Drug design and synthesis of first in class PDZ1 targeting NHERF1 inhibitors as anticancer agents

Targeted approaches aiming at modulating NHERF1 activity, rather than its overall expression, would be preferred to preserve the normal functions of this versatile protein. We focused our attention on the NHERF1/PDZ1 domain that governs its membrane recruitment/displacement through a transient phosphorylation switch. We herein report the design and synthesis of novel NHERF1 PDZ1 domain inhibitors. These compounds have potential therapeutic value when used in combination with antagonists of β-catenin to augment apoptotic death of colorectal cancer cells refractory to currently available Wnt/β-catenin-targeted agents

Use of mixed study techniques in the evaluation of coastline dynamics - the “Porto Cesareo” MPA case of study

In recent decades, the much-discussed climate changes with the consequent variations in sea and weather conditions and the rise of the mean sea level are causing an indisputable set of negative actions on the entire coastal system mainly due to the increase of the erosive phenomenon along the shorelines. These critical scenarios have a major impact even on a local scale, and because of that, we decided to study a well knows tract of rocky/sandy mixed coast, in a highly anthropized area, even if located inside the “Porto Cesareo” Marine Protected Area (MPA) (Ionian Sea, Gulf of Taranto, Puglia Region, Italy). The high naturalistic and archaeological value of this area calls for a greater institutional effort in the study of erosional phenomena. Several historical documents from other studies point out that this coastal area is an ideal place for this kind of research. The effects of coastal erosion and anthropic pressures along this tract of coast require adequate efforts for a consistent and rapid evaluation of the coastal dynamics. The methodologies proposed in this work are based on mixed techniques from different fields of study, integrating recent aero photogrammetry surveys with drones, aerial images acquired by the Italian Military Geographic Institute (IGM), elaboration of paleoshorelines related by underwater archaeological markers and their dating, and finally on the elaboration of satellite products useful for the study of vast areas. The monitoring of coastal areas and the evaluation of shoreline dynamics are core topics in the implementation of managing actions of decision makers on a local, regional, national, and international scale, above all in places like the chosen one, inside an MPA. Remote sensing through the use of RPAS (Remotely Piloted Aircraft Systems or Drones) has proved to be very useful for identifying phenomena that act on a small spatial scale and in supporting and implementing protective measures according to the adaptive management approach, through multi-year surveys on habitats of conservation interest [18]. For the implementation of fine-scale monitoring actions, we have chosen products from the Sentinel satellite of the Copernicus constellation (European Space Agency - ESA). In this context, the use of satellite products provides a recurrent view of the ground, useful in the short and long-term monitoring of changes in wide coastal areas, and in particular, offers a coastline positioning evaluation in near real-time. Local monitoring actions performed in recent years have already shown an erosive trend in the past decades, and even, negative forecasts for the next decade, so further surveys with mixed methodologies could be crucial in the evaluation of the evolution of this particular coastal area by local authorities

Left ventricular mass increase is associated with cognitive decline and dementia in the elderly independently of blood pressure

Aims Left ventricular (LV) mass increase is considered part of composite target organ damage in hypertension and an independent risk factor for cardiovascular (CV) events. This study was designed to explore whether left ventricular mass index (LVMI) is associated with cognitive decline and dementia in elderly subjects, independently of blood pressure (BP) levels. Methods and results Four hundred subjects (mean age 79 ± 6 years) were studied. Left ventricular mass was measured echocardiographically in accordance with American Society of Echocardiography and normalized for body height to the 2.7 (LVMI). Global cognitive function was evaluated with the mini-mental state examination (MMSE) (maximum score 30). Dementia was defined as an MMSE score <21. Arterial stiffness was evaluated as carotid–femoral pulse wave velocity by Complior®. Prevalence of hypertension was 70% and diabetes mellitus was diagnosed in 25%. No significant differences in traditional CV risk factors were observed across LVMI quartiles. Mini-mental state examination showed an inverse trend across LVMI quartiles (the higher the LVMI, the lower the MMSE, P for trend <0.05); systolic and diastolic BP levels were not different across LVMI quartiles. In multivariable logistic regression models, including age, sex, BP levels, and use of antihypertensive drugs as covariates, the highest LVMI was found to be independently associated with a two-fold higher likelihood of having dementia. The association persisted significant even after adjustment for arterial stiffness. Conclusion In elderly subjects, LVMI is associated with a progressive cognitive decline. This association is independent of BP levels and/or large artery stiffness

Ultrasonographic assessment of normal jugular veins in Standardbred horses

Ultrasonography (US) is the recommended imaging technique to evaluate jugular veins. This prospective randomized clinical study was designed to collect a series of B-mode US measurements of manually distended jugular veins in healthy Italian Standardbreds and to find possible correlations between ultrasound measurements and animal morphometric characteristics. Forty-two horses, eight males and 34 females (range 3-22\u2009years; bodyweight 494.4\u2009\ub1\u200941.7\u2009kg), were included in the study. The diameters and wall thicknesses of both jugular veins were measured at three different sites of the neck. The differences in ultrasound measurements based on scans, age, gender, side, and site of the neck were evaluated by ANOVA or by the Kruskal-Wallis test. The effects of the morphometric measures on each ultrasound parameter were evaluated by MANOVA (P\u2009&lt;\u20090.05)

Ultrasonographic assessment of normal jugular veins in Standardbred horses

Ultrasonography (US) is the recommended imaging technique to evaluate jugular veins. This prospective randomized clinical study was designed to collect a series of B-mode US measurements of manually distended jugular veins in healthy Italian Standardbreds and to find possible correlations between ultrasound measurements and animal morphometric characteristics. Forty-two horses, eight males and 34 females (range 3-22 years; bodyweight 494.4 ± 41.7 kg), were included in the study. The diameters and wall thicknesses of both jugular veins were measured at three different sites of the neck. The differences in ultrasound measurements based on scans, age, gender, side, and site of the neck were evaluated by ANOVA or by the Kruskal-Wallis test. The effects of the morphometric measures on each ultrasound parameter were evaluated by MANOVA (P < 0.05)

The use of platelet-rich plasma for treatment of tenodesmic lesions in horses: A systematic review and meta-analysis of clinical and experimental data

The use of platelet-rich plasma (PRP) to enhance tenodesmic lesion healing has been questioned over the years. The aim of this study was to evaluate current literature to establish the effectiveness of PRP for treating tenodesmic lesions through a systematic review, in accordance with the PRISMA guidelines, and a meta-analysis. Studies comparing PRP with placebo or other treatments for horses with tenodesmic injuries or evaluated PRP effect on tendon and ligament explants were included. Outcomes were clinical, ultrasound, histologic, molecular evaluation, and adverse effects. Two authors independently extracted data and assessed each study’s risk of bias. Treatment effects were evaluated using risk ratios for dichotomous data, together with 95% CI. Data were pooled using the random-effects model. The quality of the evidence for each outcome was assessed using GRADE criteria. Twenty-four trials met inclusion criteria for systematic review, while fifteen studies were included in the meta-analysis. Results showed no significant differences in the outcomes between PRP and control groups. Finally, there is no definitive evidence that PRP enhances tendons and ligaments healing. Therefore, there is a need for more controlled trials to draw a firmer conclusion about the efficacy of PRP as a treatment for tenodesmic lesions in the horse

Chromosomal mapping of ribosomal clusters and telomeric sequences (TTAGG)n in nine species of lobsters (Crustacea, Decapoda)

Lobsters are ubiquitous, economically important decapod crustaceans with apparently conflicting evolutionary relationships. Here, we describe the chromosomal location of the major (45S rDNA) and minor (5S rDNA) ribosomal gene families in four species of Astacidea and five of Achelata, using two-color FISH. The major ribosomal family is located in 4–16 sites per diploid chromosome set, with Nephrops norvegicus (Nephropidae) showing the highest number described so far in Decapoda. The 5S rDNA is located in two sites in eight species; only in the crayfish Procambarus clarkii the 5S FISH signals were detected in four sites together with additional weaker signals. Furthermore, in N. norvegicus the minor ribosomal genes are syntenic with one major ribosomal cluster. Moreover, we located by two-color FISH the pentanucleotide (TTAGG)n telomeric repeat in the Nephropidae studied, showing the occurrence of a colocalization with 45S ribosomal sequences in Homarus gammarus. The comparison of chromosomal locations of repetitive sequences in Mediterranean, Atlantic, and South African lobster species as well as in marine and freshwater ones provides information on chromosomal evolution and cytotaxonomy of Decapoda

Gpr investigation at the archaeological site of le cesine, lecce, italy

In this contribution, we present some results achieved in the archaeological site of Le Cesine, close to Lecce, in southern Italy. The investigations have been performed in a site close to the Adriatic Sea, only slightly explored up to now, and where the presence of an ancient Roman harbour is alleged on the basis of remains visible above all under the current sea level. This measurement campaign has been performed in the framework of a short-term scientific mission (STSM) performed in the framework of the European Cost Action 17131 (acronym SAGA), and has been aimed to identify possible points where future localized excavation might and hopefully will be performed in the next few years. Both a traditional elaboration and an innovative data processing based on a linear inverse scattering model have been performed on the data

UNDERGROUND HERITAGE DOCUMENTATION: THE CASE STUDY OF GROTTA ZINZULUSA IN CASTRO (LECCE-ITALY)

3D documentation of the Underground Built Heritage (UBH) is always fundamental for knowledge, management, conservation, and enhancement of cultural heritage, but the challenges involved in documenting this kind of site are many and various, With the aim of providing an accurate and reliable representation of the surveyed area without employing time-consuming processes, Mobile Mapping Systems (MMSs) based on SLAM (Simultaneous Localization And Mapping) technology have now the potential to overcome these challenges, proving to be a useful alternative to traditional surveying techniques. The underground site of Grotta Zinzulusa in Castro (LE), Italy, is an anchialine cave system difficult to access and document due to its narrow passages, large rooms, and poor illumination. Within this case study, the effectiveness of using an MMS approach, employing the STONEX&reg; X120GO SLAM Laser Scanner system, to document the cave system and integrates the data with those obtained from other traditional geomatics techniques, such as UAS (Uncrewed Aerial System) and TLS (Terrestrial Laser Scanning) surveys, has been proved. The study aims to define the best practices and operational methodologies for enhancing the speediness, usability, and cost-effectiveness of using MMSs in underground settings for 3D documentation of heritage sites to provide metrically correct and accurate products for researchers, scientists, and the wider public

Targeting PDZ domains as potential treatment for viral infections, neurodegeneration and cancer

The interaction between proteins is a fundamental event for cellular life that is generally mediated by specialized protein domains or modules. PDZ domains are the largest class of protein–protein interaction modules, involved in several cellular pathways such as signal transduction, cell–cell junctions, cell polarity and adhesion, and protein trafficking. Because of that, dysregulation of PDZ domain function often causes the onset of pathologies, thus making this family of domains an interesting pharmaceutical target. In this review article we provide an overview of the structural and functional features of PDZ domains and their involvement in the cellular and molecular pathways at the basis of different human pathologies. We also discuss some of the strategies that have been developed with the final goal to hijack or inhibit the interaction of PDZ domains with their ligands. Because of the generally low binding selectivity of PDZ domain and the scarce efficiency of small molecules in inhibiting PDZ binding, this task resulted particularly difficult to pursue and still demands increasing experimental efforts in order to become completely feasible and successful in vivo