused by mutations in the NEMO gene (NF-kappaB essential modulator), an essential modulator of the transcription factor nuclear factor (NF)-?B.6 NEMO maintains the viability of brain endothelial cells and stabilizes the blood-brain barrier (BBB).5 In NEMO-deficient animals, there is rarefaction of cerebral capillaries and hypoperfusion of the central nervous system (CNS). Disruption of the transforming growth factor (TGF)-?-activated kinase (TAK1) upstream of NEMO produces a similar pathology.5 Interestingly, TGF-? has also been involved in the pathogenesis of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and the vascular changes of Alzheimer disease (AD),7-11 suggesting disturbed TGF-? signaling as a common ...

The transcription factor NF-κB plays a key role in numerous physiological processes such as inflammation, immunity, cell proliferation or control of cell death. Its activation is tightly controlled by a kinase complex, IκB kinase (IKK), composed of three core proteins: IKK1/IKKα, IKK2/IKKβ and NEMO/IKKγ. The first two are structurally related kinases whereas the third one is a regulatory subunit exhibiting affinity for upstream activators modified by polyubiquitin chains. Over the years, several inherited diseases caused by mutations of each of the three subunits of IKK have been identified in humans together with diseases caused by mutations of several of its substrates. They are associated with very specific and complex phenotypes involving a broad range of abnormalities such as impaired innate and acquired immune response, perturbed skin development and defects of the central nervous system. Here, we summarize the diverse clinical, cellular and molecular manifestations of IKK-related genetic diseases and show that studying patient-related mutations affecting the IKK subunits and some of their substrates offers the opportunity to understand the various functions of NF-κB in humans, complementing studies performed with mouse models. This analysis also provides glimpses about putative functions of IKK subunits that may be NF-κB-independent.

Receptor-interacting protein kinase 3 (RIPK3) mediates necroptosis, a form of programmed cell death that promotes inflammation in various pathological conditions, suggesting that it might be a privileged pharmacological target. However, its function in glucose homeostasis and obesity has been unknown. Here we show that RIPK3 is over expressed in the white adipose tissue (WAT) of obese mice fed with a choline-deficient high-fat diet. Genetic inactivation of Ripk3 promotes increased Caspase-8-dependent adipocyte apoptosis and WAT inflammation, associated with impaired insulin signalling in WAT as the basis for glucose intolerance. Similarly to mice, in visceral WAT of obese humans, RIPK3 is overexpressed and correlates with the body mass index and metabolic serum markers. Together, these findings provide evidence that RIPK3 in WAT maintains tissue homeostasis and suppresses inflammation and adipocyte apoptosis, suggesting that systemic targeting of necroptosis might be associated with the risk of promoting insulin resistance in obese patients., The kinase RIPK3 initiates necroptosis, which has been reported to promote inflammation in various pathological conditions. Here, the authors show that genetic ablation of Ripk3 results in adipocyte apoptosis and white adipose tissue inflammation in obese mice, which promotes glucose intolerance.

CYLD deubiquitinase has been originally defined as a tumor suppressor based exclusively on genetic findings. Indeed, inactivation of CYLD in humans results in familial cylindromatosis and multiple trichoepithelioma, two pathologies characterized by the development of tumors originating specifically from the skin appendages. A set of recent publications has revealed that recurrent inactivation of CYLD occurs through diverse mechanisms in several forms of cancer, unequivocally confirming its tumor suppressor function. This property is associated with the critical role played by CYLD in negatively regulating several signaling pathway, among them the NF-κB signaling pathway.

The auditory system allows the estimation of the distance to sound-emitting objects using multiple spatial cues. In virtual acoustics over headphones, a prerequisite to render auditory distance impression is sound externalization, which denotes the perception of synthesized stimuli outside of the head. Prior studies have found that listeners with mild-to-moderate hearing loss are able to perceive auditory distance and are sensitive to externalization. However, this ability may be degraded by certain factors, such as non-linear amplification in hearing aids or the use of a remote wireless microphone. In this study, 10 normal-hearing and 20 moderate-to-profound hearing-impaired listeners were instructed to estimate the distance of stimuli processed with different methods yielding various perceived auditory distances in the vicinity of the listeners. Two different configurations of non-linear amplification were implemented, and a novel feature aiming to restore a sense of distance in wireless microphone systems was tested. The results showed that the hearing-impaired listeners, even those with a profound hearing loss, were able to discriminate nearby and far sounds that were equalized in level. Their perception of auditory distance was however more contracted than in normal-hearing listeners. Non-linear amplification was found to distort the original spatial cues, but no adverse effect on the ratings of auditory distance was evident. Finally, it was shown that the novel feature was successful in allowing the hearing-impaired participants to perceive externalized sounds with wireless microphone systems.

In this paper we investigate the growth of finitely generated groups. We recall the definition of the algebraic entropy of a group and show that if the group is acting as a discrete subgroup of the isometry group of a Cartan�Hadamard manifold with pinched negative curvature then a Tits alternative is true. More precisely the group is either virtually nilpotent or has a uniform growth bounded below by an explicit constant.

Ubiquitination has emerged over the years as the most sophisticated way to modify proteins to affect their fate and function. In particular, it has been reported to be instrumental in regulating several steps of the NF-kappaB signalling pathway which controls inflammation, immunity, adhesion and cell survival. Integrating ubiquitination into NF-kappaB activation requires the regulatory subunit of IKK, NEMO, which not only displays affinity for polyubiquitin chains, but is also posttranslationally modified by a complex set of reactions involving ubiquitin. Here, we examine how studies of the NEMO/ubiquitin relationship have provided novel insights into the IKK activation process and have uncovered molecular mechanisms that should represent in the future attractive targets for specifically modulating NF-kappaB function.

The key role of NEMO, the regulatory subunit of IKK, in the NF-kB activation process is firmly established. A series of recent publications suggests that this protein also participates in the genotoxic response, after modification by sumoylation in the nucleus, and coordinates the activation of both NF-kB and IRFs during viral infection, through its interaction with TANK adaptor and TBK1/IKKepsilon kinases.

CYLD is a protein with tumor suppressor properties which was originally discovered associated with cylindromatosis, an inherited cancer exclusively affecting the folicullo-sebaceous-apocrine unit of the epidermis. CYLD exhibits deubiquitinating activity and acts as a negative regulator of NF-kappaB and JNK signaling through its interaction with NEMO and TRAF2. Recent data suggest that this is unlikely to be its unique function in vivo. CYLD has also been shown to control other seemingly disparate cellular processes, such as proximal T cell receptor signaling, TrkA endocytosis and mitosis. In each case, this enzyme appears to act by regulating a specific type of polyubiquitination, K63 polyubiquitination, that does not result in recognition and degradation of proteins by the proteasome but instead controls their activity through diverse mechanisms.

In this paper we show that a given set of lengths of closed geodesics, there are only finitely many convex cocompact hyperbolic 3-manifolds with that specified length spectrum, homotopy equivalent to a given 3-manifold without a handlebody factor, up to orientation preserving isometries., Comment: 25 pages, one inaccurate example is removed

The Margulis lemma describes the structure of the group generated by small loops in the fundamental group of a Riemannian manifold, thus giving a picture of its local topology. Originally stated for homogeneous spaces by C. Jordan, L. Bieberbach, H. J. Zassenhaus, D. Kazhdan-G. Margulis, it has been extended to the Riemannian setting by G. Margulis for manifolds of non positive curvature. The goal of these lectures is to present the recent work of V. Kapovitch and B. Wilking who gave a sharp version of the Margulis lemma under the assumption that the Ricci curvature is bounded below. Their method uses the structure of « Ricci limit spaces » explained by T. Richard during his lectures.

The Margulis lemma describes the structure of the group generated by small loops in the fundamental group of a Riemannian manifold, thus giving a picture of its local topology. Originally stated for homogeneous spaces by C. Jordan, L. Bieberbach, H. J. Zassenhaus, D. Kazhdan-G. Margulis, it has been extended to the Riemannian setting by G. Margulis for manifolds of non positive curvature. The goal of these lectures is to present the recent work of V. Kapovitch and B. Wilking who gave a sharp version of the Margulis lemma under the assumption that the Ricci curvature is bounded below. Their method uses the structure of « Ricci limit spaces » explained by T. Richard during his lectures.

The Margulis lemma describes the structure of the group generated by small loops in the fundamental group of a Riemannian manifold, thus giving a picture of its local topology. Originally stated for homogeneous spaces by C. Jordan, L. Bieberbach, H. J. Zassenhaus, D. Kazhdan-G. Margulis, it has been extended to the Riemannian setting by G. Margulis for manifolds of non positive curvature. The goal of these lectures is to present the recent work of V. Kapovitch and B. Wilking who gave a sharp version of the Margulis lemma under the assumption that the Ricci curvature is bounded below. Their method uses the structure of « Ricci limit spaces » explained by T. Richard during his lectures.

The Margulis lemma describes the structure of the group generated by small loops in the fundamental group of a Riemannian manifold, thus giving a picture of its local topology. Originally stated for homogeneous spaces by C. Jordan, L. Bieberbach, H. J. Zassenhaus, D. Kazhdan-G. Margulis, it has been extended to the Riemannian setting by G. Margulis for manifolds of non positive curvature. The goal of these lectures is to present the recent work of V. Kapovitch and B. Wilking who gave a sharp version of the Margulis lemma under the assumption that the Ricci curvature is bounded below. Their method uses the structure of « Ricci limit spaces » explained by T. Richard during his lectures.

The Margulis lemma describes the structure of the group generated by small loops in the fundamental group of a Riemannian manifold, thus giving a picture of its local topology. Originally stated for homogeneous spaces by C. Jordan, L. Bieberbach, H. J. Zassenhaus, D. Kazhdan-G. Margulis, it has been extended to the Riemannian setting by G. Margulis for manifolds of non positive curvature. The goal of these lectures is to present the recent work of V. Kapovitch and B. Wilking who gave a sharp version of the Margulis lemma under the assumption that the Ricci curvature is bounded below. Their method uses the structure of « Ricci limit spaces » explained by T. Richard during his lectures.

The regulatory subunit NEMO is involved in the mechanism of activation of IkappaB kinase (IKK), the kinase complex that controls the NF-kappaB signaling pathway. During this process, NEMO is modified post-translationally through K63-linked polyubiquitination. We report the molecular characterization of a new missense mutation of NEMO (A323P) which causes a severe form of incontinentia pigmenti (OMIM#308300), an inherited disease characterized predominantly by skin inflammation. The A323P mutation was found to impair TNF-, IL-1-, LPS- and PMA/ionomycin-induced NF-kappaB activation, as well as to disrupt TRAF6-dependent NEMO polyubiquitination, due to a defective NEMO/TRAF6 interaction. Mutagenesis identified the affected ubiquitination sites as three lysine residues located in the vicinity of A323. Unexpectedly, these lysines were ubiquitinated together with two previously identified lysines not connected to TRAF6. Mutation of all these ubiquitination sites severely impaired NF-kappaB activation induced by stimulation with IL-1, LPS, Nod2/RICK or serum/LPA. In contrast, mutation at all of these sites had only a limited effect on stimulation by TNF. These findings indicate that post-translational modification of NEMO through K63-linked polyubiquitination is a key event in IKK activation and that perturbation of this step may cause human pathophysiology.

The IKK complex represents the core component of the canonical pathway of NF-κB activation. Any mutation affecting it should therefore impact on NF-κB signaling to some extent. Nevertheless, since IKK-1 and IKK-2 have also been shown to play NF-κB-independent functions, those functions may be affected as well, complicating the picture. Generating further complexity is the location of NEMO on the X-chromosome that can cause lyonization-related effects. Over the years, all this predictable intricacy has been confirmed with the discovery of a set of seemingly disparate pathologies, complemented with pathologies caused by mutations of NF-κB subunits regulating exclusively the canonical pathway. They allowed to confirm the essential role of canonical NF-κB activation in innate and acquired immunity or inflammation but also revealed new functions of this pathway.

Activation of NF-κB signaling pathways requires ubiquitination processes controlled by a collection of E3 ligases and deubiquitinases. More specifically, modifications by K63- and linear-linked polyubiquitin chains allow the recruitment and activation of essential kinases such as TAK1 and IKK1/IKK2. Human pathologies linked to impaired ubiquitination were recently identified with mutations affecting LUBAC, the main E3 complex catalyzing linear chain formation; TRAF6, a key regulator in immunity and skin appendages development; and CYLD, a deubiquitinase negatively regulating the NF-κB activation process at several levels. They provide an alternative entry point to analyze the consequences of deregulated NF-κB activity.

The family of inducible nuclear factor κB (NF-κB) transcription factors plays critical functions as sensor of stressful changes in the cell environment modulating the expression of hundreds of genes that regulate key physiological processes such as immunity, inflammation, cell death, and cell proliferation. Located in the cytoplasm, NF-κB proteins can be activated by a plethora of stimuli in a large variety of cell types. Two pathways of NF-κB activation exist, a canonical one and a non-canonical one, both of them requiring intricate molecular interplays involving adaptor proteins and enzymes that control phosphorylation and ubiquitination events. This culminates in translocation of NF-κB in the nucleus and modulation of gene expression.

The inherited diseases caused by impaired NF-κB signaling display a broad range of abnormalities affecting the immune and vascular systems, the skin, the bones, and the central nervous system (CNS). On one side, this allows to compare these abnormalities with those observed in mouse strains affected for the same components and, on the other, to assign specific defects in humans to discrete molecular impairments. All these information should contribute to the design and validation of therapeutic treatments.

NEMO, the regulatory subunit of the IkappaB kinase (IKK) complex that controls the activation of the transcription factor NF-kappaB, is required for IKK function in most situations, but its exact mode of action has remained elusive until recently. A series of publications now provides information about how posttranscriptional modifications of NEMO, such as ubiquitination, sumoylation or phosphorylation, regulate its function in the IKK complex. These modifications might also regulate a cytosolic pool of free NEMO that controls the activation of NF-kappaB induced by genotoxic stress. Together with a better identification of the modifications controlling partners of NEMO, a clearer picture of how IKK becomes activated upon cell stimulation is starting to emerge, providing new clues for how the NF-kappaB pathway could be modulated for therapeutic purposes.

By responding to pro-inflammatory cytokines, such as IL-1beta and TNF-alpha, and controlling itself the expression of numerous mediators of inflammation, NF-kappaB plays a pivotal role in controlling the proper sequence of events characterizing the inflammation process. Although excessive NF-kappaB activation is often associated with inflammatory signs in many different tissues, impaired NF-kappaB activation can also generate inflammation. This is the case in humans suffering from the genetic disease incontinentia pigmenti that exhibit severe skin inflammation. Identifying the molecular basis of this pathology, mutations affecting the gene coding for NEMO, has allowed production of mouse models for investigating the disease. Their characterization supports the view that a very tight positive and negative regulation of the NF-kappaB signaling pathway is required in vivo to ensure not only a fine-tuned response to injury or infection but also to maintain tissue homeostasis.

The NEMO (NF-kappaB essential modulator) protein plays a crucial role in the canonical NF-kappaB pathway as the regulatory component of the IKK (IkappaB kinase) complex. The human disease anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) has been recently linked to mutations in NEMO. We investigated the effect of an alanine to glycine substitution found in the NEMO polypeptide of an EDA-ID patient. This pathogenic mutation is located within the minimal oligomerization domain of the protein, which is required for the IKK activation in response to diverse stimuli. The mutation does not dramatically change the native-like state of the trimer, but temperature-induced unfolding studied by circular dichroism showed that it leads to an important loss in the oligomer stability. Furthermore, fluorescence studies showed that the tyrosine located in the adjacent zinc finger domain, which is possibly required for NEMO ubiquitination, exhibits an alteration in its spectral properties. This is probably due to a conformational change of this domain, providing evidence for a close interaction between the oligomerization domain and the zinc finger. In addition, functional complementation assays using NEMO-deficient pre-B and T lymphocytes showed that the pathogenic mutation reduced TNF-alpha and LPS-induced NF-kappaB activation by altering the assembly of the IKK complex. Altogether, our findings provide understanding as to how a single point mutation in NEMO leads to the observed EDA-ID phenotype in relation to the NEMO-dependent mechanism of IKK activation.

The nuclear factor-kappaB (NF-kappaB) signaling pathway plays a key role in inflammation, immune response, cell growth control and protection against apoptosis. Recently, it has been associated with several distinct genetic diseases that exhibit a large spectrum of dysfunction, such as skin inflammation, perturbed skin appendage development and immunodeficiencies. In this review, a summary of the pathophysiological consequences of impaired NF-kappaB activation in humans is provided with respect to the functions of the molecules which are mutated.

In this article we prove a differentiable rigidity result. Let $(Y, g)$ and $(X, g_0)$ be two closed $n$-dimensional Riemannian manifolds ($n\geqslant 3$) and $f:Y\to X$ be a continuous map of degree $1$. We furthermore assume that the metric $g_0$ is real hyperbolic and denote by $d$ the diameter of $(X,g_0)$. We show that there exists a number $\varepsilon:=\varepsilon (n, d)>0$ such that if the Ricci curvature of the metric $g$ is bounded below by $-n(n-1)$ and its volume satisfies $\vol_g (Y)\leqslant (1+\varepsilon) \vol_{g_0} (X)$ then the manifolds are diffeomorphic. The proof relies on Cheeger-Colding's theory of limits of Riemannian manifolds under lower Ricci curvature bound., 33 pages, 1 dessin

International audience; NEMO (NF-κB essential modulator) plays a key role in the canonical NF-κB pathway as the scaffold/regulatory component of the IκB kinase (IKK) complex. The self-association of NEMO involves the C-terminal halves of the polypeptide chains containing two putative coiled-coil motifs (a CC2 and a LZ leucine zipper), a proline-rich region, and a ZF zinc finger motif. Using purified truncation mutants, we showed that the minimal oligomerization domain of NEMO is the CC2-LZ segment and that both CC2 and LZ subdomains are necessary to restore the LPS-dependent activation of the NF-κB pathway in a NEMO-deficient cell line. We confirmed the association of the oligomerization domain in a trimer and investigated the specific role of CC2 and LZ subdomains in the building of the oligomer. Whereas a recombinant CC2-LZ polypeptide self-associated into a trimer with an association constant close to that of the wild-type protein, the isolated CC2 and LZ peptides, respectively, formed trimers and dimers with weaker association constants. Upon mixing, isolated CC2 and LZ peptides associated to form a stable hetero-hexamer as shown by gel filtration and fluorescence anisotropy experiments. We propose a structural model for the organization of the oligomerization domain of activated NEMO in which three C-terminal domains associate into a pseudo-hexamer forming a six-helix bundle. This model is discussed in relation to the mechanism of activation of the IKK complex by upstream activators.

Sucrose etherification with the 1,2-epoxydodecane was investigated using various tertiary amines as catalysts. The reversible addition of the tertiary amine on the epoxide led to the formation of a strongly basic quaternary ammonium salt, responsible for the catalytic activity observed. From those results, a new efficient heterogeneous catalytic process was also developed and consists in the use of basic anion-exchange resins as catalyst. We suggested that the 1,2-dodecanediol side production was necessary to start the reaction by increasing the interfacial area between the 1,2-epoxydodecane and the sucrose phase. To cite this article: R. Pierre et al., C. R. Chimie 7 (2004) .

The transcription factor NF-kappaB is implicated in various aspects of T cell development and function. The IkappaB kinase (IKK) complex, consisting of two kinases, IKK1/alpha and IKK2/beta, and the NEMO/IKKgamma regulatory subunit, mediates NF-kappaB activation by most known stimuli. Adoptive transfer experiments had demonstrated that IKK1 and IKK2 are dispensable for T cell development. We show here that T lineage-specific deletion of IKK2 allows survival of naive peripheral T cells but interferes with the generation of regulatory and memory T cells. T cell-specific ablation of NEMO or replacement of IKK2 with a kinase-dead mutant prevent development of peripheral T cells altogether. Thus, IKK-induced NF-kappaB activation, mediated by either IKK1 or IKK2, is essential for the generation and survival of mature T cells, and IKK2 has an additional role in regulatory and memory T cell development.

NF-kappaB transcription factors have key roles in inflammation, immune response, oncogenesis and protection against apoptosis. In most cells, these factors are kept inactive in the cytoplasm through association with IkappaB inhibitors. After stimulation by various reagents, IkappaB is phosphorylated by the IkappaB kinase (IKK) complex and degraded by the proteasome, allowing NF-kappaB to translocate to the nucleus and activate its target genes. Here we report that CYLD, a tumour suppressor that is mutated in familial cylindromatosis, interacts with NEMO, the regulatory subunit of IKK. CYLD also interacts directly with tumour-necrosis factor receptor (TNFR)-associated factor 2 (TRAF2), an adaptor molecule involved in signalling by members of the family of TNF/nerve growth factor receptors. CYLD has deubiquitinating activity that is directed towards non-K48-linked polyubiquitin chains, and negatively modulates TRAF-mediated activation of IKK, strengthening the notion that ubiquitination is involved in IKK activation by TRAFs and suggesting that CYLD functions in this process. Truncations of CYLD found in cylindromatosis result in reduced enzymatic activity, indicating a link between impaired deubiquitination of CYLD substrates and human pathophysiology.

We give a new proof of a result due to Y. Shalom: if the fundamental group of a compact real hyperbolic manifold of dim n is a free product of its subgroups A and B over the amalgamated subgroup C , then the critical exponent of C is not smaller than n −2. The proof, which is geometric, allows one to treat the equality case and an extension to variable curvature. To cite this article: G. Besson et al., C. R. Acad. Sci. Paris, Ser. I 336 (2003).

The transcription factor NF-kappaB regulates the expression of numerous genes controlling the immune and stress responses, inflammatory reaction, cell adhesion, and protection against apoptosis. Incontinentia pigmenti (IP) is the first genetic disorder to be ascribed to NF-kappaB dysfunction. IP is an X-linked dominant genodermatosis antenatally lethal in males. A complex rearrangement of the NEMO (NF-kappaB essential modulator) gene accounts for 85% of IP patients, and results in undetectable NEMO protein and absent NF-kappaB activation. On the other hand, hypohidrotic/anhidrotic ectodermal dysplasia (HED/EDA) has been ascribed to at least three genes also involved in NF-kappaB activation: ectodysplasin (EDA1), EDA-receptor (EDAR) and EDAR-associated death domain (EDARADD). During hair follicle morphogenesis, EDAR is activated by ectodysplasin, and uses EDARADD as an adapter to build a signal transducing complex that leads to NF-kappaB activation. Hence, several forms of HED/EDA also result from impaired activation of the NF-kappaB cascade. Finally, hypomorphic NEMO mutations have been found to cause anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID), whilst stop codon mutations cause a more severe phenotype associating EDA-ID with osteopetrosis and lymphoedema (OL-EDA-ID). The immunological and infectious features observed in patients result from impaired NF-kappaB signalling, including cellular response to LPS, IL-1beta, IL-18, TNF-alpha, Tlr2 and CD40 ligand. Consistently, mouse knockout models have shown the essential role of NF-kappaB in the immune, inflammatory and apoptotic responses. Unravelling the molecular bases of other forms of EDA not associated with mutations in NEMO will possibly implicate other components of the NF-kappaB signalling pathway.

Ichthyosis is a heterogeneous group of skin disorders characterized by abnormal epidermal scaling. Occasionally, extracutaneous features are associated. A novel autosomal recessive ichthyosis syndrome is described here with scalp hypotrichosis, scarring alopecia, sclerosing cholangitis, and leukocyte vacuolization in two inbred kindreds of Moroccan origin. We also report the mapping of the diseased gene to a 21.2 cM interval of chromosome 3q27-q28. Homo zygosity for polymorphic markers has enabled us to reduce the genetic interval to a 16.2 cM region. Furthermore, comparison of mutant chromosomes in the two families has suggested a common ancestral mutant haplotype. This linkage disequilibrium has reduced the genetic interval encompassing the diseased gene to less than 9.5 cM maximum. Further study of additional families from the same geographic area will hopefully reduce the genetic interval as well as help in the cloning of the gene involved in this rare disorder.

The I kappa B kinase (IKK), consisting of the IKK1 and IKK2 catalytic subunits and the NEMO (also known as IKK gamma) regulatory subunit, phosphorylates I kappa B proteins, targeting them for degradation and thus inducing activation of NF-kappa B (reviewed in refs 1, 2). IKK2 and NEMO are necessary for NF-kappa B activation through pro-inflammatory signals. IKK1 seems to be dispensable for this function but controls epidermal differentiation independently of NF-kappa B. Previous studies suggested that NF-kappa B has a function in the growth regulation of epidermal keratinocytes. Mice lacking RelB or I kappa B alpha, as well as both mice and humans with heterozygous NEMO mutations, develop skin lesions. However, the function of NF-kappa B in the epidermis remains unclear. Here we used Cre/loxP-mediated gene targeting to investigate the function of IKK2 specifically in epidermal keratinocytes. IKK2 deficiency inhibits NF-kappa B activation, but does not lead to cell-autonomous hyperproliferation or impaired differentiation of keratinocytes. Mice with epidermis-specific deletion of IKK2 develop a severe inflammatory skin disease, which is caused by a tumour necrosis factor-mediated, alpha beta T-cell-independent inflammatory response that develops in the skin shortly after birth. Our results suggest that the critical function of IKK2-mediated NF-kappa B activity in epidermal keratinocytes is to regulate mechanisms that maintain the immune homeostasis of the skin.

Until recently, no genetic disease caused by NF-κB dysfunction was known. This changed with the identification of the X-linked gene encoding a molecule of the NF-κB signaling pathway, NEMO/IKKγ. Two distinct X-linked human diseases, incontinentia pigmenti (IP) and anhidrotic ectodermal dysplasia associated with immunodeficiency (EDA-ID), have been linked to NEMO/IKKγ dysfunction, providing a unique view of the role that NF-κB plays in human development, skin homeostasis and innate and acquired immunity.