Changes in Dry State Hemoglobin over Time Do Not Increase the Potential for Oxidative DNA Damage in Dried Blood

BACKGROUND: Hemoglobin (Hb) is the iron-containing oxygen transport protein present in the red blood cells of vertebrates. Ancient DNA and forensic scientists are particularly interested in Hb reactions in the dry state because both regularly encounter aged, dried bloodstains. The DNA in such stains may be oxidatively damaged and, in theory, may be deteriorated by the presence of Hb. To understand the nature of the oxidative systems potentially available to degrade DNA in the presence of dried Hb, we need to determine what molecular species Hb forms over time. These species will determine what type of iron (i.e. Fe(2+)/Fe(3+)/Fe(4+)) is available to participate in further chemical reactions. The availability of "free" iron will affect the ability of the system to undergo Fenton-type reactions which generate the highly reactive hydroxyl radical (OH*). The OH* can directly damage DNA. METHODOLOGY/PRINCIPAL FINDINGS: Oxygenated Hb (oxyHb) converts over time to oxidized Hb (metHb), but this happens more quickly in the dry state than in the hydrated state, as shown by monitoring stabilized oxyHb. In addition, dry state oxyHb converts into at least one other unknown species other than metHb. Although "free" iron was detectable as both Fe(2+) and Fe(3+) in dry and hydrated oxyHb and metHb, the amount of ions detected did not increase over time. There was no evidence that Hb becomes more prone to generating OH* as it ages in either the hydrated or dry states. CONCLUSIONS: The Hb molecule in the dried state undergoes oxidative changes and releases reactive Fe(II) cations. These changes, however, do not appear to increase the ability of Hb to act as a more aggressive Fenton reagent over time. Nevertheless, the presence of Hb in the vicinity of DNA in dried bloodstains creates the opportunity for OH*-induced oxidative damage to the deoxyribose sugar and the DNA nucleobases

Risks in circular business models innovation: A cross-industrial case study for composite materials

Circular business models (CBMs) are key enablers to implement circular economy (CE), yet they entail risks, which often discourage organisations. This work aims to explore the main risk factors perceived by the manufacturing industry in transitioning to CBMs to enable the development of appropriate risk management strategies. A cross- industrial multiple-case study research design was used to explore risk factors across seven organisations planning the transition to CBMs for composite-based products and involving three different CBM types—‘Circular Supplies’, ‘Product Life Extension’ and ‘Hybrid’. Results evidenced that risks are multi-disciplinary but are not equally per- ceived across different CBM types. Customers' perceptions of CE products, economic cycle and take-back systems were prevalent across all CBMs. Supply and technological risks were prioritised for ‘Circular Supplies’ CBM, whereas political and regulatory risks for ‘Product Life Extension’ CBM. This research contributes to the CE field by evaluating and prioritising the perceived risk factors in transitioning to CBMs and first disaggregating such risk factors according to CBM types. Critical risk patterns identified across different industries and CBM types enable mitigating actions to be prioritised

Comprehensive molecular characterisation of epilepsy-associated glioneuronal tumours

Glioneuronal tumours are an important cause of treatment-resistant epilepsy. Subtypes of tumour are often poorly discriminated by histological features and may be difficult to diagnose due to a lack of robust diagnostic tools. This is illustrated by marked variability in the reported frequencies across different epilepsy surgical series. To address this, we used DNA methylation arrays and RNA sequencing to assay the methylation and expression profiles within a large cohort of glioneuronal tumours. By adopting a class discovery approach, we were able to identify two distinct groups of glioneuronal tumour, which only partially corresponded to the existing histological classification. Furthermore, by additional molecular analyses, we were able to identify pathogenic mutations in BRAF and FGFR1, specific to each group, in a high proportion of cases. Finally, by interrogating our expression data, we were able to show that each molecular group possessed expression phenotypes suggesting different cellular differentiation: astrocytic in one group and oligodendroglial in the second. Informed by this, we were able to identify CCND1, CSPG4, and PDGFRA as immunohistochemical targets which could distinguish between molecular groups. Our data suggest that the current histological classification of glioneuronal tumours does not adequately represent their underlying biology. Instead, we show that there are two molecular groups within glioneuronal tumours. The first of these displays astrocytic differentiation and is driven by BRAF mutations, while the second displays oligodendroglial differentiation and is driven by FGFR1 mutations

Enhancing the early student experience

This paper is concerned with identifying how the early student experience can be enhanced in order to improve levels of student retention and achievement. The early student experience is the focus of this project as the literature has consistently declared the first year to be the most critical in shaping persistence decisions. Programme managers of courses with high and low retention rates have been interviewed to identify activities that appear to be associated with good retention rates. The results show that there are similarities in the way programmes with high retention are run, with these features not being prevalent on programmes with low retention. Recommendations of activities that appear likely to enhance the early student experience are provided

Prediction of drug–target interaction networks from the integration of chemical and genomic spaces

Motivation: The identification of interactions between drugs and target proteins is a key area in genomic drug discovery. Therefore, there is a strong incentive to develop new methods capable of detecting these potential drug–target interactions efficiently

Contribution of microscopy for understanding the mechanism of action against trypanosomatids

Transmission electron microscopy (TEM) has proved to be a useful tool to study the ultrastructural alterations and the target organelles of new antitrypanosomatid drugs. Thus, it has been observed that sesquiterpene lactones induce diverse ultrastructural alterations in both T. cruzi and Leishmania spp., such as cytoplasmic vacuolization, appearance of multilamellar structures, condensation of nuclear DNA, and, in some cases, an important accumulation of lipid vacuoles. This accumulation could be related to apoptotic events. Some of the sesquiterpene lactones (e.g., psilostachyin) have also been demonstrated to cause an intense mitochondrial swelling accompanied by a visible kinetoplast deformation as well as the appearance of multivesicular bodies. This mitochondrial swelling could be related to the generation of oxidative stress and associated to alterations in the ergosterol metabolism. The appearance of multilamellar structures and multiple kinetoplasts and flagella induced by the sesquiterpene lactone psilostachyin C indicates that this compound would act at the parasite cell cycle level, in an intermediate stage between kinetoplast segregation and nuclear division. In turn, the diterpene lactone icetexane has proved to induce the external membrane budding on T. cruzi together with an apparent disorganization of the pericellar cytoskeleton. Thus, ultrastructural TEM studies allow elucidating the possible mechanisms and the subsequent identification of molecular targets for the action of natural compounds on trypanosomatids.Fil: Lozano, Esteban Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Spina Zapata, Renata María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Barrera, Patricia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Tonn, Carlos Eugenio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Investigaciones en Tecnología Química. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Investigaciones en Tecnología Química; ArgentinaFil: Sosa Escudero, Miguel Angel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentin

Drying Shrinkage Mechanisms in Portland Cement Paste

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65426/1/j.1151-2916.1987.tb05002.x.pd

Recruitment of rare 3-grams at functional sites: Is this a mechanism for increasing enzyme specificity?

<p>Abstract</p> <p>Background</p> <p>A wealth of unannotated and functionally unknown protein sequences has accumulated in recent years with rapid progresses in sequence genomics, giving rise to ever increasing demands for developing methods to efficiently assess functional sites. Sequence and structure conservations have traditionally been the major criteria adopted in various algorithms to identify functional sites. Here, we focus on the distributions of the 20³different types of <it>3</it>-grams (or triplets of sequentially contiguous amino acid) in the entire space of sequences accumulated to date in the UniProt database, and focus in particular on the rare <it>3</it>-grams distinguished by their high entropy-based information content.</p> <p>Results</p> <p>Comparison of the UniProt distributions with those observed near/at the active sites on a non-redundant dataset of 59 enzyme/ligand complexes shows that the active sites preferentially recruit <it>3</it>-grams distinguished by their low frequency in the UniProt. Three cases, Src kinase, hemoglobin, and tyrosyl-tRNA synthetase, are discussed in details to illustrate the biological significance of the results.</p> <p>Conclusion</p> <p>The results suggest that recruitment of rare <it>3</it>-grams may be an efficient mechanism for increasing specificity at functional sites. Rareness/scarcity emerges as a feature that may assist in identifying key sites for proteins function, providing information complementary to that derived from sequence alignments. In addition it provides us (for the first time) with a means of identifying potentially functional sites from sequence information alone, when sequence conservation properties are not available.</p