FOXO-regulated DEAF1 controls muscle regeneration through autophagy.

The commonality between various muscle diseases is the loss of muscle mass, function, and regeneration, which severely restricts mobility and impairs the quality of life. With muscle stem cells (MuSCs) playing a key role in facilitating muscle repair, targeting regulators of muscle regeneration has been shown to be a promising therapeutic approach to repair muscles. However, the underlying molecular mechanisms driving muscle regeneration are complex and poorly understood. Here, we identified a new regulator of muscle regeneration, Deaf1 (Deformed epidermal autoregulatory factor-1) - a transcriptional factor downstream of foxo signaling. We showed that Deaf1 is transcriptionally repressed by FOXOs and that DEAF1 targets to Pik3c3 and Atg16l1 promoter regions and suppresses their expression. Deaf1 depletion therefore induces macroautophagy/autophagy, which in turn blocks MuSC survival and differentiation. In contrast, Deaf1 overexpression inactivates autophagy in MuSCs, leading to increased protein aggregation and cell death. The fact that Deaf1 depletion and its overexpression both lead to defects in muscle regeneration highlights the importance of fine tuning DEAF1-regulated autophagy during muscle regeneration. We further showed that Deaf1 expression is altered in aging and cachectic MuSCs. Manipulation of Deaf1 expression can attenuate muscle atrophy and restore muscle regeneration in aged mice or mice with cachectic cancers. Together, our findings unveil an evolutionarily conserved role for DEAF1 in muscle regeneration, providing insights into the development of new therapeutic strategies against muscle atrophy.

Chemsex as lines of flight? Critical Deleuzean perspectives on chemical intimacies.

BACKGROUND: Public health scholars informed by a dominant biomedical paradigm have in their 'rush to risk' emphasised the problematic aspects of chemsex. Meanwhile, critical chemsex scholars have attemped to destigmatise such sexual-chemical practices and foreground how they can be transformative. Taking these two perspectives as points of departure, we make a case for understanding chemsex vis-à-vis Deleuzean lines of flight. METHODS: Semi-structured in-depth interviews were conducted with 33 purposively sampled sexual minority men seeking therapy for chemsex dependency in Singapore. Interview topics included participants' experiences and histories of chemsex, substance use, and their ongoing recovery. Interviews were audio-recorded, transcribed and then analysed according to key themes. RESULTS: We illustrate how chemically inflected sexual encounters can offer deterritorialising flights of fantasy and freedom from a heteronormative social structure that pathologises gay sex. At the same time, we argue that these flight lines are not static, neither do they extend indefinitely in space-time. Rather, we show how flights of freedom can evolve into lines of fright (or non-flight) when chemsex practitioners are met with critical thresholds that reveal the less-than-desirable aspects of being intoxicated. Consequently, they may eventually consider the reterritorialisation of their lives (i.e. abstinence and recovery) as a more constructive option. Regardless of their decisions to ride on chemically-induced flight lines or to take a step back from such deterritorialising pathways, they have troubled stereotypical perspectives of drug users as passive automatons. CONCLUSIONS: This paper enriches the chemsex scholarship by presenting a Deleuzean conceptualisation of chemical-sexual intimacies without romantacising and/or overstating the 'escape'/'freedom' that chemsex can facilitate. Future research in this arena could explore the complicated intimate relationships that users may have with their drug(s) of choice, and their varied lines of (non-)flight over a longitudinal study.

ggbulksurv: An R package for easy Drosophila and C. elegans survival analysis.

Lifespan studies on fast-aging model organisms like C.elegans and D.melanogaster are conducted with multiple organisms per vial. Lifespan data results in a "one row, multiple individuals" format, which is incompatible with R packages that require a "one row, one individual" format. We present ggbulksurv , an R package for user-friendly survival analysis and highlight three key features. (1) pivot_prism converts data for PRISM, allowing biologists to plot survival curves without manually expanding each observation. (2) run_bulksurv() takes in a "one row, multiple individuals" table and plots a customizable survival curve. (3) Advanced users who require custom survival objects can specify a custom formula, facilitating complex survival analysis. We provide a time saving solution for lifespan data analysis.

The Wnt Co-Receptor PTK7/Otk and Its Homolog Otk-2 in Neurogenesis and Patterning.

Wnt signaling is a highly conserved metazoan pathway that plays a crucial role in cell fate determination and morphogenesis during development. Wnt ligands can induce disparate cellular responses. The exact mechanism behind these different outcomes is not fully understood but may be due to interactions with different receptors on the cell membrane. PTK7/Otk is a transmembrane receptor that is implicated in various developmental and physiological processes including cell polarity, cell migration, and invasion. Here, we examine two roles of Otk-1 and Otk-2 in patterning and neurogenesis. We find that Otk-1 is a positive regulator of signaling and Otk-2 functions as its inhibitor. We propose that PTK7/Otk functions in signaling, cell migration, and polarity contributing to the diversity of cellular responses seen in Wnt-mediated processes.

An Optogenetic Method to Study Signal Transduction in Intestinal Stem Cell Homeostasis.

Homeostasis in adult organs involves replacement of cells from a stem cell pool maintained in specialized niches regulated by extracellular signals. This cell-to-cell communication employs signal transduction pathways allowing cells to respond with a variety of behaviors. To study these cellular behaviors, signaling must be perturbed within tissues in precise patterns, a technique recently made possible by the development of optogenetic tools. We developed tools to study signal transduction in vivo in an adult fly midgut stem cell model where signaling was regulated by the application of light. Activation was achieved by clustering of membrane receptors EGFR and Toll, while inactivation was achieved by clustering the downstream activators ERK/Rolled and NFκB/Dorsal in the cytoplasm, preventing nuclear translocation and transcriptional activation. We show that both pathways contribute to stem and transit amplifying cell numbers and affect the lifespan of adult flies. We further present new approaches to overcome overexpression phenotypes and novel methods for the integration of optogenetics into the already-established genetic toolkit of Drosophila.

WNT Signaling in Disease.

Developmental signaling pathways control a vast array of biological processes during embryogenesis and in adult life. The WNT pathway was discovered simultaneously in cancer and development. Recent advances have expanded the role of WNT to a wide range of pathologies in humans. Here, we discuss the WNT pathway and its role in human disease and some of the advances in WNT-related treatments.

Smoking spaces as enabling spaces of wellbeing.

A persistent emphasis on the negative biomedical effects of cigarette smoking effectively glosses over the affectual-sensual and social wellbeing that smoking can enable. In addition, while tobacco research has recently been more attuned to the stigmatizing affects brought about by smoking de-normalization efforts, a lot less attention has been placed on how smokers negotiate these feelings of stigmatization so as to restore their personal spaces of wellbeing. In this paper, I situate my investigation of smoking geographies in the burgeoning literature on enabling spaces which focuses on how places co-constitute our ability to act/affect in empowering ways. By deploying qualitative research methods such as in-depth interviews, I argue that an acknowledgment of how smoking spaces in Singapore can be enabling along affectual, sensorial and social registers is long overdue. While it is not my purpose to systematically downplay the damaging health effects that smoking can engender, a focus on enabling smoking spaces emphasizes the role of smokers as creative agents capable of (re)fashioning their own holistic and subjective versions of wellbeing. In so doing, I hope to contribute to the existing research on smoking spaces and a recent profusion of work on relational geographies of affect.