Targeting Longevity Gene SLC13A5: A Novel Approach to Prevent Age-Related Bone Fragility and Osteoporosis.

Reduced expression of the plasma membrane citrate transporter SLC13A5, also known as INDY, has been linked to increased longevity and mitigated age-related cardiovascular and metabolic diseases. Citrate, a vital component of the tricarboxylic acid cycle, constitutes 1-5% of bone weight, binding to mineral apatite surfaces. Our previous research highlighted osteoblasts' specialized metabolic pathway facilitated by SLC13A5 regulating citrate uptake, production, and deposition within bones. Disrupting this pathway impairs bone mineralization in young mice. New Mendelian randomization analysis using UK Biobank data indicated that SNPs linked to reduced SLC13A5 function lowered osteoporosis risk. Comparative studies of young (10 weeks) and middle-aged (52 weeks) osteocalcin-cre-driven osteoblast-specific Slc13a5 knockout mice (Slc13a5cKO) showed a sexual dimorphism: while middle-aged females exhibited improved elasticity, middle-aged males demonstrated enhanced bone strength due to reduced SLC13A5 function. These findings suggest reduced SLC13A5 function could attenuate age-related bone fragility, advocating for SLC13A5 inhibition as a potential osteoporosis treatment.

Exploring disease-causing traits for drug repurposing in critically ill COVID-19 patients: A causal inference approach.

Despite recent development of vaccines to prevent SARS-CoV-2 infection, treatment of critically ill COVID-19 patients remains an important goal. In principle, genome-wide association studies (GWASs) provide a shortcut to the clinical evidence needed to repurpose existing drugs; however, genes identified frequently lack a causal disease link. We report an alternative method for finding drug repurposing targets, focusing on disease-causing traits beyond immediate disease genetics. Sixty blood cell types and biochemistries, and body mass index, were screened on a cohort of critically ill COVID-19 cases and controls that exhibited mild symptoms after infection, yielding high neutrophil cell count as a possible causal trait for critical illness. Our methodology identified CDK6 and janus kinase (JAK) inhibitors as treatment targets that were validated in an ex vivo neutrophil extracellular trap (NET) formation assay. Our methodology demonstrates the increased power for drug target identification by leveraging large disease-causing trait datasets.

Human infants are aroused and concerned by moral transgressions.

Humans reason and care about ethical issues, such as avoiding unnecessary harm. But what enables us to develop a moral capacity? This question dates back at least to ancient Greece and typically results in the traditional opposition between sentimentalism (the view that morality is mainly driven by socioaffective processes) and rationalism [the view that morality is mainly driven by (socio)cognitive processes or reason]. Here, we used multiple methods (eye-tracking and observations of expressive behaviors) to assess the role of both cognitive and socioaffective processes in infants' developing morality. We capitalized on the distinction between moral (e.g., harmful) and conventional (e.g., harmless) transgressions to investigate whether 18-mo-old infants understand actions as distinctively moral as opposed to merely disobedient or unexpected. All infants watched the same social scene, but based on prior verbal interactions, an actor's tearing apart of a picture (an act not intrinsically harmful) with a tool constituted either a conventional (wrong tool), a moral (producing harm), or no violation (correct tool). Infants' anticipatory looks differentiated between conventional and no violation conditions, suggesting that they processed the verbal interactions and built corresponding expectations. Importantly, infants showed a larger increase in pupil size (physiological arousal), and more expressions indicating empathic concern, in response to a moral than to a conventional violation. Thus, infants differentiated between harmful and harmless transgressions based solely on prior verbal interactions. Together, these convergent findings suggest that human infants' moral development is fostered by both sociocognitive (inferring harm) and socioaffective processes (empathic concern for others' welfare).

Great apes and human children rationally monitor their decisions.

Several species can detect when they are uncertain about what decision to make-revealed by opting out of the choice, or by seeking more information before deciding. However, we do not know whether any nonhuman animals recognize when they need more information to make a decision because new evidence contradicts an already-formed belief. Here, we explore this ability in great apes and human children. First, we show that after great apes saw new evidence contradicting their belief about which of two rewards was greater, they stopped to recheck the evidence for their belief before deciding. This indicates the ability to keep track of the reasons for their decisions, or 'rational monitoring' of the decision-making process. Children did the same at 5 years of age, but not at 3 years. In a second study, participants formed a belief about a reward's location, but then a social partner contradicted them, by picking the opposite location. This time even 3-year-old children rechecked the evidence, while apes ignored the disagreement. While apes were sensitive only to the conflict in physical evidence, the youngest children were more sensitive to peer disagreement than conflicting physical evidence.

Preschoolers agree to and enforce prosocial, but not selfish, sharing norms.

Young children act prosocially in many contexts but are somewhat selfish when it comes to sharing their resources in individual decision-making situations (e.g., the dictator game). But when deciding collectively, would they make it a binding rule for themselves and others to act selfishly in a resource sharing context? Here we used a novel "group dictator game" in a norm creation paradigm to investigate whether 3- and 5-year-olds (N = 48) would agree to and enforce a selfish or prosocial sharing norm. Children from a Western cultural background were paired with two puppets at a time. Each group member had an endowment of four stickers and faced a photograph of a recipient. In the prosocial norm condition a proposer puppet suggested to share half of one's endowment, whereas in the selfish norm condition another proposer suggested to share nothing. The protagonist puppet then either followed or violated the suggested norm. We found that 5-year-olds (but not 3-year-olds) rejected selfish proposals more often than prosocial proposals. Importantly, older (but not younger) preschoolers also enforced the prosocial (but not the selfish) norm by protesting normatively and intervening when the protagonist acted selfishly (and thus violated the norm). These results indicate that a collective decision-making context may enhance preschoolers' prosociality and that moral considerations on the content of a proposed sharing rule influence preschoolers' creation and enforcement of such nonarbitrary norms.

Interaction-Based Feature Selection Algorithm Outperforms Polygenic Risk Score in Predicting Parkinson's Disease Status.

Polygenic risk scores (PRS) aggregating results from genome-wide association studies are the state of the art in the prediction of susceptibility to complex traits or diseases, yet their predictive performance is limited for various reasons, not least of which is their failure to incorporate the effects of gene-gene interactions. Novel machine learning algorithms that use large amounts of data promise to find gene-gene interactions in order to build models with better predictive performance than PRS. Here, we present a data preprocessing step by using data-mining of contextual information to reduce the number of features, enabling machine learning algorithms to identify gene-gene interactions. We applied our approach to the Parkinson's Progression Markers Initiative (PPMI) dataset, an observational clinical study of 471 genotyped subjects (368 cases and 152 controls). With an AUC of 0.85 (95% CI = [0.72; 0.96]), the interaction-based prediction model outperforms the PRS (AUC of 0.58 (95% CI = [0.42; 0.81])). Furthermore, feature importance analysis of the model provided insights into the mechanism of Parkinson's disease. For instance, the model revealed an interaction of previously described drug target candidate genes TMEM175 and GAPDHP25. These results demonstrate that interaction-based machine learning models can improve genetic prediction models and might provide an answer to the missing heritability problem.

Eighteen-Month-Old Infants Correct Non-Conforming Actions by Others.

At around their third birthday, children begin to enforce social norms on others impersonally, often using generic normative language, but little is known about the developmental building blocks of this abstract norm understanding. Here, we investigate whether even toddlers show signs of enforcing on others interpersonally how "we" do things. In an initial dyad, 18-month-old infants learnt a simple game-like action from an adult. In two experiments, the adult either engaged infants in a normative interactive activity (stressing that this is the way "we" do it) or, as a non-normative control, marked the same action as idiosyncratic, based on individual preference. In a test dyad, infants had the opportunity to spontaneously intervene when a puppet partner performed an alternative action. Infants intervened, corrected, and directed the puppet more in the normative than in the non-normative conditions. These findings suggest that, during the second year of life, infants develop second-personal normative expectations about their partner's behavior ("You should do X!") in social interactions, thus making an important step toward understanding the normative structure of human cultural activities. These simple normative expectations will later be scaled up to group-minded and abstract social norms.

Older (but not younger) preschoolers reject incorrect knowledge claims.

As epistemic and normative learners, children are dependent on their developing skills for evaluating others' claims. This competence seems particularly important in the current digital age in which children need to discern valid from invalid assertions about the world in both real-life and virtual interactions to ultimately gather and accumulate robust knowledge. We investigated whether younger and older preschoolers (N = 48) understand that a speaker's knowledge claim ('I know where X is') may be correct or incorrect given objectively accessible information (about whether the speaker had perceptual access to a critical event). We found that both younger and older preschoolers accepted correct knowledge claims that matched observable reality, but that only older preschoolers reliably rejected incorrect knowledge claims that did not match reality (the speaker lacked perceptual access). Nevertheless, a considerable proportion of younger preschoolers both rejected incorrect knowledge claims and gave valid explanations, suggesting that the ability to scrutinize epistemic claims develops gradually from around 3 to 4 years of age. These findings may help integrate research on children's norm and theory of mind development. Statement of contribution What is already known on this subject? Preschoolers understand that non-epistemic claims (e.g., 'This is an X!') may be correct or incorrect, and they track a speaker's relevant characteristics in testimonial situations. It is not known what preschoolers understand about the validity of epistemic (knowledge) claims (e.g., 'I know that X'). What does this study add? Younger and older preschoolers accepted correct knowledge claims (children observed that a speaker saw a critical event and was thus knowledgeable). Only older preschoolers reliably rejected incorrect knowledge claims (the speaker did not see the critical event). Nevertheless, a considerable proportion of younger preschoolers showed competence in their evaluation of, and reasoning about, incorrect knowledge claims. Findings suggest that the ability to evaluate epistemic claims develops gradually from around 3 to 4 years of age.

Preschoolers Understand the Moral Dimension of Factual Claims.

Research on children's developing moral cognition has mostly focused on their evaluation of, and reasoning about, others' intrinsically harmful (non-)verbal actions (e.g., hitting, lying). But assertions may have morally relevant (intended or unintended) consequences, too. For instance, if someone wrongly claims that "This water is clean!," such an incorrect representation of reality may have harmful consequences to others. In two experiments, we investigated preschoolers' evaluation of others' morally relevant factual claims. In Experiment 1, children witnessed a puppet making incorrect assertions that would lead to harm or to no harm. In Experiment 2, incorrect assertions would always lead to harm, but the puppet either intended the harm to occur or not. Children evaluated the puppet's factual claim more negatively when they anticipated harmful versus harmless consequences (Experiment 1) and when the puppet's intention was bad versus good over and above harmful consequences (Experiment 2). These findings suggest that preschoolers' normative understanding is not limited to evaluating others' intrinsically harmful transgressions but also entails an appreciation of the morally relevant consequences of, and intentions underlying, others' factual claims.

Children's evaluation of verified and unverified claims.

Critical to children's learning is the ability to judiciously select what information to accept-to use as the basis for learning and inference-and what information to reject. This becomes especially difficult in a world increasingly inundated with information, where children must carefully reason about the process by which claims are made in order to acquire accurate knowledge. In two experiments, we investigated whether 3- to 7-year-old children (N = 120) understand that factual claims based on verified evidence are more acceptable than claims that have not been sufficiently verified. We found that even at preschool age, children evaluated verified claims as more acceptable than insufficiently verified claims, and that the extent to which they did so was related to their explicit understanding, as evident in their explanations of why those claims were more or less acceptable. These experiments lay the groundwork for an important line of research studying the roots and development of this foundational critical thinking skill.

Preschoolers, but not adults, treat instrumental norms as categorical imperatives.

Hypothetical norms apply only when agents have specific goals, whereas categorical norms apply regardless of what agents want. Deciding whether a rule is hypothetical or categorical is crucial for navigating many social situations encountered by children and adults. The current research investigated whether preschoolers viewed instrumental norms (about how to accomplish practical tasks), prudential norms (pertaining to agent welfare), and moral norms (pertaining to others' welfare) as hypothetical or categorical. A second main question was whether preschoolers draw distinctions between instrumental and other norms. Participants were interviewed about norm violations in which the agent did or did not have the relevant goal. The goal manipulation had no effect on children's judgments of permissibility; most children treated all three norm types as categorical. Nevertheless, children distinguished instrumental events from prudential and moral events along several dimensions. In contrast, participants in two adult samples treated instrumental norms, and some prudential norms, as hypothetical, but treated moral norms as categorical (applicable regardless of agent goal). These findings suggest that preschoolers do not yet reliably distinguish between hypothetical and categorical norms, yet do view rules of instrumental rationality as a distinct type of norms.

The early development of the normative mind.

Normativity is pervasive in everyday human social interactions and perhaps even constitutive of human forms of group and societal living. During the past decade, there has been increased interest in the ontogeny of normativity and the role that norms play in early social reasoning and behavior. Given the ubiquity of normativity, it is vital to investigate the development of children's normative understanding and behavior in a variety of different contexts, ranging from prosocial behavior to rational action or from linguistic competencies to cultural norms and values. Hence, in this special issue on the early development of the normative mind, researchers from different theoretical traditions have employed a number of different methods (e.g., third-party norm enforcement, judgment and reasoning, social behavior) to address different, yet related, research questions about the ontogeny of normativity. Here, we introduce the reader to the current debate and point to important research questions for the field.

Children's developing metaethical judgments.

Human adults incline toward moral objectivism but may approach things more relativistically if different cultures are involved. In this study, 4-, 6-, and 9-year-old children (N=136) witnessed two parties who disagreed about moral matters: a normative judge (e.g., judging that it is wrong to do X) and an antinormative judge (e.g., judging that it is okay to do X). We assessed children's metaethical judgment, that is, whether they judged that only one party (objectivism) or both parties (relativism) could be right. We found that 9-year-olds, but not younger children, were more likely to judge that both parties could be right when a normative ingroup judge disagreed with an antinormative extraterrestrial judge (with different preferences and background) than when the antinormative judge was another ingroup individual. This effect was not found in a comparison case where parties disagreed about the possibility of different physical laws. These findings suggest that although young children often exhibit moral objectivism, by early school age they begin to temper their objectivism with culturally relative metaethical judgments.

miRNA Targeting Drugs: The Next Blockbusters?

Only 20 years after the discovery of small non-coding, single-stranded ribonucleic acids, so-called microRNAs (miRNAs), as post-transcriptional gene regulators, the first miRNA-targeting drug Miravirsen for the treatment of hepatitis C has been successfully tested in clinical Phase II trials. Addressing miRNAs as drug targets may enable the cure, or at least the treatment of diseases, which presently seems impossible. However, due to miRNAs' chemical structure, generation of potential drug molecules with necessary pharmacokinetic properties is still challenging and requires a re-thinking of the drug discovery process. Therefore, this chapter highlights the potential of miRNAs as drug targets, discusses the challenges, and tries to give a complete overview of recent strategies in miRNA drug discovery.

Antagonists of the miRNA-Argonaute 2 Protein Complex: Anti-miR-AGOs.

microRNAs (miRNAs) have been identified as high-value drug targets. A widely applied strategy in miRNA inhibition is the use of antisense agents. However, it has been shown that oligonucleotides are poorly cell permeable because of their complex chemical structure and due to their negatively charged backbone. Consequently, the general application of oligonucleotides in therapy is limited. Since miRNAs' functions are executed exclusively by the Argonaute 2 protein, we therefore describe a protocol for the design of a novel miRNA inhibitor class: antagonists of the miRNA-Argonaute 2 protein complex, so-called anti-miR-AGOs, that not only block the crucial binding site of the target miRNA but also bind to the protein's active site. Due to their lower molecular weight and, thus, more drug-like chemical structure, the novel inhibitor class may show better pharmacokinetic properties than reported oligonucleotide inhibitors, enabling them for potential therapeutic use.

Young Children See a Single Action and Infer a Social Norm.

Human social life depends heavily on social norms that prescribe and proscribe specific actions. Typically, young children learn social norms from adult instruction. In the work reported here, we showed that this is not the whole story: Three-year-old children are promiscuous normativists. In other words, they spontaneously inferred the presence of social norms even when an adult had done nothing to indicate such a norm in either language or behavior. And children of this age even went so far as to enforce these self-inferred norms when third parties "broke" them. These results suggest that children do not just passively acquire social norms from adult behavior and instruction; rather, they have a natural and proactive tendency to go from "is" to "ought." That is, children go from observed actions to prescribed actions and do not perceive them simply as guidelines for their own behavior but rather as objective normative rules applying to everyone equally.

Young children's behavioral and emotional responses to different social norm violations.

From an early age, children can talk meaningfully about differences between moral and conventional norms. But does their understanding of these differences manifest itself in their actual behavioral and emotional reactions to norm violations? And do children discriminate between norm violations that affect either themselves or a third party? Two studies (N=224) were conducted in which children observed conventional game rule violations and moral transgressions that either disadvantaged themselves directly or disadvantaged an absent third party. Results revealed that 3- and 5-year-olds evaluated both conventional and moral transgressions as normative breaches and protested against them. However, 5-year-olds also clearly discriminated these types of transgressions along further dimensions in that (a) they tattled largely on the moral violation and less on the conventional violation and (b) they showed stronger emotional reactions to moral violations compared to conventional violations. The 3-year-olds' responses to moral and conventional transgressions, however, were less discriminatory, and these younger children responded rather similarly to both kinds of violations. Importantly, most children intervened both as victims of the transgression and as unaffected third parties alike, providing strong evidence for their agent-neutral understanding of social norms.

Young Children Understand the Role of Agreement in Establishing Arbitrary Norms-But Unanimity Is Key.

Human cultural groups value conformity to arbitrary norms (e.g., rituals, games) that are the result of collective "agreement." Ninety-six 3-year-olds had the opportunity to agree upon arbitrary norms with puppets. Results revealed that children normatively enforced these novel norms only on a deviator who had actually entered into the agreement (not on dissenting or ignorant individuals). Interestingly, any dissent during the norm-setting process (even if a majority of 90% preferred one course of action) prevented children from seeing a norm as established for anyone at all. These findings suggest that even young children understand something of the role of agreement in establishing mutually binding social norms, but that their notion of norm formation may be confined to conditions of unanimity.