Function and fiber-type specific distribution of hsp60 and αb-crystallin in skeletal muscles: Role of physical exercise

Skeletal muscle is a plastic and complex tissue, rich in proteins that are subject to continuous rearrangements. Skeletal muscle homeostasis can be affected by different types of stresses, including physical activity, a physiological stressor able to stimulate a robust increase in different heat shock proteins (HSPs). The modulation of these proteins appears to be fundamental in facili-tating the cellular remodeling processes related to the phenomenon of training adaptations such as hypertrophy, increased oxidative capacity, and mitochondrial activity. Among the HSPs, a special attention needs to be devoted to Hsp60 and αB-crystallin (CRYAB), proteins constitutively expressed in the skeletal muscle, where their specific features could be highly relevant in understanding the impact of different volumes of training regimes on myofiber types and in explaining the complex picture of exercise-induced mechanical strain and damaging conditions on fiber pop-ulation. This knowledge could lead to a better personalization of training protocols with an opti-mal non-harmful workload in populations of individuals with different needs and healthy status. Here, we introduce for the first time to the reader these peculiar HSPs from the perspective of exercise response, highlighting the control of their expression, biological function, and specific distribution within skeletal muscle fiber-types

Genotoxic stress inhibits ewing sarcoma cell growth by modulating alternative pre-mRNA processing of the RNA helicase DHX9

Alternative splicing plays a key role in the DNA damage response and in cancer. Ewing Sarcomas (ES) are aggressive tumors caused by different chromosomal translocations that yield in-frame fusion proteins driving transformation. RNA profiling reveals genes differentially regulated by UV light irradiation in two ES cell lines exhibiting different sensitivity to genotoxic stress. In particular, irradiation induces a new isoform of the RNA helicase DHX9 in the more sensitive SK-N-MC cells, which is targeted to nonsense-mediated decay (NMD), causing its downregulation. DHX9 protein forms a complex with RNA polymerase II (RNAPII) and EWS-FLI1 to enhance transcription. Silencing of DHX9 in ES cells sensitizes them to UV treatment and impairs recruitment of EWS-FLI1 to target genes, whereas DHX9 overexpression protects ES cells from genotoxic stress. Mechanistically, we found that UV light irradiation leads to enhanced phosphorylation and decreased processivity of RNAPII in SK-N-MC cells, which in turn causes inclusion of DHX9 exon 6A. A similar effect on DHX9 splicing was also elicited by treatment with the chemotherapeutic drug etoposide, indicating a more general mechanism of regulation in response to DNA damage. Our data identify a new NMD-linked splicing event in DHX9 with impact on EWS-FLI1 oncogenic activity and ES cell viability

A parallel algorithm for the enumeration of benzenoid hydrocarbons

We present an improved parallel algorithm for the enumeration of fixed benzenoids B_h containing h hexagonal cells. We can thus extend the enumeration of B_h from the previous best h=35 up to h=50. Analysis of the associated generating function confirms to a very high degree of certainty that $B_h \sim A \kappa^h /h$ and we estimate that the growth constant $\kappa = 5.161930154(8)$ and the amplitude $A=0.2808499(1)$.Comment: 14 pages, 6 figure

Retromode imaging modality of epiretinal membranes

(1) Purpose: To determine the characteristics of macular epiretinal membranes (ERM) using non-invasive retromode imaging (RMI) and to compare retromode images with those acquired via fundus autofluorescence (FAF) and fundus photography. (2) Methods: Prospective observational case-series study including patients with macular ERM with no other ocular disease affecting their morphology and/or imaging quality. We compared RMI, FAF and fundus photography features by cropping and overlapping images to obtain topographic correspondence. (3) Results: In total, 21 eyes (21 patients) affected by ERM were included in this study. The mean area of retinal folds detected by RMI was significantly higher than that detected by FAF (11.85 ± 3.92 mm2 and 5.67 ± 2.15 mm2, respectively, p < 0.05) and similar to that revealed by fundus photography (11.85 ± 3.92 mm2 and 10.58 ± 3.45 mm2, respectively, p = 0.277). (4) Conclusions: RMI appears to be a useful tool in the evaluation of ERMs. It allows for an accurate visualization of the real extension of the retinal folds and provides a precise structural assessment of the macula before surgery. Clinicians should be aware of RMI's advantages and should be able to use them to warrant a wide range of information and, thus, a more personalized therapeutic approach

Sildenafil Reduces Expression and Release of IL-6 and IL-8 Induced by Reactive Oxygen Species in Systemic Sclerosis Fibroblasts

Oxidative stress linked to vascular damage plays an important role in the pathogenesis of systemic sclerosis (SSc). Indeed, vascular damage at nailfold capillaroscopy in patients with Raynaud’s Phenomenon (RP) is a major risk factor for the development of SSc together with the presence of specific autoantiobodies. Here, we investigated the effects of the phosphodiesterase type 5 inhibitor (PDE5i) sildenafil, currently used in the management of RP, in modulating the proinflammatory response of dermal fibroblasts to oxidative stress in vitro. Human fibroblasts isolated from SSc patients and healthy controls were exposed to exogenous reactive oxygen species (ROS) (100 µM H2O2), in the presence or absence of sildenafil (1 µM). Treatment with sildenafil significantly reduced dermal fibroblast gene expression and cellular release of IL-6, known to play a central role in the pathogenesis of tissue damage in SSc and IL-8, directly induced by ROS. This reduction was associated with suppression of STAT3-, ERK-, NF-κB-, and PKB/AKT-dependent pathways. Our findings support the notion that the employment of PDE5i in the management of RP may be explored for its efficacy in modulating the oxidative stress-induced proinflammatory activation of dermal fibroblasts in vivo and may ultimately aid in the prevention of tissue damage caused by SSc

Estrogen-receptor-positive breast cancer in postmenopausal women: The role of body composition and physical exercise

Breast cancer (BC) is the most commonly diagnosed cancer among women worldwide and the most common cause of cancer-related death. To date, it is still a challenge to estimate the magnitude of the clinical impact of physical activity (PA) on those parameters producing significative changes in future BC risk and disease progression. However, studies conducted in recent years highlight the role of PA not only as a protective factor for the development of ER+ breast cancer but, more generally, as a useful tool in the management of BC treatment as an adjuvant to traditional therapies. In this review, we focused our attention on data obtained from human studies analyzing, at each level of disease prevention (i.e., primary, secondary, tertiary and quaternary), the positive impact of PA/exercise in ER+ BC, a subtype representing approximately 70% of all BC diagnoses. Moreover, given the importance of estrogen receptors and body composition (i.e., adipose tissue) in this subtype of BC, an overview of their role will also be made throughout this review

Pattern electroretinogram detects localized glaucoma defects

Purpose: We evaluated the clinical ability of pattern electroretinogram (PERG) to detect functional losses in the affected hemifield of open-angle glaucoma patients with localized perimetric defects. Methods: Hemifield (horizontally-defined) steady-state PERGs (h-PERGs) were recorded in response to 1.7 c/deg alternating gratings from 32 eyes of 29 glaucomatous patients with a perimetric, focal one-hemifield defect, 10 eyes of 10 glaucomatous patients with a diffuse perimetric defect, and 18 eyes of 18 age-matched normal subjects. Standard automated perimetry (SAP) and spectral-domain optical coherence tomography (SD-OCT) for retinal nerve fiber layer (RNFL) thickness also were performed. h-PERG amplitudes and ratios, calculated corresponding hemifield perimetric deviations, as well as hemiretina RNFL thicknesses were analyzed. Results: h-PERG amplitudes, perimetric deviations, and RNFL thicknesses showed losses (P < 0.001) when comparing affected with unaffected hemifields of localized glaucomatous eyes. No differences were found in h-PERG amplitudes between hemifields of normal or diffuse glaucomatous eyes. h-PERG amplitude ratios (affected/ unaffected hemifield) in localized glaucoma were lower (P < 0.001) than the ratios from normal or diffuse glaucomatous eyes. The areas under the receiver operating characteristic curves for h-PERG amplitude ratios, comparing localized-defect glaucomatous eyes with normal or diffuse glaucomatous eyes, were 0.93 and 0.91, respectively. Conclusions: h-PERG assessment showed good diagnostic accuracy to confirm localized glaucomatous defects detected perimetrically. This test may be particularly useful in cognitively impaired patients or young/nonverbal patients unable to provide reliable visual fields. Translational Relevance: h-PERG provides a sensitive objective measure to confirm

Sildenafil Counteracts the In Vitro Activation of CXCL-9, CXCL-10 and CXCL-11/CXCR3 Axis Induced by Reactive Oxygen Species in Scleroderma Fibroblasts

Oxidative stress plays a key role in systemic sclerosis (SSc) pathogenesis, and an altered redox homeostasis might be responsible for abnormal inflammatory status, fibrosis and tissue damage extension. In this study, we explored the effect of the phosphodiesterase type 5 inhibitor sildenafil in modulating the activation of the CXCL-9, -10, -11/CXCR3 axis, which is fundamental in the perpetuation of inflammation in different autoimmune diseases, in the cell culture of SSc human dermal fibroblasts exposed to a pro-oxidant environment. We observed that sildenafil significantly reduced gene expression and release of CXCL-9, -10 and -11, inhibited the CXCR3 action and suppressed the activation of STAT1-, JNK- and p38MAPK pathways. This in vitro study on dermal fibroblasts supports clinical studies to consider the efficacy of sildenafil in preventing tissue damage and fibrosis in SSc by targeting central biomarkers of disease progression, vascular injuries and fibrosis and reducing the pro-inflammatory activation induced by oxidative stress

Insertion of a foldable hydrophobic IOL through the trabeculectomy fistula in cases with Microincision cataract surgery combined with trabeculectomy

BACKGROUND: The use of conventional foldable hydrophobic intraocular lenses (IOLs) in microincision cataract surgery (MICS) currently requires wound enlargement. We describe a combined surgical technique of MICS and trabeculectomy with insertion of a foldable IOL through the trabeculectomy fistula. METHODS: After completion of MICS through two side port incisions, a 3.2 mm keratome is used to enter the anterior chamber under the previously outlined scleral flap. An Acrysof multi piece IOL (Alcon labs, Fort Worth, Tx) is inserted into the capsular bag through this incision. The scleral flap is then elevated and a 2 × 2 mm fistula made with a Kelly's punch. The scleral flap and conjunctival closure is performed as usual. RESULTS: Five patients with primary open angle glaucoma with a visually significant cataract underwent the above mentioned procedure. An IOL was implated in the capsular bag in all cases with no intraperative complications. After surgery, all patients obtained a best corrected visual acuity of 20/20, IOL was well centered at 4 weeks follow up. The mean IOP (without any antiglaucoma medication) was 13.2 + 2.4 mm Hg at 12 weeks with a well formed diffuse filtering bleb in all the cases. CONCLUSION: The technique of combining MICS with trabeculectomy and insertion of a foldable IOL through the trabeculectomy fistula is a feasible and valuable technique for cases which require combined cataract and glaucoma surgery