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In a recent study, we have identified BPH03 as a promising scaffold for the development of compounds aimed at modulating the interaction between PED/PEA15 (Phosphoprotein Enriched in Diabetes/Phosphoprotein Enriched in Astrocytes 15) and PLD1 (phospholipase D1), with potential applications in type II diabetes therapy. PED/PEA15 is known to be overexpressed in certain forms of diabetes, where it binds to PLD1, thereby reducing insulin-stimulated glucose transport. The inhibition of this interaction reestablishes basal glucose transport, indicating PED as a potential target of ligands capable to recover glucose tolerance and insulin sensitivity. In this study, we employ computational methods to provide a detailed description of BPH03 interaction with PED, evidencing the presence of a hidden druggable pocket within its PLD1 binding surface. We also elucidate the conformational changes that occur during PED interaction with BPH03. Moreover, we report new NMR data supporting the in-silico findings and indicating that BPH03 disrupts the PED/PLD1 interface displacing PLD1 from its interaction with PED. Our study represents a significant advancement toward the development of potential therapeutics for the treatment of type II diabetes.

BackgroundMature T-cell neoplasms arise from the neoplastic transformation of a single T lymphocyte, and all cells in a neoplastic clone share the same V segment in the beta chain of the T-cell receptor (TCR). These segments may represent an innovative target for the development of targeted therapies.MethodsA specific V segment of the TCR beta chain (TRBV5-1) was analyzed using bioinformatic tools, identifying three potential antigenic peptides. One of these peptides, selected for synthesis, was used to screen a library of human single-chain variable fragments (scFv) through phage display. One fragment demonstrated high affinity and specificity for the antigen and was used to produce a human monoclonal antibody of the IgG1 class.ResultsSurface plasmon resonance (SPR) studies confirmed the high affinity of the monoclonal antibody for the antigen in the nanomolar range. Flow cytometry analysis on patients’ samples demonstrated that the antibody, conjugated with a fluorochrome, selectively binds to tumor T lymphocytes expressing TRBV5-1, without binding to other lymphocytes or blood cell components.ConclusionsThe development of fully human IgG1 monoclonal antibodies targeting specific V segments of the TCR beta chain represents a potential therapeutic option for patients with mature T-cell neoplasms.

Numerous research studies show that mindfulness can mitigate the negative impact of trauma on mental health by reducing symptoms of anxiety, mediating the relationship between trauma exposure and mental health, and treating symptoms resulting from traumatic events. During the COVID-19 pandemic, which was considered a traumatic event, the wellbeing of adults and children was severely compromised. Although children seem less vulnerable to the physical effects of the virus, this does not seem to be true for the psychological effects. Indeed, a prolonged period of loss of family activities and routines can have a negative impact on the mental health of children and adolescents. To investigate how mindfulness can help preschool children cope with the effects of COVID-19, a study was conducted on 46 children aged 4–5 years. The programme, based on the work of Jon Kabat-Zinn and adapted to the age of the participants, consisted of eight weekly 45-min sessions. Qualitative and quantitative results showed positive feedback, indicating that mindfulness helps children make sense of their experiences and achieve functional post-traumatic growth. This approach is seen as a challenge to guide children toward the restoration of psychological wellbeing, which is essential for good psychological balance.

Background and objective: Percutaneous nephrolithotomy (PCNL) is the recommended treatment for large or complex renal stones. This study aims to evaluate the outcomes of mini PCNL in obese and nonobese patients and to compare the outcomes of mini and standard PCNL in the obese population. Methods: We retrospectively reviewed our PCNL database to identify patients who had undergone mini (Amplatz sheath size 17.5Ch) or standard (Amplatz sheath size ≥26Ch) PCNL between 2005 and 2022. First, we compared the outcomes of the two procedures in the obese (body mass index [BMI] ≥30) and nonobese (BMI

The contribution illustrates the experience of CIS Roma Scuole Verdi, where the DiAP Research Group of the ‘Sapienza’ University of Rome supported the CSIMU Department of Roma Capitale in launching a process of energy-environmental upgrading and decarbonisation of 111 school buildings distributed across the 15 Municipalities of the City of Rome. Through a systemic and multi-scalar approach, some Key Performance Indicators (KPIs) were identified and monitored, which were significant for energy class, reduction of climate-altering emissions, reduction of energy needs, and supply from renewable sources. The positive contribution of the implemented technological-plant solutions presents a replicability potential, contributing to the intensification of climate actions, with impacts on urban regeneration and the city’s public budgets. Article info Received: 18/03/2024; Revised: 15/04/2024; Accepted: 23/04/2024

Herein, we report the structure-based selection via molecular docking of four N-heterocyclic bis-carbene gold(I) complexes, whose potential as ligands for the hTel23 G-quadruplex structure has been investigated using circular dichroism (CD) spectroscopy, CD melting, and polyacrylamide gel electrophoresis (PAGE). The complex containing a bis(1,2,3,4,6,7,8,9-octahydro-11H-11λ3-pyridazino[1,2-a]indazol-11-yl) scaffold induces a transition from the hybrid (3 + 1) topology to a prevalent parallel G-quadruplex conformation, whereas the complex featuring a bis(2-(2-acetamidoethyl)-3λ3-imidazo[1,5-a]pyridin-3(2H)-yl) moiety disrupted the original G-quadruplex structure. These results deserve particular attention in light of the recent findings on the pathological involvements of G-quadruplexes in neurodegenerative diseases.

In a trans-scalar perspective, the Bicocca district extends from the local NIL (Nucleo di Identità Locale) to part of Municipality 9, Sesto San Giovanni and Cinisello Balsamo. Recently, the University of Milan-Bicocca, as regards to the so-called ‘terza missione’, has remarked its role as a key-pole for the surrounding area by proposing research, educational (and orientation) activities, as well as institutional initiatives based in this post-industrial area of Milan. Within this scenario, our group was in charge of design-ing a project leading to an artistic image representing the district users’ sense of place. By combining geography of perception, urban sociology, participatory design and the flânerie approaches, we planned a working process starting from the ‘subjective production of images’ by the district’s users and inhabitants. The project was structured in two phases: (1) December 2020 – January 2021: we organised two workshops by inviting groups of students, teachers and shop owners and working on their mental maps to construct a final image resulting from the two teams’ negotiation processes. The reading of the maps was initially inspired by the categories identified by Kevin Lynch (1962) and then moved on to a process of co-construction of a collective image; (2) March 2021: we shared the visual body with a professional illustrator (Carlo Stanga) entrusted with the mandate to translate the images into an artistic product. The essay discusses the visual representation of users’ sense of place and the potential legacy upon communication strategies, way-findings tools and education projects.

Background: Mature T-cell neoplasms arise from the neoplastic transformation of a single T lymphocyte, and all cells in a neoplastic clone share the same V segment in the beta chain of the T-cell receptor (TCR). These segments may represent an innovative target for the development of targeted therapies. Methods: A specific V segment of the TCR beta chain (TRBV5-1) was analyzed using bioinformatic tools, identifying three potential antigenic peptides. One of these peptides, selected for synthesis, was used to screen a library of human single-chain variable fragments (scFv) through phage display. One fragment demonstrated high affinity and specificity for the antigen and was used to produce a human monoclonal antibody of the IgG1 class. Results: Surface plasmon resonance (SPR) studies confirmed the high affinity of the monoclonal antibody for the antigen in the nanomolar range. Flow cytometry analysis on patients' samples demonstrated that the antibody, conjugated with a fluorochrome, selectively binds to tumor T lymphocytes expressing TRBV5-1, without binding to other lymphocytes or blood cell components. Conclusions: The development of fully human IgG1 monoclonal antibodies targeting specific V segments of the TCR beta chain represents a potential therapeutic option for patients with mature T-cell neoplasms. [ABSTRACT FROM AUTHOR]

Abstract A plethora of different electronic and optoelectronic devices have been developed lately, for biosensing applications (e.g., label‐free, fast, and easier to operate) based on a detecting interface accommodating the biorecognition elements, anchored by thiolate self‐assembled monolayers (SAMs) on a gold surface. Here, a surface plasmon resonance (SPR) characterization of anti‐p24 anchored on different SAMs is performed to investigate the effect of the SAM structure on the antibodies’ packing efficiency and the sensors’ analytical figures of merit. Notably, the mixed SAM deposited from a solution 10:1 of 3‐mercaptopropionic acid and 11‐mercaptoundecanoic acid (11MUA) is compared to that resulting from a solution 10:1 of ad hoc synthesized N‐(2‐hydroxyethyl)‐3‐mercaptopropanamide (NMPA)/11MUA. Despite the improvement in the anti‐p24 surface coverage registered using the 11MUA/NMPA SAM, the latter produces a significant decrease in the antibodies’ binding efficiency against human immunodeficiency virus p24 protein. To provide a molecular rationale behind the SPR data, density functional theory calculations are also undertaken. A comprehensive physical view of the main competing phenomena affecting the biorecognition events at a biofunctionalized gold detecting interface is represented here.

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system in which most patients have serum autoantibodies (called NMO-IgG) that bind to astrocyte water channel aquaporin-4 (AQP4). A potential therapeutic strategy in NMO is to block the interaction of NMO-IgG with AQP4. Building on recent observation that some single-point and compound mutations of the AQP4 extracellular loop C prevent NMO-IgG binding, we carried out comparative Molecular Dynamics (MD) investigations on three AQP4 mutants, TP137-138AA, N153Q and V150G, whose 295-ns long trajectories were compared to that of wild type human AQP4. A robust conclusion of our modeling is that loop C mutations affect the conformation of neighboring extracellular loop A, thereby interfering with NMO-IgG binding. Analysis of individual mutations suggested specific hydrogen bonding and other molecular interactions involved in AQP4-IgG binding to AQP4.

Drug-induced cardiotoxicity is a common side effect of drugs in clinical use or under postmarket surveillance and is commonly due to off-target interactions with the cardiac human-ether-a-go-go-related (hERG) potassium channel. Therefore, prioritizing drug candidates based on their hERG blocking potential is a mandatory step in the early preclinical stage of a drug discovery program. Herein, we trained and properly validated 30 ligand-based classifiers of hERG-related cardiotoxicity based on 7,963 curated compounds extracted by the freely accessible repository ChEMBL (version 25). Different machine learning algorithms were tested, namely, random forest, K-nearest neighbors, gradient boosting, extreme gradient boosting, multilayer perceptron, and support vector machine. The application of 1) the best practices for data curation, 2) the feature selection method VSURF, and 3) the synthetic minority oversampling technique (SMOTE) to properly handle the unbalanced data, allowed for the development of highly predictive models (BAMAX = 0.91, AUCMAX = 0.95). Remarkably, the undertaken temporal validation approach not only supported the predictivity of the herein presented classifiers but also suggested their ability to outperform those models commonly used in the literature. From a more methodological point of view, the study put forward a new computational workflow, freely available in the GitHub repository (https://github.com/PDelre93/hERG-QSAR), as valuable for building highly predictive models of hERG-mediated cardiotoxicity.

Herein, we report the structure-based selection via molecular docking of four N-heterocyclic bis-carbene gold(I) complexes, whose potential as ligands for the hTel23 G-quadruplex structure has been investigated using circular dichroism (CD) spectroscopy, CD melting, and polyacrylamide gel electrophoresis (PAGE). The complex containing a bis(1,2,3,4,6,7,8,9-octahydro-11H-11λ3-pyridazino[1,2-a]indazol-11-yl) scaffold induces a transition from the hybrid (3 + 1) topology to a prevalent parallel G-quadruplex conformation, whereas the complex featuring a bis(2-(2-acetamidoethyl)-3λ3-imidazo[1,5-a]pyridin-3(2H)-yl) moiety disrupted the original G-quadruplex structure. These results deserve particular attention in light of the recent findings on the pathological involvements of G-quadruplexes in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Numerous research studies show that mindfulness can mitigate the negative impact of trauma on mental health by reducing symptoms of anxiety, mediating the relationship between trauma exposure and mental health, and treating symptoms resulting from traumatic events. During the COVID-19 pandemic, which was considered a traumatic event, the wellbeing of adults and children was severely compromised. Although children seem less vulnerable to the physical effects of the virus, this does not seem to be true for the psychological effects. Indeed, a prolonged period of loss of family activities and routines can have a negative impact on the mental health of children and adolescents. To investigate how mindfulness can help preschool children cope with the effects of COVID-19, a study was conducted on 46 children aged 4–5 years. The programme, based on the work of Jon Kabat-Zinn and adapted to the age of the participants, consisted of eight weekly 45-min sessions. Qualitative and quantitative results showed positive feedback, indicating that mindfulness helps children make sense of their experiences and achieve functional post-traumatic growth. This approach is seen as a challenge to guide children toward the restoration of psychological wellbeing, which is essential for good psychological balance. [ABSTRACT FROM AUTHOR]

Abstract Single‐molecule detection at a nanometric interface in a femtomolar solution, can take weeks as the encounter rate between the diffusing molecule to be detected and the transducing nanodevice is negligibly small. On the other hand, several experiments prove that macroscopic label‐free sensors based on field‐effect‐transistors, engaging micrometric or millimetric detecting interfaces are capable to assay a single‐molecule in a large volume within few minutes. The present work demonstrates why at least a single molecule out of a few diffusing in a 100 µL volume has a high probability to hit a large capturing and detecting electronic interface. To this end, sensing data, measured with an electrolyte‐gated FET whose gate is functionalized with 1012 capturing anti‐immunoglobulin G, are here provided along with a Brownian diffusion‐based modeling. The EG‐FET assays solutions down to some tens of zM in concentrations with volumes ranging from 25 µL to 1 mL in which the functionalized gates are incubated for times ranging from 30 s to 20 min. The high level of accordance between the experimental data and a model based on the Einstein's diffusion‐theory proves how the single‐molecule detection process at large‐capturing interfaces is controlled by Brownian diffusion and yet is highly probable and fast.

The fight against climate change and the right use of soil are two challenges on a global scale. The urbanization and the progressive reduction of green areas and permeable surfaces in urban settlements are amplifying some phenomena such as the increase of frequency and intensity of heatwaves and the annual average temperature, causing the growth of building energy demand. The paper examines the energy-saving potential that can be obtained by planting trees in outdoor spaces available around buildings for different urban frameworks in the Mediterranean climate. The data coming from the simulations, referred to residential sectors, expand the knowledge about the energy-environmental benefits of Green Infrastructures and are useful to guide sustainable practices of urban regeneration.

In the context of an Ageing Society, the technological innovation produced by Digital Age discovers new frontiers and research areas on the topic of living and urban spaces for the elderly. The opportunities offered by the integration of ICTs in the built environment prefigure new settlement scenarios based on the introduction of innovative digital services. Starting from the study of ‘smart homes’ prototype models, the contribution proposes a critical reflection on processes, products and services that could be implemented in future housing for the elderly, facilitating new forms of well-being, security and social inclusion. Compared to ongoing experimental researches, new possible dynamics of innovation in processes and products are delineated, hypothesizing the application of smart systems to real living environments for the elderly.

Rituximab, a murine–human chimera, is the first monoclonal antibody (mAb) developed as a therapeutic agent to target CD20 protein. Its Fab domain and its interaction with CD20 have been extensively studied and high-resolution atomic models obtained by X-ray diffraction or cryo-electron microscopy are available. However, the structure of the full-length antibody is still missing as the inherent protein flexibility hampers the formation of well-diffracting crystals and the reconstruction of 3D microscope images. The global structure of rituximab from its dilute solution is here elucidated by small-angle X-ray scattering (SAXS). The limited data resolution achievable by this technique has been compensated by intensive computational modelling that led to develop a new and effective procedure to characterize the average mAb conformation as well as that of the single domains. SAXS data indicated that rituximab adopts an asymmetric average conformation in solution, with a radius of gyration and a maximum linear dimension of 52 Å and 197 Å, respectively. The asymmetry is mainly due to an uneven arrangement of the two Fab units with respect to the central stem (the Fc domain) and reflects in a different conformation of the individual units. As a result, the Fab elbow angle, which is a crucial determinant for antigen recognition and binding, was found to be larger (169°) in the more distant Fab unit than that in the less distant one (143°). The whole flexibility of the antibody has been found to strongly depend on the relative inter-domain orientations, with one of the Fab arms playing a major role. The average structure and the amount of flexibility has been studied in the presence of different buffers and additives, and monitored at increasing temperature, up to the complete unfolding of the antibody. Overall, the structural characterization of rituximab can help in designing next-generation anti-CD20 antibodies and finding more efficient routes for rituximab production at industrial level.

The situation of multiple socioeconomic and housing emergency crises associated with the ageing of the population raises new challenges for the construction industry. Establishing a relationship between people, the environment and digital technologies opens up broad possibilities for design innovation and in relation to construction, management and use practices in housing for the elderly. This paper investigates evolved housing models composed of interoperable ICT/IoT technological and spatial solutions. The objective of the research is to draw up a code of practice, starting from environmental and technological requirements for spaces and services, as well as quality and performance indicators (KPI) for a new culture of dwelling, with provisions for their replicability, adaptability and scalability to a variety of use settings.

The endocannabinoid system (ECS) plays a very important role in numerous physiological and pharmacological processes, such as those related to the central nervous system (CNS), including learning, memory, emotional processing, as well pain control, inflammatory and immune response, and as a biomarker in certain psychiatric disorders. Unfortunately, the half-life of the natural ligands responsible for these effects is very short. This perspective describes the potential role of the inhibitors of the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL), which are mainly responsible for the degradation of endogenous ligands in psychic disorders and related pathologies. The examination was carried out considering both the impact that the classical exogenous ligands such as Δ9-tetrahydrocannabinol (THC) and (−)-trans-cannabidiol (CBD) have on the ECS and through an analysis focused on the possibility of predicting the potential toxicity of the inhibitors before they are subjected to clinical studies. In particular, cardiotoxicity (hERG liability), probably the worst early adverse reaction studied during clinical studies focused on acute toxicity, was predicted, and some of the most used and robust metrics available were considered to select which of the analyzed compounds could be repositioned as possible oral antipsychotics.

Targeting pathogenic mechanisms, rather than essential processes, represents a very attractive approach for the development of new antimycobacterial drugs. In this context, iron acquisition routes have recently emerged as potentially druggable pathways. However, the importance of siderophore biosynthesis in the virulence and pathogenicity of M. abscessus (Mab) is still poorly understood. In this study, we investigated the Salicylate Synthase (SaS) of Mab as an innovative molecular target for the development of inhibitors of siderophore production. Notably, Mab-SaS does not have any counterpart in human cells, making it an interesting candidate for drug discovery. Starting from the analysis of the binding of a series of furan-based derivatives, previously identified by our group as inhibitors of MbtI from M. tuberculosis (Mtb), we successfully selected the lead compound 1, exhibiting a strong activity against Mab-SaS (IC50 ≈ 5 µM). Computational studies characterized the key interactions between 1 and the enzyme, highlighting the important roles of Y387, G421, and K207, the latter being one of the residues involved in the first step of the catalytic reaction. These results support the hypothesis that 5-phenylfuran-2-carboxylic acids are also a promising class of Mab-SaS inhibitors, paving the way for the optimization and rational design of more potent derivatives.

Among the non-platinum antitumor agents, gold complexes have received increased attention owing to their strong antiproliferative effects, which generally occur through non-cisplatin-like mechanisms of action. Several studies have revealed that many cytotoxic gold compounds, such as N-heterocyclic carbene (NHC)-gold(I) complexes, are potent thioredoxin reductase (TrxR) inhibitors. Many other pathways have been supposed to be altered by gold coordination to protein targets. Within this frame, we have selected two gold(I) complexes based on aromatic ligands to be tested on cancer cells. Differently from bis [1,3-diethyl-4,5-bis(4-methoxyphenyl)imidazol-2-ylidene]gold(I) bromide (Au4BC), bis [1-methyl-3-acridineimidazolin-2-ylidene]gold(I) tetrafluoroborate (Au3BC) inhibited TrxR1 activity in vitro. Treatment of Huh7 hepatocellular carcinoma (HCC) cells, and MDA-MB-231 triple-negative breast cancer (TNBC) cells, with Au4BC inhibited cell viability, increased reactive oxygen species (ROS) levels, caused DNA damage, and induced autophagy and apoptosis. Notably, we found that, although Au3BC inhibited TrxR1 activity, no effect on the cell viabilities of HCC and BC cells was observed. At the molecular level, Au3BC induced a protective response mechanism in Huh7 and MDA-MB-231 cells, by inducing up-regulation of RAD51 and p62 protein expression, two proteins involved in DNA damage repair and autophagy, respectively. RAD51 gene knock-down in HCC cells increased cell sensitivity to Au3BC by significant reduction of cell viability, induction of DNA damage, and induction of apoptosis and autophagy. All together, these results suggest that the tested NHC-Gold complexes, Au3BC and Au4BC, showed different mechanisms of action, either dependent or independent of TrxR1 inhibition. As a result, Au3BC and Au4BC were found to be promising candidates as anticancer drugs for the treatment of HCC and BC.