Strategies against nonsense: oxadiazoles as translational readthrough-inducing drugs (TRIDs)

This review focuses on the use of oxadiazoles as translational readthrough-inducing drugs (TRIDs) to rescue the functional full-length protein expression in mendelian genetic diseases caused by nonsense mutations. These mutations in specific genes generate premature termination codons (PTCs) responsible for the translation of truncated proteins. After a brief introduction on nonsense mutations and their pathological effects, the features of various classes of TRIDs will be described discussing differences or similarities in their mechanisms of action. Strategies to correct the PTCs will be presented, particularly focusing on a new class of Ataluren-like oxadiazole derivatives in comparison to aminoglycosides. Additionally, recent results on the efficiency of new candidate TRIDs in restoring the production of the cystic fibrosis transmembrane regulator (CFTR) protein will be presented. Finally, a prospectus on complementary strategies to enhance the effect of TRIDs will be illustrated together with a conclusive paragraph about perspectives, opportunities, and caveats in developing small molecules as TRIDs

EChO Payload electronics architecture and SW design

EChO is a three-modules (VNIR, SWIR, MWIR), highly integrated spectrometer, covering the wavelength range from 0.55 $\mu$m, to 11.0 $\mu$m. The baseline design includes the goal wavelength extension to 0.4 $\mu$m while an optional LWIR module extends the range to the goal wavelength of 16.0 $\mu$m. An Instrument Control Unit (ICU) is foreseen as the main electronic subsystem interfacing the spacecraft and collecting data from all the payload spectrometers modules. ICU is in charge of two main tasks: the overall payload control (Instrument Control Function) and the housekeepings and scientific data digital processing (Data Processing Function), including the lossless compression prior to store the science data to the Solid State Mass Memory of the Spacecraft. These two main tasks are accomplished thanks to the Payload On Board Software (P-OBSW) running on the ICU CPUs.Comment: Experimental Astronomy - EChO Special Issue 201

Effects of parietal lesions in humans on color and location priming

To determine whether the parietal lobes contribute to the selection of nonspatial features known to be processed in the ventral stream, the current study examined the effect of chronic unilateral parietal lobe lesions in humans on color and location priming. Patients and normal controls performed a go/no-go color discrimination task in which either the same color and different color pairs of stimuli (prime and probe) were projected sequentially either in the same hemifield or in opposite hemifields. Control subjects and patients both showed independent effects of color and location priming. In the patients, primes in either field produced color priming for target probes in the ipsilesional field but not for probes in the contralesional field. This observation implicates the parietal cortex in processing activated codes of stimulus attributes not only for spatial information but also for visual features processed in the ventral visual pathways

The Visible and Near Infrared module of EChO

The Visible and Near Infrared (VNIR) is one of the modules of EChO, the Exoplanets Characterization Observatory proposed to ESA for an M-class mission. EChO is aimed to observe planets while transiting by their suns. Then the instrument had to be designed to assure a high efficiency over the whole spectral range. In fact, it has to be able to observe stars with an apparent magnitude Mv= 9-12 and to see contrasts of the order of 10-4 - 10-5 necessary to reveal the characteristics of the atmospheres of the exoplanets under investigation. VNIR is a spectrometer in a cross-dispersed configuration, covering the 0.4-2.5 micron spectral range with a resolving power of about 330 and a field of view of 2 arcsec. It is functionally split into two channels respectively working in the 0.4-1 and 1.0-2.5 micron spectral ranges. Such a solution is imposed by the fact the light at short wavelengths has to be shared with the EChO Fine Guiding System (FGS) devoted to the pointing of the stars under observation. The spectrometer makes use of a HgCdTe detector of 512 by 512 pixels, 18 micron pitch and working at a temperature of 45K as the entire VNIR optical bench. The instrument has been interfaced to the telescope optics by two optical fibers, one per channel, to assure an easier coupling and an easier colocation of the instrument inside the EChO optical bench.Comment: 26 page

Cigarette smoke increases BLT2 receptor functions in bronchial epithelial cells: in vitro and ex vivo evidence

Leukotriene B4 (LTB4) is a neutrophil chemotactic molecule with important involvement in the inflammatory responses of chronic obstructive pulmonary disease (COPD). Airway epithelium is emerging as a regulator of innate immune responses to a variety of insults including cigarette smoke, the major risk factor for COPD. In this study we have explored whether cigarette smoke extracts (CSE) or soluble mediators present in distal lung fluid samples (mini-bronchoalveolar lavages) from smokers alter the expression of the LTB4 receptor 2 (BLT2) and peroxisome proliferator- activated receptor-a (PPAR-a) in bronchial epithelial cells. We also evaluated the effects of CSE on the expression of intercellular adhesion molecule 1 (ICAM-1) and on the binding of signal transducer and activator of transcription 1 (STAT-1) to ICAM-1 promoter as well as the adhesiveness of neutrophils to bronchial epithelial cells. CSE and minibronchoalveolar lavages from smokers increased BLT2 and ICAM-1 expression as well as the adhesiveness of neutrophils to bronchial epithelial cells and decreased PPAR-a expression. CSE induced the activation of STAT-1 and its binding to ICAM-1 promoter. These findings suggest that, in bronchial epithelial cells, CSE promote a prevalent induction of pro-inflammatory BLT2 receptors and activate mechanisms leading to increased neutrophil adhesion, a mechanism that contributes to airway neutrophilia and to tissue damage

Idiopathic sensorineural hearing loss is associated with endothelial dysfunction

Hearing impairment is the most prevalent sensory deficit [1]. Sensorineural hearing loss (SNHL) is the most common type of permanent hearing loss and it occurswhen there is damage to the inner ear (cochlea), or to the nerve pathways fromthe inner ear to the brain.Most of the time, SNHL cannot be medically or surgically corrected. SNHL can result from genetic, environmental, or combined etiologies that prevent normal function of hearing, but, despite detailed investigation, the main cause remains usually unknown. Clinical and experimental studies have shown that ischemia contributes to several SNHL [2], suchas sudden sensoneural hearing loss, presbyacusis and noise-induced hearing loss. All of these SNHL can be related to alteration in blood flow [3]. The aim of the study is finding a relationship between idiopathic SNHL and endothelial dysfunction

Do we really need hazard prevention at the expense of safeguarding death dignity in covid-19?

To date, little is known regarding the transmission risks of SARS-CoV-2 infection for subjects involved in handling, transporting, and examining deceased persons with known or suspected COVID-19 positivity at the time of death. This experimental study aims to define if and/or how long SARS-CoV-2 persists with replication capacity in the tissues of individuals who died with/from COVID-19, thereby generating infectious hazards. Sixteen patients who died with/from COVID-19 who underwent autopsy between April 2020 and April 2021 were included in this study. Based on PMI, all samples were subdivided into two groups: ‘short PMI’ group (eight subjects who were autopsied between 12 to 72 h after death); ‘long PMI’ (eight subjects who were autopsied between 24 to 78 days after death). All patients tested positive for RT-PCR at nasopharyngeal swab both before death and on samples collected during post-mortem investigation. Moreover, a lung specimen was collected and frozen at −80◦ C in order to perform viral culture. The result was defined based on the cytopathic effect (subjective reading) combined with the positivity of the RT-PCR test (objective reading) in the supernatant. Only in one sample (PMI 12 h), virus vitality was demonstrated. This study, supported by a literature review, suggests that the risk of cadaveric infection in cases of a person who died from/with COVID-19 is extremely low in the first hours after death, becoming null after 12 h after death, confirming the World Health Organization (WHO) assumed in March 2020 and suggesting that the corpse of a subject who died from/with COVID-19 should be generally considered not infectious

A class of pyrrole derivatives endowed with analgesic/anti-inflammatory activity

We report the synthesis and bio-pharmacological evaluation of a class of pyrrole derivatives featuring a small appendage fragment (carbaldehyde, oxime, nitrile) on the central core. Compound 1c proved to be extremely effective in vivo, showing an interesting anti-nociceptic profile that is comparable to reference compounds already marketed, hence representing a great stimulus for a further improvement of this class of molecules