Hardwiring tissue-specific AAV transduction in mice through engineered receptor expression.

The development of transgenic mouse models that express genes of interest in specific cell types has transformed our understanding of basic biology and disease. However, generating these models is time- and resource-intensive. Here we describe a model system, SELective Expression and Controlled Transduction In Vivo (SELECTIV), that enables efficient and specific expression of transgenes by coupling adeno-associated virus (AAV) vectors with Cre-inducible overexpression of the multi-serotype AAV receptor, AAVR. We demonstrate that transgenic AAVR overexpression greatly increases the efficiency of transduction of many diverse cell types, including muscle stem cells, which are normally refractory to AAV transduction. Superior specificity is achieved by combining Cre-mediated AAVR overexpression with whole-body knockout of endogenous Aavr, which is demonstrated in heart cardiomyocytes, liver hepatocytes and cholinergic neurons. The enhanced efficacy and exquisite specificity of SELECTIV has broad utility in development of new mouse model systems and expands the use of AAV for gene delivery in vivo.

The skin crawls, the stomach turns: ectoparasites and pathogens elicit distinct defensive responses in humans.

Disgust has long been viewed as a primary motivator of defensive responses to threats posed by both microscopic pathogens and macroscopic ectoparasites. Although disgust can defend effectively against pathogens encountered through ingestion or incidental contact, it offers limited protection against ectoparasites, which actively pursue a host and attach to its surface. Humans might, therefore, possess a distinct ectoparasite defence system-including cutaneous sensory mechanisms and grooming behaviours-functionally suited to guard the body's surface. In two US studies and one in China, participants (N = 1079) viewed a range of ectoparasite- and pathogen-relevant video stimuli and reported their feelings, physiological sensations, and behavioural motivations. Participants reported more surface-guarding responses towards ectoparasite stimuli than towards pathogen stimuli, and more ingestion/contamination-reduction responses towards pathogen stimuli than towards ectoparasite stimuli. Like other species, humans appear to possess evolved psychobehavioural ectoparasite defence mechanisms that are distinct from pathogen defence mechanisms.

An In Vitro Model for Identifying Cardiac Side Effects of Anesthetics.

The understanding of anesthetic side effects on the heart has been hindered by the lack of sophisticated clinical models. Using micropatterned human-induced pluripotent stem cell-derived cardiomyocytes, we obtained cardiac muscle depressant profiles for propofol, etomidate, and our newly identified anesthetic compound KSEB01-S2. Propofol was the strongest depressant among the 3 compounds tested, exhibiting the largest decrease in contraction velocity, depression rate, and beating frequency. Interestingly, KSEB01-S2 behaved similarly to etomidate, suggesting a better cardiac safety profile. Our results provide a proof-of-concept for using human-induced pluripotent stem cell-derived cardiomyocytes as an in vitro platform for future drug design.

Prostaglandin E2 is essential for efficacious skeletal muscle stem-cell function, augmenting regeneration and strength.

Skeletal muscles harbor quiescent muscle-specific stem cells (MuSCs) capable of tissue regeneration throughout life. Muscle injury precipitates a complex inflammatory response in which a multiplicity of cell types, cytokines, and growth factors participate. Here we show that Prostaglandin E2 (PGE2) is an inflammatory cytokine that directly targets MuSCs via the EP4 receptor, leading to MuSC expansion. An acute treatment with PGE2 suffices to robustly augment muscle regeneration by either endogenous or transplanted MuSCs. Loss of PGE2 signaling by specific genetic ablation of the EP4 receptor in MuSCs impairs regeneration, leading to decreased muscle force. Inhibition of PGE2 production through nonsteroidal anti-inflammatory drug (NSAID) administration just after injury similarly hinders regeneration and compromises muscle strength. Mechanistically, the PGE2 EP4 interaction causes MuSC expansion by triggering a cAMP/phosphoCREB pathway that activates the proliferation-inducing transcription factor, Nurr1 Our findings reveal that loss of PGE2 signaling to MuSCs during recovery from injury impedes muscle repair and strength. Through such gain- or loss-of-function experiments, we found that PGE2 signaling acts as a rheostat for muscle stem-cell function. Decreased PGE2 signaling due to NSAIDs or increased PGE2 due to exogenous delivery dictates MuSC function, which determines the outcome of regeneration. The markedly enhanced and accelerated repair of damaged muscles following intramuscular delivery of PGE2 suggests a previously unrecognized indication for this therapeutic agent.

Gruesomeness conveys formidability: Perpetrators of gratuitously grisly acts are conceptualized as larger, stronger, and more likely to win.

While associated with extreme terrorist organizations in modern times, extensive accounts of grisly acts of violence exist in the archeological, historical, and ethnographic records. Though reasons for this dramatic form of violence are multifaceted and diverse, one possibility is that violence beyond what is required to win a conflict is a method by which violent actors communicate to others that they are formidable opponents. The formidability representation hypothesis predicts that formidability is cognitively represented using the dimensions of envisioned bodily size and strength. We tested the informational ramifications of gruesome acts using two vignette studies depicting individuals who either did or did not grievously damage the corpse of a deceased foe. Participants rated the individual's height, bodily size, and strength, as well as his aggressiveness, motivation, and the capacity to vanquish opponents in future conflicts. Results indicate that, as predicted, committing gruesome acts of violence enhances perceptions of formidability as measured both by envisioned bodily size and strength and expectations regarding the outcomes of agonistic conflicts. Moreover, the gruesome actor was perceived as more aggressive and more motivated to overcome his enemies, and this mediated the increase in conceptualized size and strength. These results both provide further evidence for the formidability representation hypothesis and support the thesis that overtly grisly violence is tactically employed, in part, because it conveys information about the perpetrator's formidability.

Political Orientation Predicts Credulity Regarding Putative Hazards.

To benefit from information provided by other people, people must be somewhat credulous. However, credulity entails risks. The optimal level of credulity depends on the relative costs of believing misinformation and failing to attend to accurate information. When information concerns hazards, erroneous incredulity is often more costly than erroneous credulity, given that disregarding accurate warnings is more harmful than adopting unnecessary precautions. Because no equivalent asymmetry exists for information concerning benefits, people should generally be more credulous of hazard information than of benefit information. This adaptive negatively biased credulity is linked to negativity bias in general and is more prominent among people who believe the world to be more dangerous. Because both threat sensitivity and beliefs about the dangerousness of the world differ between conservatives and liberals, we predicted that conservatism would positively correlate with negatively biased credulity. Two online studies of Americans supported this prediction, potentially illuminating how politicians' alarmist claims affect different portions of the electorate.

Direct evaluation of myocardial viability and stem cell engraftment demonstrates salvage of the injured myocardium.

RATIONALE: The mechanism of functional restoration by stem cell therapy remains poorly understood. Novel manganese-enhanced MRI and bioluminescence reporter gene imaging were applied to follow myocardial viability and cell engraftment, respectively. Human-placenta-derived amniotic mesenchymal stem cells (AMCs) demonstrate unique immunoregulatory and precardiac properties. In this study, the restorative effects of 3 AMC-derived subpopulations were examined in a murine myocardial injury model: (1) unselected AMCs, (2) ckit(+)AMCs, and (3) AMC-derived induced pluripotent stem cells (MiPSCs). OBJECTIVE: To determine the differential restorative effects of the AMC-derived subpopulations in the murine myocardial injury model using multimodality imaging. METHODS AND RESULTS: SCID (severe combined immunodeficiency) mice underwent left anterior descending artery ligation and were divided into 4 treatment arms: (1) normal saline control (n=14), (2) unselected AMCs (n=10), (3) ckit(+)AMCs (n=13), and (4) MiPSCs (n=11). Cardiac MRI assessed myocardial viability and left ventricular function, whereas bioluminescence imaging assessed stem cell engraftment during a 4-week period. Immunohistological labeling and reverse transcriptase polymerase chain reaction of the explanted myocardium were performed. The unselected AMC and ckit(+)AMC-treated mice demonstrated transient left ventricular functional improvement. However, the MiPSCs exhibited a significantly greater increase in left ventricular function compared with all the other groups during the entire 4-week period. Left ventricular functional improvement correlated with increased myocardial viability and sustained stem cell engraftment. The MiPSC-treated animals lacked any evidence of de novo cardiac differentiation. CONCLUSION: The functional restoration seen in MiPSCs was characterized by increased myocardial viability and sustained engraftment without de novo cardiac differentiation, indicating salvage of the injured myocardium.

Transient delivery of modified mRNA encoding TERT rapidly extends telomeres in human cells.

Telomere extension has been proposed as a means to improve cell culture and tissue engineering and to treat disease. However, telomere extension by nonviral, nonintegrating methods remains inefficient. Here we report that delivery of modified mRNA encoding TERT to human fibroblasts and myoblasts increases telomerase activity transiently (24-48 h) and rapidly extends telomeres, after which telomeres resume shortening. Three successive transfections over a 4 d period extended telomeres up to 0.9 kb in a cell type-specific manner in fibroblasts and myoblasts and conferred an additional 28 ± 1.5 and 3.4 ± 0.4 population doublings (PDs), respectively. Proliferative capacity increased in a dose-dependent manner. The second and third transfections had less effect on proliferative capacity than the first, revealing a refractory period. However, the refractory period was transient as a later fourth transfection increased fibroblast proliferative capacity by an additional 15.2 ± 1.1 PDs, similar to the first transfection. Overall, these treatments led to an increase in absolute cell number of more than 10(12)-fold. Notably, unlike immortalized cells, all treated cell populations eventually stopped increasing in number and expressed senescence markers to the same extent as untreated cells. This rapid method of extending telomeres and increasing cell proliferative capacity without risk of insertional mutagenesis should have broad utility in disease modeling, drug screening, and regenerative medicine.

Dressed to kill? Visible markers of coalitional affiliation enhance conceptualized formidability.

Displaying markers of coalitional affiliation is a common feature of contemporary life. In situations in which interaction with members of rival coalitions is likely, signaling coalitional affiliation may simultaneously constitute an implicit challenge to opponents and an objective commitment device, binding signalers to their coalitions. Individuals who invite conflict, and who cannot readily back out of conflict, constitute a greater threat than those who avoid conflict and preserve the option of feigning neutrality. As a consequence, the former should be viewed as more formidable than the latter. Recent research indicates that relative formidability is summarized using the envisioned physical size and strength of a potential antagonist. Thus, individuals who display markers of coalitional affiliation should be conceptualized as more physically imposing than those who do not. We tested this prediction in two experiments. In Study 1, conducted with U.S. university students, participants inspected images of sports fans' faces. In Study 2, conducted with U.S. Mechanical Turk workers, participants read vignettes depicting political partisans. In both studies, participants estimated the physical formidability of the target individuals and reported their own ability to defend themselves; in Study 2, participants estimated the target's aggressiveness. Consonant with predictions, targets depicted as signaling coalitional affiliation in situations of potential conflict were envisioned to be more physically formidable and more aggressive than were those not depicted as signaling thusly. Underscoring that the calculations at issue concern the possibility of violent conflict, participants' estimates of the protagonist's features were inversely correlated with their ability to defend themselves.

Moral parochialism and contextual contingency across seven societies.

Human moral judgement may have evolved to maximize the individual's welfare given parochial culturally constructed moral systems. If so, then moral condemnation should be more severe when transgressions are recent and local, and should be sensitive to the pronouncements of authority figures (who are often arbiters of moral norms), as the fitness pay-offs of moral disapproval will primarily derive from the ramifications of condemning actions that occur within the immediate social arena. Correspondingly, moral transgressions should be viewed as less objectionable if they occur in other places or times, or if local authorities deem them acceptable. These predictions contrast markedly with those derived from prevailing non-evolutionary perspectives on moral judgement. Both classes of theories predict purportedly species-typical patterns, yet to our knowledge, no study to date has investigated moral judgement across a diverse set of societies, including a range of small-scale communities that differ substantially from large highly urbanized nations. We tested these predictions in five small-scale societies and two large-scale societies, finding substantial evidence of moral parochialism and contextual contingency in adults' moral judgements. Results reveal an overarching pattern in which moral condemnation reflects a concern with immediate local considerations, a pattern consistent with a variety of evolutionary accounts of moral judgement.

Marching into battle: synchronized walking diminishes the conceptualized formidability of an antagonist in men.

Paralleling behaviours in other species, synchronized movement is central to institutionalized collective human activities thought to enhance cooperation, and experiments demonstrate that synchrony has this effect. The influence of synchrony on cooperation may derive from an evolutionary history wherein such actions served to signal coalitional strength to both participants and observers-including adversaries. If so, then synchronous movement should diminish individuals' estimations of a foe's formidability. Envisioned physical size and strength constitute the dimensions of a representation that summarizes relative fighting capacity. Experiencing synchrony should therefore lead individuals to conceptualize an antagonist as smaller and weaker. We found that men who walked synchronously with a male confederate indeed envisioned a purported criminal as less physically formidable than did men who engaged in this task without synchronizing.

Tracking single hiPSC-derived cardiomyocyte contractile function using CONTRAX an efficient pipeline for traction force measurement.

Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) are powerful in vitro models to study the mechanisms underlying cardiomyopathies and cardiotoxicity. Quantification of the contractile function in single hiPSC-CMs at high-throughput and over time is essential to disentangle how cellular mechanisms affect heart function. Here, we present CONTRAX, an open-access, versatile, and streamlined pipeline for quantitative tracking of the contractile dynamics of single hiPSC-CMs over time. Three software modules enable: parameter-based identification of single hiPSC-CMs; automated video acquisition of >200 cells/hour; and contractility measurements via traction force microscopy. We analyze >4,500 hiPSC-CMs over time in the same cells under orthogonal conditions of culture media and substrate stiffnesses; +/- drug treatment; +/- cardiac mutations. Using undirected clustering, we reveal converging maturation patterns, quantifiable drug response to Mavacamten and significant deficiencies in hiPSC-CMs with disease mutations. CONTRAX empowers researchers with a potent quantitative approach to develop cardiac therapies.

Friends shrink foes: the presence of comrades decreases the envisioned physical formidability of an opponent.

In situations of potential violent conflict, deciding whether to fight, flee, or try to negotiate entails assessing many attributes contributing to the relative formidability of oneself and one's opponent. Summary representations can usefully facilitate such assessments of multiple factors. Because physical size and strength are both phylogenetically ancient and ontogenetically recurrent contributors to the outcome of violent conflicts, these attributes provide plausible conceptual dimensions that may be used by the mind to summarize the relative formidability of opposing parties. Because the presence of allies is a vital factor in determining victory, we hypothesized that men accompanied by male companions would therefore envision a solitary foe as physically smaller and less muscular than would men who were alone. We document the predicted effect in two studies, one using naturally occurring variation in the presence of male companions and one employing experimental manipulation of this factor.

Baumard et al.'s moral markets lack market dynamics.

Market models are indeed indispensable to understanding the evolution of cooperation and its emotional substrates. Unfortunately, Baumard et al. eschew market thinking in stressing the supposed invariance of moral/cooperative behavior across circumstances. To the contrary, humans display contingent morality/cooperation, and these shifts are best accounted for by market models of partner choice for mutually beneficial collaboration.

Revenge without redundancy: functional outcomes do not require discrete adaptations for vengeance or forgiveness.

We question whether the postulated revenge and forgiveness systems constitute true adaptations. Revenge and forgiveness are the products of multiple motivational systems and capacities, many of which did not exclusively evolve to support deterrence. Anger is more aptly construed as an adaptation that organizes independent mechanisms to deter transgressors than as the mediator of a distinct revenge adaptation.

Prosocial aggression tracks genetic relatedness distinctly from emotional closeness.

Altruistic behavior is understood to largely stem from adaptations for kin altruism, contingent on degree of relatedness, and/or reciprocal altruism, contingent on degree of benefits conferred in exchange for help. Because kin qualify for both kin and reciprocal altruism, they should receive greater support than friends, as has been demonstrated in prior research. Here, we tested this prediction with regard to willingness to punish on another's behalf, comparing inclinations to aggress against transgressors when the victim was framed as an acquaintance, close friend, cousin, sibling, or oneself. Participants endorsed comparably greater direct aggression on behalf of the self, kin, or friends relative to acquaintances, despite reporting substantially greater emotional closeness to friends, consistent with what has been termed a kinship premium. Kin engendered greater aid than is explicable by affiliative emotion. Participants also reported less anger-yet trends toward greater disgust-when victims were acquaintances relative to all other conditions, replicating prior work distinguishing the social functions of anger and disgust. These results are discussed as they inform both the kinship premium hypothesis and sociofunctional accounts of moral emotion. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Coalitionality shapes moral elevation: evidence from the U.S. Black Lives Matter protest and counter-protest movements.

Witnessing altruistic behaviour can elicit moral elevation, an emotion that motivates prosocial cooperation. This emotion is evoked more strongly when the observer anticipates that other people will be reciprocally cooperative. Coalitionality should therefore moderate feelings of elevation, as whether the observer shares the coalitional affiliation of those observed should influence the observer's assessment of the likelihood that the latter will cooperate with the observer. We examined this thesis in studies contemporaneous with the 2020 Black Lives Matter (BLM) protests. Although BLM protests were predominantly peaceful, they were depicted by conservative media as destructive and antisocial. In two large-scale, pre-registered online studies (total N = 2172), political orientation strongly moderated feelings of state elevation elicited by a video of a peaceful BLM protest (Studies 1 and 2) or a peaceful Back the Blue (BtB) counter-protest (Study 2). Political conservatism predicted less elevation following the BLM video and more elevation following the BtB video. Elevation elicited by the BLM video correlated with preferences to defund police, whereas elevation elicited by the BtB video correlated with preferences to increase police funding. These findings extend prior work on elevation into the area of prosocial cooperation in the context of coalitional conflict.

Machine learning-based classification of dual fluorescence signals reveals muscle stem cell fate transitions in response to regenerative niche factors.

The proper regulation of muscle stem cell (MuSC) fate by cues from the niche is essential for regeneration of skeletal muscle. How pro-regenerative niche factors control the dynamics of MuSC fate decisions remains unknown due to limitations of population-level endpoint assays. To address this knowledge gap, we developed a dual fluorescence imaging time lapse (Dual-FLIT) microscopy approach that leverages machine learning classification strategies to track single cell fate decisions with high temporal resolution. Using two fluorescent reporters that read out maintenance of stemness and myogenic commitment, we constructed detailed lineage trees for individual MuSCs and their progeny, classifying each division event as symmetric self-renewing, asymmetric, or symmetric committed. Our analysis reveals that treatment with the lipid metabolite, prostaglandin E2 (PGE2), accelerates the rate of MuSC proliferation over time, while biasing division events toward symmetric self-renewal. In contrast, the IL6 family member, Oncostatin M (OSM), decreases the proliferation rate after the first generation, while blocking myogenic commitment. These insights into the dynamics of MuSC regulation by niche cues were uniquely enabled by our Dual-FLIT approach. We anticipate that similar binary live cell readouts derived from Dual-FLIT will markedly expand our understanding of how niche factors control tissue regeneration in real time.

Greater traditionalism predicts COVID-19 precautionary behaviors across 27 societies.

People vary both in their embrace of their society's traditions, and in their perception of hazards as salient and necessitating a response. Over evolutionary time, traditions have offered avenues for addressing hazards, plausibly resulting in linkages between orientations toward tradition and orientations toward danger. Emerging research documents connections between traditionalism and threat responsivity, including pathogen-avoidance motivations. Additionally, because hazard-mitigating behaviors can conflict with competing priorities, associations between traditionalism and pathogen avoidance may hinge on contextually contingent tradeoffs. The COVID-19 pandemic provides a real-world test of the posited relationship between traditionalism and hazard avoidance. Across 27 societies (N = 7844), we find that, in a majority of countries, individuals' endorsement of tradition positively correlates with their adherence to costly COVID-19-avoidance behaviors; accounting for some of the conflicts that arise between public health precautions and other objectives further strengthens this evidence that traditionalism is associated with greater attention to hazards.

Moral parochialism and causal appraisal of transgressive harm in Seoul and Los Angeles.

The evolutionary fitness payoffs of moral condemnation are greatest within an individual's immediate social milieu. Accordingly, insofar as human moral intuitions have been shaped by adaptive design, we can expect transgressive harms to be perceived as more wrong when transpiring in the here and now than when occurring at a distance, or with the approval of local authority figures. This moral parochialism hypothesis has been supported by research conducted in diverse societies, but has yet to be tested in an East Asian society, despite prior research indicating that East Asians appraise transgressive acts as being caused by situational and contextual factors to a greater extent than do Westerners, who tend to emphasize dispositional factors (i.e., the transgressor's personal nature). Here, in a quasi-experiment using field samples recruited in Seoul and Los Angeles, we tested (i) the moral parochialism hypothesis regarding the perceived wrongness of transgressions, as well as (ii) the extent to which these wrongness judgments might be influenced by cross-cultural differences in causal appraisals. Despite notably large differences across the two societies in situational versus dispositional appraisals of the causes of the transgressions, replicating previous findings elsewhere, in both societies we found that transgressions were deemed less wrong when occurring at spatial or temporal remove or with the consent of authorities. These findings add to the understanding of morality as universally focused on local affairs, notwithstanding cultural variation in perceptions of the situational versus dispositional causes of (im)moral acts.