Cationic carbosilane dendrimers and oligonucleotide binding: an energetic affair

GENERATION 2 CATIONIC CARBOSILANE DENDRIMERS HOLD GREAT PROMISE AS INTERNALIZING AGENTS FOR GENE THERAPY AS THEY PRESENT LOW TOXICITY AND RETAIN AND INTERNALIZE GENETIC MATERIAL AS OLIGONUCLEOTIDE OR SIRNA. IN THIS WORK WE CARRIED OUT A COMPLETE IN SILICO STRUCTURAL AND ENERGETICAL CHARACTERIZATION OF THE INTERACTIONS OF A SET OF 2G CARBOSILANE DENDRIMERS, SHOWING DIFFERENT AFFINITY TOWARDS TWO SINGLE STRAND OLIGONUCLEOTIDE (ODN) SEQUENCES IN VITRO. OUR SIMULATIONS PREDICT THAT THESE FOUR DENDRIMERS AND THE RELEVANT ODN COMPLEXES ARE CHARACTERIZED BY SIMILAR SIZE AND SHAPE, AND THAT THE MOLECULE-SPECIFIC ODN BINDING ABILITY CAN BE RATIONALIZED ONLY CONSIDERING A CRITICAL MOLECULAR DESIGN PARAMETER: THE NORMALIZED EFFECTIVE BINDING ENERGY \u394GBIND,EFF/NEFF I.E., THE PERFORMANCE OF EACH ACTIVE INDIVIDUAL DENDRIMER BRANCH DIRECTLY INVOLVED IN A BINDING INTERACTIO

SAFETY MONITORING BY MEANS OF SENSOR NETWORKS DISTRIBUTED WITHIN THE FOSSA SITE PLAN

Abstract. The seismic event of 6 April 2009 has inevitably left its mark on the history of the entire territory of L'Aquila (Italy), completely devastating the town and much of the province. Within such frantic and extensive reconstruction activity, the resulting construction works could not but draw attention to some issues of fundamental importance such as coordinated planning, safety, respect for the rules and above all the rebirth of the territory. This research is aimed at drawing up the site plan for Fossa, a municipality in the Province of L'Aquila and not far from the region capital of Abruzzo, Italy. The main objective is to create a monitoring standard by means of a dedicated sensors network and detailed strategies in order to coordinate, guide and support the single actions of intervention through design behaviours and highly technological tools. The Plan is configured as a tool for participatory planning, with the active involvement of planners, companies and citizens, whose common goal is the preservation of the identity of locations, the mitigation of seismic risk and the enhancement of the cultural heritage of the Municipality of Fossa. Implementation of this work is the application of technological systems for construction site monitoring: a concrete response to the growing demand for organized management of the construction process on site and safety in the workplace can be achieved through the use of systems and rational control and management procedures that include the use of innovative technologies

3D AND 4D MODELLING IN BUILDING SITE WORKING CONTROL

The purpose of this contribution is to describe the use of the HBIM method for the management of the restoration building site applied to a historic building in the heart of the historic center of L'Aquila. The construction is located in a densely constructed area and it is characterized by a high spatial complexity with various types of limitations including: small external and internal spaces and interferences due to neighboring construction sites. The proposed method involves a particularly detailed organization of the construction site, simultaneously planning both the development of the working and the safety in order to have more transparency and more control of the information shared among stakeholders. This method consists in planning the Gantt diagram from general to detailed level, according to certain parameters that will be cross-examined and checked regurarly. A screening step has been carried out regarding the current situation, the proceedings to be undertaken and the stakeholders to be included. Thank to this, it has been possible to have automated processes to control not only geometrical interferences but also the ones related to the completion of the work in the interest of enhancing the risk management. Due to a 3D and 4D BIM modelling, there are been found advanced layouts and some timeliners that have allowed a rigourus control of the building process, particularly in the case of precise working and potencial changes that are common in building sites of this type

Electrostatic binding of polyanions using self-assembled multivalent (SAMul) ligand displays-structure-activity effects on DNA/heparin binding

This paper reports that modifying the ligands in self-assembled multivalent (SAMul) displays has an impact on apparent binding selectivity towards two nanoscale biological polyanions-heparin and DNA. For the nanostructures assayed here, spermidine ligands are optimal for heparin binding but spermine ligands are preferred for DNA. Probing subtle differences in such nanoscale binding interfaces is a significant challenge, and as such, several experimental binding assays-competition assays and isothermal calorimetry-are employed to confirm differences in affinity and provide thermodynamic insights. Given the dynamic nature and hierarchical binding processes involved in SAMul systems, we employed multiscale modelling to propose reasons for the origins of polyanion selectivity differences. The modelling results, when expressed in thermodynamic terms and compared with the experimental data, suggest that DNA is a shape-persistent polyanion, and selectivity originates only from ligand preferences, whereas heparin is more flexible and adaptive, and as such, actively reinforces ligand preferences. As such, this study suggests that inherent differences between polyanions may underpin subtle binding selectivity differences, and that even simple electrostatic interfaces such as these can have a degree of tunability, which has implications for biological control and regulation on the nanoscale

BEP & MAPPING PROCESS FOR THE RESTORATION BUILDING SITE

The BEP, acronym for BIM Execution Plan, consists of the information management plan created by the design team to illustrate how to meet the requirements defined in the Employer's Information Requirement (EIR).The big amount of data will have to be organized a priori both for the professionals who will use that piece of information and for the stakeholders who will have to receive only the right information and use specific worksets. Just at this stage, the heart of the BIM method, there are different advantages compared to the traditional process, in which these informational steps were omitted, causing errors, delays and therefore an increase in active and passive costs. This paper explores the methodology applied to the mapping process of the management of a recovery site. For a better understanding of the result achieved, the stages of the process have been explained, from the acquisition of data, through the scan to BIM process up to the construction phases. In addition, the phases (Identify BIM goal and uses, Design BIM Project Execution Process, Develop information exchange) and the steps (Investigation, Identification and Strategy) necessary to achieve the objective have been analyzed. This is the Lean construction and Integrated Project Delivery (IPD), methodologies and systems that allow the improvement of the building process thanks to data sharing and communication between stakeholders before work begins so as to eliminate any possible delay.</p

COFLEX: FLEXIBLE BRACELET ANTI COVID-19 TO PROTECT CONSTRUCTION WORKERS

Abstract. To implement the protocol contrasting the diffusion of Covid-19, the employer is required, to ensure the safety and health of the worker at work, to adopt measures related to the control of body temperature (with respect for privacy), the minimum distance during work and all other activities such as breaks, canteen breaks, access to toilets, in addition to the adoption of specifically developed safety procedures, such as e.g. the use of man-down detection devices. In this context, the project aims to illustrate a system able of providing support in the safeguarding of workers' health on construction sites. This system, based on information received from sensors capable of identifying workers' positions (e.g., if less than 1m away) and their vital parameters (e.g., body temperature, gasped breathing), as well as moving objects inside the construction site area (e.g., to check if a worker is passing under a moving crane), will raise early alerts directly to the workers and/or to the central software, with respect for privacy, to immediately activate all the necessary measures to mitigate the risk. The system, based on the data communicated by the various sensors, will store and process them for the purpose of extracting useful information for risk management. The proposed system configured itself as a new product taking advantage from a high Technology Readiness Level maturated from the Smart Safety Belt already developed by some of the authors

An ionizable supramolecular dendrimer nanosystem for effective siRNA delivery with a favorable safety profile

Gene therapy using small interfering RNA (siRNA) is emerging as a novel therapeutic approach to treat various diseases. However, safe and efficient siRNA delivery still constitutes the major obstacle for clinical implementation of siRNA therapeutics. Here we report an ionizable supramolecular dendrimer vector, formed via self-assembly of a small amphiphilic dendrimer, as an effective siRNA delivery system with a favorable safety profile. By virtue of the ionizable tertiary amine terminals, the supramolecular dendrimer has a low positively charged surface potential and no notable cytotoxicity at physiological pH. Nonetheless, this ionizable feature imparted sufficient surface charge to the supramolecular dendrimer to enable formation of a stable complex with siRNA via electrostatic interactions. The resulting siRNA/dendrimer delivery system had a surface charge that was neither neutral, thus avoiding aggregation, nor too high, thus avoiding cytotoxicity, but was sufficient for favorable cellular uptake and endosomal release of the siRNA. When tested in different cancer cell lines and patient-derived cancer organoids, this dendrimer-mediated siRNA delivery system effectively silenced the oncogenes Myc and Akt2 with a potent antiproliferative effect, outperforming the gold standard vector, Lipofectamine 2000. Therefore, this ionizable supramolecular dendrimer represents a promising vector for siRNA delivery. The concept of supramolecular dendrimer nanovectors via self-assembly is new, yet easy to implement in practice, offering a new perspective for supramolecular chemistry in biomedical applications. [Figure not available: see fulltext.

Mitochondrial dysfunction induced by a SH2 domain-Targeting STAT3 inhibitor leads to metabolic synthetic lethality in cancer cells

In addition to its canonical role in nuclear transcription, signal transducer and activator of transcription 3 (STAT3) is emerging as an important regulator of mitochondrial function. Here, we demonstrate that a novel inhibitor that binds with high affinity to the STAT3 SH2 domain triggers a complex cascade of events initiated by interference with mitochondrial STAT3 (mSTAT3). The mSTAT3\u2013drug interaction leads to mitochondrial dysfunction, accumulation of proteotoxic STAT3 aggregates, and cell death. The cytotoxic effects depend directly on the drug\u2019s ability to interfere with mSTAT3 and mitochondrial function, as demonstrated by site-directed mutagenesis and use of STAT3 knockout and mitochondria-depleted cells. Importantly, the lethal consequences of mSTAT3 inhibition are enhanced by glucose starvation and by increased reliance of cancer cells and tumor-initiating cells on mitochondria, resulting in potent activity in cell cultures and tumor xenografts in mice. These findings can be exploited for eliciting synthetic lethality in metabolically stressed cancer cells using highaffinity STAT3 inhibitors. Thus, this study provides insights on the role of mSTAT3 in cancer cells and a conceptual framework for developing more effective cancer therapies

Neurogenic inducers based on the chromone scaffold, a new family of multitarget directed ligands for Alzheimer's disease

Resumen del trabajo presentado a la XXXVIII Reunión Anual del Grupo Español de Neurotransmisión y Neuroprotección (GENN), celebrada en Almagro (Ciudad Real) del 13 al 15 de diciembre de 2017.The highly complex pathophysiology of Alzheimer's disease (AD) and other neurodegenerative illnesses have led to replace the traditional one-drug - one-target by the multi-target-directed ligands (MTDLs) paradigm, in which a single molecule is designed to be active against several pharmacological targets. Continuing with our interest in neuroprotective and neurogenic compounds, in this work we describe a new family of donepezil flavonoid hybrids exhibiting nanomolar affinities for the sigma-1 receptor and a combined inhibition of key enzymes in AD, such as 5-lipoxygenase, acetylcholinesterase, and monoaminoxidases. In general, they scavenge free radical species and are predicted to be brain-permeable. In phenotypic assays, new hybrids protect neuronal cells against mitochondrial oxidative stress and promote maturation of neural stem cells into a neuronal phenotype. Therefore, new donepezil - flavonoid hybrids could contribute to the protection and even, the reparation of neuronal tissues, of great therapeutic interest in AD and neurodegenerative diseases.Spanish Ministry of Economy and Competitiveness MINECO (grant SAF2015-64948-C2-1-R) and Spanish National Research Council CSIC (grant PIE-201580E109).Peer Reviewe