Asparagine Synthetase Marks a Distinct Dependency Threshold for Cardiomyocyte Dedifferentiation.

BACKGROUND: Adult mammalian cardiomyocytes have limited proliferative capacity, but in specifically induced contexts they traverse through cell-cycle reentry, offering the potential for heart regeneration. Endogenous cardiomyocyte proliferation is preceded by cardiomyocyte dedifferentiation (CMDD), wherein adult cardiomyocytes revert to a less matured state that is distinct from the classical myocardial fetal stress gene response associated with heart failure. However, very little is known about CMDD as a defined cardiomyocyte cell state in transition. METHODS: Here, we leveraged 2 models of in vitro cultured adult mouse cardiomyocytes and in vivo adeno-associated virus serotype 9 cardiomyocyte-targeted delivery of reprogramming factors (Oct4, Sox2, Klf4, and Myc) in adult mice to study CMDD. We profiled their transcriptomes using RNA sequencing, in combination with multiple published data sets, with the aim of identifying a common denominator for tracking CMDD. RESULTS: RNA sequencing and integrated analysis identified Asparagine Synthetase (Asns) as a unique molecular marker gene well correlated with CMDD, required for increased asparagine and also for distinct fluxes in other amino acids. Although Asns overexpression in Oct4, Sox2, Klf4, and Myc cardiomyocytes augmented hallmarks of CMDD, Asns deficiency led to defective regeneration in the neonatal mouse myocardial infarction model, increased cell death of cultured adult cardiomyocytes, and reduced cell cycle in Oct4, Sox2, Klf4, and Myc cardiomyocytes, at least in part through disrupting the mammalian target of rapamycin complex 1 pathway. CONCLUSIONS: We discovered a novel gene Asns as both a molecular marker and an essential mediator, marking a distinct threshold that appears in common for at least 4 models of CMDD, and revealing an Asns/mammalian target of rapamycin complex 1 axis dependency for dedifferentiating cardiomyocytes. Further study will be needed to extrapolate and assess its relevance to other cell state transitions as well as in heart regeneration.

Why Are Some Male Alcohol Misuse Disorder Patients High Utilisers of Emergency Health Services? An Asian Qualitative Study.

BACKGROUND: Certain alcohol misuse patients heavily utilise the Emergency Department (ED) and Emergency Medical Services (EMS) and may present with intoxication or long-term sequelae of alcohol misuse. Our study explored reasons for repeated ED/EMS utilisation and sought to understand perpetuating and protective factors for drinking. METHODS: Face-to-face semi-structured qualitative interviews were conducted. Participants were recruited from an ED in Singapore. Interviews were audio-recorded, transcribed verbatim and underwent manual thematic analysis. Emergent themes were independently reviewed for agreement. Data from medical records, interview transcripts, and field notes were triangulated for analysis. RESULTS: All participants were male (n = 20) with an average age of 55.6 years (SD = 8.86). Most were unemployed (75%), did not have tertiary education (75%), were divorced (55%), and had pre-existing psychiatric conditions (60%) and chronic cardiovascular conditions (75%). Reasons for utilisation included a perceived need due to symptoms, although sometimes it was bystanders who called the ambulance. ED/EMS was preferred due to the perceived higher quality and speed of care. Persistent drinking was attributed to social and environmental factors, and as a coping mechanism for stressors. Rehabilitation programs and meaningful activities reduced drinking tendencies. CONCLUSION: ED/EMS provide sought-after services for alcohol misuse patients, resulting in high utilisation. Social and medical intervention could improve drinking behaviours and decrease overall ED/EMS utilisation.

Diffusing the bilingual lexicon: Task-based and lexical components of language switch costs.

Bilingual speakers show a response time (RT) cost when switching between languages. These costs could reflect the organization of language in a shared bilingual lexicon (Grainger, Midgley, & Holcomb, 2010) or a domain general cognitive processing cost (Green & Abutalebi, 2013). To test these accounts, we analysed RT distributions of bilingual (Spanish-English) performance on generalized lexical decision (GLD) tasks using Ratcliff (1978) diffusion model. Experiment 1 revealed that language switches decrease the rate of evidence accumulation (drift rate) and slow the cognitive processes that occur prior to decision-making (non-decision time). Experiment 2 showed that the anticipation of language switches did not change these effects. The results suggest that language switch costs originate from a combination of at least two loci: lexical access and a task-specific decision process.