Targeting the phosphatidylglycerol lipid: An amphiphilic dendrimer as a promising antibacterial candidate.

The rapid emergence and spread of multidrug-resistant bacterial pathogens require the development of antibacterial agents that are robustly effective while inducing no toxicity or resistance development. In this context, we designed and synthesized amphiphilic dendrimers as antibacterial candidates. We report the promising potent antibacterial activity shown by the amphiphilic dendrimer , composed of a long hydrophobic alkyl chain and a tertiary amine-terminated poly(amidoamine) dendron, against a panel of Gram-negative bacteria, including multidrug-resistant and exhibited effective activity against drug-resistant bacterial infections in vivo.

Molecular Ballet: Investigating the Complex Interaction between Self-Assembling Dendrimers and Human Serum Albumin via Computational and Experimental Methods.

Dendrimers, intricate macromolecules with highly branched nanostructures, offer unique attributes including precise control over size, shape, and functionality, making them promising candidates for a wide range of biomedical applications. The exploration of their interaction with biological environments, particularly human serum albumin (HSA), holds significant importance for biomedical utilization. In this study, the interaction between HSA and a recently developed self-assembling amphiphilic dendrimer (AD) was investigated using various experimental techniques.

Item Response Analysis of the Financial Capacity Instrument-Short Form.

Objective: The Financial Capacity Instrument-Short Form (FCI-SF) is a performance-based measure of everyday financial skills that takes 15 min to administer. Although the FCI-SF has demonstrated excellent psychometric properties, advanced psychometric methods such as item response theory (IRT) can provide important information on the performance of individual test items in measuring financial capacity and in distinguishing between healthy and cognitively impaired individuals.

Method: Participants were 272 older adults diagnosed with mild cognitive impairment (MCI) and 1,344 cognitively healthy controls recruited from the Mayo Clinic Study of Aging at the Mayo Clinic in Rochester, Minnesota and also from the Cognitive Observations in Seniors study at the University of Alabama at Birmingham.

Spotting Local Environments in Self-Assembled Monolayer-Protected Gold Nanoparticles.

Organic-inorganic (O-I) nanomaterials are versatile platforms for an incredible high number of applications, ranging from heterogeneous catalysis to molecular sensing, cell targeting, imaging, and cancer diagnosis and therapy, just to name a few. Much of their potential stems from the unique control of organic environments around inorganic sites within a single O-I nanomaterial, which allows for new properties that were inaccessible using purely organic or inorganic materials. Structural and mechanistic characterization plays a key role in understanding and rationally designing such hybrid nanoconstructs.

Some things old, new and borrowed: Delivery of dabrafenib and vemurafenib to melanoma cells via self-assembled nanomicelles based on an amphiphilic dendrimer.

Two clinically approved anticancer drugs targeting BRAF in melanoma patients - dabrafenib (DAB) and vemurafenib (VEM) - have been successfully encapsulated into nanomicelles formed upon self-assembly of an amphiphilic dendrimer AD based on two C aliphatic chains and a G2 PAMAM head. The process resulted in the formation of well-defined (∼10 nm) core-shell nanomicelles (NMs) with excellent encapsulation efficiency (∼70% for DAB and ∼60% for VEM) and good drug loading capacity (∼27% and ∼24% for DAB and VEM, respectively). Dynamic light scattering (DLS), transmission electron microscopy (TEM), small-angle x-ray scattering (SAXS), nuclear magnetic resonance (NMR), isothermal titration calorimetry (ITC), and molecular simulation (MS) experiments were used, respectively, to determine the size and structure of the empty and drug-loaded nanomicelles (DLNMs), along with the interactions between the NMs and their cargoes.

Development and implementation of an electronic Clinical Dementia Rating and Financial Capacity Instrument-Short Form.

Introduction: To address the need for remote assessments of cognitive decline and dementia, we developed and administered electronic versions of the Clinical Dementia Rating (CDR®) and the Financial Capacity Instrument-Short Form (FCI-SF) (F-CAP), called the eCDR and eFCI, respectively.

Methods: The CDR and FCI-SF were adapted for remote, unsupervised, online use based on item response analysis of the standard instruments. Participants completed the eCDR and eFCI first in clinic, and then at home within 2 weeks.

Transformation of L-DOPA and Dopamine on the Surface of Gold Nanoparticles: An NMR and Computational Study.

Gold nanoparticles (AuNPs) have found applications in biomedicine as diagnostic tools, but extensive research efforts have been also directed toward their development as more efficient drug delivery agents. The high specific surface area of AuNPs may provide dense loading of molecules like catechols (L-DOPA and dopamine) on nanosurfaces, enabling functionalization strategies for advancing conventional therapy and diagnostic approaches of neurodegenerative diseases. Despite numerous well-described procedures in the literature for preparation of different AuNPs, possible transformation and structural changes of surface functionalization agents have not been considered thoroughly.

Association of Performance on the Financial Capacity Instrument-Short Form With Brain Amyloid Load and Cortical Thickness in Older Adults.

Background And Objectives: To investigate the association of the Financial Capacity Instrument-Short Form (FCI-SF) performance and timing total scores with brain β-amyloid and cortical thickness in cognitively unimpaired (CU) (at baseline) older adults.

Methods: A total of 309 participants (aged 70 years or older) of the Mayo Clinic Study of Aging underwent C-Pittsburgh compound B PET amyloid imaging and MRI, and completed the FCI-SF. Abnormal amyloid PET was defined as standardized uptake value ratio ≥1.

Cognitive Correlates of Impaired Testamentary Capacity in Alzheimer's Dementia.

Background: Testamentary capacity (TC) is a legal construct about the ability to make or change a will. Although studies of financial and medical capacities have noted a strong association between capacity and cognition, no study has examined the cognitive correlates of TC in Alzheimer's disease (ad).

Methods: Study participants were 22 cognitively healthy controls and 20 persons with mild to moderate ad who were administered a neuropsychological battery and the Testamentary Capacity Instrument (TCI), a new performance-based measure of TC.

Dynamic self-assembling supramolecular dendrimer nanosystems as potent antibacterial candidates against drug-resistant bacteria and biofilms.

The alarming and prevailing antibiotic resistance crisis urgently calls for innovative "outside of the box" antibacterial agents, which can differ substantially from conventional antibiotics. In this context, we have established antibacterial candidates based on dynamic supramolecular dendrimer nanosystems self-assembled with amphiphilic dendrimers composed of a long hydrophobic alkyl chain and a small hydrophilic poly(amidoamine) dendron bearing distinct terminal functionalities. Remarkably, the amphiphilic dendrimer with amine terminals exhibited strong antibacterial activity against both Gram-positive and Gram-negative as well as drug-resistant bacteria, and prevented biofilm formation.

Assessment of Testamentary Capacity in Older Adults: Description and Initial Validation of a Standardized Interview Instrument.

Objective: Testamentary capacity (TC) is a legal construct, which concerns a person's mental capacity to make or amend a will. Although expert clinicians are frequently asked to assess TC in forensic settings, there are few instruments and little empirical research to inform and guide their assessments. The present study describes the development and psychometric properties of a standardized assessment measure of TC (Testamentary Capacity Instrument-TCI), and investigates its reliability and validity.

Binding of the B-Raf Inhibitors Dabrafenib and Vemurafenib to Human Serum Albumin: A Biophysical and Molecular Simulation Study.

Drug binding to human serum albumin (HSA) significantly affects drug transport and biological activity. To gain insight into the binding mechanism of the two B-Raf tyrosine kinase inhibitors dabrafenib and vemurafenib to HSA, in this work, we adopted a combined strategy based on fluorescence spectroscopy, isothermal titration calorimetry (ITC), circular dichroism (CD), and molecular simulations. Both anticancer drugs are found to bind spontaneously and with a 1:1 stoichiometry within the same binding pocket, located in Sudlow's site II (subdomain IIIA) of the protein with comparable affinity and without substantially perturbing the protein secondary structure.

Synthesis of Aminoethyl-Substituted Piperidine Derivatives as σ Receptor Ligands with Antiproliferative Properties.

A series of novel σ receptor ligands with a 4-(2-aminoethyl)piperidine scaffold was prepared and biologically evaluated. The underlying concept of our project was the improvement of the lipophilic ligand efficiency of previously synthesized potent σ ligands. The key steps of the synthesis comprise the conjugate addition of phenylboronic acid at dihydropyridin-4(1H)-ones 7, homologation of the ketones 8 and introduction of diverse amino moieties and piperidine N-substituents.

Molecular rationale for SARS-CoV-2 spike circulating mutations able to escape bamlanivimab and etesevimab monoclonal antibodies.

The purpose of this work is to provide an in silico molecular rationale of the role eventually played by currently circulating mutations in the receptor binding domain of the SARS-CoV-2 spike protein (S-RBD) in evading the immune surveillance effects elicited by the two Eli Lilly LY-CoV555/bamlanivimab and LY-CoV016/etesevimab monoclonal antibodies. The main findings from this study show that, compared to the wild-type SARS-CoV-2 spike protein, mutations E484A/G/K/Q/R/V, Q493K/L/R, S494A/P/R, L452R and F490S are predicted to be markedly resistant to neutralization by LY-CoV555, while mutations K417E/N/T, D420A/G/N, N460I/K/S/T, T415P, and Y489C/S are predicted to confer LY-CoV016 escaping advantage to the viral protein. A challenge of our global in silico results against relevant experimental data resulted in an overall 90% agreement.

The fellowship of the RING: BRCA1, its partner BARD1 and their liaison in DNA repair and cancer.

The breast cancer type 1 susceptibility protein (BRCA1) and its partner - the BRCA1-associated RING domain protein 1 (BARD1) - are key players in a plethora of fundamental biological functions including, among others, DNA repair, replication fork protection, cell cycle progression, telomere maintenance, chromatin remodeling, apoptosis and tumor suppression. However, mutations in their encoding genes transform them into dangerous threats, and substantially increase the risk of developing cancer and other malignancies during the lifetime of the affected individuals. Understanding how BRCA1 and BARD1 perform their biological activities therefore not only provides a powerful mean to prevent such fatal occurrences but can also pave the way to the development of new targeted therapeutics.

Thiolate end-group regulates ligand arrangement, hydration and affinity for small compounds in monolayer-protected gold nanoparticles.

The ability to control the properties of monolayer protected gold nanoparticles (MPNPs) discloses unrevealed features stemming from collective properties of the ligands forming the monolayer and presents opportunities to design new materials. To date, the influence of ligand end-group size and capacity to form hydrogen bonds on structure and hydration of small MPNPs (<5 nm) has been poorly studied. Here, we show that both features determine ligands order, solvent accessibility, capacity to host hydrophobic compounds and interfacial properties of MPNPs.

Dendrimeric nanosystem consistently circumvents heterogeneous drug response and resistance in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with no efficacious treatment. The application of nanomedicine is expected to bring new hope to PDAC treatment. In this study, we report a novel supramolecular dendrimeric nanosystem carrying the anticancer drug doxorubicin, which demonstrated potent anticancer activity, markedly overcoming the heterogeneity of drug response and resistance of primary cultured tumor cells derived from PDAC patients.

Probing Multiscale Factors Affecting the Reactivity of Nanoparticle-Bound Molecules.

The structures and physicochemical properties of surface-stabilizing molecules play a critical role in defining the properties, interactions, and functionality of hybrid nanomaterials such as monolayer-stabilized nanoparticles. Concurrently, the distinct surface-bound interfacial environment imposes very specific conditions on molecular reactivity and behavior in this setting. Our ability to probe hybrid nanoscale systems experimentally remains limited, yet understanding the consequences of surface confinement on molecular reactivity is crucial for enabling predictive nanoparticle synthon approaches for postsynthesis engineering of nanoparticle surface chemistry and construction of devices and materials from nanoparticle components.

Cationic Dendrimers for siRNA Delivery: Computational Approaches for Characterization.

Nowadays, computer simulations have been established as a fundamental tool in the design and development of new dendrimer-based nanocarriers for drug and gene delivery. Moreover, the level of detail contained in the information that can be gathered by performing atomistic-scale simulations cannot be obtained with any other available experimental technique. In this chapter we describe the main computational toolbox that can be exploited in the different stages of novel dendritic nanocarrier production-from the initial conception to the stage of biological intermolecular interactions.

ITC for Characterization of Self-Assembly Process of Cationic Dendrons for siRNA Delivery.

siRNAs are emerging as promising therapeutic agents due to their ability to inhibit specific genes in many diseases. However, these tools require specific vehicles in order to be safely delivered to the targeted site. Among different siRNA delivery systems, self-assembled nanomicelles based on amphiphilic cationic dendrons (ACDs) have recently outperformed nanovectors based on covalent carriers.

Cationic Dendrimers for siRNA Delivery: An Overview of Methods for In Vitro/In Vivo Characterization.

This chapter reviews the different techniques for analyzing the chemical-physical properties, transfection efficiency, cytotoxicity, and stability of covalent cationic dendrimers (CCDs) and self-assembled cationic dendrons (ACDs) for siRNA delivery in the presence and absence of their nucleic cargos. On the basis of the reported examples, a standard essential set of techniques is described for each step of a siRNA/nanovector (NV) complex characterization process: (1) analysis of the basic chemical-physical properties of the NV per se; (2) characterization of the morphology, size, strength, and stability of the siRNA/NV ensemble; (3) characterization and quantification of the cellular uptake and release of the siRNA fragment; (4) in vitro and (5) in vivo experiments for the evaluation of the corresponding gene silencing activity; and (6) assessment of the intrinsic toxicity of the NV and the siRNA/NV complex.

Chemoenzymatic synthesis of 2,6-disubstituted tetrahydropyrans with high σ receptor affinity, antitumor and analgesic activity.

1,3-Dioxanes 1 and cyclohexanes 2 bearing a phenyl ring and an aminoethyl moiety in 1,3-relationship to each other represent highly potent σ receptor antagonists. In order to increase the chemical stability of the acetalic 1,3-dioxanes 1 and the polarity of the cyclohexanes 2, tetrahydropyran derivatives 3 equipped with the same substituents were designed, synthesized and pharmacologically evaluated. The key step of the synthesis was a lipase-catalyzed enantioselective acetylation of the alcohol (R)-5 leading finally to enantiomerically pure test compounds 3a-g.

Computational Mutagenesis at the SARS-CoV-2 Spike Protein/Angiotensin-Converting Enzyme 2 Binding Interface: Comparison with Experimental Evidence.

The coronavirus disease-2019 (COVID-19) pandemic, caused by the pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), started in China during late 2019 and swiftly spread worldwide. Since COVID-19 emergence, many therapeutic regimens have been relentlessly explored, and although two vaccines have just received emergency use authorization by different governmental agencies, antiviral therapeutics based neutralizing antibodies and small-drug inhibitors can still be vital viable options to prevent and treat SARS-CoV-2 infections. The viral spike glycoprotein (S-protein) is the key molecular player that promotes human host cellular invasion via recognition of and binding to the angiotensin-converting enzyme 2 gene (ACE2).

Mixed-monolayer functionalized gold nanoparticles for cancer treatment: Atomistic molecular dynamics simulations study.

Gold nanoparticles (AuNPs) are employed as drug carriers due to their inertness, non-toxicity, and ease of synthesis. An experimental search for the optimal AuNP design would require a systematic variation of physico-chemical properties which is time-consuming and expensive. Computational methods provide quicker and cheaper approach to complement experiments and provide useful guidelines.