Perspectives on the Genomics of HSP Beyond Mendelian Inheritance

Hereditary Spastic Paraplegia is an extraordinarily heterogeneous disease caused by over 50 Mendelian genes. Recent applications of next-generation sequencing, large scale data analysis, and data sharing/matchmaking, have discovered a quickly expanding set of additional HSP genes. Since most recently discovered HSP genes are rare causes of the disease, there is a growing concern of a persisting diagnostic gap, estimated at 30–40%, and even higher for sporadic cases. This missing heritability may not be fully closed by classic Mendelian mutations in protein coding genes. Here we show strategies and published examples of broadening areas of attention for Mendelian and non-Mendelian causes of HSP. We suggest a more inclusive perspective on the potential final architecture of HSP genomics. Efforts to narrow the heritability gap will ultimately lead to more precise and comprehensive genetic diagnoses, which is the starting point for emerging, highly specific gene therapies

Исследование конформации и электронной структуры N-метилмочевины методом функционала плотности

В настоящей работе методами DFT и HF с использованием пакета программ для квантово-химических расчетов Gaussian проведен конформационный анализ N-метилмочевины в растворе ДМСО. Окружение молекулы учитывалось в рамках модели непрерывной поляризуемой среды PCM. Выполнено исследование стереоэлектронных взаимодействий методом NBO, произведен расчет энергий граничных орбиталей

Impaired Function is a Common Feature of Neuropathy‐Associated Glycyl‐t RNA Synthetase Mutations

C harcot– M arie– T ooth disease type 2 D ( CMT 2 D ) is an autosomal‐dominant axonal peripheral neuropathy characterized by impaired motor and sensory function in the distal extremities. Mutations in the glycyl‐t RNA synthetase ( GARS ) gene cause CMT 2 D . GARS is a member of the ubiquitously expressed aminoacyl‐ tRNA synthetase ( ARS ) family and is responsible for charging t RNA with glycine. To date, 13 GARS mutations have been identified in patients with CMT disease. While functional studies have revealed loss‐of‐function characteristics, only four GARS mutations have been rigorously studied. Here, we report the functional evaluation of nine CMT ‐associated GARS mutations in t RNA charging, yeast complementation, and subcellular localization assays. Our results demonstrate that impaired function is a common characteristic of CMT ‐associated GARS mutations. Additionally, one mutation previously associated with CMT disease (p. S er581 L eu) does not demonstrate impaired function, was identified in the general population, and failed to segregate with disease in two newly identified families with CMT disease. Thus, we propose that this variant is not a disease‐causing mutation. Together, our data indicate that impaired function is a key component of GARS ‐mediated CMT disease and emphasize the need for careful genetic and functional evaluation before implicating a variant in disease onset.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109288/1/humu22681.pd

Evaluación de los riegos de la Comunidad de Regantes V del Canal de las Bardenas

14 Pag., 2 Tabl., 1 Fig.[ES] En este artículo se presentan los resultados de las evaluaciones de riego que se han llevado a cabo dentro de la segunda fase del trabajo denominado “Mejora de la Gestión Integral del Agua de Riego en la Comunidad de Regantes V del Canal de Bardenas”. El 80 % de la superficie de esta comunidad está ocupado por suelos de plataformas residuales, mientras que el resto son suelos de aluvial. Para caracterizar la capacidad de retención de agua de los suelos (CRA) se realizó un muestro en el que se describieron 50 perfiles. Para determinar la infiltración de los suelos y los índices de calidad del riego por superficie se realizaron 50 evaluaciones de riego. Un adecuado manejo del agua a nivel de parcela y unas texturas francas-franco arenosas permiten alcanzar niveles de eficiencia medios en las parcelas de las plataformas (53 % de media), cuyos suelos se caracterizan por una baja CRA (60 mm de media). En aluviales la eficiencia llega hasta un 80 % de media, gracias a las elevadas capacidades de retención de agua de estos suelos (182 mm de media). Actualmente se está realizado un reaprovechamiento de las aguas de desagüe que posiblemente provoque que la eficiencia a nivel de comunidad sea mayor que la obtenida a nivel de parcela. Estos resultados permiten pensar que la modernización de los regadíos, mediante el cambio a un sistema de riego presurizado, tendría un fuerte impacto sobre la eficiencia en parcela, aunque el impacto sobre la eficiencia en la comunidad sería menor. La modernización tendría resultados muy beneficiosos social y económicamente para los agricultores, además de mejorar la calidad de las aguas de los ríos que atraviesan la comunidad.[EN] Results of the irrigation evaluations performed in the second phase of the project “Improvement of the Water Irrigation Integral Management in the Comunidad de Regantes V del Canal de Bardenas” are presented in this paper. An 80 % of the area of the Irrigation District is occupied by soils of residual platforms, and the rest of the soils are alluvial. A soil survey was performed for characterising the water holding capacity (WHC) of the soils, using 50 soil profiles. A total of 50 irrigation evaluations was performed for determining soil infiltration and the performance indexes of surface irrigation in the study area. An adequate water management in border irrigation and loam-sandy loam textures permit to attain 53 % application efficiency in platforms, whose soils are characterized by a low WHC (with an average of 60 mm). In alluvial soils the application efficiency is higher, with an average of 80 %, due to the high water holding capacity of these soils (an average of 182 mm). Currently, The district is enforcing a program for irrigation return flows reuse. This program surely results in an irrigation district efficiency substantially higher that the average application efficiency. With these results is possible to think that an irrigation modernization, through a change to a pressurized irrigation system will severely improve the application efficiency, but the effect on the irrigation district efficiency will only be moderate. However, this modernisation would have great social and economical benefits for farmers, and also, the water quality of rivers crossing the irrigation district will be improved.Este proyecto de investigación ha sido cofinanciado por la CICYT, por Fondos FEDER, por el CONSI+D y por la Comunidad de Regantes V de Bardenas.Peer reviewe

A Rare Novel Deletion of the Tyrosine Hydroxylase Gene in Parkinson Disease

Tyrosine hydroxylase (TH) enzyme is a rate limiting enzyme in dopamine biosynthesis. Missense mutation in both alleles of the TH gene is known to cause dopamine-related phenotypes, including dystonia and infantile Parkinsonism. However, it is not clear if single allele mutation in TH modifies the susceptibility to the adult form of Parkinson disease (PD). We reported a novel deletion of entire TH gene in an adult with PD. The deletion was first identified by copy number variation (CNV) analysis in a genome-wide association study using Illumina Infinium BeadChips. After screening 635 cases and 642 controls, the deletion was found in one PD case but not in any control. The deletion was confirmed by multiple quantitative PCR (qPCR) assays. There is no additional exonic single nucleotide variant in the one copy of TH gene of the patient. The patient has an age-at-onset of 54 years, no evidence for dystonia, and was responsive to L-DOPA. This case supports the importance of the TH gene in PD pathogenesis and raises more attention to rare variants in candidate genes being a risk factor for Parkinson disease. © 2010 Wiley-Liss, Inc

Plum pudding random medium model of biological tissue toward remote microscopy from spectroscopic light scattering

Biological tissue has a complex structure and exhibits rich spectroscopic behavior. There is \emph{no} tissue model up to now able to account for the observed spectroscopy of tissue light scattering and its anisotropy. Here we present, \emph{for the first time}, a plum pudding random medium (PPRM) model for biological tissue which succinctly describes tissue as a superposition of distinctive scattering structures (plum) embedded inside a fractal continuous medium of background refractive index fluctuation (pudding). PPRM faithfully reproduces the wavelength dependence of tissue light scattering and attributes the "anomalous" trend in the anisotropy to the plum and the powerlaw dependence of the reduced scattering coefficient to the fractal scattering pudding. Most importantly, PPRM opens up a novel venue of quantifying the tissue architecture and microscopic structures on average from macroscopic probing of the bulk with scattered light alone without tissue excision. We demonstrate this potential by visualizing the fine microscopic structural alterations in breast tissue (adipose, glandular, fibrocystic, fibroadenoma, and ductal carcinoma) deduced from noncontact spectroscopic measurement

Spinocerebellar ataxia 27B: episodic symptoms and acetazolamide response in 34 patients

Ashton C et al report a retrospective multi-centre cohort of 34 patients from Canada, France, Austria and Australia with spinocerebellar ataxia 27B, describing the common feature of episodic ataxia and other episodic features, as well as the inefficacy of acetazolamide in these patients