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Methadone regulations have changed minimally since 1974, despite advances in the understanding of the nature of opioid use disorder (OUD) and the role of medications in its treatment. At that time, most patients with OUD were considered to have anti-social personality disorders and the regulations aimed to exert maximal control over medication access. Six- or seven-day clinic attendance is required for months, regardless of distance, or childcare and other social responsibilities. Take home medications are not allowed unless rigid and formulaic conditions are met. Although addiction medicine has rejected the "criminal" paradigm in favor of OUD as a treatable medical disorder, methadone regulations have not kept pace with the science. Pregnancy is characterized by an ultra-rapid metabolic state, but regulations prevent the use of daily divided doses of methadone to maintain stability. This results in repeated episodes of maternal/fetal opioid withdrawal, as well as other fetal physiologic abnormalities. Interference with dose regimen adjustments prevents optimal outcomes. Further, methadone clinics are mostly urban, leaving patients in rural areas without access. This led to excessive morbidity and mortality when the opioid crisis hit. The response of merely expanding capacity in overcrowded urban clinics created a contagion menace when Covid-19 arrived. Pregnant women (and parents with children) were forced to negotiate dosing in dangerous conditions. A revised methadone system must provide treatment that is local, flexible, and limited in size to manage viral contagion risks. This regulatory change can most easily be started by changing regulations that adversely affect pregnant women.

Adult muscle stem cells (MuSCs) are known to replicate upon activation before differentiating and fusing to regenerate myofibers. It is unclear whether MuSC differentiation is intrinsically linked to cell division, which has implications for stem cell population maintenance. We use single-cell RNA-sequencing to identify transcriptionally diverse subpopulations of MuSCs after 5 days of a growth stimulus in adult muscle. Trajectory inference in combination with a novel mouse model for tracking MuSC-derived myonuclei and in vivo labeling of DNA replication revealed an MuSC population that exhibited division-independent differentiation and fusion. These findings demonstrate that in response to a growth stimulus in the presence of intact myofibers, MuSC division is not obligatory. [ABSTRACT FROM AUTHOR]

The central dogma of molecular biology dictates the general flow of molecular information from DNA that leads to a functional cellular outcome. In skeletal muscle fibers, the extent to which global myonuclear transcriptional alterations, accounting for epigenetic and post-transcriptional influences, contribute to an adaptive stress response is not clearly defined. In this investigation, we leveraged an integrated analysis of the myonucleus-specific DNA methylome and transcriptome, as well as myonuclear small RNA profiling to molecularly define the early phase of skeletal muscle fiber hypertrophy. The analysis of myonucleus-specific mature microRNA and other small RNA species provides new directions for exploring muscle adaptation and complemented the methylation and transcriptional information. Our integrated multi-omics interrogation revealed a coordinated myonuclear molecular landscape during muscle loading that coincides with an acute and rapid reduction of oxidative metabolism. This response may favor a biosynthesis-oriented metabolic program that supports rapid hypertrophic growth. Graphical Abstract [ABSTRACT FROM AUTHOR]

Prince & Smolensky (1993) describe a version of OT, one in which maximal harmony is achieved in small steps of gradual harmonic improvement, because a more restrained GEN is limited to making modest changes in the input one at a time.In this chapter, I explore some of the differences between classic OT with free GEN on the one hand and persistent OT with restrained GEN on the other. We will see, as Prince and Smolensky (1993) suggest, that the single-operation and harmonic-improvement requirements do indeed have consequences that are different from those of the familiar OT model. This chapter's goal is not to decide squarely for one version of OT over the other, though elsewhere (McCarthy 2006) I argue in favor of a derivative of persistent OT called OT-CC (for OT with candidate chains).