Return of genomic results does not motivate intent to participate in research for all: Perspectives across 22 countries.

PURPOSE: The aim of this study was to determine how attitudes toward the return of genomic research results vary internationally. METHODS: We analyzed the "Your DNA, Your Say" online survey of public perspectives on genomic data sharing including responses from 36,268 individuals across 22 low-, middle-, and high-income countries, and these were gathered in 15 languages. We analyzed how participants responded when asked whether return of results (RoR) would motivate their decision to donate DNA or health data. We examined variation across the study countries and compared the responses of participants from other countries with those from the United States, which has been the subject of the majority of research on return of genomic results to date. RESULTS: There was substantial variation in the extent to which respondents reported being influenced by RoR. However, only respondents from Russia were more influenced than those from the United States, and respondents from 20 countries had lower odds of being partially or wholly influenced than those from the United States. CONCLUSION: There is substantial international variation in the extent to which the RoR may motivate people's intent to donate DNA or health data. The United States may not be a clear indicator of global attitudes. Participants' preferences for return of genomic results globally should be considered.

Demonstrating trustworthiness when collecting and sharing genomic data: public views across 22 countries.

BACKGROUND: Public trust is central to the collection of genomic and health data and the sustainability of genomic research. To merit trust, those involved in collecting and sharing data need to demonstrate they are trustworthy. However, it is unclear what measures are most likely to demonstrate this. METHODS: We analyse the 'Your DNA, Your Say' online survey of public perspectives on genomic data sharing including responses from 36,268 individuals across 22 low-, middle- and high-income countries, gathered in 15 languages. We examine how participants perceived the relative value of measures to demonstrate the trustworthiness of those using donated DNA and/or medical information. We examine between-country variation and present a consolidated ranking of measures. RESULTS: Providing transparent information about who will benefit from data access was the most important measure to increase trust, endorsed by more than 50% of participants across 20 of 22 countries. It was followed by the option to withdraw data and transparency about who is using data and why. Variation was found for the importance of measures, notably information about sanctions for misuse of data-endorsed by 5% in India but almost 60% in Japan. A clustering analysis suggests alignment between some countries in the assessment of specific measures, such as the UK and Canada, Spain and Mexico and Portugal and Brazil. China and Russia are less closely aligned with other countries in terms of the value of the measures presented. CONCLUSIONS: Our findings highlight the importance of transparency about data use and about the goals and potential benefits associated with data sharing, including to whom such benefits accrue. They show that members of the public value knowing what benefits accrue from the use of data. The study highlights the importance of locally sensitive measures to increase trust as genomic data sharing continues globally.

Global Public Perceptions of Genomic Data Sharing: What Shapes the Willingness to Donate DNA and Health Data?

Analyzing genomic data across populations is central to understanding the role of genetic factors in health and disease. Successful data sharing relies on public support, which requires attention to whether people around the world are willing to donate their data that are then subsequently shared with others for research. However, studies of such public perceptions are geographically limited and do not enable comparison. This paper presents results from a very large public survey on attitudes toward genomic data sharing. Data from 36,268 individuals across 22 countries (gathered in 15 languages) are presented. In general, publics across the world do not appear to be aware of, nor familiar with, the concepts of DNA, genetics, and genomics. Willingness to donate one's DNA and health data for research is relatively low, and trust in the process of data's being shared with multiple users (e.g., doctors, researchers, governments) is also low. Participants were most willing to donate DNA or health information for research when the recipient was specified as a medical doctor and least willing to donate when the recipient was a for-profit researcher. Those who were familiar with genetics and who were trusting of the users asking for data were more likely to be willing to donate. However, less than half of participants trusted more than one potential user of data, although this varied across countries. Genetic information was not uniformly seen as different from other forms of health information, but there was an association between seeing genetic information as special in some way compared to other health data and increased willingness to donate. The global perspective provided by our "Your DNA, Your Say" study is valuable for informing the development of international policy and practice for sharing genomic data. It highlights that the research community not only needs to be worthy of trust by the public, but also urgent steps need to be taken to authentically communicate why genomic research is necessary and how data donation, and subsequent sharing, is integral to this.

How to responsibly acknowledge research work in the era of big data and biobanks: ethical aspects of the Bioresource Research Impact Factor (BRIF).

Currently, a great deal of biomedical research in fields such as epidemiology, clinical trials and genetics is reliant on vast amounts of biological and phenotypic information collected and assembled in biobanks. While many resources are being invested to ensure that comprehensive and well-organised biobanks are able to provide increased access to, and sharing of biomedical samples and information, many barriers and challenges remain to such responsible and extensive sharing. Germane to the discussion herein is the barrier to collecting and sharing bioresources related to the lack of proper recognition of researchers and clinicians who developed the bioresource. Indeed, the efforts and resources invested to set up and sustain a bioresource can be enormous and such work should be easily traced and properly recognised. However, there is currently no such system that systematically and accurately traces and attributes recognition to those doing this work or the bioresource institution itself. As a beginning of a solution to the "recognition problem", the Bioresource Research Impact Factor/Framework (BRIF) initiative was proposed almost a decade and a half ago and is currently under further development. With the ultimate aim of increasing awareness and understanding of the BRIF, in this article, we contribute the following: (1) a review of the objectives and functions of the BRIF including the description of two tools that will help in the deployment of the BRIF, the CoBRA (Citation of BioResources in journal Articles) guideline, and the Open Journal of Bioresources (OJB); (2) the results of a small empirical study on stakeholder awareness of the BRIF and (3) a brief analysis of the ethical dimensions of the BRIF which allow it to be a positive contribution to responsible biobanking.

CREB is necessary for synaptic maintenance and learning-induced changes of the AMPA receptor GluA1 subunit.

The transcription factor cAMP response element binding protein (CREB) is a key protein implicated in memory, synaptic plasticity and structural plasticity in mammals. Whether CREB regulates the synaptic incorporation of hippocampal glutamatergic receptors under basal and learning-induced conditions remains, however, mostly unknown. Using double-transgenic mice conditionally expressing a dominant negative form of CREB (CREBS133A, mCREB), we analyzed how chronic loss of CREB function in adult hippocampal glutamatergic neurons impacts the levels of the AMPA and NMDA receptors subunits within the post-synaptic densities (PSD). In basal (naïve) conditions, we report that inhibition of CREB function was associated with a specific reduction of the AMPAR subunit GluA1 and a proportional increase in its Ser845 phosphorylated form within the PSD. These molecular alterations correlated with a reduction in AMPA receptors mEPSC frequency, with a decrease in long-term potentiation (LTP), and with an increase in long-term depression (LTD). The basal levels other major synaptic proteins (GluA2/3, GluN1, GluN2A, and PSD95) within the PSD were not affected by CREB inhibition. Blocking CREB function also impaired contextual fear conditioning (CFC) and selectively blocked the CFC-driven enhancement of GluA1 and its Ser845 phosphorylated form within the PSD, molecular changes normally observed in wild-type mice. CFC-driven enhancement of other synaptic proteins (GluA2/3, GluN1, GluN2A, and PSD95) within the PSD was not significantly perturbed by the loss of CREB function. These findings provide the first evidence that, in vivo, CREB is necessary for the specific maintenance of the GluA1 subunit within the PSD of hippocampal neurons in basal conditions and for its trafficking within the PSD during the occurrence of learning.

Transgenic mice with chronic NGF deprivation and Alzheimer's disease-like pathology display hippocampal region-specific impairments in short- and long-term plasticities.

The etiology of Alzheimer's disease (AD) remains elusive. The "amyloid" hypothesis states that toxic action of accumulated ß-amyloid peptide (Aß) on synaptic function causes AD cognitive decline. This hypothesis is supported by analysis of familial AD (FAD)-based transgenic mouse models, where altered amyloid precursor protein (APP) processing leads to Aß accumulation correlating with hippocampal-dependent memory deficits. Some studies report prominent dentate gyrus (DG) glutamatergic plasticity alterations in these mice, while CA1 plasticity remains relatively unaffected. The "neurotrophic unbalance" hypothesis, on the other hand, states that AD-related loss of cholinergic signaling and altered APP processing are due to alterations in nerve growth factor (NGF) trophic support. This hypothesis is supported by analysis of the AD11 mouse, which exhibits chronic NGF deprivation during adulthood and displays AD-like pathology, including Aß accumulation and hippocampal-dependent memory deficits. In this study, we analyzed CA1 and DG glutamatergic plasticity in AD11 mice to evaluate whether these mice also share with FAD models a common phenotype in hippocampal synaptic dysfunction. We report that AD11 mice display age-dependent short- and long-term DG plasticity deficits, while CA1 plasticity remains relatively spared. We also report that both structures exhibit enhanced glutamatergic transmission under lower, yet physiological, neurotransmitter release conditions, a defect that should be considered when further evaluating hippocampal synaptic deficits underlying AD pathology. We conclude that severe deficits in DG plasticity represent another common denominator between these two etiologically different types of AD mouse models, independent of the initial insult (overexpression of FAD mutation or NGF deprivation).

PKC modulation of transmitter release by SNAP-25 at sensory-to-motor synapses in aplysia.

Activation of phosphokinase C (PKC) can increase transmitter release at sensory-motor neuron synapses in Aplysia, but the target of PKC phosphorylation has not been determined. One putative target of PKC at synapses is the synaptosomal-associated protein of 25 kDa (SNAP-25), a member of the SNARE protein complex implicated in synaptic vesicle docking and fusion. To determine whether PKC regulated transmitter release through phosphorylation of SNAP-25, we cloned Aplysia SNAP-25 and expressed enhanced green fluorescent protein (EGFP)-coupled SNAP-25 constructs mutated at the PKC phosphorylation site Ser198 in Aplysia sensory neurons. We found several distinct effects of expression of EGFP-SNAP-25 constructs. First, the rates of synaptic depression were slowed when cells contained SNAP-25 with phosphomimetic residues Glu or Asp. Second, PDBu-mediated increases in transmitter release at naïve synapses were blocked in cells expressing nonphosphorylated-state SNAP-25. Finally, expression of EGFP-coupled SNAP-25 but not uncoupled SNAP-25 inhibited 5-HT-mediated reversal of depression and the ability of EGFP-coupled SNAP-25 to inhibit the reversal of depression was affected by changes at Ser198. These results suggest SNAP-25 and phosphorylation of SNAP-25 by PKC can regulate transmitter release at Aplysia sensory-motor neuron synapses by a number of distinct processes.

Identification and characterization of a novel C2B splice variant of synaptotagmin I.

We have identified an alternatively spliced form of synaptotagmin I in Aplysia neurons. This isoform, synaptotagmin I C2B-beta, is generated by alternative exon usage in the C2B domain leading to nine amino acid changes in the C2B sequence from the previously characterized synaptotagmin I, now designated as synaptotagmin I C2B-alpha. Quantitative reverse transcriptase-polymerase chain reaction demonstrated that approximately 25% of mRNA encoding synaptotagmin I contained the C2B-beta exon in the nervous system. Synaptotagmin I C2B-beta showed greater resistance to digestion by chymotrypsin in the absence of calcium than did synaptotagmin I C2B-alpha, although both isoforms required the same amount of calcium to resist chymotrypsin digestion. The source of these changes in C2B properties was mapped to a single amino acid (threonine 358). We have also cloned SNAP 25 in Aplysia and show that it binds synaptotagmin I C2B-beta with a higher affinity than synaptotagmin I C2B-alpha. These results suggest that this splicing alters biochemical properties of the C2B domain, affecting a number of its important known interactions.

Differential regulation of transmitter release by alternatively spliced forms of synaptotagmin I.

We discovered a novel alternatively spliced form of synaptotagmin I (Syt I). This splicing event is conserved over evolution and, in Aplysia, results in a two amino acid insert in the juxtamembrane domain of Syt I (Syt IVQ). Both Syt I and Syt IVQ are localized to synaptic vesicles; however, we also observed punctae that contained one or the other spliced products. Both Syt I and Syt IVQ are phosphorylated at the adjacent PKC site. Overexpression of Syt IVQ, but not of Syt I, in Aplysia neurons blocked the ability of serotonin to reverse synaptic depression. This effect is upstream of PKC activation, because neither Syt IVQ nor Syt I blocked the effects of phorbol esters on reversing synaptic depression or the effects of serotonin on facilitating nondepressed synapses. Our results demonstrate a physiological role for splicing in the juxtamembrane domain of Syt I.