The caspase-3-p120-RasGAP module generates a NF-κB repressor in response to cellular stress.

The nuclear factor κB (NF-κB) transcription factor is a master regulator of inflammation. Short-term NF-κB activation is generally beneficial. However, sustained NF-κB might be detrimental, directly causing apoptosis of cells or leading to a persistent damaging inflammatory response. NF-κB activity in stressed cells needs therefore to be controlled for homeostasis maintenance. In mildly stressed cells, caspase-3 cleaves p120 RasGAP, also known as RASA1, into an N-terminal fragment, which we call fragment N. We show here that this fragment is a potent NF-κB inhibitor. Fragment N decreases the transcriptional activity of NF-κB by promoting its export from the nucleus. Cells unable to generate fragment N displayed increased NF-κB activation upon stress. Knock-in mice expressing an uncleavable p120 RasGAP mutant showed exaggerated NF-κB activation when their epidermis was treated with anthralin, a drug used for the treatment of psoriasis. Our study provides biochemical and genetic evidence of the importance of the caspase-3-p120-RasGAP stress-sensing module in the control of stress-induced NF-κB activation

Double Internal Limiting Membrane Insertion for Macular Hole-Associated Retinal Detachment

Purpose. To describe a modified technique of internal limiting membrane (ILM) insertion for macular hole- (MH-) associated retinal detachment (RD) in highly myopic eyes. Methods. Nine eyes underwent pars plana vitrectomy, cortical vitreous removal, and fovea-sparing ILM peeling. Double ILM insertion into the hole was performed with inverted perifoveal ILM and a free ILM flap followed by air-fluid exchange. Results. Two of the 9 eyes had perifoveal ILM partially torn after cortical vitreous or epiretinal removal. All eyes had the ILM plug stabilized within the MH after double ILM insertion. Postoperatively, MH was sealed with the retina reattached in all the eyes. Conclusion. Double ILM insertion may further secure the ILM flap in place in the eyes with MH-associated RD, especially in cases in which insufficient perifoveal ILM was left. This trial is registered with the clinical registration number Clinicaltrials.gov NCT03174639

Transmission of mitochondrial DNA following assisted reproduction and nuclear transfer

Review of the articleMitochondria are the organelles responsible for producing the majority of a cell's ATP and also play an essential role in gamete maturation and embryo development. ATP production within the mitochondria is dependent on proteins encoded by both the nuclear and the mitochondrial genomes, therefore co-ordination between the two genomes is vital for cell survival. To assist with this co-ordination, cells normally contain only one type of mitochondrial DNA (mtDNA) termed homoplasmy. Occasionally, however, two or more types of mtDNA are present termed heteroplasmy. This can result from a combination of mutant and wild-type mtDNA molecules or from a combination of wild-type mtDNA variants. As heteroplasmy can result in mitochondrial disease, various mechanisms exist in the natural fertilization process to ensure the maternal-only transmission of mtDNA and the maintenance of homoplasmy in future generations. However, there is now an increasing use of invasive oocyte reconstruction protocols, which tend to bypass mechanisms for the maintenance of homoplasmy, potentially resulting in the transmission of either form of mtDNA heteroplasmy. Indeed, heteroplasmy caused by combinations of wild-type variants has been reported following cytoplasmic transfer (CT) in the human and following nuclear transfer (NT) in various animal species. Other techniques, such as germinal vesicle transfer and pronuclei transfer, have been proposed as methods of preventing transmission of mitochondrial diseases to future generations. However, resulting embryos and offspring may contain mtDNA heteroplasmy, which itself could result in mitochondrial disease. It is therefore essential that uniparental transmission of mtDNA is ensured before these techniques are used therapeutically

Chitosan Oligosaccharides Attenuate Ocular Inflammation in Rats with Experimental Autoimmune Anterior Uveitis

We investigated the protective effects and mechanisms of chitosan oligosaccharides (COS) on experimental autoimmune anterior uveitis (EAAU) in rats. EAAU was induced in Lewis rats by footpad and intraperitoneal injections of melanin-associated antigen. The rats received intraperitoneal injections of low-dose (5 mg/kg) or high-dose (10 mg/kg) COS or PBS daily after the immunization. The effects of COS were evaluated by determining the clinical scores and the morphology of the iris/ciliary body (ICB). The expression of inflammatory mediators was evaluated using western blot, immunofluorescence, and ELISA. Treatment with COS significantly attenuated the clinical scores and the leukocyte infiltration in the ICB in a dose-dependent manner. COS effectively reduced the expression of inflammatory mediators (TNF-α, iNOS, MCP-1, RANTES, fractalkine, and ICAM-1). Moreover, COS decreased the IκB degradation and p65 presence in the ICB, which resulted in the inhibition of NF-κB/DNA binding activity. In an in vitro study, sensitized spleen-derived lymphocytes of the COS-treated group showed less chemotaxis toward their aqueous humor and decreased secretion of the above inflammatory mediators in the culture media. COS treated EAAU by inhibiting the activation of NF-κB and reducing the expression of inflammatory mediators. COS might be a potential treatment for acute anterior uveitis

Peroxiredoxin II Regulates Effector and Secondary Memory CD8+ T cell Responses

Reactive oxygen intermediates (ROI) generated in response to receptor stimulation play an important role in cellular responses. However, the effect of increased H2O2on an antigen-specific CD8+ T cell response was unknown. Following T cell receptor (TCR) stimulation, the expression and oxidation of peroxiredoxin II (PrdxII), a critical antioxidant enzyme, increased in CD8+ T cells. Deletion of PrdxII increased ROI, S phase entry, division, and death during in vitro division. During primary acute viral and bacterial infection, the number of effector CD8+ T cells in PrdxII-deficient mice was increased, while the number of memory cells were similar to those of the wild-type cells. Adoptive transfer of P14 TCR transgenic cells demonstrated that the increased expansion of effector cells was T cell autonomous. After rechallenge, effector CD8+ T cells in mutant animals were more skewed to memory phenotype than cells from wild-type mice, resulting in a larger secondary memory CD8+ T cell pool. During chronic viral infection, increased antigen-specific CD8+ T cells accumulated in the spleens of PrdxII mutant mice, causing mortality. These results demonstrate that PrdxII controls effector CD8+ T cell expansion, secondary memory generation, and immunopathology

Combined Tractional and Rhegmatogenous Retinal Detachment in Proliferative Diabetic Retinopathy in the Anti-VEGF Era

Purpose. To investigate the clinical features, surgical outcomes, and prognostic factors of combined rhegmatogenous and tractional detachment (combined RD) in proliferative diabetic retinopathy (PDR) in recent years. Methods. Medical records of PDR and combined RD treated with vitrectomy from 2008 to 2013 were retrospectively reviewed. Results. A total of 57 eyes from 49 patients were included. Nine eyes had received panretinal photocoagulation (PRP) and 7 eyes had intravitreal bevacizumab (IVB) within 3 months before RD developed. Thirty-eight eyes (66.7%) had ≧3 sites of broad adhesion of fibrovascular proliferation (FVP). Thirty-three eyes (57.9%) showed active FVP. Thirty-four eyes (59.6%) had extent of RD involving 3 or 4 quadrants. The primary reattachment rate was 93.0%, and the final visual acuity (VA) improved by more than 3 lines in 80.7% of eyes. Neovascular glaucoma occurred in 4 eyes postoperatively. Poor preoperative VA, severe vitreoretinal adhesion, and broad extent of RD had significant correlation with poor visual outcomes. Conclusion. PRP or IVB might play a role in provoking combined RD. The anatomical and functional success rates of surgery were high. Poor preoperative VA and severe proliferations predicted poor visual outcomes

Search For Heavy Pointlike Dirac Monopoles

We have searched for central production of a pair of photons with high transverse energies in $p\bar p$ collisions at $\sqrt{s} = 1.8$ TeV using $70 pb^{-1}$ of data collected with the D\O detector at the Fermilab Tevatron in 1994--1996. If they exist, virtual heavy pointlike Dirac monopoles could rescatter pairs of nearly real photons into this final state via a box diagram. We observe no excess of events above background, and set lower 95% C.L. limits of $610, 870, or 1580 GeV/c^2$ on the mass of a spin 0, 1/2, or 1 Dirac monopole.Comment: 12 pages, 4 figure

Limits on Anomalous WWgamma and WWZ Couplings

Limits on the anomalous WWgamma and WWZ couplings are presented from a simultaneous fit to the data samples of three gauge boson pair final states in pbar-p collisions at sqrt(s)=1.8 TeV: Wgamma production with the W boson decaying to enu or munu, W boson pair production with both of the W bosons decaying to enu or munu, and WW or WZ production with one W boson decaying to enu and the other W boson or the Z boson decaying to two jets. Assuming identical WWgamma and WWZ couplings, 95 % C.L. limits on the anomalous couplings of -0.30<Delta kappa<0.43 (lambda = 0) and -0.20<lambda<0.20 (Delta kappa = 0) are obtained using a form factor scale Lambda = 2.0 TeV. Limits found under other assumptions on the relationship between the WWgamma and WWZ couplings are also presented.Comment: 13 pages, 3 figures, submitted to Physical Review

Second Generation Leptoquark Search in p\bar{p} Collisions at s\sqrt{s} = 1.8 TeV

We report on a search for second generation leptoquarks with the D\O\ detector at the Fermilab Tevatron $p\bar{p}$ collider at $\sqrt{s}$ = 1.8 TeV. This search is based on 12.7 pb$^{-1}$ of data. Second generation leptoquarks are assumed to be produced in pairs and to decay into a muon and quark with branching ratio $\beta$ or to neutrino and quark with branching ratio $(1-\beta)$. We obtain cross section times branching ratio limits as a function of leptoquark mass and set a lower limit on the leptoquark mass of 111 GeV/c$^{2}$ for $\beta = 1$ and 89 GeV/c$^{2}$ for $\beta = 0.5$ at the 95%\ confidence level.Comment: 18 pages, FERMILAB-PUB-95/185-

Search for Top Squark Pair Production in the Dielectron Channel

This report describes the first search for top squark pair production in the channel stop_1 stopbar_1 -> b bbar chargino_1 chargino_1 -> ee+jets+MEt using 74.9 +- 8.9 pb^-1 of data collected using the D0 detector. A 95% confidence level upper limit on sigma*B is presented. The limit is above the theoretical expectation for sigma*B for this process, but does show the sensitivity of the current D0 data set to a particular topology for new physics.Comment: Five pages, including three figures, submitted to PRD Brief Report