Pervasive nuclear envelope ruptures precede ECM signaling and disease onset without activating cGAS-STING in Lamin-cardiomyopathy mice.

Nuclear envelope (NE) ruptures are emerging observations in Lamin-related dilated cardiomyopathy, an adult-onset disease caused by loss-of-function mutations in Lamin A/C, a nuclear lamina component. Here, we test a prevailing hypothesis that NE ruptures trigger the pathological cGAS-STING cytosolic DNA-sensing pathway using a mouse model of Lamin cardiomyopathy. The reduction of Lamin A/C in cardio-myocyte of adult mice causes pervasive NE ruptures in cardiomyocytes, preceding inflammatory transcription, fibrosis, and fatal dilated cardiomyopathy. NE ruptures are followed by DNA damage accumulation without causing immediate cardiomyocyte death. However, cGAS-STING-dependent inflammatory signaling remains inactive. Deleting cGas or Sting does not rescue cardiomyopathy in the mouse model. The lack of cGAS-STING activation is likely due to the near absence of cGAS expression in adult cardiomyocytes at baseline. Instead, extracellular matrix (ECM) signaling is activated and predicted to initiate pro-inflammatory communication from Lamin-reduced cardiomyocytes to fibroblasts. Our work nominates ECM signaling, not cGAS-STING, as a potential inflammatory contributor in Lamin cardiomyopathy.

The cGAS-STING pathway is dispensable in a mouse model of LMNA-cardiomyopathy despite nuclear envelope rupture.

Mutations in the nuclear Lamin A/C gene (LMNA) cause diverse degenerative disorders, including malignant dilated cardiomyopathy in adults. A prevailing hypothesis postulates that LMNA mutations cause nuclear envelope ruptures that trigger pathogenic inflammatory signaling via the cGAS-STING cytosolic DNA-sensing pathway. Here, we provide evidence against this hypothesis, using a mouse model of LMNA-related cardiomyopathy that mimics Lamin A/C protein reduction observed in patient cardiomyocytes. We observed that pervasive nuclear envelope ruptures preceded the onset of cardiac transcriptional modulation and dilated cardiomyopathy. Nuclear ruptures activated DNA damage response without causing immediate cardiomyocyte death. However, cGAS-STING downstream cytokine genes remained inactive in the mutant cardiomyocytes. Deleting cGas or Sting did not alleviate cardiomyopathy. Instead, extracellular matrix signaling was predicted to emanate from Lamin A/C-reduced cardiomyocytes to communicate with fibroblasts in the heart. These findings suggest that cGAS-STING is not a major pathogenetic contributor to LMNA-related dilated cardiomyopathy in adult humans.

The Healthy Nurse: Identifying Barriers to Healthy Eating at Work.

OBJECTIVES: To identify the barriers to healthy eating in a nurse's work environment by utilizing the PhotoVoice method, a self-report survey, and semi-structured interviews. METHODS: Recruitment of participants consisted of friends and acquaintances (i.e., convenience sample) that are current nurses in the field. Research design comprised of three parts: photo collection, a self-report survey, and individual semi-structured interviews. Participants used PhotoVoice to take pictures of their experiences and environment. This tool focused on barriers, strengths and weaknesses. Participants were allotted two weeks to collect pictures, and used personal devices such as a cell phone. Pictures were then sent directly to the researcher via email and securely stored. Surveys were administered by Qualtrics to each participant to complete on their own time. The self-report survey was a compilation of variables the researcher sought to analyze: nutrition habits, mental and emotional health, physical health, and demographics. During the interviews, the participants explained and discussed their photographs. A list of follow-up questions were constructed to provide supplemental information. Each interview was completed under 30 minutes. Participants were informed the interviews were audio recorded, and were later transcribed verbatim by the researcher. RESULTS: The final sample size concluded 6 participants. Over half the nurses worked in a hospital setting. Common themes to barriers comprised of inconsistent break patterns, lack of availability and quality of food, and the abundance of accessible unhealthy options. Participant recommendations included bringing in healthier options, easier access and availability to healthy food, a nurse buddy system and accountability among staff. CONCLUSIONS: Attention and research are lacking in this area and further studies are necessary to shine light on the importance of a nurse's health. Future organizational support for nurses involves an extension on cafeteria hours to allow all shifts to obtain quality food, ordering healthier options, allow for water bottles or dispensers to be heavily present and to implement a plan for sufficient breaks. FUNDING SOURCES: There was not a need for funding.