Length functions on currents and applications to dynamics and counting

The aim of this (mostly expository) article is twofold. We first explore a variety of length functions on the space of currents, and we survey recent work regarding applications of length functions to counting problems. Secondly, we use length functions to provide a proof of a folklore theorem which states that pseudo-Anosov homeomorphisms of closed hyperbolic surfaces act on the space of projective geodesic currents with uniform north-south dynamics.Comment: 35pp, 2 figures, comments welcome! Second version: minor corrections. To appear as a chapter in the forthcoming book "In the tradition of Thurston" edited by V. Alberge, K. Ohshika and A. Papadopoulo

Iodoarene-Catalyzed Cyclizations of Unsaturated Amides

The cyclization of N-alkenylamides catalyzed by iodoarenes under oxidative conditions is presented. Five-, six-, and seven-membered rings with a range of substitutions can be prepared by this route. Preliminary data from the use of chiral iodoarenes as precatalysts show that enantiocontrol is feasible

Genotype-phenotype correlation in seven motor neuron disease families with novel ALS2 mutations

Autosomal-recessive mutations in the Alsin Rho guanine nucleotide exchange factor (ALS2) gene may cause specific subtypes of childhood-onset progressive neurodegenerative motor neuron diseases (MND). These diseases can manifest with a clinical continuum from infantile ascending hereditary spastic paraplegia (IAHSP) to juvenile-onset forms with or without lower motor neuron involvement, the juvenile primary lateral sclerosis (JPLS) and the juvenile amyotrophic lateral sclerosis (JALS). We report 11 patients from seven unrelated Turkish and Yemeni families with clinical signs of IAHSP or JPLS. We performed haplotype analysis or next-generation panel sequencing followed by Sanger Sequencing to unravel the genetic disease cause. We described their clinical phenotype and analyzed the pathogenicity of the detected variants with bioinformatics tools. We further reviewed all previously reported cases with ALS2-related MND. We identified five novel homozygous pathogenic variants in ALS2 at various positions: c.275_276delAT (p.Tyr92CysfsTer11), c.1044C>G (p.Tyr348Ter), c.1718C>A (p.Ala573Glu), c.3161T>C (p.Leu1054Pro), and c.1471+1G>A (NM_020919.3, NP_065970.2). In our cohort, disease onset was in infancy or early childhood with rapid onset of motor neuron signs. Muscle weakness, spasticity, severe dysarthria, dysphagia, and facial weakness were common features in the first decade of life. Frameshift and nonsense mutations clustered in the N-terminal Alsin domains are most prevalent. We enriched the mutational spectrum of ALS2-related disorders with five novel pathogenic variants. Our study indicates a high detection rate of ALS2 mutations in patients with a clinically well-characterized early onset MND. Intrafamilial and even interfamilial diversity in patients with identical pathogenic variants suggest yet unknown modifiers for phenotypic expression

SIL1 mutations and clinical spectrum in patients with Marinesco-Sjögren syndrome

Marinesco-Sjögren syndrome is a rare autosomal recessive multisystem disorder featuring cerebellar ataxia, early-onset cataracts, chronic myopathy, variable intellectual disability and delayed motor development. More recently, mutations in the SIL1 gene, which encodes an endoplasmic reticulum resident co-chaperone, were identified as the main cause of Marinesco-Sjögren syndrome. Here we describe the results of SIL1 mutation analysis in 62 patients presenting with early-onset ataxia, cataracts and myopathy or combinations of at least two of these. We obtained a mutation detection rate of 60% (15/25) among patients with the characteristic Marinesco-Sjögren syndrome triad (ataxia, cataracts, myopathy) whereas the detection rate in the group of patients with more variable phenotypic presentation was below 3% (1/37). We report 16 unrelated families with a total of 19 different SIL1 mutations. Among these mutations are 15 previously unreported changes, including single- and multi-exon deletions. Based on data from our screening cohort and data compiled from the literature we found that SIL1 mutations are invariably associated with the combination of a cerebellar syndrome and chronic myopathy. Cataracts were observed in all patients beyond the age of 7 years, but might be missing in infants. Six patients with SIL1 mutations had no intellectual disability, extending the known wide range of cognitive capabilities in Marinesco-Sjögren syndrome to include normal intelligence. Modestly constant features were somatic growth retardation, skeletal abnormalities and pyramidal tract signs. Examination of mutant SIL1 expression in cultured patient lymphoblasts suggested that SIL1 mutations result in severely reduced SIL1 protein levels irrespective of the type and position of mutations. Our data broaden the SIL1 mutation spectrum and confirm that SIL1 is the major Marinesco-Sjögren syndrome gene. SIL1 patients usually present with the characteristic triad but cataracts might be missing in young children. As cognitive impairment is not obligatory, patients without intellectual disability but a Marinesco-Sjögren syndrome-compatible phenotype should receive SIL1 mutation analysis. Despite allelic heterogeneity and many families with private mutations, the phenotype related to SIL1 mutations is relatively homogenous. Based on SIL1 expression studies we speculate that this may arise from a uniform effect of different mutations on protein expressio

Ratunku! or just tunku! : evidence for the reliability and concurrent validity of the Language Use Inventory : LUI-Polish

Purpose: To date, there is no tool for assessing early pragmatic development of Polish-speaking children. This study aimed to adapt to Polish a standardized parent report measure, the Language Use Inventory (LUI; O’Neill, 2009, in order to enable cross-cultural comparisons and to use the LUI-Polish to screen for pragmatic development in children 18-47 months of age. We concentrated on the sociocultural and functional adaptation of LUI and aimed to demonstrate its reliability, developmental sensitivity, and concurrent validity. Method: Parents completed an online version of LUIPolish, longitudinally at 3 time points (when the child was 20, 32, and 44 months old). In addition, parents completed the Polish adaptations of the Questionnaire for Communication and Early Language at 22 months and the Language Development Survey at 24 months. Children’s spontaneous speech was assessed at 24 months, and their expressive and receptive vocabulary was assessed at 36 months. Results: All 3 parts of the LUI-Polish (Gestures, Words, and Sentences) showed very good levels of internal consistency at each time point. Significant correlations were observed between all parts of the LUI-Polish at all 3 measurement time points. The expected developmental trajectory was observed for boys and girls providing evidence of its developmental sensitivity for children between the ages of 2 and 4 years: an increase with age in the total score (due to an increase in Words and Sentences) and a decrease in Gestures. Supporting concurrent validity, significant correlations were found between children’s performance on (a) the LUI-Polish at 20 months and the Questionnaire for Communication and Early Language at 22 months as well as the Language Development Survey and spontaneous speech measures at 24 months and (b) the LUI-Polish at 32 months and the 2 measures of vocabulary comprehension and production at 36 months. Conclusion: The Polish adaptation of the LUI demonstrated good psychometric properties that provide a sound basis for cross-cultural comparisons and further research toward norming of the LUI-Polish. Moreover, the expected developmental trajectory in the pragmatic development of Polish children was observed

Mutations in the nuclear localization sequence of the Aristaless related homeobox; sequestration of mutant ARX with IPO13 disrupts normal subcellular distribution of the transcription factor and retards cell division

The electronic version of this article is the complete one and can be found online at: http://www.pathogeneticsjournal.com/content/3/1/1Background: Aristaless related homeobox (ARX) is a paired-type homeobox gene. ARX function is frequently affected by naturally occurring mutations. Nonsense mutations, polyalanine tract expansions and missense mutations in ARX cause a range of intellectual disability and epilepsy phenotypes with or without additional features including hand dystonia, lissencephaly, autism or dysarthria. Severe malformation phenotypes, such as X-linked lissencephaly with ambiguous genitalia (XLAG), are frequently observed in individuals with protein truncating or missense mutations clustered in the highly conserved paired-type homeodomain. Results: We have identified two novel point mutations in the R379 residue of the ARX homeodomain; c.1135C>A, p.R379S in a patient with infantile spasms and intellectual disability and c.1136G>T, p.R379L in a patient with XLAG. We investigated these and other missense mutations (R332P, R332H, R332C, T333N: associated with XLAG and Proud syndrome) predicted to affect the nuclear localisation sequences (NLS) flanking either end of the ARX homeodomain. The NLS regions are required for correct nuclear import facilitated by Importin 13 (IPO13). We demonstrate that missense mutations in either the N- or C-terminal NLS regions of the homeodomain cause significant disruption to nuclear localisation of the ARX protein in vitro. Surprisingly, none of these mutations abolished the binding of ARX to IPO13. This was confirmed by co-immunoprecipitation and immmuno fluorescence studies. Instead, tagged and endogenous IPO13 remained bound to the mutant ARX proteins, even in the RanGTP rich nuclear environment. We also identify the microtubule protein TUBA1A as a novel interacting protein for ARX and show cells expressing mutant ARX protein accumulate in mitosis, indicating normal cell division may be disrupted. Conclusions: We show that the most likely, common pathogenic mechanism of the missense mutations in NLS regions of the ARX homeodomain is inadequate accumulation and distribution of the ARX transcription factor within the nucleus due to sequestration of ARX with IPO13.Cheryl Shoubridge, May Huey Tan, Tod Fullston, Desiree Cloosterman, David Coman, George McGillivray, Grazia M Mancini, Tjitske Kleefstra and Jozef Géc

Role of cytoskeletal abnormalities in the neuropathology and pathophysiology of type I lissencephaly

Type I lissencephaly or agyria-pachygyria is a rare developmental disorder which results from a defect of neuronal migration. It is characterized by the absence of gyri and a thickening of the cerebral cortex and can be associated with other brain and visceral anomalies. Since the discovery of the first genetic cause (deletion of chromosome 17p13.3), six additional genes have been found to be responsible for agyria–pachygyria. In this review, we summarize the current knowledge concerning these genetic disorders including clinical, neuropathological and molecular results. Genetic alterations of LIS1, DCX, ARX, TUBA1A, VLDLR, RELN and more recently WDR62 genes cause migrational abnormalities along with more complex and subtle anomalies affecting cell proliferation and differentiation, i.e., neurite outgrowth, axonal pathfinding, axonal transport, connectivity and even myelination. The number and heterogeneity of clinical, neuropathological and radiological defects suggest that type I lissencephaly now includes several forms of cerebral malformations. In vitro experiments and mutant animal studies, along with neuropathological abnormalities in humans are of invaluable interest for the understanding of pathophysiological mechanisms, highlighting the central role of cytoskeletal dynamics required for a proper achievement of cell proliferation, neuronal migration and differentiation

2D characterization of near-surface V P/V S: surface-wave dispersion inversion versus refraction tomography

International audienceThe joint study of pressure (P-) and shear (S-) wave velocities (Vp and Vs ), as well as their ratio (Vp /Vs), has been used for many years at large scales but remains marginal in near-surface applications. For these applications, and are generally retrieved with seismic refraction tomography combining P and SH (shear-horizontal) waves, thus requiring two separate acquisitions. Surface-wave prospecting methods are proposed here as an alternative to SH-wave tomography in order to retrieve pseudo-2D Vs sections from typical P-wave shot gathers and assess the applicability of combined P-wave refraction tomography and surface-wave dispersion analysis to estimate Vp/Vs ratio. We carried out a simultaneous P- and surface-wave survey on a well-characterized granite-micaschists contact at Ploemeur hydrological observatory (France), supplemented with an SH-wave acquisition along the same line in order to compare Vs results obtained from SH-wave refraction tomography and surface-wave profiling. Travel-time tomography was performed with P- and SH- wave first arrivals observed along the line to retrieve Vtomo p and Vtomo s models. Windowing and stacking techniques were then used to extract evenly spaced dispersion data from P-wave shot gathers along the line. Successive 1D Monte Carlo inversions of these dispersion data were performed using fixed Vp values extracted from Vtomo p the model and no lateral constraints between two adjacent 1D inversions. The resulting 1D Vsw s models were then assembled to create a pseudo-2D Vsw s section, which appears to be correctly matching the general features observed on the section. If the pseudo-section is characterized by strong velocity incertainties in the deepest layers, it provides a more detailed description of the lateral variations in the shallow layers. Theoretical dispersion curves were also computed along the line with both and models. While the dispersion curves computed from models provide results consistent with the coherent maxima observed on dispersion images, dispersion curves computed from models are generally not fitting the observed propagation modes at low frequency. Surface-wave analysis could therefore improve models both in terms of reliability and ability to describe lateral variations. Finally, we were able to compute / sections from both and models. The two sections present similar features, but the section obtained from shows a higher lateral resolution and is consistent with the features observed on electrical resistivity tomography, thus validating our approach for retrieving Vp/Vs ratio from combined P-wave tomography and surface-wave profiling

The importance of disease associations and concomitant therapy for the long-term management of psoriasis patients

It is well established that several inflammatory-type conditions, such as arthritis, diabetes, cardiovascular disease, and irritable bowel disease exist comorbidly and at an increased incidence in patients with psoriasis. Psoriasis and other associated diseases are thought to share common inflammatory pathways. Conditions such as these, with similar pathogenic mechanisms involving cytokine dysregulation, are referred to as immune-mediated inflammatory diseases (IMIDs). Considerable evidence for the genetic basis of cormobidities in psoriasis exists. The WHO has reported that the occurrence of chronic diseases, including IMIDs, are a rising global burden. In addition, conditions linked with psoriasis have been associated with increasing rates of considerable morbidity and mortality. The presence of comorbid conditions in psoriasis patients has important implications for clinical management. QoL, direct health care expenditures and pharmacokinetics of concomitant therapies are impacted by the presence of comorbid conditions. For example, methotrexate is contraindicated in hepatic impairment, while patients on ciclosporin should be monitored for kidney function. In addition, some agents, such as beta blockers, lithium, synthetic antimalarial drugs, NSAIDs and tetracycline antibiotics, have been implicated in the initiation or exacerbation of psoriasis. Consequently, collaboration between physicians in different specialties is essential to ensuring that psoriasis treatment benefits the patient without exacerbating associated conditions