Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Spatially assessing plant diversity for conservation: A Mediterranean case study

In this paper, we present a spatially explicit procedure for mapping and assessing coastal plant diversity value in the context of biodiversity monitoring and conservation planning. Our objective was to devise a replicable and easy to understand methodology framework, which can represent an expedient tool for coastal management and decision making at spatial scales between 1:25,000 and 1:50,000. For this purpose, we adopted a small number of key descriptors that refer to easily quantifiable information on species and habitats: plant species richness, species of conservation value, floristic consistency, habitat diversity, and habitats of conservation interest under the Council Directive 92/43/EEC. We built an expedient sampling strategy that combines systematic sampling by grid cells of fixed size with stratification per habitat type, and apply a plain equal weighting scoring system for assessing overall plant diversity. All floristic and habitat data were entered into a spatial database built within a GIS environment and referred to a 1 × 1 square km spatial grid overlaid on two selected test sites in southern Sardinia (Italy). The descriptors we chose were successful surrogates of plant diversity, as they were able to represent the known conservation importance of both test sites and of specific areas within them, both individually and in combination. In particular, our results show that integrating indicators at different levels of biodiversity enabled to represent aspects with marked differences in distribution as well as to compensate possible biases in data collection, as habitat data are more easily available than floristic information and spatially continuous even in less accessible areas. Being based on well-known criteria and policies, and on data that are most widely and consistently available, our assessment procedure proved effective and easily transferable, and provides a spatial reference framework for systematically evaluating and monitoring coastal plant diversity at national level and across the Mediterranean Basin

A longitudinal 1H-NMR metabolomics analysis of urine from newborns with hypoxic-ischemic encephalopathy undergoing hypothermia therapy. Clinical and medical legal insights.

Perinatal asphyxia is an event affecting around four million newborns worldwide. The 0.5 to 2 per 1000 of full term asphyxiated newborns suffer from hypoxic-ischemic encephalopathy (HIE), which is a frequent cause of death or severe disability and, as consequence, the most common birth injury claim for obstetrics, gynaecologists, and paediatricians. Perinatal asphyxia results from a compromised gas exchange that leads to hypoxemia, hypercapnia, and metabolic acidosis. In this work, we applied a metabolomics approach to investigate the metabolic profiles of urine samples collected from full term asphyxiated newborns with HIE undergoing therapeutic hypothermia (TH), with the aim of identifying a pattern of metabolites associated with HIE and to follow their modifications over time. Urine samples were collected from 10 HIE newborns at birth, during hypothermia (48 hours), at the end of the therapeutic treatment (72 hours), at 1 month of life, and compared with a matched control population of 16 healthy full term newborns. The metabolic profiles were investigated by H-1 NMR spectroscopy coupled with multivariate statistical methods such as principal component analysis and orthogonal partial least square discriminant analysis. Multivariate analysis indicated significant differences between the urine samples of HIE and healthy newborns at birth. The altered metabolic patterns, mainly originated from the depletion of cellular energy and homeostasis, seem to constitute a characteristic of perinatal asphyxia. The HIE urine metabolome changes over time reflected either the effects of TH and the physiological growth of the newborns. Of interest, the urine metabolic profiles of the HIE non-surviving babies, characterized by the increased excretion of lactate, resulted significantly different from the rest of HIE population

Clinical parameters of the study population in the first 30 days of life.

<p>Clinical parameters of the study population in the first 30 days of life.</p

Comparative analysis of urine samples of HIE newborns at birth and at 30 days of life.

<p>Score scatter plots of (<b>A</b>) PCA and (<b>B</b>) OPLS-DA models of urine samples collected from HIE babies at birth (HIE day 1, empty circles) and at 30 days of life (HIE day 30, light blue diamonds). (<b>C</b>) Permutation test of the corresponding PLS-DA model (n = 400 random permutations). (<b>D</b>) OPLS-DA loading column plot of discriminant variables.</p

The effect of 72 hours of TH on the urine metabolome of HIE newborns.

<p>(<b>A</b>) Score scatter plot of the PCA model of urine samples collected from HIE newborns (HIE day 1, empty circles) and at the end of TH treatment (HIE day 3, blue triangles). The label NS indicates the non-surviving newborns. (<b>B</b>) Score scatter plot of the PCA model after removal of the samples belonging to non-surviving newborns (<b>C</b>) Score scatter plot of the OPLS-DA model of the samples belonging to surviving newborns. (<b>D</b>) Permutation test of the corresponding PLS-DA model (n = 400 random permutations). (<b>E</b>) OPLS-DA loading column plot of discriminant variables.</p

The effect of 48 hours of TH on the urine metabolome of HIE newborns.

<p>Score scatter plots of (A) PCA model of urine samples collected from HIE babies at birth (HIE day 1, empty circles) and during the TH treatment at 48 hours (HIE day 2, red squares). The label NS indicates the non-surviving babies, and (<b>B</b>) corresponding PCA model after removal of the samples belonging to non-surviving newborns.</p

Clinical parameters of the study population at birth.

<p>Clinical parameters of the study population at birth.</p

Comparative analysis of urine samples of HIE newborns and healthy controls at birth.

<p>Score scatter plots of (<b>A</b>) PCA and (<b>B</b>) OPLS-DA models of urine samples collected from HIE newborns (HIE day 1, empty circles) and from healthy newborns (Healthy day 1, green circles). The label NS indicates the non-surviving babies. (<b>C</b>) Permutation test of the corresponding PLS-DA model (n = 400 random permutations). (<b>D</b>) OPLS-DA loading column plot of discriminant variables.</p