Novel colchicine derivative CR42-24 demonstrates potent anti-tumor activity in urothelial carcinoma

5 days 6 hours ago
Bladder cancers, and specifically urothelial carcinoma, have few effective treatment options, and tumors typically develop resistance against standard of care chemotherapies leading to significant mortality. The development of alternative therapies with increased selectivity and improved tolerability would significantly impact this patient population. Here, we investigate a novel colchicine derivative, CR42-24, with increased selectivity for the βIII tubulin subtype as a treatment for urothelial...
Clayton J Bell

Disassembly of microtubules by intense terahertz pulses

1 month 1 week ago
The biological effects of terahertz (THz) radiation have been observed across multiple levels of biological organization, however the sub-cellular mechanisms underlying the phenotypic changes remain to be elucidated. Filamentous protein complexes such as microtubules are essential cytoskeletal structures that regulate diverse biological functions, and these may be an important target for THz interactions underlying THz-induced effects observed at the cellular or tissue level. Here, we show...
Cameron M Hough

Computational determination of toxicity risks associated with a selection of approved drugs having demonstrated activity against COVID-19

1 month 1 week ago
CONCLUSION: In summary, this manuscript aims to provide a potentially useful source of essential knowledge on toxicity assessment of 90 compounds for healthcare practitioners and researchers to find off-label alternatives for the treatment for COVID-19. The majority of the molecules discussed in this manuscript have already moved into clinical trials and thus their known pharmacological and human safety profiles are expected to facilitate a fast track preclinical and clinical assessment for...
Maral Aminpour

Computational Study of Potential Galectin-3 Inhibitors in the Treatment of COVID-19

2 months ago
Galectin-3 is a carbohydrate-binding protein and the most studied member of the galectin family. It regulates several functions throughout the body, among which are inflammation and post-injury remodelling. Recent studies have highlighted the similarity between Galectin-3's carbohydrate recognition domain and the so-called "galectin fold" present on the N-terminal domain of the S1 sub-unit of the SARS-CoV-2 spike protein. Sialic acids binding to the N-terminal domain of the Spike protein are...
Maral Aminpour

<em>In silico</em> identification of RBD subdomain of spike protein from Pro<sup>322</sup>-Thr<sup>581</sup> for applications in vaccine development against SARS-CoV2

6 months 3 weeks ago
The three-dimensional hybrid structures of coronavirus spike proteins including the C-terminal sequence and receptor binding motif (RBM) was remodeled and energy minimized. Further, protein-protein docking show that Receptor Binding Domain (RBD) of SARS-CoV 2 Lys^(457)-Pro^(490) bind on the surface of ACE2 receptor near N-terminal helices to form host-pathogen attachment. In this binding interface, SARS-CoV 2 shows a tight network of hydrogen bonds than other spike proteins from BtRsRaTG13-CoV,...
Nataraj S Pagadala

Modeling Microtubule Counterion Distributions and Conductivity Using the Poisson-Boltzmann Equation

7 months 3 weeks ago
Microtubules are highly negatively charged proteins which have been shown to behave as bio-nanowires capable of conducting ionic currents. The electrical characteristics of microtubules are highly complicated and have been the subject of previous work; however, the impact of the ionic concentration of the buffer solution on microtubule electrical properties has often been overlooked. In this work we use the non-linear Poisson Boltzmann equation, modified to account for a variable permittivity...
Boden B Eakins

The Uniqueness of Albumin as a Carrier in Nanodrug Delivery

8 months ago
Albumin is an appealing carrier in nanomedicine because of its unique features. First, it is the most abundant protein in plasma, endowing high biocompatibility, biodegradability, nonimmunogenicity, and safety for its clinical application. Second, albumin chemical structure and conformation allows interaction with many different drugs, potentially protecting them from elimination and metabolism in vivo, thus improving their pharmacokinetic properties. Finally, albumin can interact with receptors...
Alessandra Spada

Insights into the interaction dynamics between volatile anesthetics and tubulin through computational molecular modelling

8 months 2 weeks ago
General anesthetics, able to reversibly suppress all conscious brain activity, have baffled medical science for decades, and little is known about their exact molecular mechanism of action. Given the recent scientific interest in the exploration of microtubules as putative functional targets of anesthetics, and the involvement thereof in neurodegenerative disorders, the present work focuses on the investigation of the interaction between human tubulin and four volatile anesthetics: ethylene,...
Eric A Zizzi

First Search for Dyons with the Full MoEDAL Trapping Detector in 13 TeV pp Collisions

8 months 4 weeks ago
The MoEDAL trapping detector consists of approximately 800 kg of aluminum volumes. It was exposed during run 2 of the LHC program to 6.46 fb^{-1} of 13 TeV proton-proton collisions at the LHCb interaction point. Evidence for dyons (particles with electric and magnetic charge) captured in the trapping detector was sought by passing the aluminum volumes comprising the detector through a superconducting quantum interference device (SQUID) magnetometer. The presence of a trapped dyon would be...
B Acharya

An insight into the anticancer potential of carbamates and thiocarbamates of 10-demethoxy-10-methylaminocolchicine

9 months 1 week ago
Colchicine shows very high antimitotic activity, therefore, it is used as a lead compound for generation of new anticancer agents. In the hope of developing novel, useful drugs with more favourable pharmacological profiles, a series of doubly modified colchicine derivatives has been designed, synthesized and characterized. These novel carbamate or thiocarbamate derivatives of 10-demethoxy-10-methylaminocolchicine have been tested for their antiproliferative activity against four human cancer...
Julia Krzywik

JAK inhibitors in immune-mediated rheumatic diseases: From a molecular perspective to clinical studies

10 months 2 weeks ago
The Janus Kinase signalling pathway is implicated in the pathogenesis of immune-related diseases. The potency of small-molecule Janus Kinase inhibitors in the treatment of inflammatory diseases demonstrates that this pathway can be successfully targeted for therapeutic purposes. The outstanding relevant questions concerning drugs' efficacy and toxicity challenge the research to enhance the selectivity of these drugs. The promising results of computational techniques, such as Molecular Dynamics...
Michela Sperti

Modeling the structure of the frameshift-stimulatory pseudoknot in SARS-CoV-2 reveals multiple possible conformers

10 months 2 weeks ago
The coronavirus causing the COVID-19 pandemic, SARS-CoV-2, uses -1 programmed ribosomal frameshifting (-1 PRF) to control the relative expression of viral proteins. As modulating -1 PRF can inhibit viral replication, the RNA pseudoknot stimulating -1 PRF may be a fruitful target for therapeutics treating COVID-19. We modeled the unusual 3-stem structure of the stimulatory pseudoknot of SARS-CoV-2 computationally, using multiple blind structural prediction tools followed by μs-long molecular...
Sara Ibrahim Omar

Synthesis, anticancer activity and molecular docking studies of N-deacetylthiocolchicine and 4-iodo-N-deacetylthiocolchicine derivatives

10 months 2 weeks ago
Colchicine is a plant alkaloid with a broad spectrum of biological and pharmacological properties. It has found application as an anti-inflammatory agent and also shows anticancer effects through its ability to destabilize microtubules by preventing tubulin dimers from polymerizing leading to mitotic death. However, adverse side effects have so far restricted its use in cancer therapy. This has led to renewed efforts to identify less toxic derivatives. In this article, we describe the synthesis...
Greta Klejborowska

How Do Tumor-Treating Fields Work?

11 months ago
Since approved by the FDA for the treatment of glioblastoma brain cancer in 2015, tumor-treating fields (TTFields) have rapidly become the fourth modality to treat cancer, along with surgery, chemotherapy, and radiation [1]. TTFields are now in clinical trials for a variety of cancer types. While efficacy has been proven in the clinic, the higher efficacy is demonstrated in vitro and in animal models, which indicates much greater clinical efficacy is possible. To attain the great promise of...
Kristen W. Carlson

From quantum chemistry to quantum biology: a path toward consciousness

11 months ago
This paper presents a historical overview of quantum physics methodology's development and application to various science fields beyond physics, especially biology and consciousness. Following a successful interpretation of several early 20t⁢h century experiments, quantum physics gradually provided a conceptual framework for molecular bonds via quantum chemistry. In recent years individual biological phenomena such as photosynthesis and bird navigation have been experimentally and theoretically...
Jack A Tuszynski

Revealing and Attenuating the Electrostatic Properties of Tubulin and Its Polymers

11 months 3 weeks ago
Tubulin is an electrostatically negative protein that forms cylindrical polymers termed microtubules, which are crucial for a variety of intracellular roles. Exploiting the electrostatic behavior of tubulin and microtubules within functional microfluidic and optoelectronic devices is limited due to the lack of understanding of tubulin behavior as a function of solvent composition. This work displays the tunability of tubulin surface charge using dimethyl sulfoxide (DMSO) for the first time....
Aarat P Kalra

Non-Equilibrium Quantum Electrodynamics in Open Systems as a Realizable Representation of Quantum Field Theory of the Brain

11 months 3 weeks ago
We derive time evolution equations, namely the Klein-Gordon equations for coherent fields and the Kadanoff-Baym equations in quantum electrodynamics (QED) for open systems (with a central region and two reservoirs) as a practical model of quantum field theory of the brain. Next, we introduce a kinetic entropy current and show the H-theorem in the Hartree-Fock approximation with the leading-order (LO) tunneling variable expansion in the 1st order approximation for the gradient expansion. Finally,...
Akihiro Nishiyama