Two timescales control the creation of large protein aggregates in cells

Protein aggregation is of particular interest because of its connection with many diseases and disorders. Many factors can alter the dynamics and result of this process, one of them being the diffusivity of the monomers and aggregates in the system. Here, we study experimentally and theoretically an aggregation process in cells, and we identify two distinct physical timescales that set the number and size of aggregates. The first timescale involves fast aggregation of small clusters freely diffusing in the cytoplasm, whereas in the second one, the aggregates are larger than the pore size of the cytoplasm and thus barely diffuse, and the aggregation process is slowed down. However, the process is not entirely halted, potentially reflecting a myriad of active but random forces that stir the aggregates. Such a slow timescale is essential to account for the experimental results of the aggregation process. These results could also have implications in other processes of spatial organization in cell biology, such as phase-separated droplets.     

Analysis of digital patterns in the Basque valley of Deba: multivariate comparison with other populations

Eighty-six females and 79 males from the Basque valley of Deba were analyzed with respect to their digital patterns using correspondence analysis. We found that there was a significant sexual difference for only one type of pattern, tented arch. Also, this population was compared with other Basque valley populations and with other Spanish populations. We found great variability among Basque subpopulations, despite their supposed common origin. Dermatoglyphic distances for some traits can be interpreted as genetic distances because there is high heritability of these traits. The results of the comparison between the Deba valley population and other Spanish populations showed that the Deba population is markedly distant from the other populations.     

Mapa de la enfermedad de Alzheimer y otras demencias en España. Proyecto MapEA

Introduction

In the current context of increased life expectancy and progressive aging of the population a very significant increase in the number of people with cognitive impairment and dementia is expected.Consequently, Spain will face an enormous social and health problem in the next decades. The Mapa de la enfermedad de Alzheimer y otras demencias en España project aims to analyse plans, prevention and early diagnosis activities, process of care and resources available across the 17 Spanish regions for the management of cognitive impairment and dementia in order to identify improvement areas, as well as to provide a list of recommendations.

Vanillic acid metabolism by the white-rot fungus Sporotrichum pulverulentum

Vanillic acid metabolism was studied in wild-type Sporotrichum pulverulentum and three different mutants. Vanillic acid was found to be oxidatively decarboxylated to methoxyhydroquinone (MHQ) and simultaneously reduced to vanillin and vanillyl alcohol to different degrees depending upon the cultivation conditions. The reducing pathway cannot be utilized unless the fungus has access to an easily metabolized carbon source such as glucose or cellobiose, while decarboxylation takes place in cultures with only vanillic acid present. Polymerization reactions also occurred in the culture solutions. Some evidence for reoxidation of vanillin and vanillyl alcohol was obtained in vivo, and in vitro experiments using horseradish peroxidase.Using vanillic acids labelled in the carboxyl, methoxyl and the aromatic ring it was shown that decarboxylation occures before ring-cleavage, which in turn takes place earlier than the release of ¹⁴CO₂ from O¹⁴CH₃-vanillate. The ¹⁴CO₂ evolution from the methoxyl group is repressed by 1% cellobiose as compared to 0.25% cellobiose, but is stimulated by 26 mM nitrogen (as asparagine plus NH₄NO₃) compared to 2.6 mM nitrogen. Since S. pulverulentum appears to require three hydroxyl groups attached to the benzene ring before ring-cleavage can occur, preparation for ring-cleavage is apparently achieved by hydroxylation rather than by demethylation.A scheme for metabolism of vanillic acid by S. pulverulentum based upon these results is proposed.Non-Standard Abbreviations WT wild type Sporotrichum pulverulentum - MHQ methoxyhydroquinone - MQ methoxyquinone - NKM Norkrans medium - DMS dimethylsuccinate - DHP dehydropolymer of coniferyl alcohol     

Correspondence analysis of digital pattern types in Basque valleys

Fingers pattern types of a sample of 834 unrelated individuals (353 males and 481 females) from the Biscaian Basque valleys of Uribe, Gernika, Markina, Arratia and Durango were subjected to correspondence analysis. The results show that there are different local subpopulations with regard to these dermatoglyphic traits. The importance of whorls in the separation of these populations is observed. Isolation may have been the factor differentiating between the valleys.     

Antiviral action of the tumor suppressor ARF

Oncogenic viruses frequently target the pathways controlled by tumor suppressor genes, suggesting an extra function for these proteins as antiviral factors. The control exerted by the tumor suppressor Arf on cellular proliferation is crucial to restrict tumor development; however, a potential contribution of Arf to prevent viral infectivity has remained unexplored. In the present study, we investigated the consequences of loss or increased expression of Arf on viral infection. Our results reveal that ARF expression is induced by interferon and after viral infection. Furthermore, we show that ARF protects against viral infection in a gene dosage-dependent manner, and that this antiviral action is mediated in part by PKR through a mechanism that involves ARF-induced release of PKR from nucleophosmin complexes. Finally, Arf-null mice were hypersensitive to viral infection compared to wild-type mice. Together, our results reveal a novel and unexpected role for the tumor suppressor ARF in viral infection surveillance.     

Effects of mixing system and pilot fuel quality on diesel–biogas dual fuel engine performance

This paper describes results obtained from CI engine performance running on dual fuel mode at fixed engine speed and four loads, varying the mixing system and pilot fuel quality, associated with fuel composition and cetane number. The experiments were carried out on a power generation diesel engine at 1500 m above sea level, with simulated biogas (60% CH₄–40% CO₂) as primary fuel, and diesel and palm oil biodiesel as pilot fuels. Dual fuel engine performance using a naturally aspirated mixing system and diesel as pilot fuel was compared with engine performance attained with a supercharged mixing system and biodiesel as pilot fuel. For all loads evaluated, was possible to achieve full diesel substitution using biogas and biodiesel as power sources. Using the supercharged mixing system combined with biodiesel as pilot fuel, thermal efficiency and substitution of pilot fuel were increased, whereas methane and carbon monoxide emissions were reduced.     

Role of whole brain radiotherapy in the management of infratentorial metastases from lung and breast cancer

BackgroundBrain metastases (BM) occur in almost one third of patients with systemic malignancies. Only a small number of studies focus on infratentorial location and whole brain radiotherapy (WBRT) as the main non-surgical management. The aim of the study was to compare the prognosis of patients treated with WBRT among patients with supra- or infratentorial lesions.Materials and methodsAt a single center, 263 patients with either breast (BC) or lung (LC) cancer, that had developed BM and received treatment with WBRT, were analyzed during an 8-year period.ResultsA total of 152 patients with BC and 111 with LC were analyzed, median age at the time of BM was 50.7 years, systemic activity other than BM was detected in 91%. Newly diagnosed BM were supratentorial in 40%, infratentorial in 10% and 51% in both locations. Median overall survival was 13 months (95% CI: 11.1–14.8 months), without significant difference between supra- or infratentorial location. WBRT alone was administered in 79% of patients, whereas WBRT with chemtoreapy was provided for 21%.ConclusionIn patients with BM from LC or BC that were not candidates for surgical resection, palliative WBRT appears to be equally effective in those with supra- or infratentorial locations.     

Mechanism of DNA Methylation: The Double Role of DNA as a Substrate and as a Cofactor

Methylation of cytosine residues in the DNA is one of the most important epigenetic marks central to the control of differential expression of genes. We perform quantum mechanical calculations to investigate the catalytic mechanism of the bacterial HhaI DNA methyltransferase. We find that the enzyme nucleophile, Cys81, can attack C6 of cytosine only after it is deprotonated by the DNA phosphate group, a reaction facilitated by a bridging water molecule. This finding, which indicates that the DNA acts as both the substrate and the cofactor, can explain the total loss of activity observed in an analogous enzyme, thymidylate synthase, when the phosphate group of the substrate was removed. Furthermore, our results displaying the inability of the phosphate group to deprotonate the side chain of serine is in agreement with the total, or the large extent of, inactivity observed for the C81S mutant. In contrast to results from previous calculations, we find that the active site conserved residues, Glu119, Arg163, and Arg165, are crucial for catalysis. In addition, the enzyme-DNA adduct formation and the methyl transfer from the cofactor S-adenosyl-l-methionine are not concerted but proceed via stepwise mechanism. In many of the different steps of this methylation reaction, the transfer of a proton is found to be necessary. To render these processes possible, we find that several water molecules, found in the crystal structure, play an important role, acting as a bridge between the donating and accepting proton groups.