G93A SOD1 alters cell cycle in a cellular model of Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative multifactorial disease characterized, like other diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) or frontotemporal dementia (FTD), by the degeneration of specific neuronal cell populations. Motor neuron loss is distinctive of ALS. However, the causes of onset and progression of motor neuron death are still largely unknown. In about 2% of all cases, mutations in the gene encoding for the Cu/Zn superoxide dismutase (SOD1) are implicated in the disease. Several alterations in the expression or activation of cell cycle proteins have been described in the neurodegenerative diseases and related to cell death. In this work we show that mutant SOD1 can alter cell cycle in a cellular model of ALS. Our findings suggest that modifications in the cell cycle progression could be due to an increased interaction between mutant G93A SOD1 and Bcl-2 through the cyclins regulator p27. As previously described in post mitotic neurons, cell cycle alterations could fatally lead to cell death.     

The Complex Interaction between Home Environment,Socioeconomic Status,Maternal IQ and Early Child Neurocognitive Development: A Multivariate Analysis of Data Collected in a Newborn Cohort Study

BackgroundThe relative role of socioeconomic status (SES), home environment and maternal intelligence, as factors affecting child cognitive development in early childhood is still unclear. The aim of this study is to analyze the association of SES, home environment and maternal IQ with child neurodevelopment at 18 months.MethodsThe data were collected prospectively in the PHIME study, a newborn cohort study carried out in Italy between 2007 and 2010. Maternal nonverbal abilities (IQ) were evaluated using the Standard Progressive Matrices, a version of the Raven’s Progressive Matrices; a direct evaluation of the home environment was carried out with the AIRE instrument, designed using the HOME (Home Observation for Measurement of the Environment) model; the socioeconomic characteristics were evaluated using the SES index which takes into account parents occupation, type of employment, educational level, homeownership. The study outcome was child neurodevelopment evaluated at 18 months, with the Bayley Scales of Infant and Toddler Development Third Edition (BSID III). Linear regression analyses and mediation analyses were carried out to evaluate the association between the three exposures, and the scaled scores of the three main scales of BSID III (cognitive, language and motor scale), with adjustment for a wide range of potential explanatory variables.ResultsData from 502 mother-child pairs were analyzed. Mediation analysis showed a relationship between SES and maternal IQ, with a complete mediation effect of home environment in affecting cognitive and language domains. A direct significant effect of maternal IQ on the BSID III motor development scale and the mediation effect of home environment were found.ConclusionsOur results show that home environment was the variable with greater influence on neurodevelopment at 18 months. The observation of how parents and children interact in the home context is crucial to adequately evaluate early child development.     

Plasmodium falciparum: Antimalarial activity in culture of sinefungin and other methylation inhibitors

A culture line of Plasmodium falciparum (FCR-3/Gambia) was exposed in vitro for a 2-day period to several analogs of adenosylhomocysteine. Minimal concentrations giving complete inhibition of growth were 0.2 mM for 3-deazaadenosine, 0.2 mM for 5′-deoxy-5′-(isobutylthio)-3-deazaadenosine, and 0.3 μM for sinefungin. The effects of the first two of these compounds were potentiated by homocysteine-thiolactone, suggesting that they were inhibiting methylation reaction(s) indirectly via adenosylhomocysteine hydrolase (EC 3.3.1.1).     

Developmental Programming Mediated by Complementary Roles of Imprinted Grb10 in Mother and Pup

Developmental programming links growth in early life with health status in adulthood. Although environmental factors such as maternal diet can influence the growth and adult health status of offspring, the genetic influences on this process are poorly understood. Using the mouse as a model, we identify the imprinted gene Grb10 as a mediator of nutrient supply and demand in the postnatal period. The combined actions of Grb10 expressed in the mother, controlling supply, and Grb10 expressed in the offspring, controlling demand, jointly regulate offspring growth. Furthermore, Grb10 determines the proportions of lean and fat tissue during development, thereby influencing energy homeostasis in the adult. Most strikingly, we show that the development of normal lean/fat proportions depends on the combined effects of Grb10 expressed in the mother, which has the greater effect on offspring adiposity, and Grb10 expressed in the offspring, which influences lean mass. These distinct functions of Grb10 in mother and pup act complementarily, which is consistent with a coadaptation model of imprinting evolution, a model predicted but for which there is limited experimental evidence. In addition, our findings identify Grb10 as a key genetic component of developmental programming, and highlight the need for a better understanding of mother-offspring interactions at the genetic level in predicting adult disease risk.     

Polymorphisms of the ITGAM gene confer higher risk of discoid cutaneous than of systemic lupus erythematosus

Background

Lupus erythematosus (LE) is a heterogeneous disease ranging from mainly skin-restricted manifestations (discoid LE [DLE] and subacute cutaneous LE) to a progressive multisystem disease (systemic LE [SLE]). Genetic association studies have recently identified several strong susceptibility genes for SLE, including integrin alpha M (ITGAM), also known as CD11b, whereas the genetic background of DLE is less clear.

Principal Findings

To specifically investigate whether ITGAM is a susceptibility gene not only for SLE, but also for cutaneous DLE, we genotyped 177 patients with DLE, 85 patients with sporadic SLE, 190 index cases from SLE families and 395 population control individuals from Finland for nine genetic markers at the ITGAM locus. SLE patients were further subdivided by the presence or absence of discoid rash and renal involvement. In addition, 235 Finnish and Swedish patients positive for Ro/SSA-autoantibodies were included in a subphenotype analysis. Analysis of the ITGAM coding variant rs1143679 showed highly significant association to DLE in patients without signs of systemic disease (P-value  = 4.73×10⁻¹¹, OR  = 3.20, 95% CI  = 2.23–4.57). Significant association was also detected to SLE patients (P-value  = 8.29×10⁻⁶, OR  = 2.14, 95% CI  = 1.52–3.00), and even stronger association was found when stratifying SLE patients by presence of discoid rash (P-value  = 3.59×10⁻⁸, OR  = 3.76, 95% CI  = 2.29–6.18).

Significance

We propose ITGAM as a novel susceptibility gene for cutaneous DLE. The risk effect is independent of systemic involvement and has an even stronger genetic influence on the risk of DLE than of SLE.     

Thioredoxin targets of the plant chloroplast lumen and their implications for plastid function

The light‐dependent regulation of stromal enzymes by thioredoxin (Trx)‐catalysed disulphide/dithiol exchange is known as a classical mechanism for control of chloroplast metabolism. Recent proteome studies show that Trx targets are present not only in the stroma but in all chloroplast compartments, from the envelope to the thylakoid lumen. Trx‐mediated redox control appears to be a common feature of important pathways, such as the Calvin cycle, starch synthesis and tetrapyrrole biosynthesis. However, the extent of thiol‐dependent redox regulation in the thylakoid lumen has not been previously systematically explored. In this study, we addressed Trx‐linked redox control in the chloroplast lumen of Arabidopsis thaliana. Using complementary proteomics approaches, we identified 19 Trx target proteins, thus covering more than 40% of the currently known lumenal chloroplast proteome. We show that the redox state of thiols is decisive for degradation of the extrinsic PsbO1 and PsbO2 subunits of photosystem II. Moreover, disulphide reduction inhibits activity of the xanthophyll cycle enzyme violaxanthin de‐epoxidase, which participates in thermal dissipation of excess absorbed light. Our results indicate that redox‐controlled reactions in the chloroplast lumen play essential roles in the function of photosystem II and the regulation of adaptation to light intensity.     

Splitting placodes: effects of bone morphogenetic protein and Activin on the patterning and identity of mouse incisors

SUMMARY The single large rodent incisor in each jaw quadrant is evolutionarily derived from a mammalian ancestor with many small incisors. The embryonic placode giving rise to the mouse incisor is considerably larger than the molar placode, and the question remains whether this large incisor placode is a developmental requisite to make a thick incisor. Here we used in vitro culture system to experiment with the molecular mechanism regulating tooth placode development and how mice have thick incisors. We found that large placodes are prone to disintegration and formation of two to three small incisor placodes. The balance between one large or multiple small placodes was altered through the regulation of bone morphogenetic protein (BMP) and Activin signaling. Exogenous Noggin, which inhibits BMP signaling, or exogenous Activin cause the development of two to three incisors. These incisors were more slender than normal incisors. Additionally, two inhibitor molecules, Sostdc1 and Follistatin, which regulate the effects of BMPs and Activin and have opposite expression patterns, are likely to be involved in the incisor placode regulation in vivo. Furthermore, inhibition of BMPs by recombinant Noggin has been previously suggested to cause a change in the tooth identity from the incisor to the molar. This evidence has been used to support a homeobox code in determining tooth identity. Our work provides an alternative interpretation, where the inhibition of BMP signaling can lead to splitting of the large incisor placode and the formation of partly separate incisors, thereby acquiring molar‐like morphology without a change in tooth identity.     

Genetic Determinants of Height Growth Assessed Longitudinally from Infancy to Adulthood in the Northern Finland Birth Cohort 1966

Recent genome-wide association (GWA) studies have identified dozens of common variants associated with adult height. However, it is unknown how these variants influence height growth during childhood. We derived peak height velocity in infancy (PHV1) and puberty (PHV2) and timing of pubertal height growth spurt from parametric growth curves fitted to longitudinal height growth data to test their association with known height variants. The study consisted of N=3,538 singletons from the prospective Northern Finland Birth Cohort 1966 with genotype data and frequent height measurements (on average 20 measurements per person) from 0–20 years. Twenty-six of the 48 variants tested associated with adult height (p<0.05, adjusted for sex and principal components) in this sample, all in the same direction as in previous GWA scans. Seven SNPs in or near the genes HHIP, DLEU7, UQCC, SF3B4/SV2A, LCORL, and HIST1H1D associated with PHV1 and five SNPs in or near SOCS2, SF3B4/SV2A, C17orf67, CABLES1, and DOT1L with PHV2 (p<0.05). We formally tested variants for interaction with age (infancy versus puberty) and found biologically meaningful evidence for an age-dependent effect for the SNP in SOCS2 (p=0.0030) and for the SNP in HHIP (p=0.045). We did not have similar prior evidence for the association between height variants and timing of pubertal height growth spurt as we had for PHVs, and none of the associations were statistically significant after correction for multiple testing. The fact that in this sample, less than half of the variants associated with adult height had a measurable effect on PHV1 or PHV2 is likely to reflect limited power to detect these associations in this dataset. Our study is the first genetic association analysis on longitudinal height growth in a prospective cohort from birth to adulthood and gives grounding for future research on the genetic regulation of human height during different periods of growth.