The multifaceted role of glial cells in amyotrophic lateral sclerosis

Despite indisputable progress in the molecular and genetic aspects of amyotrophic lateral sclerosis (ALS), a mechanistic comprehension of the neurodegenerative processes typical of this disorder is still missing and no effective cures to halt the progression of this pathology have yet been developed. Therefore, it seems that a substantial improvement of the outcome of ALS treatments may depend on a better understanding of the molecular mechanisms underlying neuronal pathology and survival as well as on the establishment of novel etiological therapeutic strategies. Noteworthy, a convergence of recent data from multiple studies suggests that, in cellular and animal models of ALS, a complex pathological interplay subsists between motor neurons and their non-neuronal neighbours, particularly glial cells. These observations not only have drawn attention to the physiopathological changes glial cells undergo during ALS progression, but they have moved the focus of the investigations from intrinsic defects and weakening of motor neurons to glia–neuron interactions. In this review, we summarize the growing body of evidence supporting the concept that different glial populations are critically involved in the dreadful chain of events leading to motor neuron sufferance and death in various forms of ALS. The outlined observations strongly suggest that glial cells can be the targets for novel therapeutic interventions in ALS.     

SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis

SHARPIN is a ubiquitin-binding and ubiquitin-like-domain-containing protein which, when mutated in mice, results in immune system disorders and multi-organ inflammation. Here we report that SHARPIN functions as a novel component of the linear ubiquitin chain assembly complex (LUBAC) and that the absence of SHARPIN causes dysregulation of NF-κB and apoptotic signalling pathways, explaining the severe phenotypes displayed by chronic proliferative dermatitis (cpdm) in SHARPIN-deficient mice. Upon binding to the LUBAC subunit HOIP (also known as RNF31), SHARPIN stimulates the formation of linear ubiquitin chains in vitro and in vivo. Coexpression of SHARPIN and HOIP promotes linear ubiquitination of NEMO (also known as IKBKG), an adaptor of the IκB kinases (IKKs) and subsequent activation of NF-κB signalling, whereas SHARPIN deficiency in mice causes an impaired activation of the IKK complex and NF-κB in B cells, macrophages and mouse embryonic fibroblasts (MEFs). This effect is further enhanced upon concurrent downregulation of HOIL-1L (also known as RBCK1), another HOIP-binding component of LUBAC. In addition, SHARPIN deficiency leads to rapid cell death upon tumour-necrosis factor α (TNF-α) stimulation via FADD- and caspase-8-dependent pathways. SHARPIN thus activates NF-κB and inhibits apoptosis via distinct pathways in vivo.     

Hyperoxia and formation of chromolipoid pigments

Zusammenfassung Ratten, die wiederholt hohen O₂-Drucken ausgesetzt wurden, zeigten nach 4 Wochen erhöhte chromolipoide Pigmentation. Die Pigmentation blieb relativ gering und lag hauptsächlich in der Gefässwand und deren Umgebung bzw. den Stellen höchsten O₂-Druckes.     

The mechanical and biochemical effects of pentoxifylline on the perfused rat heart

Summary Perfusion of the isolated rat heart at constant heart rate and coronary flow with the inhibitor of cyclic nucleotide phosphodiesterase, pentoxifylline (10^–4 moles/l), produced no significant effect on the maximum rate and the peak of contraction, but increased the maximum rate of relaxation. cAMP level and cAMP-dependent protein kinase activity were increased in the absence of changes in cGMP. The results were identical in hearts of reserpinized rats.This work was supported by grants from the Consejo Nacional de Investigaciones Cientificas y Técnicas and the Comisión de Investigaciones Científicas. Buenos Aires, Argentina.We thank Hoechst Laboratories for the partial support and Mrs Alicia R. Ramirez and María Prinzo for the excellent technical assistance.     

A population-specific HTR2B stop codon predisposes to severe impulsivity

Impulsivity, describing action without foresight, is an important feature of several psychiatric diseases, suicidality and violent behaviour. The complex origins of impulsivity hinder identification of the genes influencing it and the diseases with which it is associated. Here we perform exon-focused sequencing of impulsive individuals in a founder population, targeting fourteen genes belonging to the serotonin and dopamine domain. A stop codon in HTR2B was identified that is common (minor allele frequency >?1%) but exclusive to Finnish people. Expression of the gene in the human brain was assessed, as well as the molecular functionality of the stop codon, which was associated with psychiatric diseases marked by impulsivity in both population and family-based analyses. Knockout of Htr2b increased impulsive behaviours in mice, indicative of predictive validity. Our study shows the potential for identifying and tracing effects of rare alleles in complex behavioural phenotypes using founder populations, and indicates a role for HTR2B in impulsivity.     

Hydrothermal synthesis of pyrrhotite (Fex-1S) nanoplates and their antibacterial, cytotoxic activity study

The aim of this study was to synthesize and characterize Fe_(x-1)S 2D-nanostructures with pyrrhotite phase,as well as to explore their biological(antibacterial and cytotoxic)properties,namely the expression of reactive oxygen species(ROS)in the exposure of cells and bacteria.Based on hydrothermal synthesis,the characterization of asprepared 2D-nanostructures was performed by XRD,SEM,EDS,and TEM,in which the single-crystalline pyrrhotite phased Fe_(x-1)S nanoplate morphology was observed.The antibacterial activities of Fe_(x-1)S nanoplates against human pathogenic strains such as Staphylococcus aureus,Escherichia coli,and Enterococcus faecalis were tested.Minimum inhibitory concentration(MIC)and minimum bactericidal concentration(MBC)were determined following the broth microdilution method.Cytotoxicity and expression of intracellular ROS of pyrrhotite nanoplates on Human Gingival Fibroblast(HGF),Human Pulp Cells(HPC)and Human Osteoblast(HBC)were calculated.Cell viability was determined by the MTT method.All experiments were performed of three independent experiments and data were analyzed by Kruskal-Wallis and Mann-Whitney tests,also Pearson′s Correlation was performed.The nanoplates exhibited good bactericidal effect.All types of cells tested showed slight cytotoxicity.It was found that intracellular ROS is produced when cells and bacteria tested are exposed to pyrrhotite nanoplates in presence of both air and peroxide hydrogen.ROS production levels were higher in the bacteria than the cells exposed to these nanoplates.     

R-spondin1 is essential in sex determination, skin differentiation and malignancy

R-spondins are a recently characterized small family of growth factors. Here we show that human R-spondin1 (RSPO1) is the gene disrupted in a recessive syndrome characterized by XX sex reversal, palmoplantar hyperkeratosis and predisposition to squamous cell carcinoma of the skin. Our data show, for the first time, that disruption of a single gene can lead to complete female-to-male sex reversal in the absence of the testis-determining gene, SRY.