Functional and molecular characterization of hyposensitive underactive bladder tissue and urine in streptozotocin-induced diabetic rat

Background: The functional and molecular alterations of nerve growth factor (NGF) and Prostaglandin E2 (PGE2) and its receptors were studied in bladder and urine in streptozotocin (STZ)-induced diabetic rats. Methodology/Principal Findings: Diabetes mellitus was induced with a single dose of 45 mg/kg STZ Intraperitoneally (i.p) in female Sprague-Dawley rats. Continuous cystometrogram were performed on control rats and STZ treated rats at week 4 or 12 under urethane anesthesia. Bladder was then harvested for histology, expression of EP receptors and NGF by western blotting, PGE2 levels by ELISA, and detection of apoptosis by TUNEL staining. In addition, 4-hr urine was collected from all groups for urine levels of PGE2, and NGF assay. DM induced progressive increase of bladder weight, urine production, intercontraction interval (ICI) and residual urine in a time dependent fashion. Upregulation of Prostaglandin E receptor (EP)1 and EP3 receptors and downregulation of NGF expression, increase in urine NGF and decrease levels of urine PGE2 at week 12 was observed. The decrease in ICI by intravesical instillation of PGE2 was by 51% in control rats and 31.4% in DM group at week 12. Conclusions/Significance: DM induced hyposensitive underactive bladder which is characterized by increased inflammatory reaction, apoptosis, urine NGF levels, upregulation of EP1 and EP3 receptors and decreased bladder NGF and urine PGE2. The data suggest that EP3 receptor are potential targets in the treatment of diabetes induced underactive bladder. © 2014 Nirmal et al

Adenosine A2A receptors: localization and function

Adenosine is an endogenous purine nucleoside present in all mammalian tissues, that originates from the breakdown of ATP. By binding to its four receptor subtypes (A1, A2A, A2B, and A3), adenosine regulates several important physiological functions at both the central and peripheral levels. Therefore, ligands for the different adenosine receptors are attracting increasing attention as new potential drugs to be used in the treatment of several diseases. This chapter is aimed at providing an overview of adenosine metabolism, adenosine receptors localization and their signal transduction pathways. Particular attention will be paid to the biochemistry and pharmacology of A2A receptors, since antagonists of these receptors have emerged as promising new drugs for the treatment of Parkinson's disease. The interactions of A2A receptors with other nonadenosinergic receptors, and the effects of the pharmacological manipulation of A2A receptors on different body organs will be discussed, together with the usefulness of A2A receptor antagonists for the treatment of Parkinson's disease and the potential adverse effects of these drugs

An integrated magneto-optic modulator for cryogenic applications

Superconducting circuits can operate at higher energy efficiencies than their room-temperature counterparts and have the potential to enable large-scale control and readout of quantum computers. However, the required interface with room-temperature electronics creates difficulties in scaling up such cryogenic systems. One option is to use optical fibres as a medium in conjunction with fast optical modulators that can be efficiently driven by electrical signals at low temperatures. However, as superconducting circuits are current operated with low impedances, they interface poorly with conventional electro-optical modulators. Here we report an integrated current-driven modulator that is based on the magneto-optic effect and can operate at temperatures as low as 4 K. The device combines a magneto-optic garnet crystal with a silicon waveguide resonator and integrates an electromagnet to modulate the refractive index of the garnet. The modulator offers data rates of up to 2 Gbps with an energy consumption below 4 pJ per bit of transferred information, which could be reduced to less than 50 fJ per bit by replacing dissipative electrodes with superconductors and optimizing the geometric parameters

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

RNAseq Analysis of Novel 1,3,4-Oxadiazole Chalcogen Analogues Reveals Anti-Tubulin Properties on Cancer Cell Lines

Stefano Zoroddu and Luca Sanna contributed equally to this work.Data Availability Statement: The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy.Supplementary Materials: The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ijms241411263/s1 .1,3,4-Oxadiazole derivatives are among the most studied anticancer drugs. Previous studies have analyzed the action of different 1,3,4-oxadiazole derivatives and their effects on cancer cells. This study investigated the characterization of two new compounds named 6 and 14 on HeLa and PC-3 cancer cell lines. Based on the previously obtained IC50, cell cycle effects were monitored by flow cytometry. RNA sequencing (RNAseq) was performed to identify differentially expressed genes, followed by functional annotation using gene ontology (GO), KEGG signaling pathway enrichment, and protein–protein interaction (PPI) network analyses. The tubulin polymerization assay was used to analyze the interaction of both compounds with tubulin. The results showed that 6 and 14 strongly inhibited the proliferation of cancer cells by arresting them in the G2/M phase of the cell cycle. Transcriptome analysis showed that exposure of HeLa and PC-3 cells to the compounds caused a marked reprograming of gene expression. Functional enrichment analysis indicated that differentially expressed genes were significantly enriched throughout the cell cycle and cancer-related biological processes. Furthermore, PPI network, hub gene, and CMap analyses revealed that compounds 14 and 6 shared target genes with established microtubule inhibitors, indicating points of similarity between the two molecules and microtubule inhibitors in terms of the mechanism of action. They were also able to influence the polymerization process of tubulin, suggesting the potential of these new compounds to be used as efficient chemotherapeutic agents.University of Sassari (Fondo di Ateneo per la ricerca FAR 2020)

Search for Dark Matter and Supersymmetry with a Compressed Mass Spectrum in the Vector Boson Fusion Topology in Proton-Proton Collisions at root s=8 TeV

Peer reviewe

PHANGS-JWST First Results: A Combined HST and JWST Analysis of the Nuclear Star Cluster in NGC 628

We combine archival Hubble Space Telescope and new James Webb Space Telescope imaging data covering the ultraviolet to mid-infrared regime to morphologically analyze the nuclear star cluster (NSC) of NGC 628, a grand-design spiral galaxy. The cluster is located in a 200 pc × 400 pc cavity lacking both dust and gas. We find roughly constant values for the effective radius (r eff ∼ 5 pc) and ellipticity (ε ∼ 0.05), while the Sérsic index (n) and position angle (PA) drop from n ∼ 3 to ∼2 and PA ∼ 130° to 90°, respectively. In the mid-infrared, r eff ∼ 12 pc, ε ∼ 0.4, and n ∼ 1-1.5, with the same PA ∼ 90°. The NSC has a stellar mass of log 10 ( M ⋆ nsc / M ⊙ ) = 7.06 ± 0.31 , as derived through B − V, confirmed when using multiwavelength data, and in agreement with the literature value. Fitting the spectral energy distribution (SED), excluding the mid-infrared data, yields a main stellar population age of (8 ± 3) Gyr with a metallicity of Z = 0.012 ± 0.006. There is no indication of any significant star formation over the last few gigayears. Whether gas and dust were dynamically kept out or evacuated from the central cavity remains unclear. The best fit suggests an excess of flux in the mid-infrared bands, with further indications that the center of the mid-infrared structure is displaced with respect to the optical center of the NSC. We discuss five potential scenarios, none of them fully explaining both the observed photometry and structure

PHANGS-JWST First Results: Spurring on Star Formation: JWST Reveals Localized Star Formation in a Spiral Arm Spur of NGC 628

We combine JWST observations with Atacama Large Millimeter/submillimeter Array CO and Very Large Telescope MUSE Hα data to examine off-spiral arm star formation in the face-on, grand-design spiral galaxy NGC 628. We focus on the northern spiral arm, around a galactocentric radius of 3-4 kpc, and study two spurs. These form an interesting contrast, as one is CO-rich and one CO-poor, and they have a maximum azimuthal offset in MIRI 21 μm and MUSE Hα of around 40° (CO-rich) and 55° (CO-poor) from the spiral arm. The star formation rate is higher in the regions of the spurs near spiral arms, but the star formation efficiency appears relatively constant. Given the spiral pattern speed and rotation curve of this galaxy and assuming material exiting the arms undergoes purely circular motion, these offsets would be reached in 100-150 Myr, significantly longer than the 21 μm and Hα star formation timescales (both < 10 Myr). The invariance of the star formation efficiency in the spurs versus the spiral arms indicates massive star formation is not only triggered in spiral arms, and cannot simply occur in the arms and then drift away from the wave pattern. These early JWST results show that in situ star formation likely occurs in the spurs, and that the observed young stars are not simply the “leftovers” of stellar birth in the spiral arms. The excellent physical resolution and sensitivity that JWST can attain in nearby galaxies will well resolve individual star-forming regions and help us to better understand the earliest phases of star formation

PHANGS-JWST First Results: Multiwavelength View of Feedback-driven Bubbles (the Phantom Voids) across NGC 628

We present a high-resolution view of bubbles within the Phantom Galaxy (NGC 628), a nearby (similar to 10 Mpc), star-forming (similar to 2 M (circle dot) yr(-1)), face-on (i similar to 9 degrees) grand-design spiral galaxy. With new data obtained as part of the Physics at High Angular resolution in Nearby GalaxieS (PHANGS)-JWST treasury program, we perform a detailed case study of two regions of interest, one of which contains the largest and most prominent bubble in the galaxy (the Phantom Void, over 1 kpc in diameter), and the other being a smaller region that may be the precursor to such a large bubble (the Precursor Phantom Void). When comparing to matched-resolution H alpha observations from the Hubble Space Telescope, we see that the ionized gas is brightest in the shells of both bubbles, and is coincident with the youngest (similar to 1 Myr) and most massive (similar to 10(5) M (circle dot)) stellar associations. We also find an older generation (similar to 20 Myr) of stellar associations is present within the bubble of the Phantom Void. From our kinematic analysis of the H I, H-2 (CO), and H ii gas across the Phantom Void, we infer a high expansion speed of around 15 to 50 km s(-1). The large size and high expansion speed of the Phantom Void suggest that the driving mechanism is sustained stellar feedback due to multiple mechanisms, where early feedback first cleared a bubble (as we observe now in the Precursor Phantom Void), and since then supernovae have been exploding within the cavity and have accelerated the shell. Finally, comparison to simulations shows a striking resemblance to our JWST observations, and suggests that such large-scale, stellar-feedback-driven bubbles should be common within other galaxies