Spectroscopic and in silico studies on the interaction of substituted pyrazolo[1,2-a]benzo[1,2,3,4]tetrazine-3-one derivatives with c-myc g4-dna

Herein we describe a combined experimental and in silico study of the interaction of a series of pyrazolo[1,2-a]benzo[1,2,3,4]tetrazin-3-one derivatives (PBTs) with parallel G-quadruplex (GQ) DNA aimed at correlating their previously reported anticancer activities and the stabilizing effects observed by us on c-myc oncogene promoter GQ structure. Circular dichroism (CD) melting experiments were performed to characterize the effect of the studied PBTs on the GQ thermal stability. CD measurements indicate that two out of the eight compounds under investigation induced a slight stabilizing effect (2–4 °C) on GQ depending on the nature and position of the substituents. Molecular docking results allowed us to verify the modes of interaction of the ligands with the GQ and estimate the binding affinities. The highest binding affinity was observed for ligands with the experimental melting temperatures (Tms). However, both stabilizing and destabilizing ligands showed similar scores, whilst Molecular Dynamics (MD) simulations, performed across a wide range of temperatures on the GQ in water solution, either unliganded or complexed with two model PBT ligands with the opposite effect on the Tms, consistently confirmed their stabilizing or destabilizing ability ascertained by CD. Clues about a relation between the reported anticancer activity of some PBTs and their ability to stabilize the GQ structure of c-myc emerged from our study. Furthermore, Molecular Dynamics simulations at high temperatures are herein proposed for the first time as a means to verify the stabilizing or destabilizing effect of ligands on the GQ, also disclosing predictive potential in GQ-targeting drug discovery

Muscle Oxygen Delivery in the Forearm and in the Vastus Lateralis Muscles in Response to Resistance Exercise: A Comparison Between Nepalese Porters and Italian Trekkers

Altitude ascending represents an intriguing experimental model reproducing physiological and pathophysiological conditions sharing hypoxemia as the denominator. The aim of the present study was to investigate fractional oxygen extraction and blood dynamics in response to hypobaric hypoxia and to acute resistance exercises, taking into account several factors including different ethnic origin and muscle groups. As part of the “Kanchenjunga Exploration & Physiology” project, six Italian trekkers and six Nepalese porters took part in a high altitude trek in the Himalayas. The measurements were carried out at low (1,450 m) and high altitude (HA; 4,780 m). Near-infrared spectroscopy (NIRS)-derived parameters, i.e., Tot-Hb and tissue saturation index (TSI), were gathered at rest and after bouts of 3-min resistive exercise, both in the quadriceps and in the forearm muscles. TSI decreased with altitude, particularly in forearm muscles (from 66.9 to 57.3%), whereas the decrement was less in the quadriceps (from 62.5 to 57.2%); Nepalese porters were characterized by greater values in thigh TSI than Italian trekkers. Tot-Hb was increased after exercise. At altitude, such increase appeared to be higher in the quadriceps. This effect might be a consequence of the long-term adaptive memory due to the frequent exposures to altitude. Although speculative, we suggest a long-term adaptation of the Nepalese porters due to improved oxygenation of muscles frequently undergoing hypoxic exercise. Muscle structure, individual factors, and altitude exposure time should be taken into account to move on the knowledge of oxygen delivery and utilization at altitude

A brief bout of exercise in hypoxia reduces ventricular filling rate and stroke volume response during muscle metaboreflex activation

Purpose: The hemodynamic consequences of exercise in hypoxia have not been completely investigated. The present investigation aimed at studying the hemodynamic effects of contemporary normobaric hypoxia and metaboreflex activation. Methods: Eleven physically active, healthy males (age 32.7 ± 7.2 years) completed a cardiopulmonary test on an electromagnetically braked cycle-ergometer to determine their maximum workload (Wmax). On separate days, participants performed two randomly assigned exercise sessions (3 minutes pedalling at 30% of Wmax): (1) one in normoxia (NORMO), and (2) one in normobaric hypoxia with FiO2 set to 13.5% (HYPO). After each session, the following protocol was randomly assigned: either (1) post-exercise muscle ischemia (PEMI) to study the metaboreflex, or (2) a control exercise recovery session, i.e., without metaboreflex activation. Hemodynamics were assessed with impedance cardiography. Results: The main result was that the HYPO session impaired the ventricular filling rate (measured as stroke volume/diastolic time) response during PEMI versus control condition in comparison to the NORMO test (31.33 ± 68.03 vs. 81.52 ± 49.23 ml·s−1,respectively, p = 0.003). This caused a reduction in the stroke volume response (1.45 ± 9.49 vs. 10.68 ± 8.21 ml, p = 0.020). As a consequence, cardiac output response was impaired during the HYPO test. Conclusions: The present investigation suggests that a brief exercise bout in hypoxia is capable of impairing cardiac filling rate as well as stroke volume during the metaboreflex. These results are in good accordance with recent findings showing that among hemodynamic modulators, ventricular filling is the most sensible variable to hypoxic stimuli

Androgen receptor immunoreactivity in rat occipital cortex after callosotomy

Gonadal steroidogenesis can be influenced by direct neural links between the central nervous system and the gonads. It is known that androgen receptor (AR) is expressed in many areas of the rat brain involved in neuroendocrine control of reproduction, such as the cerebral cortex. It has been recently shown that the occipital cortex exerts an inhibitory effect on testicular stereoidogenesis by a pituitary-independent neural mechanism. Moreover, the complete transection of the corpus callosum leads to an increase in testosterone (T) secretion of hemigonadectomized rats. The present study was undertaken to analyze the possible corticocortical influences regulating male reproductive activities. Adult male Wistar rats were divided into 4 groups: 1) intact animals as control; 2) rats undergoing sham callosotomy; 3) posterior callosotomy; 4) gonadectomy and posterior callosotomy. Western blot analysis showed no remarkable variations in cortical AR expression in any of the groups except in group I where a significant decrease in AR levels was found. Similarly, both immunocytochemical study and cell count estimation showed a lower AR immunoreactivity in occipital cortex of callosotomized rats than in other groups. In addition, there was no difference in serum T and LH concentration between sham-callosotomized and callosotomized rats. In conclusion, our results show that posterior callosotomy led to a reduction in AR in the right occipital cortex suggesting a putative inhibiting effect of the contralateral cortical area

A simulation tool for MRPC telescopes of the EEE project

The Extreme Energy Events (EEE) Project is mainly devoted to the study of the secondary cosmic ray radiation by using muon tracker telescopes made of three Multigap Resistive Plate Chambers (MRPC) each. The experiment consists of a telescope network mainly distributed across Italy, hosted in different building structures pertaining to high schools, universities and research centers. Therefore, the possibility to take into account the effects of these structures on collected data is important for the large physics programme of the project. A simulation tool, based on GEANT4 and using GEMC framework, has been implemented to take into account the muon interaction with EEE telescopes and to estimate the effects on data of the structures surrounding the experimental apparata.A dedicated event generator producing realistic muon distributions, detailed geometry and microscopic behavior of MRPCs have been included to produce experimental-like data. The comparison between simulated and experimental data, and the estimation of detector resolutions is here presented and discussed

Outreach activities of the Extreme Energy Events Project

The Extreme Energy Events Project (EEE) represents a breakthrough in outreach activities in Cosmic Ray Physics: high school students are protagonists of an experiment to measure Extensive Air Showers at ground. They start their experience at CERN with the construction of the three high performing Multigap Resistive Plate Chambers constituting the telescope that is then installed inside their school; then they take care of the telescope operation and data analysis. Presently 60 telescopes are installed in Italy and, since 2014, coordinated data taking have been performed during each school year providing a huge amount of candidate muon tracks. Every year hundreds of students and teachers are involved in the activities directly correlated to EEE. The COVID-19 pandemic has strongly affected the experimental activities of the EEE Project. However in the last two years the online activities were strengthened, with an intense programme of collaboration meetings, masterclasses, and hugely successful topical seminars. Starting from the fall of 2021, the improvement of epidemiological situation made it possible to start some of the EEE activities in presence

Simulation tool for MRPC telescopes of EEE experiment

The Extreme Energy Events (EEE) experiment consists in a network of cosmic muon tracker telescopes, each made of three Multi-gap Resistive Plate Chambers (MRPC), able to precisely measure the absolute muon crossing time and the muon integrated angular flux at the ground level. To investigate the MRPC telescope response and performance, a simulation tool was developed in GEMC, software package based on GEANT4 libraries. The framework was validated by comparing simulations with the EEE experimental data. Detailed description of telescope response is fundamental to carry on the physics program of the EEE project, and it could open other research avenues, such as using the telescope in combination with other detectors to perform a (muon) tomography of material surrounding the telescope. In this paper, the EEE simulation framework will be presented reporting results and discussing further applications

New high precision measurements of the cosmic charged particle rate beyond the Arctic Circle with the PolarquEEEst experiment

The goal of the PolarquEEEst experiment was to measure the cosmic charged particle rate at latitudes greater than 66° N, where no systematic and accurate measurements at sea level have ever been performed. A latitude range well above the Arctic Circle was explored on board of a sailboat, up to the unprecedented northernmost value of 82° 07' N. In this paper a description of the experimental set-up is reported, then the procedures for calibration and ata analysis are described in detail. The results show that the rate measured in this latitude range stays constant within a novel accuracy of ±1%

Measurement of the cosmic charged particle rate at sea level in the latitude range 35∘ ÷ 82∘ N with the PolarquEEEst experiment

After its successful campaign of measurements beyond the Polar Arctic Circle, the PolarquEEEst experiment measured the cosmic charged particle rate at sea level in a latitude interval between 35∘ N and 82∘ N. In this paper, these measurements are described and the corresponding results are discussed