Calcium-dependent O-GlcNAc signaling drives liver autophagy in adaptation to starvation.

Starvation induces liver autophagy, which is thought to provide nutrients for use by other organs and thereby maintain whole-body homeostasis. Here we demonstrate that O-linked ß-N-acetylglucosamine (O-GlcNAc) transferase (OGT) is required for glucagon-stimulated liver autophagy and metabolic adaptation to starvation. Genetic ablation of OGT in mouse livers reduces autophagic flux and the production of glucose and ketone bodies. Upon glucagon-induced calcium signaling, calcium/calmodulin-dependent kinase II (CaMKII) phosphorylates OGT, which in turn promotes O-GlcNAc modification and activation of Ulk proteins by potentiating AMPK-dependent phosphorylation. These findings uncover a signaling cascade by which starvation promotes autophagy through OGT phosphorylation and establish the importance of O-GlcNAc signaling in coupling liver autophagy to nutrient homeostasis.

Systemic Heparinization After Neuraxial Anesthesia in Vascular Surgery: A Retrospective Analysis.

OBJECTIVES: The American Society of Regional Anesthesia and Pain Medicine's guidelines recommend a 1-hour interval after neuraxial anesthesia (NA) before systemic heparinization to mitigate the risk of spinal hematoma (SH). The study authors aimed to characterize the time interval between NA and systemic heparinization in vascular surgery patients (primary outcome). The secondary outcomes included the historic incidence of SH, and risk estimation of the SH formation based on available data. Heparin dose, length of surgery, difficulty and/or the number of NA attempts, and patient demographics were recorded. DESIGN: A retrospective analysis between April 2012 and April 2022. SETTING: A single (academic) center. PARTICIPANTS: Vascular surgery patients. INTERVENTIONS: Intravenous heparin administration. MEASUREMENTS AND MAIN RESULTS: All (N = 311) vascular patients were reviewed, of whom 127 (5 femoral-femoral bypass, 67 femoral-popliteal bypass, and 55 endovascular aneurysm repairs [EVAR]) received NA and were included in the final analysis. Patients receiving general anesthesia alone (N = 184) were excluded. Neuraxial anesthesia included spinal (N = 119), epidural (N = 4), or combined spinal-epidural (N = 4) blocks. The average time between NA and heparin administration was 42.8 ± 22.1 minutes, with 83.7% of patients receiving heparin within 1 hour of NA. The time between NA and heparin administration was 40.4 ± 22.3, 50.1 ± 23.4, and 31.3 ± 12.5 minutes for femoral-femoral bypass, femoral-popliteal bypass, and EVAR, respectively. Heparin was administered after 1 hour of NA in 20% of femoral-femoral bypass, 27% of femoral-popliteal bypass, and 3.9% of EVAR patients. No SHs were reported during the study period. CONCLUSIONS: The vast majority of vascular surgery patients at the authors' center received heparin within 1 hour of NA. Further studies are required to assess if their findings are consistent in other vascular surgery settings and/or centers.

OGT suppresses S6K1-mediated macrophage inflammation and metabolic disturbance.

Enhanced inflammation is believed to contribute to overnutrition-induced metabolic disturbance. Nutrient flux has also been shown to be essential for immune cell activation. Here, we report an unexpected role of nutrient-sensing O-linked ß-N-acetylglucosamine (O-GlcNAc) signaling in suppressing macrophage proinflammatory activation and preventing diet-induced metabolic dysfunction. Overnutrition stimulates an increase in O-GlcNAc signaling in macrophages. O-GlcNAc signaling is down-regulated during macrophage proinflammatory activation. Suppressing O-GlcNAc signaling by O-GlcNAc transferase (OGT) knockout enhances macrophage proinflammatory polarization, promotes adipose tissue inflammation and lipolysis, increases lipid accumulation in peripheral tissues, and exacerbates tissue-specific and whole-body insulin resistance in high-fat-diet-induced obese mice. OGT inhibits macrophage proinflammatory activation by catalyzing ribosomal protein S6 kinase beta-1 (S6K1) O-GlcNAcylation and suppressing S6K1 phosphorylation and mTORC1 signaling. These findings thus identify macrophage O-GlcNAc signaling as a homeostatic mechanism maintaining whole-body metabolism under overnutrition.

Cost of COVID-19: Using life course theory as a lens to understand the consequences of the pandemic.

Context: The COVID-19 pandemic and associated countermeasures have had broad implications across society which will have implications for physical and mental health for years to come. Understanding these experiences through the lens of life course constructs may help communities, service providers including family doctors, and governments to recognize and respond more effectively to the lasting impacts. Objective: To use life course theory to explore the impacts of the COVID-19 pandemic and associated countermeasures on child and family mental, social, and emotional well-being. Study Design: Qualitative study including anonymous micro-narrative collection using Spryng.io software (n=210); in-depth interviews with health and social service providers (n=30). Directed content analysis was used to examine the experiences of the COVID-19 pandemic as they relate to key constructs in life course theory. Setting: Kingston, Frontenac, Lennox and Addington counties in South-Eastern Ontario (pop. 210,000). Population Studied: Participants were recruited to the micronarrative collection through convenience sampling using the online data collection tool, as well as through intentional sampling targeting Indigenous people and people experiencing socio economic deprivation and homelessness. Participants for the in-depth interviews were intentionally recruited as key informants from local health and social service organizations. Results: All of the key constructs of life course theory were relevant when applied to our findings. Our data identified meaningful impacts on life course trajectory components including transitions, turning points, and social pathways, as well as using the principles of agency, life span development, linked lives, timing, and time and place. Conclusions: Our data illustrate the pervasive impact of the COVID-19 pandemic on all aspects of the life course. While service providers and policy makers are attuned to the acute crises currently unfolding, the long term impacts of life course disruption will play out over years, or potentially over the entire lifespan of this cohort. Responses to the pandemic cannot limit themselves to crisis management in the next 12-18 months, but will need to integrate an understanding of life course theory to support long term healing of individuals and communities.

Transcriptional regulation of O-GlcNAc homeostasis is disrupted in pancreatic cancer.

Many intracellular proteins are reversibly modified by O-linked GlcNAc (O-GlcNAc), a post-translational modification that dynamically regulates fundamental cellular processes in response to diverse environmental cues. Accumulating evidence indicates that both excess and deficiency of protein O-GlcNAcylation can have deleterious effects on the cell, suggesting that maintenance of O-GlcNAc homeostasis is essential for proper cellular function. However, the mechanisms through which O-GlcNAc homeostasis is maintained in the physiologic state and altered in the disease state have not yet been investigated. Here, we demonstrate the existence of a homeostatic mechanism involving mutual regulation of the O-GlcNAc-cycling enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) at the transcriptional level. Specifically, we found that OGA promotes Ogt transcription through cooperation with the histone acetyltransferase p300 and transcription factor CCAAT/enhancer-binding protein ß (C/EBPß). To examine the role of mutual regulation of OGT and OGA in the disease state, we analyzed gene expression data from human cancer data sets, which revealed that OGT and OGA expression levels are highly correlated in numerous human cancers, particularly in pancreatic adenocarcinoma. Using a KrasG12D -driven primary mouse pancreatic ductal adenocarcinoma (PDAC) cell line, we found that inhibition of extracellular signal-regulated kinase (ERK) signaling decreases OGA glycosidase activity and reduces OGT mRNA and protein levels, suggesting that ERK signaling may alter O-GlcNAc homeostasis in PDAC by modulating OGA-mediated Ogt transcription. Our study elucidates a transcriptional mechanism that regulates cellular O-GlcNAc homeostasis, which may lay a foundation for exploring O-GlcNAc signaling as a therapeutic target for human disease.

The sweet tooth of the circadian clock.

The endogenous circadian clock is a key regulator of daily metabolic processes. On the other hand, circadian clocks in a broad range of tissues can be tuned by extrinsic and intrinsic metabolic cues. The bidirectional interaction between circadian clocks and metabolism involves both transcriptional and post-translational mechanisms. Nuclear receptors exemplify the transcriptional programs that couple molecular clocks to metabolism. The post-translational modifications of the core clock machinery are known to play a key role in metabolic entrainment of circadian clocks. O-linked N-acetylglucosamine modification (O-GlcNAcylation) of intracellular proteins is a key mediator of metabolic response to nutrient availability. This review highlights our current understanding of the role of protein O-GlcNAcylation in mediating metabolic input and output of the circadian clock.

O-GlcNAc transferase inhibits visceral fat lipolysis and promotes diet-induced obesity.

Excessive visceral fat accumulation is a primary risk factor for metabolically unhealthy obesity and related diseases. The visceral fat is highly susceptible to the availability of external nutrients. Nutrient flux into the hexosamine biosynthetic pathway leads to protein posttranslational modification by O-linked ß-N-acetylglucosamine (O-GlcNAc) moieties. O-GlcNAc transferase (OGT) is responsible for the addition of GlcNAc moieties to target proteins. Here, we report that inducible deletion of adipose OGT causes a rapid visceral fat loss by specifically promoting lipolysis in visceral fat. Mechanistically, visceral fat maintains a high level of O-GlcNAcylation during fasting. Loss of OGT decreases O-GlcNAcylation of lipid droplet-associated perilipin 1 (PLIN1), which leads to elevated PLIN1 phosphorylation and enhanced lipolysis. Moreover, adipose OGT overexpression inhibits lipolysis and promotes diet-induced obesity. These findings establish an essential role for OGT in adipose tissue homeostasis and indicate a unique potential for targeting O-GlcNAc signaling in the treatment of obesity.

The equivalent internal orientation and position noise for contour integration.

Contour integration is the joining-up of local responses to parts of a contour into a continuous percept. In typical studies observers detect contours formed of discrete wavelets, presented against a background of random wavelets. This measures performance for detecting contours in the limiting external noise that background provides. Our novel task measures contour integration without requiring any background noise. This allowed us to perform noise-masking experiments using orientation and position noise. From these we measure the equivalent internal noise for contour integration. We found an orientation noise of 6° and position noise of 3 arcmin. Orientation noise was 2.6x higher in contour integration compared to an orientation discrimination control task. Comparing against a position discrimination task found position noise in contours to be 2.4x lower. This suggests contour integration involves intermediate processing that enhances the quality of element position representation at the expense of element orientation. Efficiency relative to the ideal observer was lower for the contour tasks (36% in orientation noise, 21% in position noise) compared to the controls (54% and 57%).