Critical Role of the Virus-Encoded MicroRNA-155 Ortholog in the Induction of Marek's Disease Lymphomas

Notwithstanding the well-characterised roles of a number of oncogenes in neoplastic transformation, microRNAs (miRNAs) are increasingly implicated in several human cancers. Discovery of miRNAs in several oncogenic herpesviruses such as KSHV has further highlighted the potential of virus-encoded miRNAs to contribute to their oncogenic capabilities. Nevertheless, despite the identification of several possible cancer-related genes as their targets, the direct in vivo role of virus-encoded miRNAs in neoplastic diseases such as those induced by KSHV is difficult to demonstrate in the absence of suitable models. However, excellent natural disease models of rapid-onset Marek's disease (MD) lymphomas in chickens allow examination of the oncogenic potential of virus-encoded miRNAs. Using viruses modified by reverse genetics of the infectious BAC clone of the oncogenic RB-1B strain of MDV, we show that the deletion of the six-miRNA cluster 1 from the viral genome abolished the oncogenicity of the virus. This loss of oncogenicity appeared to be primarily due to the single miRNA within the cluster, miR-M4, the ortholog of cellular miR-155, since its deletion or a 2-nucleotide mutation within its seed region was sufficient to inhibit the induction of lymphomas. The definitive role of this miR-155 ortholog in oncogenicity was further confirmed by the rescue of oncogenic phenotype by revertant viruses that expressed either the miR-M4 or the cellular homolog gga-miR-155. This is the first demonstration of the direct in vivo role of a virus-encoded miRNA in inducing tumors in a natural infection model. Furthermore, the use of viruses deleted in miRNAs as effective vaccines against virulent MDV challenge, enables the prospects of generating genetically defined attenuated vaccines

Legal Ableism, Interrupted: Developing Tort Law & Policy Alternatives to Wrongful Birth & Wrongful Life Claims

Early in 2016, the widely acclaimed film Me Before You premiered nationally to a spate of disabled-led protests against the ableism in the film's core story – that of a wealthy, physically disabled young man whose romantic and sexual relationship with a young woman hired as his caregiver (and quasi-maternal or mentoring figure) leads to his choice to kill himself to avoid living further while disabled, and to bequeath his assets to her. Protested as a "disability snuff film" by leading groups like Not Dead Yet, disabled activists lambasted the film for its glorification of assisted suicide as a brave and heroic choice because of the protagonist's disability – criticizing the writers for sending a very strong message that it is better to be dead than to live as disabled, however that might be defined or understood. U.S. law has often embodied that very same message despite the existence of civil rights protections for people with disabilities, and most particularly and glaringly in its adoption of wrongful birth and wrongful life claims as cognizable in tort. In this paper, I aim to provide brief context on the nature and history of wrongful birth and wrongful life claims, examine the myriad social harms toward disabled people that stem from their assertion, explore non-ableist purposes for which these claims might be brought, and propose potential legal and policy mechanisms as alternative means for achieving their possible legitimate purposes without reliance on them

Digital Futures in Mind: Reflecting on Technological Experiments in Mental Health and Crisis Support

 Urgent public attention  is needed to make sense of the expanding use of algorithmic and  data-driven technologies in the mental health context. On the one hand,  well-designed digital technologies that offer high degrees of public  involvement and can be used to promote good mental health and crisis  support in communities. They can be employed safely, reliably and in a  trustworthy way, including to help build relationships, allocate  resources, and promote human flourishing. On the other hand,  there is clear potential for harm. The list of ‘data harms’ in the  mental health context is growing longer, in which people are in worse  shape than they would be had the activity not occurred.  Examples in  this report include the hacking of psychotherapeutic records and the  extortion of victims, algorithmic hiring programs that discriminate  against people with histories of mental healthcare, and criminal justice  and border agencies weaponising data concerning mental health against  individuals. Issues also come up not where technologies are misused or  faulty, but where technologies like biometric monitoring or surveillance  work as intended, and where the very process of ‘datafying’ and  digitising individuals’ behaviour – observing, recording and logging  them to an excessive degree – carry the potential for inherent harm. Part 1 of this report charts the rise  of algorithmic and data-driven technology in the mental health context.  It outlines issues which make mental health unique in legal and policy  terms, particularly the significance of involuntary or coercive  psychiatric interventions in any analysis of mental health and  technology. The section makes a case for elevating the perspective of  people with lived experience of profound psychological distress, mental  health conditions, psychosocial disabilities, and so on, in all activity  concerning mental health and technology. Part 2 looks at  prominent themes of accountability. Eight key themes are discussed –  fairness and non-discrimination, human control of technology,  professional responsibility, privacy, accountability, safety and  security, transparency and explainability, and promotion of public  interest. International law, and particularly the Convention on the  Rights of Persons with Disabilities, is also discussed as a source of  data governance. Case studies throughout show the diversity of  technological developments and draw attention to their real-life  implications. Many case studies demonstrate instances of harm. The case  studies also seek to ground discussion in the actual agonies of existing  technology rather than speculative worries about technology whose  technical feasibility is often exaggerated in misleading and harmful  ways (for example, Elon Musk’s claim that his ‘AI-brain chips will  “solve” autism and schizophrenia’).     </p

Centering the Inner Experience of Autism: Development of the Self-Assessment of Autistic Traits

Current tools for identifying autism are critiqued for their lack of specificity and sensitivity, especially in autistic people who are older, have higher verbal ability or significant compensatory skills, and are not cisgender boys. This may reflect the following: the historical focus of autism research on White (cisgender) male, upper and middle class children; limited interest in the inner, lived experience of autism; and the predominance of a deficit-based model of autism. We report here on the first attempt of which we are aware to develop a clinical self-report measure of autistic traits as described by autistic people. We believe this is an advance in methodology because prior work in the development of autistic trait/diagnostic measures has prioritized the perspectives of nonautistic clinicians and scientists. The measure was developed under the leadership of two autistic researchers and constructed by leveraging descriptions of autism by autistic people to generate items designed to encompass the range of the autistic experience, using strength-based, accessible language. The team utilized iterative feedback from a panel of autistic experts to refine and enhance the measure, called the Self Assessment of Autistic Traits (SAAT). It is intended for people 16 years or older and uses a format that is designed to increase its accessibility and acceptability for autistic respondents. Future work will report on the preliminary psychometrics of the SAAT, with a long-term goal of advancing our understanding of the inner autistic experience and enhancing the clinical and scientific assessment of autism

Anti‐ableist language is fully compatible with high‐quality autism research: Response to Singer et al. (2023)

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DNA methylation networks underlying mammalian traits

Using DNA methylation profiles ( = 15,456) from 348 mammalian species, we constructed phyloepigenetic trees that bear marked similarities to traditional phylogenetic ones. Using unsupervised clustering across all samples, we identified 55 distinct cytosine modules, of which 30 are related to traits such as maximum life span, adult weight, age, sex, and human mortality risk. Maximum life span is associated with methylation levels in subclass homeobox genes and developmental processes and is potentially regulated by pluripotency transcription factors. The methylation state of some modules responds to perturbations such as caloric restriction, ablation of growth hormone receptors, consumption of high-fat diets, and expression of Yamanaka factors. This study reveals an intertwined evolution of the genome and epigenome that mediates the biological characteristics and traits of different mammalian species