CytoDirect: A Nucleic Acid Nanodevice for Specific and Efficient Delivery of Functional Payloads to the Cytoplasm.

Direct and efficient delivery of functional payloads such as chemotherapy drugs, siRNA, or small-molecule inhibitors into the cytoplasm, bypassing the endo/lysosomal trapping, is a challenging task for intracellular medicine. Here, we take advantage of the programmability of DNA nanotechnology to develop a DNA nanodevice called CytoDirect, which incorporates disulfide units and human epidermal growth factor receptor 2 (HER2) affibodies into a DNA origami nanostructure, enabling rapid cytosolic uptake into targeted cancer cells and deep tissue penetration. We further demonstrated that therapeutic oligonucleotides and small-molecule chemotherapy drugs can be easily delivered by CytoDirect and showed notable effects on gene knockdown and cell apoptosis, respectively. This study demonstrates the synergistic effect of disulfide and HER2 affibody modifications on the rapid cytosolic delivery of DNA origami and its payloads to targeted cells and deep tissues, thereby expanding the delivery capabilities of DNA nanostructures in a new direction for disease treatment.

High-affinity binding to the SARS-CoV-2 spike trimer by a nanostructured, trivalent protein-DNA synthetic antibody.

Multivalency enables nanostructures to bind molecular targets with high affinity. Although antibodies can be generated against a wide range of antigens, their shape and size cannot be tuned to match a given target. DNA nanotechnology provides an attractive approach for designing customized multivalent scaffolds due to the addressability and programmability of the nanostructure shape and size. Here, we design a nanoscale synthetic antibody ("nano-synbody") based on a three-helix bundle DNA nanostructure with one, two, or three identical arms terminating in a mini-binder protein that targets the SARS-CoV-2 spike protein. The nano-synbody was designed to match the valence and distance between the three receptor binding domains (RBDs) in the spike trimer, in order to enhance affinity. The protein-DNA nano-synbody shows tight binding to the wild-type, Delta, and several Omicron variants of the SARS-CoV-2 spike trimer, with affinity increasing as the number of arms increases from one to three. The effectiveness of the nano-synbody was also verified using a pseudovirus neutralization assay, with the three-arm nanostructure inhibiting two Omicron variants against which the structures with only one or two arms are ineffective. The structure of the three-arm nano-synbody bound to the Omicron variant spike trimer was solved by negative-stain transmission electron microscopy reconstruction, and shows the protein-DNA nanostructure with all three arms attached to the RBD domains, confirming the intended trivalent attachment. The ability to tune the size and shape of the nano-synbody, as well as its potential ability to attach two or more different binding ligands, will enable the high-affinity targeting of a range of proteins not possible with traditional antibodies.

Brain-computer interfaces, disability, and the stigma of refusal: A factorial vignette study.

As brain-computer interfaces are promoted as assistive devices, some researchers worry that this promise to "restore" individuals worsens stigma toward disabled people and fosters unrealistic expectations. In three web-based survey experiments with vignettes, we tested how refusing a brain-computer interface in the context of disability affects cognitive (blame), emotional (anger), and behavioral (coercion) stigmatizing attitudes (Experiment 1, N = 222) and whether the effect of a refusal is affected by the level of brain-computer interface functioning (Experiment 2, N = 620) or the risk of malfunctioning (Experiment 3, N = 620). We found that refusing a brain-computer interface increased blame and anger, while brain-computer interface functioning did change the effect of a refusal. Higher risks of device malfunctioning partially reduced stigmatizing attitudes and moderated the effect of refusal. This suggests that information about disabled people who refuse a technology can increase stigma toward them. This finding has serious implications for brain-computer interface regulation, media coverage, and the prevention of ableism.

Principles for the design of multicellular engineered living systems.

Remarkable progress in bioengineering over the past two decades has enabled the formulation of fundamental design principles for a variety of medical and non-medical applications. These advancements have laid the foundation for building multicellular engineered living systems (M-CELS) from biological parts, forming functional modules integrated into living machines. These cognizant design principles for living systems encompass novel genetic circuit manipulation, self-assembly, cell-cell/matrix communication, and artificial tissues/organs enabled through systems biology, bioinformatics, computational biology, genetic engineering, and microfluidics. Here, we introduce design principles and a blueprint for forward production of robust and standardized M-CELS, which may undergo variable reiterations through the classic design-build-test-debug cycle. This Review provides practical and theoretical frameworks to forward-design, control, and optimize novel M-CELS. Potential applications include biopharmaceuticals, bioreactor factories, biofuels, environmental bioremediation, cellular computing, biohybrid digital technology, and experimental investigations into mechanisms of multicellular organisms normally hidden inside the "black box" of living cells.

Rehabilitation culture and its impact on technology: unpacking practical conditions for ultrabilitation.

Purpose: It has been proposed that rehabilitation practice expand its aims beyond recovery to "ultrabilitation," but only if certain biological, technological, and psychosocial conditions are met. There is thus an opportunity to connect ultrabilitation, as a concept, to adjacent literature on assistive technology and sociotechnical systems.Method: We draw on insights from sociology of technology and responsible innovation, as well as concrete examples of neural devices and the culture of rehabilitation practice, to further refine our understanding of the conditions of possibility for ultrabilitation.Results: "Assistive" technologies can indeed be re-imagined as "ultrabilitative," but this shift is both psychosocial and technological in nature, such that rehabilitation professionals will likely play a key role in this shift. There is not, however, sufficient evidence to suggest whether they will support or hinder ultrabilitative uses of technology.Conclusion: Advancing the idea and project of ultrabilitation must be grounded in a nuanced understanding of actual rehabilitation practice and the norms of broader society, which can be gained from engaging with adjacent literatures and by conducting further research on technology use in rehabilitation contexts.Implications for rehabilitation"Assistive" technologies can be conceptually re-imagined as "ultrabilitative" technologies, expanding their utility from recovery to enhancement and flourishing.Actual development and use of ultrabilitative technology is both a technical and psychosocial challenge, and its success depends on the cultural context in which technology is situated.Further empirical research is needed on the ways in which rehabilitation culture and the norms of broader society might impact or even inhibit the use of ultrabilitative technology.

Brain-computer interfaces and personhood: interdisciplinary deliberations on neural technology.

OBJECTIVE: Scientists, engineers, and healthcare professionals are currently developing a variety of new devices under the category of brain-computer interfaces (BCIs). Current and future applications are both medical/assistive (e.g. for communication) and non-medical (e.g. for gaming). This array of possibilities has been met with both enthusiasm and ethical concern in various media, with no clear resolution of these conflicting sentiments. APPROACH: To better understand how BCIs may either harm or help the user, and to investigate whether ethical guidance is required, a meeting entitled 'BCIs and Personhood: A Deliberative Workshop' was held in May 2018. MAIN RESULTS: We argue that the hopes and fears associated with BCIs can be productively understood in terms of personhood, specifically the impact of BCIs on what it means to be a person and to be recognized as such by others. SIGNIFICANCE: Our findings suggest that the development of neural technologies raises important questions about the concept of personhood and its role in society. Accordingly, we propose recommendations for BCI development and governance.

Multi-cellular engineered living systems: building a community around responsible research on emergence.

Ranging from miniaturized biological robots to organoids, multi-cellular engineered living systems (M-CELS) pose complex ethical and societal challenges. Some of these challenges, such as how to best distribute risks and benefits, are likely to arise in the development of any new technology. Other challenges arise specifically because of the particular characteristics of M-CELS. For example, as an engineered living system becomes increasingly complex, it may provoke societal debate about its moral considerability, perhaps necessitating protection from harm or recognition of positive moral and legal rights, particularly if derived from cells of human origin. The use of emergence-based principles in M-CELS development may also create unique challenges, making the technology difficult to fully control or predict in the laboratory as well as in applied medical or environmental settings. In response to these challenges, we argue that the M-CELS community has an obligation to systematically address the ethical and societal aspects of research and to seek input from and accountability to a broad range of stakeholders and publics. As a newly developing field, M-CELS has a significant opportunity to integrate ethically responsible norms and standards into its research and development practices from the start. With the aim of seizing this opportunity, we identify two general kinds of salient ethical issues arising from M-CELS research, and then present a set of commitments to and strategies for addressing these issues. If adopted, these commitments and strategies would help define M-CELS as not only an innovative field, but also as a model for responsible research and engineering.

Healthcare uses of artificial intelligence: Challenges and opportunities for growth.

Forms of Artificial Intelligence (AI), like deep learning algorithms and neural networks, are being intensely explored for novel healthcare applications in areas such as imaging and diagnoses, risk analysis, lifestyle management and monitoring, health information management, and virtual health assistance. Expected benefits in these areas are wide-ranging and include increased speed in imaging, greater insight into predictive screening, and decreased healthcare costs and inefficiency. However, AI-based clinical tools also create a host of situations wherein commonly-held values and ethical principles may be challenged. In this short column, we highlight three potentially problematic aspects of AI use in healthcare: (1) dynamic information and consent, (2) transparency and ownership, and (3) privacy and discrimination. We discuss their impact on patient/client, clinician, and health institution values and suggest ways to tackle this impact. We propose that AI-related ethical challenges may represent an opportunity for growth in organizations.

Keeping Disability in Mind: A Case Study in Implantable Brain-Computer Interface Research.

Brain-Computer Interface (BCI) research is an interdisciplinary area of study within Neural Engineering. Recent interest in end-user perspectives has led to an intersection with user-centered design (UCD). The goal of user-centered design is to reduce the translational gap between researchers and potential end users. However, while qualitative studies have been conducted with end users of BCI technology, little is known about individual BCI researchers' experience with and attitudes towards UCD. Given the scientific, financial, and ethical imperatives of UCD, we sought to gain a better understanding of practical and principled considerations for researchers who engage with end users. We conducted a qualitative interview case study with neural engineering researchers at a center dedicated to the creation of BCIs. Our analysis generated five themes common across interviews. The thematic analysis shows that participants identify multiple beneficiaries of their work, including other researchers, clinicians working with devices, device end users, and families and caregivers of device users. Participants value experience with device end users, and personal experience is the most meaningful type of interaction. They welcome (or even encourage) end-user input, but are skeptical of limited focus groups and case studies. They also recognize a tension between creating sophisticated devices and developing technology that will meet user needs. Finally, interviewees espouse functional, assistive goals for their technology, but describe uncertainty in what degree of function is "good enough" for individual end users. Based on these results, we offer preliminary recommendations for conducting future UCD studies in BCI and neural engineering.

Two Problematic Foundations of Neuroethics and Pragmatist Reconstructions.

Common understandings of neuroethics, that is, of its distinctive nature, are premised on two distinct sets of claims: (1) neuroscience can change views about the nature of ethics itself and neuroethics is dedicated to reaping such an understanding of ethics, and (2) neuroscience poses challenges distinct from other areas of medicine and science and neuroethics tackles those issues. Critiques have rightfully challenged both claims, stressing how the first may lead to problematic forms of reductionism whereas the second relies on debatable assumptions about the nature of bioethics specialization and development. Informed by philosophical pragmatism and our experience in neuroethics, we argue that these claims are ill founded and should give way to pragmatist reconstructions; namely, that neuroscience, much like other areas of empirical research on morality, can provide useful information about the nature of morally problematic situations, but does not need to promise radical and sweeping changes to ethics based on neuroscientism. Furthermore, the rationale for the development of neuroethics as a specialized field need not to be premised on the distinctive nature of the issues it tackles or of neurotechnologies. Rather, it can espouse an understanding of neuroethics as both a scholarly and a practical endeavor dedicated to resolving a series of problematic situations raised by neurological and psychiatric conditions.

Ethical aspects of brain computer interfaces: a scoping review.

BACKGROUND: Brain-Computer Interface (BCI) is a set of technologies that are of increasing interest to researchers. BCI has been proposed as assistive technology for individuals who are non-communicative or paralyzed, such as those with amyotrophic lateral sclerosis or spinal cord injury. The technology has also been suggested for enhancement and entertainment uses, and there are companies currently marketing BCI devices for those purposes (e.g., gaming) as well as health-related purposes (e.g., communication). The unprecedented direct connection created by BCI between human brains and computer hardware raises various ethical, social, and legal challenges that merit further examination and discussion. METHODS: To identify and characterize the key issues associated with BCI use, we performed a scoping review of biomedical ethics literature, analyzing the ethics concerns cited across multiple disciplines, including philosophy and medicine. RESULTS: Based on this investigation, we report that BCI research and its potential translation to therapeutic intervention generate significant ethical, legal, and social concerns, notably with regards to personhood, stigma, autonomy, privacy, research ethics, safety, responsibility, and justice. Our review of the literature determined, furthermore, that while these issues have been enumerated extensively, few concrete recommendations have been expressed. CONCLUSIONS: We conclude that future research should focus on remedying a lack of practical solutions to the ethical challenges of BCI, alongside the collection of empirical data on the perspectives of the public, BCI users, and BCI researchers.

Silent performances: Are "repertoires" really post-Kuhnian?

Ankeny and Leonelli (2016) propose "repertoires" as a new way to understand the stability of certain research programs as well as scientific change in general. By bringing a more complete range of social, material, and epistemic elements into one framework, they position their work as a correction to the Kuhnian impulse in philosophy of science and other areas of science studies. I argue that this "post-Kuhnian" move is not complete, and that repertoires maintain an internalist perspective. Comparison with an alternative framework, the "sociotechnical imaginaries" of Jasanoff and Kim (2015), illustrates precisely which elements of practice are externalized by Ankeny and Leonelli. Specifically, repertoires discount the role of audience, without whom the repertoires of science are unintelligible, and lack an explicit place for ethical and political imagination, which provide meaning for otherwise mechanical promotion of particular research programs. This comparison reveals, I suggest, two distinct modes of scholarship, one internalist and the other critical. While repertoires can be modified to meet the needs of critical STS scholars and to completely reject Kuhn's internalism, whether or not we do so depends on what we want our scholarship to achieve.

Engineering the Brain: Ethical Issues and the Introduction of Neural Devices.

Neural devices now under development stand to interact with and alter the human brain in ways that may challenge standard notions of identity, normality, authority, responsibility, privacy and justice.

Minimally invasive fibrillating mitral valve replacement for patients with advanced cardiomyopathy: a safe and effective approach to treat a complex problem.

OBJECTIVE: The optimal management of mitral regurgitation (MR) in patients with cardiomyopathy has been controversial. Minimally invasive fibrillating mitral valve replacement (mini-MVR) might limit postoperative morbidity and mortality by minimizing recurrent MR. We hypothesized that mini-MVR with complete chordal sparing would offer low mortality and halt left ventricular (LV) remodeling in patients with severe cardiomyopathy and severe MR. METHODS: From January 2006 to August 2009, 65 patients with an LV ejection fraction (LVEF) of ≤35% underwent mini-MVR. The demographic, echocardiographic, and clinical outcomes were analyzed. RESULTS: The operative mortality compared with the Society of Thoracic Surgeons-predicted mortality was 6.2% versus 6.6%. It was 5.6% versus 7.4% for patients with an LVEF of ≤20% and 8.3% versus 17.9% among patients with a Society of Thoracic Surgeons-predicted mortality of ≥10%. At a median follow-up of 17 months, no recurrent MR or change in the LV dimensions or LVEF had developed, but the right ventricular systolic pressure had decreased (P=.02). At the first postoperative visit and latest follow-up visit, the New York Heart Association class had decreased from 3.0±0.6 to 1.7±0.7 and 2.0±1.0, respectively (P<.0001 for both). Patients with an LVEF of ≤20% and LV end-diastolic diameter of ≥6.5 cm were more likely to meet a composite of death, transplantation, or LV assist device insertion (P=.046). CONCLUSIONS: Our results have shown that mini-MVR is safe in patients with advanced cardiomyopathy and resulted in no recurrent MR, stabilization of the LVEF and LV dimensions, and a decrease in right ventricular systolic pressure. This mini-MVR technique can be used to address severe MR in patients with advanced cardiomyopathy.