Leucine Zipper-Bearing Kinase Is a Critical Regulator of Astrocyte Reactivity in the Adult Mammalian CNS.

Reactive astrocytes influence post-injury recovery, repair, and pathogenesis of the mammalian CNS. Much of the regulation of astrocyte reactivity, however, remains to be understood. Using genetic loss and gain-of-function analyses in vivo, we show that the conserved MAP3K13 (also known as leucine zipper-bearing kinase [LZK]) promotes astrocyte reactivity and glial scar formation after CNS injury. Inducible LZK gene deletion in astrocytes of adult mice reduced astrogliosis and impaired glial scar formation, resulting in increased lesion size after spinal cord injury. Conversely, LZK overexpression in astrocytes enhanced astrogliosis and reduced lesion size. Remarkably, in the absence of injury, LZK overexpression alone induced widespread astrogliosis in the CNS and upregulated astrogliosis activators pSTAT3 and SOX9. The identification of LZK as a critical cell-intrinsic regulator of astrocyte reactivity expands our understanding of the multicellular response to CNS injury and disease, with broad translational implications for neural repair

The Anaphase-Promoting Complex or Cyclosome Supports Cell Survival in Response to Endoplasmic Reticulum Stress

The anaphase-promoting complex or cyclosome (APC/C) is a multi-subunit ubiquitin ligase that regulates exit from mitosis and G1 phase of the cell cycle. Although the regulation and function of APC/CCdh1 in the unperturbed cell cycle is well studied, little is known of its role in non-genotoxic stress responses. Here, we demonstrate the role of APC/CCdh1 (APC/C activated by Cdh1 protein) in cellular protection from endoplasmic reticulum (ER) stress. Activation of APC/CCdh1 under ER stress conditions is evidenced by Cdh1-dependent degradation of its substrates. Importantly, the activity of APC/CCdh1 maintains the ER stress checkpoint, as depletion of Cdh1 by RNAi impairs cell cycle arrest and accelerates cell death following ER stress. Our findings identify APC/CCdh1 as a regulator of cell cycle checkpoint and cell survival in response to proteotoxic insults

The partial characterization of Cucurbita foetidissima (the buffalo gourd)

Digitized by Kansas Correctional Industrie

Characterization of the ER stress checkpoint in mammalian cells

Progression through the cell cycle adapts to both internal and environmental stimuli to ensure fidelity of cell division. Endoplasmic reticulum (ER) stress arising from an imbalance between cellular demand for protein folding and ER capacity has been described to cause G1 cell cycle arrest. The molecular components of this ER stress checkpoint have just begun to be uncovered. Although evidence emerge to suggest a prosurvival role for the ER stress-induced cell cycle arrest, the functional significance of this checkpoint in mammalian cells largely remains as an open question. Given the implication of ER stress in multiple human diseases like cancer and neurological disorders, elucidation of the link between ER stress and cell cycle may provide new insights to the pathogenesis and treatment of these diseases. In Chapter 1, I introduce the principles of cell cycle regulation and checkpoint responses, leading to a discussion on the discoveries that support an emerging ER stress checkpoint in eukaryotic cells. In Chapter 2, I investigate the mechanisms underlying cell cycle delay in G1 in response to ER stress in mammalian cells, showing that ER stress reduces the protein expression of Skp2 by downregulating Ufd1, a protein that stabilizes Skp2 through its ability to recruit the deubiquitinating enzyme USP13. This results in an accumulation of p27 that partly contributes to G1 arrest in ER-stressed cells. In Chapter 3, I identify another regulator of the ER stress checkpoint, APC/C-Cdh1, and begin to examine the upstream signals responsible for activating APC/C-Cdh1 under ER stress conditions. In Chapter 4, I provide a summary of the work and discuss the implications of my finding

Astrocytic Contribution to Motor Recovery After Spinal Cord Injury

Spinal cord injury results in loss of motor, sensory, and autonomic functions. Astrocytes, a cell type in the central nervous system, react to injury in a process called astrogliosis that impacts repair. At the site of injury, reactive astrocytes form an astrocytic scar that yields neuroprotective effects. Impaired formation of this scar causes increased tissue damage along with worsened motor recovery. Our lab identified leucine zipper-bearing kinase (LZK) as a key activator of astrogliosis that promotes wound healing after spinal cord injury in mice. This project examines the effect of astrocyte-specific LZK gene manipulation on hind-limb motor recovery following spinal cord injury. To determine the role of LZK on functional recovery post-injury, a complete crush was performed at thoracic level T8. Hindlimb function was measured using i) Basso Mouse Scale, an open field test that assesses gross motor function; and ii) regular horizontal ladder test that measures skilled stepping over 2 months after injury. Analysis demonstrated decreased function following LZK gene deletion. Decreased gross and fine motor function improvement was seen for the LZK-knock out when compared to the control genotype, suggesting that LZK is necessary for functional recovery. This is further suggested through increased gross motor function observed for the LZK-over expression when compared to the control genotype. Further research must be done to determine the role of LZK-over expression in fine motor recovery

Visfatin associated with major adverse cardiovascular events in patients with acute myocardial infarction

Abstract Background Visfatin is an adipokine that related with the inflammation in atherosclerosis and the destabilization of atherosclerotic plaque. The aim of this study was to observe the relationship between visfatin and major adverse cardiovascular events (MACEs) in acute myocardial infarction (AMI) patients. Methods We enrolled a total of 238 patients (183 AMI and 55 control) who underwent coronary angiography. Patients with AMI were followed for an average of 19.3 months and 159 patients were finally included in the study. Results It was observed patients with AMI had higher serum visfatin levels than controls. The total incidence of MACEs was 11.32% (18/159) in AMI patients. After calculation of the Youden index, the best cut-off value of visfatin on the curve of receiver-operating characteristic was 8.799 ng/mL for predicting the occurrence of MACEs. The occurrence of MACEs was elevated in high-visfatin group (≥8.799 ng/mL) compared with low-visfatin group (≤8.799 ng/mL). The time to MACEs was correlated with visfatin (HR = 1.235, 95%CI 1.051–1.451, P = 0.01) and high-visfatin group had an earlier time to MACEs and a shorter time of cumulative survival. Conclusions Increased serum visfatin levels were observed in AMI patients, and correlated with an earlier onset and higher incidence of MACEs. </jats:sec