No Harm Done? An Experimental Approach to the Nonidentity Problem

Discussions of the non-identity problem presuppose a widely shared intuition that actions or policies that change who comes into existence don't, thereby, become morally unproblematic. We hypothesize that this intuition isn’t generally shared by the public, which could have widespread implications concerning how to generate support for large-scale, identity-affecting policies relating to matters like climate change. To test this, we ran a version of the well-known dictator game designed to mimic the public's behavior over identity-affecting choices. We found the public does seem to behave more selfishly when making identity-affecting choices, which should be concerning. We further hypothesized that one possible mechanism is the notion of harm the public uses in their decision-making and find that substantial portions of the population seem to each employ distinct notions of harm in their normative thinking. These findings raise puzzling features about the public’s normative thinking that call out for further empirical examination

When Rational Reasoners Reason Differently

Different people reason differently, which means that sometimes they reach different conclusions from the same evidence. We maintain that this is not only natural, but rational. In this essay we explore the epistemology of that state of affairs. First we will canvass arguments for and against the claim that rational methods of reasoning must always reach the same conclusions from the same evidence. Then we will consider whether the acknowledgment that people have divergent rational reasoning methods should undermine one’s confidence in one’s own reasoning. Finally we will explore how agents who employ distinct yet equally rational methods of reasoning should respond to interactions with the products of each others’ reasoning. We find that the epistemology of multiple reasoning methods has been misunderstood by a number of authors writing on epistemic permissiveness and peer disagreement

Game Theory and the Self-Fulfilling Climate Tragedy

Game theorists tend to model climate negotiations as a so-called ‘tragedy of the commons’. This is rather worrisome, since the conditions under which such commons problems have historically been solved are almost entirely absent in the case of international greenhouse gas emissions. In this paper, I will argue that the predictive accuracy of the tragedy model might not stem from the model’s inherent match with reality but rather from the model’s ability to make self-fulfilling predictions. I then sketch some possible ways to dispel the tragedy, including (1) recognizing some ways the assumptions of the model fail, (2) taking seriously recent work suggesting that increasing greenhouse gas emissions is not in most nations’ own self-interest, and (3) preferring alternative models like collective risk dilemmas, bargaining games, or cooperative models

Plausible Permissivism

Abstract. Richard Feldman’s Uniqueness Thesis holds that “a body of evidence justifies at most one proposition out of a competing set of proposi- tions”. The opposing position, permissivism, allows distinct rational agents to adopt differing attitudes towards a proposition given the same body of evidence. We assess various motivations that have been offered for Uniqueness, including: concerns about achieving consensus, a strong form of evidentialism, worries about epistemically arbitrary influences on belief, a focus on truth-conduciveness, and consequences for peer disagreement. We argue that each of these motivations either misunderstands the commitments of permissivism or is question-begging. Better understanding permissivism makes it a much more plausible position

Brain delivery of BDNF and a monoclonal antibody for the treatment of neurodegenerative animal models

There are a large number of protein-based therapeutics (biologics) that are FDA approved and available on the market for a number of diseases, and the number of biologics being approved every year has tripled in the past two decades. Biologics are highly attractive as therapeutic options due to their safety and efficacy; however, of all the marketed biologics, only several proteins are FDA approved for treatment of CNS. This is due to efficacy limitation of most proteins in the CNS. One of the reasons is due to the presence of the blood–brain barrier (BBB), which selectively limits protein drugs from entering the brain. Although the BBB is critical for things such as maintaining proper concentration of ions and preventing infection as well as harmful toxins from entering the brain, its selectivity makes it difficult to deliver diagnostic and therapeutic agents into the brain. Only a small fraction (i.e., 2%) of marketed small drugs has appreciable penetration into the CNS. Thus, there is a large unmet need to improve drug delivery to the brain for treatment of brain diseases such as multiple sclerosis (MS), Alzheimer’s disease (AD), Parkinson’s, and brain tumors. Currently, drugs that are not able to cross the BBB are sometimes administered via direct cranial injection or cerebral spinal fluid infusion; however, these are relatively invasive methods and they increase the risk for CNS infections. The goals of this project were specifically to investigate (i) if BBB modulation via the cadherin cyclic peptide, ADTC5, could be used to deliver brain-derived neurotrophic factor (BDNF) across the BBB to treat an experimental autoimmune encephalomyelitis (EAE), a mouse model of MS; (ii) if ADTC5 could also be used to deliver BDNF to treat an aggressive mouse model for Alzheimer’s disease (i.e., APP/PS1 mice); and (iii) how ADTC5 can improve brain delivery a monoclonal antibody (mAbs) for evaluating its clearance from the brain in healthy mice. First, we observed that ADTC5 was able to significantly enhance the deposition of BDNF to have efficacies in the EAE and Alzheimer’s disease animal models. Compared to when BDNF was delivered alone or placebo, BDNF + ADTC5 improved clinical body scores and cognitive performance in EAE mice and APP/PS1, respectively. Additionally, both EAE and APP/PS1 mice that were treated with BDNF + ADTC5 showed increase levels of NG2 microglia, and EGR and ARC mRNA transcripts compared to BDNF alone or vehicle. In the EAE model, the NG2 glia was associated with increased levels of myelin. Second, we monitored monoclonal antibody (mAb) brain deposition and clearance after its brain delivery with ADTC5 peptide. In addition, the effect of ADTC5 in mAb depositions in other organs was also determined. We observed a rapid clearance of mAb from the brain after enhanced delivery by ADTC5 with two different phases. The estimated t1/2alpha and t1/2beta of IgG mAb were 0.34 ¬± 0.22 h and 65.50 ± 12.09¬ h, respectively. This clearance was heavily facilitated by the liver and ADTC5 did not affect antibody deposition into liver, spleen, kidney, lung, or heart. Overall, this project demonstrates a proof-of-concept that brain diseases can be effectively treated via brain delivery of therapeutic proteins using BBB modulation by cadherin peptides (e.g., ADTC5)

Informational Quality Labeling on Social Media: In Defense of a Social Epistemology Strategy

Social media platforms have been rapidly increasing the number of informational labels they are appending to user-generated content in order to indicate the disputed nature of messages or to provide context. The rise of this practice constitutes an important new chapter in social media governance, as companies are often choosing this new “middle way” between a laissez-faire approach and more drastic remedies such as removing or downranking content. Yet information labeling as a practice has, thus far, been mostly tactical, reactive, and without strategic underpinnings. In this paper, we argue against defining success as merely the curbing of misinformation spread. The key to thinking about labeling strategically is to consider it from an epistemic perspective and to take as a starting point the “social” dimension of online social networks. The strategy we articulate emphasizes how the moderation system needs to improve the epistemic position and relationships of platform users — i.e., their ability to make good judgements about the sources and quality of the information with which they interact on the platform — while also appropriately respecting sources, seekers, and subjects of information. A systematic and normatively grounded approach can improve content moderation efforts by providing clearer accounts of what the goals are, how success should be defined and measured, and where ethical considerations should be taken into consideration. We consider implications for the policies of social media companies, propose new potential metrics for success, and review research and innovation agendas in this regard

The Effectiveness of Embedded Values Analysis Modules in Computer Science Education: An Empirical Study

Embedding ethics modules within computer science courses has become a popular response to the growing recognition that CS programs need to better equip their students to navigate the ethical dimensions of computing technologies like AI, machine learning, and big data analytics. However, the popularity of this approach has outpaced the evidence of its positive outcomes. To help close that gap, this empirical study reports positive results from Northeastern's program that embeds values analysis modules into CS courses. The resulting data suggest that such modules have a positive effect on students' moral attitudes and that students leave the modules believing they are more prepared to navigate the ethical dimensions they will likely face in their eventual careers. Importantly, these gains were accomplished at an institution without a philosophy doctoral program, suggesting this strategy can be effectively employed by a wider range of institutions than many have thought

Thrombin promotes diet-induced obesity through fibrin-driven inflammation

Obesity promotes a chronic inflammatory and hypercoagulable state that drives cardiovascular disease, type 2 diabetes, fatty liver disease, and several cancers. Elevated thrombin activity underlies obesity-linked thromboembolic events, but the mechanistic links between the thrombin/fibrin(ogen) axis and obesity-associated pathologies are incompletely understood. In this work, immunohistochemical studies identified extravascular fibrin deposits within white adipose tissue and liver as distinct features of mice fed a high-fat diet (HFD) as well as obese patients. Fibγ390–396A mice carrying a mutant form of fibrinogen incapable of binding leukocyte αMβ2-integrin were protected from HFD-induced weight gain and elevated adiposity. Fibγ390–396A mice had markedly diminished systemic, adipose, and hepatic inflammation with reduced macrophage counts within white adipose tissue, as well as near-complete protection from development of fatty liver disease and glucose dysmetabolism. Homozygous thrombomodulin-mutant ThbdPro mice, which have elevated thrombin procoagulant function, gained more weight and developed exacerbated fatty liver disease when fed a HFD compared with WT mice. In contrast, treatment with dabigatran, a direct thrombin inhibitor, limited HFD-induced obesity development and suppressed progression of sequelae in mice with established obesity. Collectively, these data provide proof of concept that targeting thrombin or fibrin(ogen) may limit pathologies in obese patients

Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Genetic factors have been implicated in stroke risk but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) in ischemic stroke and its subtypes in 3,548 cases and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 cases and 6,281 controls. We replicated reported associations between variants close to PITX2 and ZFHX3 with cardioembolic stroke, and a 9p21 locus with large vessel stroke. We identified a novel association for a SNP within the histone deacetylase 9(HDAC9) gene on chromosome 7p21.1 which was associated with large vessel stroke including additional replication in a further 735 cases and 28583 controls (rs11984041, combined P = 1.87×10−11, OR=1.42 (95% CI) 1.28-1.57). All four loci exhibit evidence for heterogeneity of effect across the stroke subtypes, with some, and possibly all, affecting risk for only one subtype. This suggests differing genetic architectures for different stroke subtypes