Selective expression of presenilin 1 in neural progenitor cells rescues the cerebral hemorrhages and cortical lamination defects in presenilin 1-null mutant mice

Mice with a null mutation of the presenilin 1 gene (Psen1(-/-)) die during late intrauterine life or shortly after birth and exhibit multiple CNS and non-CNS abnormalities, including cerebral hemorrhages and altered cortical development. The cellular and molecular basis for the developmental effects of Psen1 remain incompletely understood. Psen1 is expressed in neural progenitors in developing brain, as well as in postmitotic neurons. We crossed transgenic mice with either neuron-specific or neural progenitor-specific expression of Psen1 onto the Psen1(-/-) background. We show that neither neuron-specific nor neural progenitor-specific expression of Psen1 can rescue the embryonic lethality of the Psen1(-/-) embryo. Indeed neuron-specific expression rescued none of the abnormalities in Psen1(-/-) mice. However, Psen1 expression in neural progenitors rescued the cortical lamination defects, as well as the cerebral hemorrhages, and restored a normal vascular pattern in Psen1(-/-) embryos. Collectively, these studies demonstrate that Psen1 expression in neural progenitor cells is crucial for cortical development and reveal a novel role for neuroectodermal expression of Psen1 in development of the brain vasculature.     

Tectonostratigraphy of Middle and Upper Palaeozoic black shales from the Porto-Tomar-Ferreira do Alentejo shear zone (W Portugal): new perspectives on the Iberian Massif

Middle/late Devonian and early Carboniferous metasedimentary sequences in the northernmost region (Porto-Espinho-Tomar) of the Ossa-Morena Zone (Portuguese Iberian Variscan Massif) contain black shales of very low to low-grade metamorphism. These metasedimentary rocks form a discrete NNW-SSE structure within a major shear zone (Porto-Tomar-Ferreira do Alentejo) and remain subparallel to the observed regional major structures (folding, thrusts or overthrusts). These black shales are overhanged and then imbricated in an upper Proterozoic metamorphic substratum. A multi-disciplinary study of these metasedimentary rocks from the Espinho-Tomar region has tectonostratigraphy, palynology, organic petrology and clay mineralogy combined methods. This approach provides new insights into the tectonic evolution and geological framework of Palaeozoic basement of the Iberian Variscides. Palaeoenvironmental and tectonostratigraphic implications on the Iberian geodynamic framework are discussed.     

Colorectal cancer DNA methylation patterns from patients in Manaus,Brazil

Background

DNA methylation is commonly linked with the silencing of the gene expression for many tumor suppressor genes. As such, determining DNA methylation patterns should aid, in times to come, in the diagnosis and personal treatment for various types of cancers. Here, we analyzed the methylation pattern from five colorectal cancer patients from the Amazon state in Brazil for four tumor suppressor genes, viz.: DAPK, CDH1, CDKN2A, and TIMP2 by employing a polymerase chain reaction (PCR) specific to methylation. Efforts in the study of colorectal cancer are fundamental as it is the third most of highest incidence in the world.

Results

Tumor biopsies were methylated in 1/5 (20 %), 2/5 (40 %), 4/5 (80 %), and 4/5 (80 %) for CDH1, CDKN2A, DAPK, and TIMP2 genes, respectively. The margin biopsies were methylated in 3/7 (43 %), 2/7 (28 %), 7/7 (100 %), and 6/7 (86 %) for CDH1, CDKN2A, DAPK, and TIMP2, respectively.

Conclusions

Our findings showed DAPK and TIMP2 to be methylated in most samples from both tumor tissues and adjacent non-neoplastic margins; thus presenting distinct methylation patterns. This emphasizes the importance of better understanding of the relation of these patterns with cancer in the context of different populations.     

Acute effects of incremental inspiratory loads on compartmental chest wall volume and predominant activity frequency of inspiratory muscle

AimThis research aims to analyze the acute effect of incremental inspiratory loads on respiratory pattern and on the predominant activity frequency of inspiratory muscle, taking into account differences in gender responses. Optoelectronic Plethysmography was performed during loads in 39 healthy subjects (20 women), placing 89 markers on the thoracic-abdominal wall to obtain total and regional volumes. Surface electromyography (SEMG) was taken simultaneously on the Sternocleidomastoid and Diaphragm muscles, to calculate the predominant muscle activity frequency through wavelet analysis. Inspiratory loads were performed using Threshold® with 2 min of breathing at different levels, ranging from a load of 10 cmH₂O plus 5 cmH₂O to 40 cmH₂O or fatigue.ResultsInspiratory Time increased during loads. Total and compartmental volumes increased with different regions, changing at different loads. These changes in volume occur earlier in women (20 cmH₂O) than in men (30 cmH₂O). The predominant activity frequency of Sternocleidmastoid muscle decreased at 30 cmH₂O, while Diaphragm activity decreased at 40 cmH₂O.ConclusionThe acute effects of incremental inspiratory loads are increases of total and regional volumes and inspiratory time. As for muscle activity, the predominant activity frequency declined in Sternocleidomastoid and Diaphragm muscles, but at different loads. Such respiratory and SEMG patterns and gender differences should be considered when clinical interventions are performed.     

Enzymatic Modification of Paper Fibres

The enzymatic mode of action in paper fibre upgrading is still uncertain. In an attempt to clarify how enzymes modify pulp and paper properties, several parameters were analysed in the present work: (i) thermal analysis of the water-solid surface interactions; (ii) fibre cake permeability; (iii) particle size analysis. The results obtained suggest that enzymes modify the interfacial properties of fibres, increasing the water affinity, which in turn change the technical properties of pulp and paper, such as drainability and strength. The modification of paper and pulps following a treatment with cellulose-binding domains further supports this hypothesis.     

Inhibition of IL-10 production by maternal antibodies against Group B Streptococcus GAPDH confers immunity to offspring by favoring neutrophil recruitment

Group B Streptococcus (GBS) is the leading cause of neonatal pneumonia, septicemia, and meningitis. We have previously shown that in adult mice GBS glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is an extracellular virulence factor that induces production of the immunosuppressive cytokine interleukin-10 (IL-10) by the host early upon bacterial infection. Here, we investigate whether immunity to neonatal GBS infection could be achieved through maternal vaccination against bacterial GAPDH. Female BALB/c mice were immunized with rGAPDH and the progeny was infected with a lethal inoculum of GBS strains. Neonatal mice born from mothers immunized with rGAPDH were protected against infection with GBS strains, including the ST-17 highly virulent clone. A similar protective effect was observed in newborns passively immunized with anti-rGAPDH IgG antibodies, or F(ab')(2) fragments, indicating that protection achieved with rGAPDH vaccination is independent of opsonophagocytic killing of bacteria. Protection against lethal GBS infection through rGAPDH maternal vaccination was due to neutralization of IL-10 production soon after infection. Consequently, IL-10 deficient (IL-10(-/-)) mice pups were as resistant to GBS infection as pups born from vaccinated mothers. We observed that protection was correlated with increased neutrophil trafficking to infected organs. Thus, anti-rGAPDH or anti-IL-10R treatment of mice pups before GBS infection resulted in increased neutrophil numbers and lower bacterial load in infected organs, as compared to newborn mice treated with the respective control antibodies. We showed that mothers immunized with rGAPDH produce neutralizing antibodies that are sufficient to decrease IL-10 production and induce neutrophil recruitment into infected tissues in newborn mice. These results uncover a novel mechanism for GBS virulence in a neonatal host that could be neutralized by vaccination or immunotherapy. As GBS GAPDH is a structurally conserved enzyme that is metabolically essential for bacterial growth in media containing glucose as the sole carbon source (i.e., the blood), this protein constitutes a powerful candidate for the development of a human vaccine against this pathogen.     

Ubiquitin–Proteasome System Impairment and MPTP-Induced Oxidative Stress in the Brain of C57BL/6 Wild-type and GSTP Knockout Mice

The ubiquitin–proteasome system (UPS) is the primary proteolytic complex responsible for the elimination of damaged and misfolded intracellular proteins, often formed upon oxidative stress. Parkinson’s disease (PD) is neuropathologically characterized by selective death of dopaminergic neurons in the substantia nigra (SN) and accumulation of intracytoplasmic inclusions of aggregated proteins. Along with mitochondrial dysfunction and oxidative stress, defects in the UPS have been implicated in PD. Glutathione S-transferase pi (GSTP) is a phase II detoxifying enzyme displaying important defensive roles against the accumulation of reactive metabolites that potentiate the aggression of SN neuronal cells, by regulating several processes including S-glutathionylation, modulation of glutathione levels and control of kinase-catalytic activities. In this work we used C57BL/6 wild-type and GSTP knockout mice to elucidate the effect of both MPTP and MG132 in the UPS function and to clarify if the absence of GSTP alters the response of this pathway to the neurotoxin and proteasome inhibitor insults. Our results demonstrate that different components of the UPS have different susceptibilities to oxidative stress. Importantly, when compared to the wild-type, GSTP knockout mice display decreased ubiquitination capacity and overall increased susceptibility to UPS damage and inactivation upon MPTP-induced oxidative stress.     

Genomic sequencing of two isolates of Ralstonia solanacearum causing Sergipe facies and comparative analysis with Bugtok disease isolates

Ralstonia solanacearum is the causal agent of Moko disease in bananas, which in the state of Sergipe in northeastern Brazil causes “Sergipe facies”. This disease induces atypical symptoms similar to those of Bugtok disease in the Philippines. This study was conducted to sequence, assemble, and annotate the genomes of the Sergipe facies-causing isolates SFC and IBSBF2570 (sequevar IIA-53) and compare their genomes with two representative isolates causing Bugtok disease. The genomes were sequenced and assembled, resulting in lengths of 5.58 Mb (SFC) and 5.46 Mb (IBSBF2570) in 185 and 174 contigs, respectively. The isolates of Sergipe facies and Bugtok disease showed similarities in their gene contents. We identified 5,668 information clusters, 3,752 of which were shared by all genomes (core genes). Moreover, 3,585 single-copy genes were identified. Isolates causing Bugtok disease exclusively shared 266 more information clusters than the isolates causing Sergipe facies. These results suggest that Sergipe facies and Bugtok disease isolates show high genomic similarity. However, the similarity is even greater between the Bugtok disease isolates. This may be because of their longer period of interaction compared to Sergipe facies isolates.