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The receptor-interacting serine/threonine-protein kinases RIPK1 and RIPK3 play important roles in necroptosis that are closely linked to the inflammatory response. Although the activation of necroptosis is well characterized, the mechanism that tunes down necroptosis is largely unknown. Here we find that Parkin (also known as PARK2), an E3 ubiquitin ligase implicated in Parkinson's disease and as a tumour suppressor, regulates necroptosis and inflammation by regulating necrosome formation. Parkin prevents the formation of the RIPK1-RIPK3 complex by promoting polyubiquitination of RIPK3. Parkin is phosphorylated and activated by the cellular energy sensor AMP-activated protein kinase (AMPK). Parkin deficiency potentiates the RIPK1-RIPK3 interaction, RIPK3 phosphorylation and necroptosis. Parkin deficiency enhances inflammation and inflammation-associated tumorigenesis. These findings demonstrate that the AMPK-Parkin axis negatively regulates necroptosis by inhibiting RIPK1-RIPK3 complex formation; this regulation may serve as an important mechanism to fine-tune necroptosis and inflammation.

Introduction Upper tract urothelial carcinomas (UTUCs) account for 5% to 10% of urothelial cancers. The phenomenon of stage migration in tumors has been evident with increased use and higher resolution of cross-sectional imaging. Using the National Cancer Database, we analyzed trends in stage at presentation and overall survival for UTUCs. Patients and Methods We analyzed UTUCs in the renal pelvis or ureter from 2004 to 2016. Pathologic tumor stage data were available for 71.3% of patients and clinical tumor staging were available for 28.7% of patients. Five-year overall survival was analyzed comparing patients between 2004-2007 and 2008-2011. Tumor stage was categorized as early (0-1), intermediate (2-3), or late (4) for survival analyses. Linear regression and Kaplan-Meier analyses were utilized. Results A total of 37,210 renal pelvic and 23,200 ureteral origin UTUC cases were evaluated. Stage migration toward stage 0 and stage 4 was observed. There was a significant increase in proportion of stage 0 Ta/Tis (22.8%-33.4%, R2 = 0.86, P Conclusion There is a stage migration toward stage 0 and stage 4 disease for UTUC. Five-year survival data from 2004 to 2011 remained stable across early, intermediate, and late stage groups.

Genomic stress leads to various forms of DNA damage, of which DNA double strand breaks (DSBs) are the most lethal. An army of signaling molecules is called to action as soon as these DNA breaks are detected. Various protein modifications, such as phosphorylation and ubiquitination, are an integral part of the reaction. While phosphorylation activates various proteins, ubiquitin (Ub) adducts typically act as docking sites for DNA repair factors. The response to DNA DSB starts with the protein kinase ATM phosphorylating various substrates including MDC1 and histone H2AX. This mediator protein, MDC1, then recognizes phosphorylated histone H2AX and amplifies the damage response. The E3 ligase, RNF8, recognizes and binds to phosphorylated MDC1. RNF8 then modifies an unknown protein to call a second ubiquitin ligase, RNF168, into action. It has been recognized that these two ubiquitin ligases are recruited sequentially but there is an unknown linker protein between them. These two ubiquitin ligases are crucial to the formation of DSB-associated ubiquitin conjugates and, as a result, there has been long standing interest in the field in identifying the link between the two factors. In this paper we identify lethal(3) malignant brain tumor like 2 (L3MBTL2) as the substrate of RNF8 (Nowsheen S, et al. Nat Cell Biol 20:455-464, 2018). We report that ATM-mediated phosphorylation of the polycomb group like protein L3MBTL2 and subsequent interaction with MDC1 brings it to the vicinity of the DNA lesion. RNF8 acts upon this phosphorylated L3MBTL2 and generates K63-linked polyubiquitin chains. This modified substrate is subsequently recognized by RNF168 and tethers the protein to the DNA lesion. RNF168 then ubiquitinates proteins such as histone H2A and H2AX to further amplify the damage response and recruit repair proteins such as BRCA1 and 53BP1 (Figure 1).

Cellular senescence, which is characterized by an irreversible cell-cycle arrest1 accompanied by a distinctive secretory phenotype2, can be induced through various intracellular and extracellular factors. Senescent cells that express the cell cycle inhibitory protein p16INK4A have been found to actively drive naturally occurring age-related tissue deterioration3,4 and contribute to several diseases associated with ageing, including atherosclerosis5 and osteoarthritis6. Various markers of senescence have been observed in patients with neurodegenerative diseases7–9; however, a role for senescent cells in the aetiology of these pathologies is unknown. Here we show a causal link between the accumulation of senescent cells and cognition-associated neuronal loss. We found that the MAPTP301SPS19 mouse model of tau-dependent neurodegenerative disease10 accumulates p16INK4A-positive senescent astrocytes and microglia. Clearance of these cells as they arise using INK-ATTAC transgenic mice prevents gliosis, hyperphosphorylation of both soluble and insoluble tau leading to neurofibrillary tangle deposition, and degeneration of cortical and hippocampal neurons, thus preserving cognitive function. Pharmacological intervention with a first-generation senolytic modulates tau aggregation. Collectively, these results show that senescent cells have a role in the initiation and progression of tau-mediated disease, and suggest that targeting senescent cells may provide a therapeutic avenue for the treatment of these pathologies. In a mouse model of tau-dependent neurodegenerative disease, the clearance of senescent glial cells prevents the degeneration of cortical and hippocampal neurons and preserves cognitive function.

Cellular effects of ionizing radiation (IR) are of great variety and level, but they are mainly damaging since radiation can perturb all important components of the cell, from the membrane to the nucleus, due to alteration of different biological molecules ranging from lipids to proteins or DNA. Regarding DNA damage, which is the main focus of this review, as well as its repair, all current knowledge indicates that IR-induced DNA damage is always more complex than the corresponding endogenous damage resulting from endogenous oxidative stress. Specifically, it is expected that IR will create clusters of damage comprised of a diversity of DNA lesions like double strand breaks (DSBs), single strand breaks (SSBs) and base lesions within a short DNA region of up to 15–20 bp. Recent data from our groups and others support two main notions, that these damaged clusters are: (1) repair resistant, increasing genomic instability (GI) and malignant transformation and (2) can be considered as persistent “danger” signals promoting chronic inflammation and immune response, causing detrimental effects to the organism (like radiation toxicity). Last but not least, the paradigm shift for the role of radiation-induced systemic effects is also incorporated in this picture of IR-effects and consequences of complex DNA damage induction and its erroneous repair.

Doping of aluminium into titanium dioxide (TiO2) thin film matrix has been achieved by the solution method. The doping concentrations have been varied from 0·0 at-% (undoped) to 5·0 at-%. The current–voltage measurement shows conductivity increment for the aluminium doped TiO2 thin films compared to the undoped sample. Scanning electron microscopy images reveal that the thin films have a mesoporous structure suitable for application in the dye sensitised solar cell.

This paper is aimed at investigating how the positive dc corona performance of conductor-to-plane gaps is influenced by grounded and negatively stressed metallic grids located underneath the coronating conductor. A systematic experimental study is made to investigate the corona current–voltage characteristics and the current density distribution at the ground plane with and without grid. The wire-to-wire spacing, number, lateral distribution and height of grid wires as well as the conductor diameter are varied. The current density distribution at the ground plane is correlated with Warburg law that was proposed for point-plane coronas.

Breast cancer is the leading cause of cancer death in women, the second most common cancer worldwide, and the fifth most common cause of cancer-related deaths [1-3]. Not only are the incidence rates of breast cancer increasing, partly due to improved screening and detection techniques, but also the global burden of breast cancer exceeds all other cancers. So it is imperative to improve the quality of life of these patients.

We describe two patients with established antiphospholipidsyndrome, who during periods of subtheraputic anticoagulation, developed acute optic neuropathy and transverse myelopathy. Treatment with optimal anticoagulation and high dose glucocorticoids was followed by resolution of the neurologic deficits.

Treatment of patients with acute respiratory failure (ARF) involves mechanical ventilation via endotracheal intubation (INV). Noninvasive positive pressure ventilation (NIV) using the Bi-level positive airway pressure (BiPAP) can be safe and effective in improving gas exchange. The aim of the study is to assess NIV (BiPAP) as an alternative method for ventilation in ARF and to determine factors that predict the successful use of BiPAP.

The use of intravenous immunoglobulins (IVIG) in the treatment of human sepsis remains controversial. The aim of this study was to assess the effects of IVIG in patients with severe sepsis with or without septic shock on mortality and morbidity compared with standard treatment of sepsis.