TNF-Like Weak Inducer of Apoptosis (TWEAK) Promotes Beta Cell Neogenesis from Pancreatic Ductal Epithelium in Adult Mice

Aim/Hypothesis The adult mammalian pancreas has limited ability to regenerate in order to restore adequate insulin production from multipotent progenitors, the identity and function of which remain poorly understood. Here we test whether the TNF family member TWEAK (TNF-like weak inducer of apoptosis) promotes β-cell neogenesis from proliferating pancreatic ductal epithelium in adult mice. Methods: C57Bl/6J mice were treated with Fc-TWEAK and pancreas harvested at different time points for analysis by histology and immunohistochemistry. For lineage tracing, 4 week old double transgenic mice CAII-CreERTM: R26R-eYFP were implanted with tamoxifen pellet, injected with Fc-TWEAK or control Ig twice weekly and analyzed at day 18 for TWEAK-induced duct cell progeny by costaining for insulin and YFP. The effect of TWEAK on pancreatic regeneration was determined by pancytokeratin immunostaining of paraffin embedded sections from wildtype and TWEAK receptor (Fn14) deficient mice after Px. Results: TWEAK stimulates proliferation of ductal epithelial cells through its receptor Fn14, while it has no mitogenic effect on pancreatic α- or β-cells or acinar cells. Importantly, TWEAK induces transient expression of endogenous Ngn3, a master regulator of endocrine cell development, and induces focal ductal structures with characteristics of regeneration foci. In addition, we identify by lineage tracing TWEAK-induced pancreatic β-cells derived from pancreatic duct epithelial cells. Conversely, we show that Fn14 deficiency delays formation of regenerating foci after Px and limits their expansion. Conclusions/Interpretation We conclude that TWEAK is a novel factor mediating pancreatic β-cell neogenesis from ductal epithelium in normal adult mice

Urinary TWEAK as a biomarker of lupus nephritis: a multicenter cohort study

Introduction: TNF-like weak inducer of apoptosis (TWEAK) has been implicated as a mediator of chronic inflammatory processes via prolonged activation of the NF-κB pathway in several tissues, including the kidney. Evidence for the importance of TWEAK in the pathogenesis of lupus nephritis (LN) has been recently introduced. Thus, TWEAK levels may serve as an indication of LN presence and activity. Methods: Multicenter cohorts of systemic lupus erythematosus (SLE) patients and controls were recruited for cross-sectional and longitudinal analysis of urinary TWEAK (uTWEAK) and/or serum TWEAK (sTWEAK) levels as potential biomarkers of LN. The performance of TWEAK as a biomarker for nephritis was compared with routinely used laboratory tests in lupus patients, including anti-double stranded DNA antibodies and levels of C3 and C4. Results: uTWEAK levels were significantly higher in LN patients than in non-LN SLE patients and other disease control groups (P = 0.039). Furthermore, uTWEAK was better at distinguishing between LN and non-LN SLE patients than anti-DNA antibodies and complement levels, while high uTWEAK levels predicted LN in SLE patients with an odds ratio of 7.36 (95% confidence interval = 2.25 to 24.07; P = 0.001). uTWEAK levels peaked during LN flares, and were significantly higher during the flare than at 4 and 6 months prior to or following the flare event. A linear mixed-effects model showed a significant association between uTWEAK levels in SLE patients and their disease activity over time (P = 0.008). sTWEAK levels, however, were not found to correlate with the presence of LN or the degree of nephritis activity. Conclusions: High uTWEAK levels are indicative of LN, as opposed to non-LN SLE and other healthy and disease control populations, and reflect renal disease activity in longitudinal follow-up. Thus, our study further supports a role for TWEAK in the pathogenesis of LN, and provides strong evidence for uTWEAK as a candidate clinical biomarker for LN

TL1A–DR3 interaction regulates Th17 cell function and Th17-mediated autoimmune disease

T helper type 17 (Th17) cells play an important pathogenic function in autoimmune diseases; their regulation, however, is not well understood. We show that the expression of a tumor necrosis factor receptor family member, death receptor 3 (DR3; also known as TNFRSF25), is selectively elevated in Th17 cells, and that TL1A, its cognate ligand, can promote the proliferation of effector Th17 cells. To further investigate the role of the TL1A–DR3 pathway in Th17 regulation, we generated a TL1A-deficient mouse and found that TL1A−/− dendritic cells exhibited a reduced capacity in supporting Th17 differentiation and proliferation. Consistent with these data, TL1A−/− animals displayed decreased clinical severity in experimental autoimmune encephalomyelitis (EAE). Finally, we demonstrated that during EAE disease progression, TL1A was required for the optimal differentiation as well as effector function of Th17 cells. These observations thus establish an important role of the TL1A–DR3 pathway in promoting Th17 cell function and Th17-mediated autoimmune disease

An Yb3+-doped Lu2SiO5 mode-locked laser using a reflective graphene oxide absorber

Reflective graphene oxide played the part of the saturable absorber to achieve a continuous wave mode-locking (CWML) laser based on Yb3+:Lu2SiO5 (Yb:LSO) crystal for the first time. The laser operated at a repetition frequency of 87 MHz at a maximum average output power of 0.95 W with a single pulse energy of 10.9 nJ. A 9.8 ps ultra-short pulse was yielded at 1058 nm with a full width at half maximum (FWHM) of 2.09 nm, corresponding to a peak power of 1.11 kW

Dual-wavelength synchronous mode-locked Yb:LSO laser using a double-walled carbon nanotube saturable absorber

A dual-wavelength, passively mode-locked Yb:LSO laser was demonstrated using a double-walled carbon nanotube as a saturable absorber. The maximum average output power of the laser was 1.34 W at the incident pump power of 9.94 W. The two central wavelengths were 1057 and 1058 nm. The corresponding pulse duration of the autocorrelation interference pattern was about 15 ps, while the beat pulse repetition rate was 0.17 THz and the width of one beat pulse about 2 ps. When the incident pump power was above 10.25 W, a multiwavelength mode-locked oscillation phenomenon was observed. After employing a pair of SF10 prisms, a 1058.7 nm single-wavelength mode-locked laser was obtained with a pulse width of 7 ps. (C) 2016 Optical Society of Americ

Kerr-Lens Mode-Locked Femtosecond Yb:GdYSiO5 Laser Directly Pumped by a Laser Diode

We demonstrate the first Kerr-lens mode-locked operation in a diode-pumped Yb:GdYSiO5 oscillator. Under a diode pump power of 5 W, 141 fs pulses with an average power of 237 mW were obtained at a repetition rate of 118 MHz. The central wavelength was at 1094 nm with a bandwidth of 10.1 nm. Shorter pulses were obtained by adjusting the cavity to operate at a shorter wavelength, resulting in 55 fs pulse duration at the central wavelength of 1054 nm with a bandwidth of 23.5 nm