Systematic documentation and analysis of human genetic variation in hemoglobinopathies using the microattribution approach

We developed a series of interrelated locus-specific databases to store all published and unpublished genetic variation related to hemoglobinopathies and thalassemia and implemented microattribution to encourage submission of unpublished observations of genetic variation to these public repositories. A total of 1,941 unique genetic variants in 37 genes, encoding globins and other erythroid proteins, are currently documented in these databases, with reciprocal attribution of microcitations to data contributors. Our project provides the first example of implementing microattribution to incentivise submission of all known genetic variation in a defined system. It has demonstrably increased the reporting of human variants, leading to a comprehensive online resource for systematically describing human genetic variation in the globin genes and other genes contributing to hemoglobinopathies and thalassemias. The principles established here will serve as a model for other systems and for the analysis of other common and/or complex human genetic diseases.     

Site-specific DICER and DROSHA RNA products control the DNA-damage response

Non-coding RNAs (ncRNAs) are involved in an increasingly recognized number of cellular events. Some ncRNAs are processed by DICER and DROSHA RNases to give rise to small double-stranded RNAs involved in RNA interference (RNAi). The DNA-damage response (DDR) is a signalling pathway that originates from a DNA lesion and arrests cell proliferation3. So far, DICER and DROSHA RNA products have not been reported to control DDR activation. Here we show, in human, mouse and zebrafish, that DICER and DROSHA, but not downstream elements of the RNAi pathway, are necessary to activate the DDR upon exogenous DNA damage and oncogene-induced genotoxic stress, as studied by DDR foci formation and by checkpoint assays. DDR foci are sensitive to RNase A treatment, and DICER- and DROSHA-dependent RNA products are required to restore DDR foci in RNase-A-treated cells. Through RNA deep sequencing and the study of DDR activation at a single inducible DNA double-strand break, we demonstrate that DDR foci formation requires site-specific DICER- and DROSHA-dependent small RNAs, named DDRNAs, which act in a MRE11–RAD50–NBS1-complex-dependent manner (MRE11 also known as MRE11A; NBS1 also known as NBN). DDRNAs, either chemically synthesized or in vitro generated by DICER cleavage, are sufficient to restore the DDR in RNase-A-treated cells, also in the absence of other cellular RNAs. Our results describe an unanticipated direct role of a novel class of ncRNAs in the control of DDR activation at sites of DNA damage.     

Microdeletions in the human H19 DMR result in loss of IGF2 imprinting and Beckwith-Wiedemann syndrome

The overgrowth- and tumor-associated Beckwith-Wiedemann syndrome results from dysregulation of imprinted genes on chromosome 11p15.5. Here we show that inherited microdeletions in the H19 differentially methylated region (DMR) that abolish two CTCF target sites cause this disease. Maternal transmission of the deletions results in hypermethylation of the H19 DMR, biallelic IGF2 expression, H19 silencing and Beckwith-Wiedemann syndrome, indicative of loss of function of the IGF2-H19 imprinting control element.     

Abrupt reversal in ocean overturning during the Palaeocene/Eocene warm period

An exceptional analogue for the study of the causes and consequences of global warming occurs at the Palaeocene/Eocene Thermal Maximum, 55 million years ago. A rapid rise of global temperatures during this event accompanied turnovers in both marine and terrestrial biota, as well as significant changes in ocean chemistry and circulation. Here we present evidence for an abrupt shift in deep-ocean circulation using carbon isotope records from fourteen sites. These records indicate that deep-ocean circulation patterns changed from Southern Hemisphere overturning to Northern Hemisphere overturning at the start of the Palaeocene/Eocene Thermal Maximum. This shift in the location of deep-water formation persisted for at least 40,000 years, but eventually recovered to original circulation patterns. These results corroborate climate model inferences that a shift in deep-ocean circulation would deliver relatively warmer waters to the deep sea, thus producing further warming. Greenhouse conditions can thus initiate abrupt deep-ocean circulation changes in less than a few thousand years, but may have lasting effects; in this case taking 100,000 years to revert to background conditions.     

An Action Research Study for Elaborating and Implementing an Electronic Waste Collection Program in Brazil

The objective of this study was to conduct Action Research (AR) to create and implement a WEEE management program that was in line with the BNPSW regulations. The city chosen for this study was São João del Rei (SJDR) located in the state of Minas Gerais, Brazil. Using AR it was possible to structure a WEEE management program that involved stakeholders from the city administration, the Federal University of São João del Rei, and representatives from the private sector. The program ultimately collected 1710 kg of WEEE that received an environmentally appropriate destination. Although no major difficulties were observed with respect to the AR process itself, some challenges were encountered. Lack of infrastructure and hesitance on behalf of the public with respect to implementing WEEE Reverse Logistics were complicating factors. The action research as methodology proved to be highly efficient in dealing with e-waste reverse logistics. It resulted in faster decision making, in turn generating better results. Good decisions were repeated and errors were corrected. The Action Research project highlighted the need for raising public awareness about WEEE disposal. It also showed that the public was ultimately interested in participating and contributing to the proposed WEEE management program. The awareness of the population has led to a significant increase in the amount of collected waste. The model resulting from this research serve as a reference for decision makers in implementing similar programs around the world and to contribute to the existing body of knowledge on the subject.

     

Reichenbach on causality in 1923: Scientific inference,coordination, and confirmation

In The Theory of Relativity and A Priori Knowledge (1920b), Reichenbach developed an original account of cognition as coordination of formal structures to empirical ones. One of the most salient features of this account is that it is explicitly not a top-down type of coordination, and in fact it is crucially “directed” by the empirical side. Reichenbach called this feature “the mutuality of coordination” but, in that work, did not elaborate sufficiently on how this is supposed to work. In a paper that he wrote less than two years afterwards (but that he published only in 1932), “The Principle of Causality and the Possibility of its Empirical Confirmation” (1923/1932), he described what seems to be a model for this idea, now within an analysis of causality that results in an account of scientific inference. Recent reassessments of his early proposal do not seem to capture the extent of Reichenbach's original worries. The present paper analyses Reichenbach's early account and suggests a new way to look at his early work. According to it, we perform measurements, individuate parameters, collect and analyse data, by using a “constructive” approach, such as the one with which we formulate and test hypotheses, which paradigmatically requires some simplicity assumptions. Reichenbach's attempt to account for all these aspects in 1923 was obviously limited and naive in many ways, but it shows that, in his view, there were multiple ways in which the idea of “constitution” is embodied in scientific practice.     

The role of synapsins in neuronal development

The synapsins, the first identified synaptic vesicle-specific proteins, are phosphorylated on multiple sites by a number of protein kinases and are involved in neurite outgrowth and synapse formation as well as in synaptic transmission. In mammals, the synapsin family consists of at least 10 isoforms encoded by 3 distinct genes and composed by a mosaic of conserved and variable domains. The synapsins are highly conserved evolutionarily, and orthologues have been found in invertebrates and lower vertebrates. Within nerve terminals, synapsins are implicated in multiple interactions with presynaptic proteins and the actin cytoskeleton. Via these interactions, synapsins control several mechanisms important for neuronal homeostasis. In this review, we describe the main functional features of the synapsins, in relation to the complex role played by these phosphoproteins in neuronal development.