Nuclear factor κB-inducing kinase activation as a mechanism of pancreatic β cell failure in obesity

The nuclear factor κB (NF-κB) pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic β cell dysfunction in the metabolic syndrome. Whereas canonical NF-κB signaling is well studied, there is little information on the divergent noncanonical NF-κB pathway in the context of pancreatic islet dysfunction. Here, we demonstrate that pharmacological activation of the noncanonical NF-κB-inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. We identify NIK as a critical negative regulator of β cell function, as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of noncanonical NF-κB components p100 to p52, and accumulation of RelB. TNF and receptor activator of NF-κB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive β cell-intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the noncanonical NF-κB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to β cell failure. These studies reveal that NIK contributes a central mechanism for β cell failure in diet-induced obesity.</p

A TRAF3-NIK module differentially regulates DNA vs RNA pathways in innate immune signaling.

Detection of viral genomes by the innate immune system elicits an antiviral gene program mediated by type I interferons (IFNs). While viral RNA and DNA species induce IFN via separate pathways, the mechanisms by which these pathways are differentially modulated are unknown. Here we show that the positive regulator of IFN in the RNA pathway, TRAF3, has an inhibitory function in the DNA pathway. Loss of TRAF3 coincides with increased expression of the alternative NF-κB-inducing molecule, NIK, which interacts with the DNA pathway adaptor, STING, to enhance IFN induction. Cells lacking NIK display defective IFN activation in the DNA pathway due to impaired STING signaling, and NIK-deficient mice are more susceptible to DNA virus infection. Mechanistically, NIK operates independently from alternative NF-κB signaling components and instead requires autophosphorylation and oligomerization to activate STING. Thus a previously undescribed pathway for NIK exists in activating IFN in the DNA pathway

Generation of tunable q-switched erbium-doped fiber laser based on graphite flakes saturable absorber

Pulsed fiber laser has tremendous application in laser processing and laser sensor. The key element to produce a passively Q-switched fiber laser is by using a saturable absorber (SA). Passively Q-switched fiber laser is the most desirable pulse in laser technology due to its ability to generate optical pulses in microsecond and nanosecond. The aim of this study is to construct a single ring erbium-doped fiber (EDF) laser based on graphite flakes SA to produce short pulse laser. Graphite flakes SA were prepared by mechanical exfoliation techniques and was transferred onto a fiber ferrule tip. The saturable absorption property of the graphite was measured using twin detector method which resulted in a modulation depth of 23.82% with a saturation intensity of 0.031 MW/cm2. Surface morphology, elemental analysis and absorbance characteristics of the graphite flakes were analyzed by the field emission scanning electron microscope (FESEM), energy dispersive X-ray spectroscopy (EDX) and ultraviolet visible spectroscopy (UV-VIS). The result showed that the carbon element on the SA has a very strong peak intensity. The two different EDF coefficient of 6.43 dB/m and 18.93 dB/m (EDF M-5 and EDF I-12) showed a repetition rate of 41.62 kHz and 60.00 kHz with a pulse width of 6.45 μs and 3.38 μs, respectively at a pump power of 268.8 mW. The wavelength tunability of passively Q-switched fiber laser for EDF M-5 and EDF I-12 were optimized at fixed pump power where the tuning range of EDF M-5 occurred between 1544 nm to 1560 nm and 1552 nm to 1570 nm for EDF I-12. The passively Q-switched fiber laser with different EDF coefficients were successfully constructed in a single ring configuration with more selection of wavelength that is up to L band by using higher EDF coefficient

Performance and wake analysis of rotors in axial flight using computational fluid dynamics

Flow field around rotors in axial flight is known to be complex especially in steep descent where the rotor is operating inside its own wake. It is often reported that, in this flight condition, the rotor is susceptible to severe wake interactions causing unsteady blade load, severe vibration, loss of performance, as well as poor control and handling. So far, there is little data from experimental and numerical analysis available for rotors in axial flight. In this paper, the steady Reynolds-Averaged Navier-Stokes Computational Fluid Dynamics solver Helicopter Multi-Block was used to predict the performance of rotors in axial flight. The main objective of this study was to improve the basic knowledge about the subject and to validate the flow solver used. The results obtained are presented in the form of surface pressure, rotor performance parameters, and vortex wake trajectories. The detailed velocity field of the tip vortex for a rotor in hover was also investigated, and a strong self-similarity of the swirl velocity profile was found. The predicted results obtained when compared with available experimental data showed a reasonably agreement for hover and descent rate, suggesting unsteady solution for rotors in vortex-ring state

The RET/PTC3 oncogene activates classical NF-κB by stabilizing NIK.

The oncogenic fusion protein RET/PTC3 (RP3) that is expressed in papillary thyroid carcinoma (PTC) and thyroid epithelia in Hashimoto\u27s thyroiditis activates nuclear factor-kappa B (NF-κB) and induces pro-inflammatory gene expression; however, the mechanism of this activation is unknown. To address this, we expressed RP3 in murine embryonic fibroblasts (MEFs) lacking key classical and noncanonical NF-κB signaling components. In wild-type MEFs, RP3 upregulated CCL2, CXCL1, granulocyte-macrophage colony-stimulating factor and tumor necrosis factor expression and activated classical but not noncanonical NF-κB. RP3-activated NF-κB in IκB kinase (IKK)β(-/-) MEFs but not IKKα- or NF-κB essential modulator (NEMO)-deficient cells and activation was inhibited by a peptide that blocks NEMO binding to the IKKs. RP3 increased the levels of NF-κB-inducing kinase (NIK) and did not activate NF-κB in NIK-deficient MEFs. Notably, NIK stabilization was not accompanied by TRAF3 degradation demonstrating that RP3 disrupts normal basal NIK regulation. Dominant-negative NIK blocked RP3-induced NF-κB activation and an RP3 signaling mutant (RP3(Y588F)) did not stabilize NIK. Finally, examination of PTC specimens revealed strong positive staining for NIK. We therefore conclude that RP3 activates classical NF-κB via NIK, NEMO and IKKα. Importantly, our findings reveal a novel mechanism for oncogene-induced NF-κB activation via stabilization of NIK