The Multifaceted Role of GPCRs in Amyotrophic Lateral Sclerosis: A New Therapeutic Perspective?

Amyotrophic lateral sclerosis (ALS) is a degenerating disease involving the motor neurons, which causes a progressive loss of movement ability, usually leading to death within 2 to 5 years from the diagnosis. Much effort has been put into research for an effective therapy for its eradication, but still, no cure is available. The only two drugs approved for this pathology, Riluzole and Edaravone, are onlyable to slow down the inevitable disease progression. As assessed in the literature, drug targets such as protein kinases have already been extensively examined as potential drug targets for ALS, with some molecules already in clinical trials. Here, we focus on the involvement of another very important and studied class of biological entities, G protein-coupled receptors (GPCRs), in the onset and progression of ALS. This workaimsto give an overview of what has been already discovered on the topic, providing useful information and insights that can be used by scientists all around the world who are putting efforts into the fight against this very important neurodegenerating disease

A Computational Workflow for the Identification of Novel Fragments Acting as Inhibitors of the Activity of Protein Kinase CK1δ

Fragment-Based Drug Discovery (FBDD) has become, in recent years, a consolidated approach in the drug discovery process, leading to several drug candidates under investigation in clinical trials and some approved drugs. Among these successful applications of the FBDD approach, kinases represent a class of targets where this strategy has demonstrated its real potential with the approved kinase inhibitor Vemurafenib. In the Kinase family, protein kinase CK1 isoform δ (CK1δ) has become a promising target in the treatment of different neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. In the present work, we set up and applied a computational workflow for the identification of putative fragment binders in large virtual databases. To validate the method, the selected compounds were tested in vitro to assess the CK1δ inhibition

The Multifaceted Role of GPCRs in Amyotrophic Lateral Sclerosis: A New Therapeutic Perspective?

Amyotrophic lateral sclerosis (ALS) is a degenerating disease involving the motor neurons, which causes a progressive loss of movement ability, usually leading to death within 2 to 5 years from the diagnosis. Much effort has been put into research for an effective therapy for its eradication, but still, no cure is available. The only two drugs approved for this pathology, Riluzole and Edaravone, are onlyable to slow down the inevitable disease progression. As assessed in the literature, drug targets such as protein kinases have already been extensively examined as potential drug targets for ALS, with some molecules already in clinical trials. Here, we focus on the involvement of another very important and studied class of biological entities, G protein‐coupled receptors (GPCRs), in the onset and progression of ALS. This workaimsto give an overview of what has been already discovered on the topic, providing useful information and insights that can be used by scientists all around the world who are putting efforts into the fight against this very important neurodegenerating disease

Lower Cretaceous dinosaur footprints from the Molfetta tracksite (Apulia, southern Italy)

The lower Albian track-bearing surface of the San Leonardo quarry (Molfetta, Apulia) is characterised by more than 800 footprints, produced by both quadrupedal and bipedal dinosaurs. Six well-preserved bipedal trackways, composed of tridactyl footprints are attributed to medium-to large-sized theropod dinosaurs. Only one clear but poorly preserved trackway and numerous isolated manus-pes couples have been attributed to quadrupedal dinosaurs. The tridactyl ichnoassemblage, analysed using both traditional methods and close-range photogrammetry, is represented by weakly mesaxonic and robust specimens. Morphological comparison with Upper Jurassic and Lower Cretaceous theropod tracks from surrounding areas, supported by morphometric analyses, points out a highest affinity with the specimens from Switzerland and North Africa. Nevertheless, a set of unique characters appears to justify the establishment of a new ichnospecies, Jurabrontes melphicticus. Additionally, the photogrammetric models of the quadrupedal trackway and four isolated manus-pes sets suggest they belong to the same morphotype, represented by asymmetrical tetradactyl pes and highly digitigrade tetra- or pentadactyl manus. These tracks share numerous morphological characters with both the ichnogenera Tetrapodosaurus and Metatetrapodus and thus can be attributed to a medium-sized ankylosaurian trackmaker

{\textquotedblleft}Dual Anta-Inhibitors{\textquotedblright} of the A2A Adenosine Receptor and Casein Kinase {CK}1delta: Synthesis, Biological Evaluation, and Molecular Modeling Studies

Based on a screening of a chemical library of A2A adenosine receptor (AR) antagonists, a series of di- and tri-substituted adenine derivatives were synthesized and tested for their ability to inhibit the activity of the enzyme casein kinase 1 delta (CK1δ) and to bind adenosine receptors (ARs). Some derivatives, here called “dual anta-inhibitors”, demonstrated good CK1δ inhibitory activity combined with a high binding affinity, especially for the A2AAR. The N6-methyl-(2-benzimidazolyl)-2-dimethyamino-9-cyclopentyladenine (17, IC50 = 0.59 μM and KiA2A = 0.076 μM) showed the best balance of A2AAR affinity and CK1δ inhibitory activity. Computational studies were performed to simulate, at the molecular level, the protein–ligand interactions involving the compounds of our series. Hence, the dual anta-inhibitor 17 could be considered the lead compound of new therapeutic agents endowed with synergistic effects for the treatment of chronic neurodegenerative and cancer diseases

Geological Uniqueness and Potential Geotouristic Appeal of Murge and Premurge, the First Territory in Puglia (Southern Italy) Aspiring to Become a UNESCO Global Geopark

At the end of November 2021, a large area of Puglia (an administrative region in Southern Italy) was officially nominated as new aUGGp (aspiring UNESCO Global Geopark) by the Italian National Commission of UNESCO. This area comprises the northwestern part of the Murge territory, where a Cretaceous sector of the Apulia Carbonate Platform crops out, and part of the adjacent Premurge territory, where the southwestward lateral continuation of the same platform (being flexed toward the Southern Apennines Chain) is covered by thin Plio Quaternary foredeep deposits. The worldwide geological uniqueness of the aspiring Geopark (Murge aUGGp) is that the area is the only in situ remnant of the Adria Plate, the old continental plate almost entirely squeezed between the Africa and Eurasia Plates. In such a context, the Murge area (part of the Apulia Foreland) is a virtually undeformed sector of Adria, while other territories of the plate are and/or were involved in the subduction/collision processes. In the aspiring Geopark, the crust of Adria is still rooted to its mantle, and the Cretaceous evolution of the continent is widely recorded in the Murge area thanks to the shallow-water carbonate succession of one of the largest peri-Tethys carbonate platforms (the Apulia Carbonate Platform). The aspiring Geopark also comprises the Premurge area, which represents the outer Southern Apennines foredeep, whose Plio-Quaternary evolution is spectacularly exposed thanks to an “anomalous” regional middle-late Quaternary uplift. Despite the presence of numerous geological singularities of international importance, it would be important, from a geotourist point of view, to propose a regional framework of the geology of the aUGGp before introducing visitors to the significance of the individual geosites, whose importance could be amplified if included in the geoevolutionary context of the Murge aUGGp

Surgeons’ practice and preferences for the anal fissure treatment: results from an international survey

The best nonoperative or operative anal fissure (AF) treatment is not yet established, and several options have been proposed. Aim is to report the surgeons' practice for the AF treatment. Thirty-four multiple-choice questions were developed. Seven questions were about to participants' demographics and, 27 questions about their clinical practice. Based on the specialty (general surgeon and colorectal surgeon), obtained data were divided and compared between two groups. Five-hundred surgeons were included (321 general and 179 colorectal surgeons). For both groups, duration of symptoms for at least 6 weeks is the most important factor for AF diagnosis (30.6%). Type of AF (acute vs chronic) is the most important factor which guide the therapeutic plan (44.4%). The first treatment of choice for acute AF is ointment application for both groups (59.6%). For the treatment of chronic AF, this data is confirmed by colorectal surgeons (57%), but not by the general surgeons who prefer the lateral internal sphincterotomy (LIS) (31.8%) (p = 0.0001). Botulin toxin injection is most performed by colorectal surgeons (58.7%) in comparison to general surgeons (20.9%) (p = 0.0001). Anal flap is mostly performed by colorectal surgeons (37.4%) in comparison to general surgeons (28.3%) (p = 0.0001). Fissurectomy alone is statistically significantly most performed by general surgeons in comparison to colorectal surgeons (57.9% and 43.6%, respectively) (p = 0.0020). This analysis provides useful information about the clinical practice for the management of a debated topic such as AF treatment. Shared guidelines and consensus especially focused on operative management are required to standardize the treatment and to improve postoperative results