Systematic Characterization of Stress-Induced RNA Granulation.

Upon stress, cytoplasmic mRNA is sequestered to insoluble ribonucleoprotein (RNP) granules, such as the stress granule (SG). Partially due to the belief that translationally suppressed mRNAs are recruited to SGs in bulk, stress-induced dynamic redistribution of mRNA has not been thoroughly characterized. Here, we report that endoplasmic reticulum (ER) stress targets only a small subset of translationally suppressed mRNAs into the insoluble RNP granule fraction (RG). This subset, characterized by extended length and adenylate-uridylate (AU)-rich motifs, is highly enriched with genes critical for cell survival and proliferation. This pattern of RG targeting was conserved for two other stress types, heat shock and arsenite toxicity, which induce distinct responses in the total cytoplasmic transcriptome. Nevertheless, stress-specific RG-targeting motifs, such as guanylate-cytidylate (GC)-rich motifs in heat shock, were also identified. Previously underappreciated, transcriptome profiling in the RG may contribute to understanding human diseases associated with RNP dysfunction, such as cancer and neurodegeneration.

Lipotoxicity induces hepatic protein inclusions through TANK binding kinase 1-mediated p62/sequestosome 1 phosphorylation.

Obesity commonly leads to hepatic steatosis, which often provokes lipotoxic injuries to hepatocytes that cause nonalcoholic steatohepatitis (NASH). NASH, in turn, is associated with the accumulation of insoluble protein aggregates that are composed of ubiquitinated proteins and ubiquitin adaptor p62/sequestosome 1 (SQSTM1). Formation of p62 inclusions in hepatocytes is the critical marker that distinguishes simple fatty liver from NASH and predicts a poor prognostic outcome for subsequent liver carcinogenesis. However, the molecular mechanism by which lipotoxicity induces protein aggregation is currently unknown. Here, we show that, upon saturated fatty acid-induced lipotoxicity, TANK binding kinase 1 (TBK1) is activated and phosphorylates p62. TBK1-mediated p62 phosphorylation is important for lipotoxicity-induced aggregation of ubiquitinated proteins and formation of large protein inclusions in hepatocytes. In addition, cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING), upstream regulators of TBK1, are involved in lipotoxic activation of TBK1 and subsequent p62 phosphorylation in hepatocytes. Furthermore, TBK1 inhibition prevented formation of ubiquitin-p62 aggregates not only in cultured hepatocytes, but also in mouse models of obesity and NASH. CONCLUSION: These results suggest that lipotoxic activation of TBK1 and subsequent p62 phosphorylation are critical steps in the NASH pathology of protein inclusion accumulation in hepatocytes. This mechanism can provide an explanation for how hypernutrition and obesity promote the development of severe liver pathologies, such as steatohepatitis and liver cancer, by facilitating the formation of p62 inclusions. (Hepatology 2018).

Autophagy and Human Neurodegenerative Diseases-A Fly's Perspective.

Neurodegenerative diseases in humans are frequently associated with prominent accumulation of toxic protein inclusions and defective organelles. Autophagy is a process of bulk lysosomal degradation that eliminates these harmful substances and maintains the subcellular environmental quality. In support of autophagy's importance in neuronal homeostasis, several genetic mutations that interfere with autophagic processes were found to be associated with familial neurodegenerative disorders. In addition, genetic mutations in autophagy-regulating genes provoked neurodegenerative phenotypes in animal models. The Drosophila model significantly contributed to these recent developments, which led to the theory that autophagy dysregulation is one of the major underlying causes of human neurodegenerative disorders. In the current review, we discuss how studies using Drosophila enhanced our understanding of the relationship between autophagy and neurodegenerative processes.

Biochemical Basis of Sestrin Physiological Activities.

Excessive accumulation of reactive oxygen species (ROS) and chronic activation of mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) are well-characterized promoters of aging and age-associated degenerative pathologies. Sestrins, a family of highly conserved stress-inducible proteins, are important negative regulators of both ROS and mTORC1 signaling pathways; however, the mechanistic basis of how Sestrins suppress these pathways remains elusive. In the past couple of years, breakthrough discoveries about Sestrin signaling and its molecular nature have markedly increased our biochemical understanding of Sestrin function. These discoveries have also uncovered new potential therapeutic strategies that may eventually enable us to attenuate aging and age-associated diseases.

Tumor suppressive role of sestrin2 during colitis and colon carcinogenesis.

The mTOR complex 1 (mTORC1) and endoplasmic reticulum (ER) stress pathways are critical regulators of intestinal inflammation and colon cancer growth. Sestrins are stress-inducible proteins, which suppress both mTORC1 and ER stress; however, the role of Sestrins in colon physiology and tumorigenesis has been elusive due to the lack of studies in human tissues or in appropriate animal models. In this study, we show that human SESN2 expression is elevated in the colon of ulcerative colitis patients but is lost upon p53 inactivation during colon carcinogenesis. In mouse colon, Sestrin2 was critical for limiting ER stress and promoting the recovery of epithelial cells after inflammatory injury. During colitis-promoted tumorigenesis, Sestrin2 was shown to be an important mediator of p53's control over mTORC1 signaling and tumor cell growth. These results highlight Sestrin2 as a novel tumor suppressor, whose downregulation can accelerate both colitis and colon carcinogenesis.

Sestrin2, a Regulator of Thermogenesis and Mitohormesis in Brown Adipose Tissue.

Sestrin2 is a stress-inducible protein that functions as an antioxidant and inhibitor of mTOR complex 1. In a recent study, we found that Sestrin2 overexpression in brown adipocytes interfered with normal metabolism by reducing mitochondrial respiration through the suppression of uncoupling protein 1 (UCP1) expression. The metabolic effects of Sestrin2 in brown adipocytes were dependent on its antioxidant activity, and chemical antioxidants produced similar effects in inhibiting UCP1-dependent thermogenesis. These observations suggest that low levels of reactive oxygen species (ROS) in brown adipocytes can actually be beneficial and necessary for proper metabolic homeostasis. In addition, considering that Sestrins are ROS inducible and perform ROS detoxifying as well as other metabolism-controlling functions, they are potential regulators of mitohormesis. This is a concept in which overall beneficial effects result from low-level oxidative stress stimuli, such as the ones induced by caloric restriction or physical exercise. In this perspective, we incorporate our recent insight obtained from the Sestrin2 study toward a better understanding of the relationship between ROS, Sestrin2, and mitochondrial metabolism in the context of brown adipocyte physiology.

Competitive inhibition reaction mechanisms for the two-step model of protein aggregation.

We propose three new reaction mechanisms for competitive inhibition of protein aggregation for the two-step model of protein aggregation. The first mechanism is characterized by the inhibition of native protein, the second is characterized by the inhibition of aggregation-prone protein and the third mechanism is characterized by the mixed inhibition of native and aggregation-prone proteins. Rate equations are derived for these mechanisms, and a method is described for plotting kinetic results to distinguish these three types of inhibitors. The derived rate equations provide a simple way of estimating the inhibition constant of native or aggregation-prone protein inhibitors in protein aggregation. The new approach is used to estimate the inhibition constants of different peptide inhibitors of insulin aggregation.

Variation in the incidence of distal radius fractures in the U.S. elderly as related to slippery weather conditions.

BACKGROUND: Distal radius fractures are costly and debilitating injuries, especially for the elderly. These fractures often occur from falls and commonly occur outdoors. Inclement weather may increase the risk of fall-related injuries. Small studies have reported an increased risk of distal radius fracture caused by inclement winter weather; larger studies are lacking. METHODS: The authors analyzed a sample of 2007 Medicare claims for distal radius fracture. Weather data were collected for the date and location of each distal radius fracture in the authors' analysis cohort. A novel slipperiness score was used as a measure of the severity of slippery outdoor conditions. Negative binomial regression models evaluated the correlation between slipperiness and distal radius fracture occurrence. RESULTS: Risk of distal radius fracture was higher in winter months (incidence rate ratio, 1.2; p < 0.001). Days with average temperature less than or equal to 32°F (incidence rate ratio, 1.36; p < 0.001), snow/ice on the ground at the start of the day (incidence rate ratio, 1.45; p < 0.001), and freezing rain (incidence rate ratio, 1.24; p = 0.025) all had an increased risk of distal radius fracture. The risk of sustaining a distal radius fracture was increased 21 percent on days with a slipperiness score above 4 (incidence rate ratio, 1.21; p = 0.007). For each increase in slipperiness score above 4, the incidence rate ratio of distal radius fracture increased as well. CONCLUSIONS: Weather events that create slippery walking conditions, often in the winter, result in an increased risk of distal radius fracture in the elderly. This finding can be used to support resource allocation and awareness and prevention campaigns. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, IV.

Postural reorganization induced by torso cutaneous covibration.

Cutaneous information from joints has been attributed proprioceptive properties similar to those of muscle spindles. This study aimed to assess whether vibration-induced changes in torso cutaneous information contribute to whole-body postural reorganization in humans. Ten healthy young adults stood in normal and Romberg stances with six vibrating actuators positioned on the torso in contact with the skin over the left and right external oblique, internal oblique, and erector spinae muscle locations at the L4/L5 vertebrae level. Vibrations around the torso were randomly applied at two locations simultaneously (covibration) or at all locations simultaneously. Kinematic analysis of the body segments indicated that covibration applied to the skin over the internal oblique muscles induced shifts of both the head and torso in the anterior direction (torso flexion) while the hips shifted in the posterior direction (ankle plantar flexion). Conversely, covibration applied to the skin over the erector spinae muscle locations produced opposite effects. However, covibration applied to the skin over the left internal oblique and left erector spinae, the right internal oblique and right erector spinae, or at all locations simultaneously did not induce any significant postural changes. In addition, the center of pressure position as measured by the force plate was unaffected by all covibration conditions tested. These results were independent of stance and suggest an integrated and coordinated reorganization of posture in response to vibration-induced changes in cutaneous information. In addition, combinations of vibrotactile stimuli over multiple locations exhibit directional summation properties in contrast to the individual responses we observed in our previous work.

History and evolution of the Kessler repair.

The "grasping technique" described by Isidor Kessler and Fuad Nissim in 1969 is a popular method of flexor tendon repair. Different authors have modified this technique to the point where the so-called "modified Kessler technique" bears little resemblance to the original description. This article sheds light on the life and contributions of Isidor Kessler, and examines the evolution of the Kessler technique and the origin of grasping and locking tendon repairs. We also discuss the problems associated with eponymous descriptions of tendon repair techniques and propose an alternative descriptive system.

Effects of co-vibrotactile stimulations around the torso on non-volitional postural responses.

The purpose of this study was to characterize the effects of co-vibrotactile stimulations around the torso on non-volitional postural responses in the absence of instructions. Four healthy young adults maintained an upright, erect posture with their eyes closed in two different stance conditions: normal and Romberg stance. Six vibrotactile transducers (tactors) were placed on the skin over the right and left external oblique, internal oblique, and erector spinae muscles. Either a combination of vibration at two locations or all locations around the torso was applied for 5 s during each experimental trial. Regardless of stance condition, vibration applied concurrently over the right and left internal oblique muscle locations and the right and left erector spinae muscle locations induced a postural shift in the anterior and posterior directions, respectively. For these two stimulation conditions, the root-mean-square of sway in the anterior-posterior direction was significantly greater during vibration than before or after stimulation. However, simultaneous activation of all tactors, a combination of right internal oblique and right erector spinae locations, and a combination of left internal oblique and left erector spinae locations did not produce significant directional postural shifts or increases in sway, regardless of the stance condition. These findings suggest that stimuli combinations contribute to a vector summation of individual postural responses described in our previous work and that they could be leveraged in balance-related applications of sensory augmentation vibrotactile displays.