Technology, autonomy, and manipulation

Since 2016, when the Facebook/Cambridge Analytica scandal began to emerge, public concern has grown around the threat of “online manipulation”. While these worries are familiar to privacy researchers, this paper aims to make them more salient to policymakers — first, by defining “online manipulation”, thus enabling identification of manipulative practices; and second, by drawing attention to the specific harms online manipulation threatens. We argue that online manipulation is the use of information technology to covertly influence another person’s decision-making, by targeting and exploiting their decision-making vulnerabilities. Engaging in such practices can harm individuals by diminishing their economic interests, but its deeper, more insidious harm is its challenge to individual autonomy. We explore this autonomy harm, emphasising its implications for both individuals and society, and we briefly outline some strategies for combating online manipulation and strengthening autonomy in an increasingly digital world

Online Manipulation: Hidden Influences in a Digital World

Privacy and surveillance scholars increasingly worry that data collectors can use the information they gather about our behaviors, preferences, interests, incomes, and so on to manipulate us. Yet what it means, exactly, to manipulate someone, and how we might systematically distinguish cases of manipulation from other forms of influence—such as persuasion and coercion—has not been thoroughly enough explored in light of the unprecedented capacities that information technologies and digital media enable. In this paper, we develop a definition of manipulation that addresses these enhanced capacities, investigate how information technologies facilitate manipulative practices, and describe the harms—to individuals and to social institutions—that flow from such practices. We use the term “online manipulation” to highlight the particular class of manipulative practices enabled by a broad range of information technologies. We argue that at its core, manipulation is hidden influence—the covert subversion of another person’s decision-making power. We argue that information technology, for a number of reasons, makes engaging in manipulative practices significantly easier, and it makes the effects of such practices potentially more deeply debilitating. And we argue that by subverting another person’s decision-making power, manipulation undermines his or her autonomy. Given that respect for individual autonomy is a bedrock principle of liberal democracy, the threat of online manipulation is a cause for grave concern

Cantu syndrome–associated SUR2 (ABCC9) mutations in distinct structural domains result in KATP channel gain-of-function by differential mechanisms

The complex disorder Cantu syndrome (CS) arises from gainof-function mutations in either KCNJ8 or ABCC9, the genes encoding the Kir6.1 and SUR2 subunits of ATP-sensitive potassium (KATP) channels, respectively. Recent reports indicate that such mutations can increase channel activity by multiple molecular mechanisms. In this study, we determined the mechanism by which KATP function is altered by several substitutions in distinct structural domains of SUR2: D207E in the intracellular L0-linker and Y985S, G989E, M1060I, and R1154Q/R1154W in TMD2. We engineered substitutions at their equivalent positions in rat SUR2A (D207E, Y981S, G985E, M1056I, and R1150Q/R1150W) and investigated functional consequences using macroscopic rubidium (86Rb-) efflux assays and patchclamp electrophysiology. Our results indicate that D207E increases KATP channel activity by increasing intrinsic stability of the open state, whereas the cluster of Y981S/G985E/M1056I substitutions, as well as R1150Q/R1150W, augmented Mg-nucleotide activation. We also tested the responses of these channel variants to inhibition by the sulfonylurea drug glibenclamide, a potential pharmacotherapy for CS. None of the D207E, Y981S, G985E, or M1056I substitutions had a significant effect on glibenclamide sensitivity. However, Gln and Trp substitution at Arg-1150 significantly decreased glibenclamide potency. In summary, these results provide additional confirmation that mutations in CS-Associated SUR2 mutations result in KATP gain-of-function. They help link CS genotypes to phenotypes and shed light on the underlying molecular mechanisms, including consequences for inhibitory drug sensitivity, insights that may inform the development of therapeutic approaches to manage CS

Drug Repurposing for Rare Diseases

Currently, there are about 7000 identified rare diseases, together affecting 10% of the population. However, fewer than 6% of all rare diseases have an approved treatment option, highlighting their tremendous unmet needs in drug development. The process of repurposing drugs for new indications, compared with the development of novel orphan drugs, is a time-saving and cost-efficient method resulting in higher success rates, which can therefore drastically reduce the risk of drug development for rare diseases. Although drug repurposing is not novel, new strategies have been developed in recent years to do it in a systematic and rational way. Here, we review applied methodologies, recent accomplished progress, and the challenges associated in drug repurposing for rare diseases

Three-dimensional facial morphology in Cantu syndrome

Cantú syndrome (CS) was first described in 1982, and is caused by pathogenic variants in ABCC9 and KCNJ8 encoding regulatory and pore forming subunits of ATP-sensitive potassium (KATP) channels, respectively. It is characterized by congenital hypertrichosis, osteochondrodysplasia, extensive cardiovascular abnormalities and distinctive facial anomalies including a broad nasal bridge, long philtrum, epicanthal folds, and prominent lips. Many genetic syndromes, such as CS, involve facial anomalies that serve as a significant clue in the initial identification of the respective disorder before clinical or molecular diagnosis are undertaken. However, an overwhelming number of CS patients receive misdiagnoses based on an evaluation of coarse facial features. By analyzing three-dimensional images of CS faces, we quantified facial dysmorphology in a cohort of both male and female CS patients with confirmed ABCC9 variants. Morphometric analysis of different regions of the face revealed gender-specific significant differences in face shape. Moreover, we show that 3D facial photographs can distinguish between CS and other genetic disorders with specific facial dysmorphologies that have been mistaken for CS-associated anomalies in the past, hence assisting in an earlier clinical and molecular diagnosis. This optimizes genetic counseling and reduces stress for patients and parents by avoiding unnecessary misdiagnosis

Behavioral and cognitive functioning in individuals with Cantu syndrome

Cantú syndrome (CS) is caused by pathogenic variants in ABCC9 and KCNJ8 encoding the regulatory and pore-forming subunits of ATP-sensitive potassium (KATP ) channels. CS is characterized by congenital hypertrichosis, distinctive facial features, peripheral edema, and cardiac and neurodevelopmental abnormalities. Behavioral and cognitive issues have been self-reported by some CS individuals, but results of formal standardized investigations have not been published. To assess the cognitive profile, social functioning, and psychiatric symptoms in a large group of CS subjects systematically in a cross-sectional manner, we invited 35 individuals (1-69 years) with confirmed ABCC9 variants and their relatives to complete various commonly applied standardized age-related questionnaires, including the Kaufman brief intelligence test 2, the social responsiveness scale-2, and the Achenbach system of empirically based assessment. The majority of CS individuals demonstrated average verbal and nonverbal intelligence compared to the general population. Fifteen percent of cases showed social functioning strongly associated with a clinical diagnosis of autism spectrum disorder. Both externalizing and internalizing problems were also present in this cohort. In particular, anxiety, anxiety or attention deficit hyperactivity disorder, and autism spectrum behaviors were predominantly observed in the younger subjects in the cohort (≥25%), but this percentage decreased markedly in adults

B cell receptor accessory molecule CD79α : characterisation and expression analysis in a cartilaginous fish, the spiny dogfish (Squalus acanthias)

Copyright © 2013. Published by Elsevier Ltd.Peer reviewedPublisher PD

Maternal high-fat diet interacts with embryonic Cited2 genotype to reduce Pitx2c expression and enhance penetrance of left–right patterning defects

Deficiency of the transcription factor Cited2 in mice results in cardiac malformation, adrenal agenesis, neural tube, placental defects and partially penetrant cardiopulmonary laterality defects resulting from an abnormal Nodal->Pitx2c pathway. Here we show that a maternal high-fat diet more than doubles the penetrance of laterality defects and, surprisingly, induces palatal clefting in Cited2-deficient embryos. Both maternal diet and Cited2 deletion reduce embryo weight and kidney and thymus volume. Expression profiling identified 40 embryonic transcripts including Pitx2 that were significantly affected by embryonic genotype-maternal diet interaction. We show that a high-fat diet reduces Pitx2c levels >2-fold in Cited2-deficient embryos. Taken together, these results define a novel interaction between maternal high-fat diet and embryonic Cited2 deficiency that affects Pitx2c expression and results in abnormal laterality. They suggest that appropriate modifications of maternal diet may prevent such defects in humans

Molecular characterization of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis

Background and aims: Non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) is increasing globally, but its molecular features are not well defined. We aimed to identify unique molecular traits characterising NASH-HCC compared to other HCC aetiologies. Methods: We collected 80 NASH-HCC and 125 NASH samples from 5 institutions. Expression array (n = 53 NASH-HCC; n = 74 NASH) and whole exome sequencing (n = 52 NASH-HCC) data were compared to HCCs of other aetiologies (n = 184). Three NASH-HCC mouse models were analysed by RNA-seq/expression-array (n = 20). Activin A receptor type 2A (ACVR2A) was silenced in HCC cells and proliferation assessed by colorimetric and colony formation assays. Results: Mutational profiling of NASH-HCC tumours revealed TERT promoter (56%), CTNNB1 (28%), TP53 (18%) and ACVR2A (10%) as the most frequently mutated genes. ACVR2A mutation rates were higher in NASH-HCC than in other HCC aetiologies (10% vs. 3%, p <0.05). In vitro, ACVR2A silencing prompted a significant increase in cell proliferation in HCC cells. We identified a novel mutational signature (MutSig-NASH-HCC) significantly associated with NASH-HCC (16% vs. 2% in viral/alcohol-HCC, p = 0.03). Tumour mutational burden was higher in non-cirrhotic than in cirrhotic NASH-HCCs (1.45 vs. 0.94 mutations/megabase; p <0.0017). Compared to other aetiologies of HCC, NASH-HCCs were enriched in bile and fatty acid signalling, oxidative stress and inflammation, and presented a higher fraction of Wnt/TGF-β proliferation subclass tumours (42% vs. 26%, p = 0.01) and a lower prevalence of the CTNNB1 subclass. Compared to other aetiologies, NASH-HCC showed a significantly higher prevalence of an immunosuppressive cancer field. In 3 murine models of NASH-HCC, key features of human NASH-HCC were preserved. Conclusions: NASH-HCCs display unique molecular features including higher rates of ACVR2A mutations and the presence of a newly identified mutational signature. Lay summary: The prevalence of hepatocellular carcinoma (HCC) associated with non-alcoholic steatohepatitis (NASH) is increasing globally, but its molecular traits are not well characterised. In this study, we uncovered higher rates of ACVR2A mutations (10%) - a potential tumour suppressor - and the presence of a novel mutational signature that characterises NASH-related HCC

Towards the treatment of Cantú syndrome. Drug repurposing for rare genetic diseases

Individually, rare genetic diseases affect a small number of individuals. However, collectively they represent an important public health burden by impacting 8% of the EU population. Many rare genetic diseases have a large impact on the quality of life of people affected often resulting in disability or early death. Usually, these diseases are caused by a single genetic defect. The study of rare genetic diseases teaches us how a gene functions in health and disease, thereby providing insights for processes in common diseases. Rare genetic disorders form a unique category of disorders and therefore face incomparable challenges when it comes to diagnosis and therapy options. Despite scientific advances in modern genetics and genomics, the diagnosis of rare diseases is often delayed or incorrect, and most rare conditions still lack effective treatment options. This is also the case for Cantú syndrome (CS), a rare autosomal dominant condition caused by gain-of-function (GoF) mutations in genes encoding subunits of ATP-sensitive potassium (KATP) channels (ABCC9, KCNJ8). CS patients present with coarse facial features, excessive body hair, and extensive cardiovascular anomalies. To generate a critical mass of CS patients to find further clinical characteristics of the disease as well as to ensure a rapid progression towards future interventional studies we developed an international standardized registry. Clinical data is obtained during annual CS research clinics. Clinical management of CS currently involves symptomatic treatments to address second-order complications such as heart failure. The off-patent KATP inhibitor glibenclamide which is already widely applied in clinic to block GoF KATP channels involved in Type 2 diabetes holds promise as a potential treatment for CS. To perform therapeutic drug screening, we have developed novel CS zebrafish models in which disease-causing mutations were knocked-in to the endogenous abcc9 and kcnj8 loci using CRISPR/Cas9 genome engineering. Resulting models recapitulate key cardiovascular features of CS including hypercontractility and abnormally high cardiac output which significantly reverse after glibenclamide administration in zebrafish larvae. These results provide key pre-clinical evidence for the in vivo efficacy of glibenclamide for the treatment of CS. Hence, a clinical trial to test glibenclamide in CS patients has been designed. In conclusion, applying Cantú syndrome as an example, this thesis highlights a path from gene discovery to investigating treatment options for a rare genetic disorder by successfully applying multiple tools and technologies available nowadays: (i) accurate and in-depth phenotyping to establish a detailed natural history and improve diagnosis, (ii) functional modeling of patient-specific variants in zebrafish to validate diagnosis and elucidate underlying pathophysiology as well as (iii) repurposing an existing drug to establish treatment