Pepducins as a potential treatment strategy for asthma and COPD.

Current therapies to treat asthma and other airway diseases primarily include anti-inflammatory agents and bronchodilators. Anti-inflammatory agents target trafficking and resident immunocytes and structural cells, while bronchodilators act to prevent or reverse shortening of airway smooth muscle (ASM), the pivotal tissue regulating bronchomotor tone. Advances in our understanding of the biology of G protein-coupled receptors (GPCRs) and biased agonism offers unique opportunities to modulate GPCR function that include the use of pepducins and allosteric modulators. Recent evidence suggests that small molecule inhibitors of Gα q as well as pepducins targeting G q -coupled receptors can broadly inhibit contractile agonist-induced ASM function. Given these advances, new therapeutic approaches can be leveraged to diminish the global rise in morbidity and mortality associated with asthma and chronic obstructive pulmonary disease

Surgical anatomy of the facial nerve: from middle cranial fossa approach to endoscopic approach. A pictorial review.

Purpose: The pathology of the facial nerve is extremely varied and extensive knowledge of the surgical anatomy in different approaches is required to manage it. During the last 15 years, the development of endoscopic ear surgery has significantly changed anatomical concepts, introducing new surgical approaches. The aim of this review is to illustrate five different surgical approaches to the facial nerve: the endoscopic approach, the middle cranial fossa approach, two translabyrinthine approaches (one simple and one endoscopic-assisted) with decompression of the whole petrous portion of the facial nerve, and a transotic approach with temporal craniotomy. Methods: Representative cases of middle and/or inner ear pathologies, surgically treated at our ENT Department, were selected to illustrate each of the five different approaches involving the facial nerve throughout its course. Results: In all cases, the pathology was removed with effective decompression of the facial nerve. The surgical anatomy in each surgical approach is described and illustrated. Conclusions: Facial nerve surgery is challenging for ENT specialists. An excellent knowledge of facial nerve anatomy is needed to eradicate pathology, avoiding nerve injuries and providing a good outcome after surgery

Congenital Pyriform Sinus Fistula: Systematic Review and Proposal for Treatment Using a Novel Endoscopic Approach

The pyriform sinus fistula (PSF) is a congenital developmental defect of the third or fourth branchial pouch. It presents as acute inflammatory swelling of the neck with recurrent deep neck abscesses, recurrent neck cystic lesions or suppurative thyroiditis. The literature reports various surgical approaches to treat this condition in children. A systematic review of the literature related to management protocols for PSF was conducted and we report a case exemplifying treatment in our department. Traditionally, treatment for PSF has been open surgery; however, in the last few decades, the minimally invasive transoral endoscopic approach has gained in importance, demonstrating long-term outcomes comparable to open surgery and with lower morbidity, and it has now become the first-choice treatment. We further describe a case of PSF treated by a transoral endoscopic approach with electric cauterization, fibrin glue obliteration of the fistula and Polydimethylsiloxane (Vox-Implants®, Bioplasty, Geleen, The Netherlands) submucosal injection. According to the authors, application of Vox-Implants® injection, in addition to standard techniques, may be helpful to reduce fistula recurrence rate after surgery

Depletion oil recovery for systems with widely varying initial composition

Abstract The principal depletion drive mechanism is the expansion of oil and gas initially in the reservoir-neglecting water influx. The main factors in depletion drive reservoir performance are total cumulative compressibility, determined mostly by initial composition (gas-oil ratio), saturation pressure, PVT properties, and relative permeability. In this paper, we systematically study the effect of initial composition on oil recovery, all other parameters held constant. We also evaluate other aspects of reservoir performance, but the main emphasis is surface oil recovery including condensate. To analyze the effect of initial composition, a series of fluid systems was selected by a recombination of separator samples at varying gas-oil ratios. The systems ranged from low-GOR oils to high-GOR gas condensates, with a continuous transition from gas to oil through a critical mixture. Black oil and compositional material balance calculations, 2D fine-grid, and 3D coarse-grid models have been used to investigate the effect of initial fluid composition on reservoir depletion performance. Systematic variation of relative permeabilities was also used to map the range of fluid systems, which were most sensitive to relative permeability. For reservoir oils, the depletion recovery of surface oil initially increases with increasing initial gas-oil ratio. Oil recovery reaches a maximum for moderate-GOR oil reservoirs, followed by decreasing oil recoveries with increasing initial solution GOR. A minimum oil recovery is reached at a near-critical oil. For gas reservoirs, depletion drive condensate recovery increases monotonically from a near-critical gas towards near 100% condensate recovery for veryhigh GOR systems. STO recovery from oil reservoirs depends increasingly on gas-oil relative permeabilities as initial solution GOR increases, up to a point. At higher initial solution GORs, oil recovery becomes less dependent on relative permeability and, as the fluid system transitions to a gas at the critical point, relative permeability dependence rapidly diminishes. Condensate recovery from www.elsevier.com/locate/petrol gas condensate systems is more or less independent of gas-oil relative permeabilities, with only slight dependence for nearcritical gases.

Shotgun and targeted MS analyses pinpoint the zampanolide-tubulin interacting site

Comunicaciones a congreso

Telomere Dynamics in Human Cells Reprogrammed to Pluripotency

BACKGROUND:Human induced pluripotent stem cells (IPSCs) have enormous potential in the development of cellular models of human disease and represent a potential source of autologous cells and tissues for therapeutic use. A question remains as to the biological age of IPSCs, in particular when isolated from older subjects. Studies of cloned animals indicate that somatic cells reprogrammed to pluripotency variably display telomere elongation, a common indicator of cell "rejuvenation." METHODOLOGY/PRINCIPAL FINDINGS:We examined telomere lengths in human skin fibroblasts isolated from younger and older subjects, fibroblasts converted to IPSCs, and IPSCs redifferentiated through teratoma formation and explant culture. In IPSCs analyzed at passage five (P5), telomeres were significantly elongated in 6/7 lines by >40% and approximated telomere lengths in human embryonic stem cells (hESCs). In cell lines derived from three IPSC-teratoma explants cultured to P5, two displayed telomeres shortened to lengths similar to input fibroblasts while the third line retained elongated telomeres. CONCLUSIONS/SIGNIFICANCE:While these results reveal some heterogeneity in the reprogramming process with respect to telomere length, human somatic cells reprogrammed to pluripotency generally displayed elongated telomeres that suggest that they will not age prematurely when isolated from subjects of essentially any age

Genome-wide identification of direct HBx genomic targets

Background: The Hepatitis B Virus (HBV) HBx regulatory protein is required for HBV replication and involved in HBV-related carcinogenesis. HBx interacts with chromatin modifying enzymes and transcription factors to modulate histone post-translational modifications and to regulate viral cccDNA transcription and cellular gene expression. Aiming to identify genes and non-coding RNAs (ncRNAs) directly targeted by HBx, we performed a chromatin immunoprecipitation sequencing (ChIP-Seq) to analyse HBV recruitment on host cell chromatin in cells replicating HBV. Results: ChIP-Seq high throughput sequencing of HBx-bound fragments was used to obtain a high-resolution, unbiased, mapping of HBx binding sites across the genome in HBV replicating cells. Protein-coding genes and ncRNAs involved in cell metabolism, chromatin dynamics and cancer were enriched among HBx targets together with genes/ncRNAs known to modulate HBV replication. The direct transcriptional activation of genes/miRNAs that potentiate endocytosis (Ras-related in brain (RAB) GTPase family) and autophagy (autophagy related (ATG) genes, beclin-1, miR-33a) and the transcriptional repression of microRNAs (miR-138, miR-224, miR-576, miR-596) that directly target the HBV pgRNA and would inhibit HBV replication, contribute to HBx-mediated increase of HBV replication. Conclusions: Our ChIP-Seq analysis of HBx genome wide chromatin recruitment defined the repertoire of genes and ncRNAs directly targeted by HBx and led to the identification of new mechanisms by which HBx positively regulates cccDNA transcription and HBV replication

Viral Single-Strand DNA Induces p53-Dependent Apoptosis in Human Embryonic Stem Cells

Human embryonic stem cells (hESCs) are primed for rapid apoptosis following mild forms of genotoxic stress. A natural form of such cellular stress occurs in response to recombinant adeno-associated virus (rAAV) single-strand DNA genomes, which exploit the host DNA damage response for replication and genome persistence. Herein, we discovered a unique DNA damage response induced by rAAV transduction specific to pluripotent hESCs. Within hours following rAAV transduction, host DNA damage signaling was elicited as measured by increased gamma-H2AX, ser15-p53 phosphorylation, and subsequent p53-dependent transcriptional activation. Nucleotide incorporation assays demonstrated that rAAV transduced cells accumulated in early S-phase followed by the induction of apoptosis. This lethal signaling sequalae required p53 in a manner independent of transcriptional induction of Puma, Bax and Bcl-2 and was not evident in cells differentiated towards a neural lineage. Consistent with a lethal DNA damage response induced upon rAAV transduction of hESCs, empty AAV protein capsids demonstrated no toxicity. In contrast, DNA microinjections demonstrated that the minimal AAV origin of replication and, in particular, a 40 nucleotide G-rich tetrad repeat sequence, was sufficient for hESC apoptosis. Our data support a model in which rAAV transduction of hESCs induces a p53-dependent lethal response that is elicited by a telomeric sequence within the AAV origin of replication