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.

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.

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.

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).

Elevated CD47 is a hallmark of dysfunctional aged muscle stem cells that can be targeted to augment regeneration.

In aging, skeletal muscle strength and regenerative capacity decline, due in part to functional impairment of muscle stem cells (MuSCs), yet the underlying mechanisms remain elusive. Here, we capitalize on mass cytometry to identify high CD47 expression as a hallmark of dysfunctional MuSCs (CD47hi) with impaired regenerative capacity that predominate with aging. The prevalent CD47hi MuSC subset suppresses the residual functional CD47lo MuSC subset through a paracrine signaling loop, leading to impaired proliferation. We uncover that elevated CD47 levels on aged MuSCs result from increased U1 snRNA expression, which disrupts alternative polyadenylation. The deficit in aged MuSC function in regeneration can be overcome either by morpholino-mediated blockade of CD47 alternative polyadenylation or antibody blockade of thrombospondin-1/CD47 signaling, leading to improved regeneration in aged mice, with therapeutic implications. Our findings highlight a previously unrecognized age-dependent alteration in CD47 levels and function in MuSCs, which underlies reduced muscle repair in aging.

Multiparameter analysis of timelapse imaging reveals kinetics of megakaryocytic erythroid progenitor clonal expansion and differentiation.

Single-cell assays have enriched our understanding of hematopoiesis and, more generally, stem and progenitor cell biology. However, these single-end-point approaches provide only a static snapshot of the state of a cell. To observe and measure dynamic changes that may instruct cell fate, we developed an approach for examining hematopoietic progenitor fate specification using long-term (> 7-day) single-cell time-lapse imaging for up to 13 generations with in situ fluorescence staining of primary human hematopoietic progenitors followed by algorithm-assisted lineage tracing. We analyzed progenitor cell dynamics, including the division rate, velocity, viability, and probability of lineage commitment at the single-cell level over time. We applied a Markov probabilistic model to predict progenitor division outcome over each generation in culture. We demonstrated the utility of this methodological pipeline by evaluating the effects of the cytokines thrombopoietin and erythropoietin on the dynamics of self-renewal and lineage specification in primary human bipotent megakaryocytic-erythroid progenitors (MEPs). Our data support the hypothesis that thrombopoietin and erythropoietin support the viability and self-renewal of MEPs, but do not affect fate specification. Thus, single-cell tracking of time-lapse imaged colony-forming unit assays provides a robust method for assessing the dynamics of progenitor self-renewal and lineage commitment.

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.

Posterior medial frontal cortex regulates sympathy: A TMS study.

Harm to some elicits greater sympathy than harm to others. Here, we examine the role of posterior medial frontal cortex (PMFC) in regulating sympathy, and explore the potential role of PMFC in the related phenomena of mentalizing and representing others as connected with oneself. We down-regulated either PMFC or a control region (middle temporal visual area), then assessed feelings of sympathy for and self-other overlap with two characters described as having suffered physical harm, and who were framed as adversarial or affiliative, respectively. We also measured mentalizing performance with regard to inferring the cognitive and affective states of the adversarial character. As hypothesized, down-regulating PMFC increased sympathy for both characters. Whereas we had predicted that down-regulating PMFC would decrease mentalizing ability given the postulated role of PMFC in the mentalizing network, participants in the PMFC down-regulation condition evinced greater second-order cognitive inference ability relative to controls. We observed no effect of the TMS manipulation on self-other overlap, although sympathy and self-other overlap were positively correlated. These findings are discussed as they may inform understanding of the functional role(s) of PMFC in regulating responses broadly linked with empathy.

Biophysical matrix cues from the regenerating niche direct muscle stem cell fate in engineered microenvironments.

Skeletal muscle stem cells (MuSCs) are essential for efficacious muscle repair, making MuSCs promising therapeutic targets for tissue engineering and regenerative medicine. MuSCs are presented with a diverse and temporally defined set of cues from their microenvironment during regeneration that direct stem cell expansion, differentiation, and return to quiescence. Understanding the complex interplay among these biophysical and biochemical cues is necessary to develop therapies targeting or employing MuSCs. To probe the role of mechanical cues presented by the extracellular matrix, we leverage chemically defined hydrogel substrates with controllable stiffness and adhesive ligand composition to characterize the MuSC response to matrix cues presented during early and late phases of regeneration. We demonstrate that relatively soft hydrogels recapitulating healthy muscle stiffness promote MuSC activation and expansion, while relatively stiff hydrogels impair MuSC proliferation and arrest myogenic progression. These effects are seen on soft and stiff hydrogels presenting laminin-111 and exacerbated on hydrogels presenting RGD adhesive peptides. Soluble factors present in the MuSC niche during different phases of regeneration, prostaglandin E2 and oncostatin M, synergize with matrix-presented cues to enhance stem cell expansion on soft substrates and block myogenic progression on stiff substrates. To determine if temporally varied matrix stiffness reminiscent of the regenerating microenvironment alters MuSC fate, we developed a photoresponsive hydrogel system with accelerated reaction kinetics that can be rapidly softened on demand. MuSCs cultured on these materials revealed that the cellular response to a stiff microenvironment is fixed within the first three days of culture, as subsequent softening back to a healthy stiffness did not rescue MuSC proliferation or myogenic progression. These results highlight the importance of temporally controlled biophysical and biochemical cues in regulating MuSC fate that can be harnessed to improve regenerative medicine approaches to restore skeletal muscle tissue.

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.

Of pathogens and party lines: Social conservatism positively associates with COVID-19 precautions among U.S. Democrats but not Republicans.

Social liberals tend to be less pathogen-avoidant than social conservatives, a pattern consistent with a model wherein ideological differences stem from differences in threat reactivity. Here we investigate if and how individual responses to a shared threat reflect those patterns of ideological difference. In seeming contradiction to the general association between social conservatism and pathogen avoidance, the more socially conservative political party in the United States has more consistently downplayed the dangers of COVID-19 during the ongoing pandemic. This puzzle offers an opportunity to examine the contributions of multiple factors to disease avoidance. We investigated the relationship between social conservatism and COVID-19 precautionary behavior in light of the partisan landscape of the United States. We explored whether consumption of, and attitudes toward, different sources of information, as well as differential evaluation of various threats caused by the pandemic-such as direct health costs versus indirect harms to the economy and individual liberties-shape partisan differences in responses to the pandemic in ways that overwhelm the contributions of social conservatism. In two pre-registered studies, socially conservative attitudes correlate with self-reported COVID-19 prophylactic behaviors, but only among Democrats. Reflecting larger societal divisions, among Republicans and Independents, the absence of a positive relationship between social conservatism and COVID-19 precautions appears driven by lower trust in scientists, lower trust in liberal and moderate sources, lesser consumption of liberal news media, and greater economic conservatism.

Increased tissue stiffness triggers contractile dysfunction and telomere shortening in dystrophic cardiomyocytes.

Duchenne muscular dystrophy (DMD) is a rare X-linked recessive disease that is associated with severe progressive muscle degeneration culminating in death due to cardiorespiratory failure. We previously observed an unexpected proliferation-independent telomere shortening in cardiomyocytes of a DMD mouse model. Here, we provide mechanistic insights using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Using traction force microscopy, we show that DMD hiPSC-CMs exhibit deficits in force generation on fibrotic-like bioengineered hydrogels, aberrant calcium handling, and increased reactive oxygen species levels. Furthermore, we observed a progressive post-mitotic telomere shortening in DMD hiPSC-CMs coincident with downregulation of shelterin complex, telomere capping proteins, and activation of the p53 DNA damage response. This telomere shortening is blocked by blebbistatin, which inhibits contraction in DMD cardiomyocytes. Our studies underscore the role of fibrotic stiffening in the etiology of DMD cardiomyopathy. In addition, our data indicate that telomere shortening is progressive, contraction dependent, and mechanosensitive, and suggest points of therapeutic intervention.

Morality is relative: Anger, disgust, and aggression as contingent responses to sibling versus acquaintance harm.

Angry reactions to moral violations should be heightened when wrongs befall oneself in comparison with when wrongs befall acquaintances, as prior research by Molho, Tybur, Güler, Balliet, and Hofmann (2017) demonstrates, because aggressive confrontation is inherently risky and therefore only incentivized by natural selection to curtail significant fitness costs. Here, in 3 preregistered studies, we extend this sociofunctional perspective to cases of wrongs inflicted on siblings. We observed equivalently heightened anger in response to transgressions against either oneself or one's sibling relative to transgressions against acquaintances across studies, whereas transgressions against acquaintances evoked greater disgust and/or fear (both associated with social avoidance) in 2 of the 3 studies. Studies 2 and 3, which incorporated measures of tendencies to confront the transgressor, confirmed that the elevated anger elicited by self or sibling harm partially mediated heightened inclinations toward direct aggression. Finally, in Study 3 we compared tendencies to experience anger and to directly aggress on behalf of siblings and close friends. Despite reporting greater affiliative closeness for friends than for siblings, harm to friends failed to evoke heightened anger relative to acquaintance harm, and participants were inclined to directly aggress against those who had harmed their sibling to a significantly greater extent than when the harm befell their friend. These overall results broadly replicate Molho et al.'s (2017) findings and theoretically extend the sociofunctionalist account of moral emotions to kinship. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Posterior medial frontal cortex and threat-enhanced religious belief: a replication and extension.

Research indicates that the posterior medial frontal cortex (pMFC) functions as a 'neural alarm' complex broadly involved in registering threats and helping to muster relevant responses. Holbrook and colleagues investigated whether pMFC similarly mediates ideological threat responses, finding that downregulating pMFC via transcranial magnetic stimulation (TMS) caused (i) less avowed religious belief despite being reminded of death and (ii) less group bias despite encountering a sharp critique of the national in-group. While suggestive, these findings were limited by the absence of a non-threat comparison condition and reliance on sham rather than control TMS. Here, in a pre-registered replication and extension, we downregulated pMFC or a control region (MT/V5) and then primed participants with either a reminder of death or a threat-neutral topic. As mentioned previously, participants reminded of death reported less religious belief when pMFC was downregulated. No such effect of pMFC downregulation was observed in the neutral condition, consistent with construing pMFC as monitoring for salient threats (e.g. death) and helping to recruit ideological responses (e.g. enhanced religious belief). However, no effect of downregulating pMFC on group bias was observed, possibly due to reliance on a collegiate in-group framing rather than a national framing as in the prior study.

Factors Predicting Willingness to Share COVID-19 Misinformation.

We conducted a preregistered exploratory survey to assess whether patterns of individual differences in political orientation, social dominance orientation (SDO), traditionalism, conspiracy ideation, or attitudes about science predict willingness to share different kinds of misinformation regarding the COVID-19 pandemic online. Analyses revealed two orthogonal models of individual differences predicting the willingness to share misinformation over social media platforms. Both models suggest a sizable role of different aspects of political belief, particularly SDO, in predicting tendencies to share different kinds of misinformation, predominantly conspiracy theories. Although exploratory, results from this study can contribute to the formulation of a socio-cognitive profile of individuals who act as vectors for the spread of scientific misinformation online, and can be useful for computationally modeling misinformation diffusion.

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.

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.

Elevation, an emotion for prosocial contagion, is experienced more strongly by those with greater expectations of the cooperativeness of others.

A unique emotion, elevation, is thought to underlie prosocial contagion, a process whereby witnessing a prosocial act leads to acting prosocially. Individuals differ in their propensity to experience elevation, and thus their proneness to prosocial contagion, but little is known about the causes of such variation. We introduce an adaptationist model wherein elevation marks immediate circumstances in which generalized prosociality is advantageous, with this evaluation of circumstances hinging in part on prior expectations of others' prosociality. In 15 studies, we add to evidence that elevation can reliably be elicited and mediates prosocial contagion. Importantly, we confirm a novel prediction-generated by our adaptationist account-that an idealistic attitude, which indexes others' expected degree of prosociality, moderates the relationship between exposure to prosocial cues and experiencing elevation. We discuss how our findings inform both basic theorizing in the affective sciences and translational efforts to engineer a more harmonious world, and we offer future research directions to further test and extend our model.

Does observing reciprocity or exploitation affect elevation, a mechanism driving prosociality?

Fitness is enhanced by determining when to behave prosocially. Elevation, an uplifting emotion elicited by witnessing exemplary prosociality, upregulates prosociality in the presence of prosocial others, as such contexts render prosociality profitable and/or antisociality costly. Prior research examines responses to a single highly prosocial individual. However, the profitability of enhancing prosociality hinges not only on potential interactions with a single actor, but also on the actions of others. Accordingly, information regarding how others respond to the prosocial exemplar may influence elevation elicitation and corresponding changes in prosocial motivation. If others reciprocate the exemplar's prosociality, or pay prosociality forward, this expands opportunities for the observer to profit by increasing prosociality, and thus could enhance elevation elicitation. Conversely, if others exploit the exemplar, this may diminish the profitability of prosociality, as the observer who acts prosocially may similarly be exploited and/or the resources with which the exemplar could reciprocate will be depleted. Conducting three online studies of Americans in which information regarding the responses of others to a prosocial exemplar was manipulated, we find that, against predictions, prosocial responses by the beneficiaries of prosociality generally do not enhance elevation among observers, whereas, consonant with predictions, antisocial responses markedly diminish elevation among observers.