Systemic inflammation, oxidative damage and neurocognition predict telomere length in a transdiagnostic sample stratified by global DNA methylation levels.

Epigenetic mechanisms contribute to the maintenance of both type 2 diabetes mellitus (T2DM) and psychiatric disorders. Emerging evidence suggests that molecular pathways and neurocognitive performance regulate epigenetic dynamics in these disorders. The current combined and transdiagnostic study investigated whether inflammatory, oxidative stress, adhesion molecule, neurocognitive and functional performance are significant predictors of telomere dynamics in a sample stratified by global DNA methylation levels. Peripheral blood inflammation, oxidative stress and adhesion molecule biomarkers and neurocognitive function were assessed twice over a 1-year period in 80 individuals, including 16 with schizophrenia (SZ), 16 with bipolar disorder (BD), 16 with major depressive disorder (MDD), 15 with T2DM, and 17 healthy controls (HCs). Leukocyte telomere length (LTL) was measured by qRT-PCR using deoxyribonucleic acid (DNA) extracted from peripheral blood samples. A posteriori, individuals were classified based on their global methylation score (GMS) at baseline into two groups: the below-average methylation (BM) and above-average methylation (AM) groups. Hierarchical and k-means clustering methods, mixed one-way analysis of variance and linear regression analyses were performed. Overall, the BM group showed a significantly higher leukocyte telomere length (LTL) than the AM group at both time points (p = 0.02; η2p = 0.06). Moreover, the BM group had significantly lower levels of tumor necrosis factor alpha (TNF-α) (p = 0.03; η2p = 0.06) and C-reactive protein (CRP) (p = 0.03; η2p = 0.06) than the AM group at the 1-year follow-up. Across all participants, the regression models showed that oxidative stress (reactive oxygen species [ROS]) (p = 0.04) and global cognitive score [GCS] (p = 0.02) were significantly negatively associated with LTL, whereas inflammatory (TNF-α) (p = 0.04), adhesion molecule biomarkers (inter cellular adhesion molecule [ICAM]) (p = 0.009), and intelligence quotient [IQ] (p = 0.03) were significantly positively associated with LTL. Moreover, the model predictive power was increased when tested in both groups separately, explaining 15.8% and 28.1% of the LTL variance at the 1-year follow-up for the AM and BM groups, respectively. Heterogeneous DNA methylation in individuals with T2DM and severe mental disorders seems to support the hypothesis that epigenetic dysregulation occurs in a transdiagnostic manner. Our results may help to elucidate the interplay between epigenetics, molecular processes and neurocognitive function in these disorders. DNA methylation and LTL are potential therapeutic targets for transdiagnostic interventions to decrease the risk of comorbidities.

The lincRNA JUNI regulates the stress-dependent induction of c-Jun, cellular migration and survival through the modulation of the DUSP14-JNK axis.

Cancer cells employ adaptive mechanisms to survive various stressors, including genotoxic drugs. Understanding the factors promoting survival is crucial for developing effective treatments. In this study, we unveil a previously unexplored long non-coding RNA, JUNI (JUN-DT, LINC01135), which is upregulated by genotoxic drugs through the activation of stress-activated MAPKs, JNK, and p38 and consequently exerts positive control over the expression of its adjacent gene product c-Jun, a well-known oncoprotein, which transduces signals to multiple transcriptional outputs. JUNI regulates cellular migration and has a crucial role in conferring cellular resistance to chemotherapeutic drugs or UV radiation. Depletion of JUNI markedly increases the sensitivity of cultured cells and spheroids to chemotherapeutic agents. We identified 57 proteins interacting with JUNI. The activity of one of them the MAPK phosphatase and inhibitor, DUSP14, is counteracted by JUNI, thereby, facilitating efficient JNK phosphorylation and c-Jun induction when cells are exposed to UV radiation. The antagonistic interplay with DUSP14 contributes not only to c-Jun induction but also augments the survival of UV-exposed cells. In summary, we introduce JUNI as a novel stress-inducible regulator of c-Jun, positioning it as a potential target for enhancing the sensitivity of cancer cells to chemotherapy.

Oxidative stress-mediated alterations in histone post-translational modifications.

Epigenetic regulation of gene expression provides a finely tuned response capacity for cells when undergoing environmental changes. However, in the context of human physiology or disease, any cellular imbalance that modulates homeostasis has the potential to trigger molecular changes that result either in physiological adaptation to a new situation or pathological conditions. These effects are partly due to alterations in the functionality of epigenetic regulators, which cause long-term and often heritable changes in cell lineages. As such, free radicals resulting from unbalanced/extended oxidative stress have been proved to act as modulators of epigenetic agents, resulting in alterations of the epigenetic landscape. In the present review we will focus on the particular effect that oxidative stress and free radicals produce in histone post-translational modifications that contribute to altering the histone code and, consequently, gene expression. The pathological consequences of the changes in this epigenetic layer of regulation of gene expression are thoroughly evidenced by data gathered in many physiological adaptive processes and in human diseases that range from age-related neurodegenerative pathologies to cancer, and that include respiratory syndromes, infertility, and systemic inflammatory conditions like sepsis.

Dilatometric and Microstructural Study of Martensite Tempering in 4% Mn Steel.

This paper presents the results of martensite tempering resistance in 4% Mn steel. The material was quenched and tempered at 350 °C for 15, 30, and 60 min. The analysis of the quenching and tempering was carried out using dilatometric and microstructural approaches. The phase composition was assessed using X-ray diffraction. The Ms temperature and tempering progress were simulated using JMatPro software. The dilatometric analysis revealed a small decrease in the relative change in length (RCL) during tempering. This decrease was connected to the precipitation kinetics of cementite within the martensite laths. The microstructure investigation using a scanning electron microscope showed a very small amount of carbides, even for the longest tempering time. This showed the high tempering resistance of the martensite in medium-Mn steels. The hardness results showed an insignificant decrease in the hardness depending on the tempering time, which confirmed the high tempering resistance of martensite.

Dilatometric Study of Phase Transformations in 5 Mn Steel Subjected to Different Heat Treatments.

The work presents results of phase transformation kinetics of hot-rolled 5% Mn steel subjected to different heat treatments. Three different schedules were introduced: isothermal holding in a bainite region, coiling simulation and intercritical annealing. The evolution of microstructure components was investigated using dilatometric and metallographic analyses. According to obtained results, the medium-Mn steel exhibits high resistance for γ/α transformation during the bainite transformation and coiling simulation (upon cooling from the austenite region). During 5 h isothermal holding, no bainite and/or ferrite formation was detected. This results in the formation of martensite upon cooling to room temperature. Differently, when the steel was subjected to the intercritical annealing at 720 and 700 °C (upon heating from room temperature), a final microstructure consisted of ferrite, martensite and retained austenite. At 700 °C, no fresh martensite formation was detected upon cooling to room temperature. This means that the austenite was enriched in carbon during the intercritical annealing step enough to keep its thermal stability.

Comparative study of penetrating keratoplasty and vitreoretinal surgery with Eckardt temporary keratoprosthesis in ocular trauma versus non-trauma patients.

PURPOSE: To evaluate the effectiveness of temporary keratoprosthesis combined with vitreoretinal surgery and penetrating keratoplasty in patients with or without trauma. METHODS: This retrospective study included 49 eyes in 49 non-trauma patients and 51 eyes in 48 ocular trauma patients who underwent penetrating keratoplasty and vitreoretinal surgery with Eckardt temporary keratoprosthesis between 2009 and 2016, with a follow-up of at least 12 months. Study variables included previous corneal, glaucoma, or retinal surgeries; various intraoperative surgical maneuvers; lens status; vitreoretinal and corneal pathology; functional outcomes; anatomical retinal reattachment; graft clarity; and need for glaucoma surgery or treatment. RESULTS: The mean age was 56 years in the non-trauma group and 42 years in the ocular trauma group. A total of 45% of the non-trauma cases and 24% of the ocular trauma cases had a single functional eye. Pseudophakic and aphakic keratopathy was diagnosed in 41% of the non-trauma group and corneal laceration in 65% of the ocular trauma group. In the ocular trauma group, injuries were open globe injury in 78%, closed globe injury in 12%, and intraocular foreign body in 10%. Retinal detachment with proliferative vitreoretinopathy was present in 39% of patients in the non-trauma group and in 35% of the ocular trauma group. Improvement or stability of visual acuity was higher among ocular trauma patients (86%) than in non-trauma patients (78%). The rate of clear corneal grafts was 49% in both groups. Retinal attachment was achieved in 90% and 78% of patients in the non-trauma and ocular trauma groups, respectively. The use of retinotomy had a positive influence on the final attached retina (p = 0.016). The placement of a scleral buckle significantly increased the risk of glaucoma (p = 0.004). Poor functional outcome was related to persistent retinal detachment (10% versus 16% in the non-trauma and ocular trauma groups, respectively), phthisis (25% versus 12%), hypotony (33% versus 18%), corneal graft end failure (51% in both groups), and secondary glaucoma (18% versus 24%). CONCLUSION: In patients with both vitreoretinal and corneal pathology, the use of Eckardt temporary keratoprosthesis combined with vitreoretinal surgery and penetrating keratoplasty resulted in improvement of visual acuity, particularly in the groups of ocular trauma and monocular patients. The high rate of retinal reattachment and the low rate of graft rejection was probably related to the use of new vitreoretinal techniques, including retinotomy in selected patients.

Oxidative post-translational modifications in histones.

Epigenetic regulation is attracting much attention because it explains many of the effects that the external environment induces in organisms. Changes in the cellular redox status and even more specifically in its nuclear redox compartment is one of these examples. Redox changes can induce modulation of the epigenetic regulation in cells. Here we present a few cases where reactive oxygen or nitrogen species induces epigenetic marks in histones. Posttranslational modification of these proteins like histone nitrosylation, carbonylation, or glutathionylation together with other mechanisms not reviewed here are the cornerstones of redox-related epigenetic regulation. We currently face a new field of research with potential important consequences for the treatment of many pathologies.

Extracellular histones activate autophagy and apoptosis via mTOR signaling in human endothelial cells.

Circulating histones have been proposed as targets for therapy in sepsis and hyperinflammatory symptoms. However, the proposed strategies have failed in clinical trials. Although different mechanisms for histone-related cytotoxicity are being explored, those mediated by circulating histones are not fully understood. Extracellular histones induce endothelial cell death, thereby contributing to the pathogenesis of complex diseases such as sepsis and septic shock. Therefore, the comprehension of cellular responses triggered by histones is capital to design effective therapeutic strategies. Here we report how extracellular histones induce autophagy and apoptosis in a dose-dependent manner in cultured human endothelial cells. In addition, we describe how histones regulate these pathways via Sestrin2/AMPK/ULK1-mTOR and AKT/mTOR. Furthermore, we evaluate the effect of Toll-like receptors in mediating autophagy and apoptosis demonstrating how TLR inhibitors do not prevent apoptosis and/or autophagy induced by histones. Our results confirm that histones and autophagic pathways can be considered as novel targets to design therapeutic strategies in endothelial damage.

Macular buckle technique in myopic traction maculopathy: a 16-year review of the literature and a comparison with vitreous surgery.

PURPOSE: The aim of this study is to review anatomical and functional outcomes following macular buckling (MB) in high myopia and to compare such results with those obtained by pars plana vitrectomy (PPV). METHODS: PubMed articles on MB in high myopia (2000-2016) were reviewed. Main outcomes included retinal reattachment and macular hole (MH) closure rates, resolution of myopic foveoschisis (MFS), and postoperative visual acuity. RESULTS: Thirty-one articles included 16 in patients with retinal detachment due to MH (MHRD group), 11 in MFS with or without foveal detachment (MFS group), and 4 in MH patients with MFS (MH-MFS group). Surgical techniques mainly differed in the type of buckle, rectus muscles involvement, and concurrent PPV. In eyes with persistent MH, prognosis in the MHRD and MH-MFS groups differed between eyes receiving MB compared to PPV: functional outcome was markedly poorer and there was a higher risk of retinal redetachment associated with PPV. In the MSF group, secondary MHs were more likely to develop in eyes treated with PPV and internal limiting membrane peeling than those undergoing MB alone or combined with PPV. Retinal pigment epithelium changes, malpositioning, perforation, and choroidal detachment were the main complications. CONCLUSIONS: Although different approaches are used, complete resolution of foveoschisis, retinal reattachment, and MH closure seem to be achieved more frequently with MB than PPV.

Oxidative Stress and the Epigenetics of Cell Senescence: Insights from Progeroid Syndromes.

BACKGROUND: Cell senescence constitutes a critical process to respond to a variety of insults and adverse circumstances. Senescence involves the detention of DNA replication and cell proliferation, and hence, genetic programs associated with DNA damage response, chromosome stability, chromatin rearrangement, epigenetic reprogramming, and cell cycle are tightly linked to the senescent phenotype. Although senescence increases with age, the real implication of senescence regulation in the progress of aging in humans is largely discussed. In this context, reactive oxygen species (ROS) accumulation has also been postulated to play a critical role in cell homeostasis, aging processes, and control of proliferation. METHODS: The previous years have produced a high increase in data that refine our understanding of the role of ROS, and their relationship with epigenetic events, in determining cellular fate. RESULTS: The accumulating evidence regarding the epigenetic regulation of ROS-mediated processes provides promising tools to deepen in our comprehension of the process of senescence, and to develop novel therapeutic strategies. In this review, we aim to provide an overview of the relationships between oxidative stress and cell senescence. CONCLUSION: We provide information about the role of epigenetic regulation in senescence and aging, collecting recent data from some examples of progeroid syndromes in which cell senescence, oxidative stress and epigenetic mechanisms are severely impaired. Finally, a collection of data is presented regarding current pharmacological approaches that either target or use oxidative stress-related factors or epigenetic regulators as strategies for disease treatment.

Role of glutathione in the regulation of epigenetic mechanisms in disease.

Epigenetics is a rapidly growing field that studies gene expression modifications not involving changes in the DNA sequence. Histone H3, one of the basic proteins in the nucleosomes that make up chromatin, is S-glutathionylated in mammalian cells and tissues, making Gamma-L-glutamyl-L-cysteinylglycine, glutathione (GSH), a physiological antioxidant and second messenger in cells, a new post-translational modifier of the histone code that alters the structure of the nucleosome. However, the role of GSH in the epigenetic mechanisms likely goes beyond a mere structural function. Evidence supports the hypothesis that there is a link between GSH metabolism and the control of epigenetic mechanisms at different levels (i.e., substrate availability, enzymatic activity for DNA methylation, changes in the expression of microRNAs, and participation in the histone code). However, little is known about the molecular pathways by which GSH can control epigenetic events. Studying mutations in enzymes involved in GSH metabolism and the alterations of the levels of cofactors affecting epigenetic mechanisms appears challenging. However, the number of diseases induced by aberrant epigenetic regulation is growing, so elucidating the intricate network between GSH metabolism, oxidative stress and epigenetics could shed light on how their deregulation contributes to the development of neurodegeneration, cancer, metabolic pathologies and many other types of diseases.

Radio-over-fiber linearization with optimized genetic algorithm CPWL model.

This article proposes an optimized version of a canonical piece-wise-linear (CPWL) digital predistorter in order to enhance the linearity of a radio-over-fiber (RoF) LTE mobile fronthaul. In this work, we propose a threshold allocation optimization process carried out by a genetic algorithm (GA) in order to optimize the CPWL model (GA-CPWL). Firstly, experiments show how the CPWL model outperforms the classical memory polynomial DPD in an intensity modulation/direct detection (IM/DD) RoF link. Then, the GA-CPWL predistorter is compared with the CPWL model in several scenarios, in order to verify that the proposed DPD offers better performance in different optical transmission conditions. Experimental results reveal that with a proper threshold allocation, the GA-CPWL predistorter offers very promising outcomes.

Direct transretinal removal of subfoveal perfluorocarbon liquid: the role and timing of internal limiting membrane peeling.

PURPOSE: To describe a case series including 4 patients undergoing direct transretinal aspiration of subfoveal perfluorocarbon liquid (PFCL) and internal limiting membrane (ILM) peeling after macula-off retinal detachment surgery. METHODS: Four patients who had undergone vitreoretinal surgery due to primary rhegmatogenous retinal detachment were further treated because of retained subfoveal PFCL. Direct transretinal aspiration of PFCL through a self-sealing foveal retinotomy was performed in all cases using a 41-G needle placed on the top of the bubble. The ILM was peeled off prior to and after PFCL removal in 2 cases, respectively. Optical coherence tomography (OCT) scans were obtained preoperatively and postoperatively to assess the status of the macula. RESULTS: Subfoveal PFCL was successfully removed in all cases. Two patients had silicone oil tamponade at the time of the second surgery, which was temporarily removed in both cases and then reapplied in one. Best-corrected visual acuity improved in all cases. No postoperative macular hole was observed by OCT. CONCLUSIONS: Direct transretinal aspiration of subfoveal PFCL with a 41-G cannula combined with conventional ILM peeling is a safe and effective technique to avoid long-term damage to the retinal layers with good functional outcomes. Performing the ILM peeling immediately before or after the PFCL aspiration does not seem to influence anatomic results.

Use of a lyophilized bovine pericardium graft to repair tunical defect in patients with Peyronie's disease: experience in a clinical setting.

Many different materials are available for grafting during surgery for Peyronie's disease (PD). To study the outcomes associated with the use of a lyophilized bovine pericardium graft (Peri-Guard®) to repair tunical defects in patients with PD, descriptive study of 43 patients with disabling penile curvature was performed. Curvature was measured before and after the intervention using a standardized procedure. Surgical technique was plaque excision and grafting of the tunical defect carried out by a single surgeon. A lyophilized bovine pericardium patch was used for grafting. We measured the change in penile curvature and length, the ability to perform successful sexual intercourse without further pharmacological or surgical treatment, and the satisfaction with treatment. Follow-up data were available for a total of 41 patients. Median age was 50 years (IQR 48-52); mean follow-up time was 14 ± 6 months. Complete penile straightening was achieved in 33 patients (80.5%) and five patients (12.2%) had curvature under 20°. Three months after surgery and stretching therapy, mean (s.d.) flaccid penile length increased from 11.2 ± 2.8 cm to 12.1 ± 2.9 cm (P = 0.062). Seventy-five percentage of patients reported being able to achieve successful intercourse without further treatment. Eighty-five percentage of patients reported to be satisfied with the treatment. There was no evidence of tissue rejection or infection, and only four patients suffered an adverse event. Plaque excision and grafting of the tunical defect with lyophilized bovine pericardium seems to be a safe and effective treatment for patients with PD.

MACULAR BUCKLING WITH ANDO PLOMBE MAY INCREASE CHOROIDAL THICKNESS AND MIMIC SEROUS RETINAL DETACHMENT SEEN IN THE TILTED DISK SYNDROME.

PURPOSE: Serous subfoveal detachment has been described in the literature as a complication that appears at the border of the staphyloma. Macular buckling induces a postoperative inward bulge that resembles the ridge of a staphyloma. We describe three patients who developed a serous subfoveal detachment after uneventful macular buckling. To our knowledge, this complication, that shares similarities with the staphyloma ridge detachment, has not been previously reported. METHODS: The clinical records of all cases that underwent macular buckling at our clinic were reviewed. RESULTS: Three patients developed a serous subfoveal detachment that could not be explained by choroidal neovascularization or polypoidal vascular choroidopathy. Along with the development of the subfoveal detachment, we observed an increase of the choroidal thickness beneath the fovea. This thickening, that tended to progress during the follow-up, resolved spontaneously after explantation of the buckle. The decrease in foveal thickness did also lead to resolution of the subfoveal detachment. CONCLUSION: The development of the subfoveal detachment in our patients was closely associated with a focal increase of the choroidal thickness after the macular buckling. After the buckle was removed, the choroidal thickness went back to the normal prebuckling values and the detachment resolved in all three patients. This leads us to think that there is a close association between choroidal thickness and the serous subfoveal detachment.

Nanomechanical characterization of nanostructured bainitic steel: Peak Force Microscopy and Nanoindentation with AFM.

The full understanding of the deformation mechanisms in nanostructured bainite requires the local characterization of its mechanical properties, which are expected to change from one phase, bainitic ferrite, to another, austenite. This study becomes a challenging process due to the bainitic nanostructured nature and high Young's modulus. In this work, we have carried out such study by means of the combination of AFM-based techniques, such as nanoindentation and Peak Force Quantitative Nanomechanical Mapping (PF-QNM) measurements. We have addressed critically the limits and advantages of these techniques and been able to measure some elastoplastic parameters of both phases. Specifically, we have analyzed by PF-QNM two nanostructured bainitic steels, with a finer and a coarser structure, and found that both phases have a similar Young's modulus.

Effect of intravitreal injection of dexamethasone 0.7 mg (Ozurdex®) on intraocular pressure in patients with macular edema.

BACKGROUND: To evaluate the effect of Ozurdex® on intraocular pressure in patients with macular edema alone (group 1) or associated with glaucoma or ocular hypertension (group 2). METHODS: A clinical, retrospective, observational, comparative study included 92 eyes with macular edema treated with a single injection of Ozurdex®; 27 eyes were previously diagnosed with glaucoma or ocular hypertension. RESULTS: The mean intraocular pressure (group 1 vs. group 2) after injection was 12.1 versus 19.9 mm Hg, (p < 0.05; day 1); 17.5 versus 19.7 mm Hg (p < 0.05; month 1); 18.4 versus 20.9 mm Hg (p < 0.05; month 2); 15 versus 17.4 mm Hg (p < 0.05; month 3); 13.9 versus 16.7 mm Hg (p > 0.05; month 6); 13.8 versus 15.1 mm Hg (p > 0.05; month 9) and 13.1 versus 16.4 mm Hg (p > 0.05; month 12). Thirty eyes (32.6%) showed ocular hypertension (intraocular pressure >21 mm Hg) after the injection: 21.5% of group 1 and 59.3% of group 2. In group 2, 27 eyes (100%) needed medical treatment to reduce intraocular pressure in comparison to 8 patients (12.3%) in group 1 (p < 0.001). CONCLUSIONS: Intravitreal injection of Ozurdex® was associated with ocular hypertension in 32.6% of the eyes. Previous glaucoma or ocular hypertension are risk factors for this increase.

Dexamethasone intravitreal implant in vitrectomized versus nonvitrectomized eyes for treatment of patients with persistent diabetic macular edema.

PURPOSE: To compare the 6-month anatomic and best-corrected visual acuity (BCVA) response after sustained-release dexamethasone (DEX) intravitreal implant between nonvitrectomized and vitrectomized eyes with persistent diabetic macular edema (DME). METHODS: Retrospective, comparative, and consecutive review of the medical records of 58 patients with decreased visual acuity, due to refractory DME, who underwent a single injection of Ozurdex between November 2010 and January 2012, at the Instituto de Microcirurgia Ocular, Barcelona, Spain. Then, we divided patients into 2 groups: 24 eyes who had undergone standard pars plana vitrectomy (vitrectomized group), and 34 eyes that were not operated on (nonvitrectomized group). Outcomes measured were BCVA and foveal thickness (FT) at baseline and at months 1, 3, and 6. RESULTS: Twenty-four of 58 eyes had prior vitrectomy (41%). Statistically significant improvement in BCVA also was seen at 1 month after treatment with a DEX implant and at each subsequent follow-up visit, in either groups (P<0.05). All of the FT reduction outcomes were statistically significant in both groups, with respect to baseline data (P<0.05). There were no statistically significant differences in BCVA and FT between nonvitrectomized and vitrectomized eyes at any time point (P<0.05). CONCLUSION: In this study, the clinical findings were similar between nonvitrectomized and vitrectomized eyes. Intravitreal treatment with a DEX implant safely reduced DME and improved visual acuity in both groups. No statistically significant differences were found between the 2 groups regarding FT and BCVA.