Observe without disturbing: tracer particles sense local stresses in cell collectives without affecting the cancer cell dynamics.

Measurements of local stresses on the cancer cells (CCs), inferred by embedding inert compressible tracer particles (TPs) in a growing multicellular spheroid (MCS), show that pressure decreases monotonically as the distance from the core of the MCS increases. How faithfully do the TPs report the local stresses in the CCs is an important question because pressure buildup in the MCS is dynamically generated due to CC division, which implies that the CC dynamics should be minimally altered by the TPs. Here using theory and simulations, we show that although the TP dynamics is unusual, exhibiting sub-diffusive behavior on times less than the CC division times and hyper-diffusive dynamics in the long-time limit, they do not affect the long-time CC dynamics.

Effect of pectin and attapulgite filler on swelling, network parameters and controlled release of diltiazem hydrochloride from polyacrylic copolymer gel.

Pectin grafted polyacrylic copolymer hydrogels were made by free radical crosslink copolymerization of acrylic acid (AA) and acrylamide (AM) in an aqueous solution of pectin. N'N-methylene bis acrylamide (MBA) was used as a crosslinker. During the polymerization reaction the attapulgite (APG) filler was also incorporated in situ into the network of the copolymer gel.

Correction: Spatially heterogeneous dynamics of cells in a growing tumor spheroid: comparison between theory and experiments.

Correction for 'Spatially heterogeneous dynamics of cells in a growing tumor spheroid: comparison between theory and experiments' by Sumit Sinha et al., Soft Matter, 2020, 16, 5294-5304, DOI: .

Spatially heterogeneous dynamics of cells in a growing tumor spheroid: comparison between theory and experiments.

Collective cell movement, characterized by multiple cells that are in contact for substantial periods of time and undergo correlated motion, plays a central role in cancer and embryogenesis. Recent imaging experiments have provided time-dependent traces of individual cells, thus providing an unprecedented picture of tumor spheroid growth. By using simulations of a minimal cell model, we analyze the experimental data that map the movement of cells in a fibrosarcoma tumor spheroid embedded in a collagen matrix.

Heterocycle amide isosteres: An approach to overcoming resistance for HIV-1 integrase strand transfer inhibitors.

A series of heterocyclic pyrimidinedione-based HIV-1 integrase inhibitors was prepared and screened for activity against purified integrase enzyme and/or viruses modified with the following mutations within integrase: Q148R, Q148H/G140S and N155H. These are mutations that result in resistance to the first generation integrase inhibitors raltegravir and elvitegravir. Based on consideration of drug-target interactions, an approach was undertaken to replace the amide moiety of the first generation pyrimidinedione inhibitor with azole heterocycles that could retain potency against these key resistance mutations.

Universal Nature of Collapsibility in the Context of Protein Folding and Evolution.

Theory and simulations predicted that the sizes of the unfolded states of globular proteins should decrease as the denaturant concentration is reduced from a high to a low value. However, small angle X-ray scattering (SAXS) data were used to assert the opposite, while interpretation of single molecule Förster resonance energy transfer experiments (FRET) supported the theoretical predictions. The disagreement between the two experiments is the SAXS-FRET controversy.

Giant Casimir Nonequilibrium Forces Drive Coil to Globule Transition in Polymers.

We develop a theory to probe the effect of nonequilibrium fluctuation-induced forces on the size of a polymer confined between two horizontal, thermally conductive plates subject to a constant temperature gradient, ∇ T. We assume that (a) the solvent is good and (b) the distance between the plates is large so that in the absence of a thermal gradient the polymer is a coil, whose size scales with the number of monomers as N, with ν ≈ 0.6.

Origin of superdiffusive behavior in a class of nonequilibrium systems.

Experiments and simulations have established that dynamics in a class of living and abiotic systems that are far from equilibrium exhibit superdiffusive behavior at long times, which in some cases (for example, an evolving tumor) is preceded by slow glass-like dynamics. By using the evolution of a collection of tumor cells, driven by mechanical forces and subject to cell birth and apoptosis, as a case study we show theoretically that on short timescales the mean-square displacement is subdiffusive due to jamming, whereas at long times it is superdiffusive. The results obtained by using a stochastic quantization method, which is needed because of the absence of the fluctuation-dissipation theorem, show that the superdiffusive behavior is universal and impervious to the nature of cell-cell interactions.

Charge fluctuation effects on the shape of flexible polyampholytes with applications to intrinsically disordered proteins.

Random polyampholytes (PAs) contain positively and negatively charged monomers that are distributed randomly along the polymer chain. The interaction between charges is assumed to be given by the Debye-Huckel potential. We show that the size of the PA is determined by an interplay between electrostatic interactions, giving rise to the polyelectrolyte effect due to net charge per monomer () and an effective attractive PA interaction due to charge fluctuations, .

Design, Synthesis, and SAR of C-3 Benzoic Acid, C-17 Triterpenoid Derivatives. Identification of the HIV-1 Maturation Inhibitor 4-((1 R,3a S,5a R,5b R,7a R,11a S,11b R,13a R,13b R)-3a-((2-(1,1-Dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1 H-cyclopenta[ a]chrysen-9-yl)benzoic Acid (GSK3532795, BMS-955176).

GSK3532795, formerly known as BMS-955176 (1), is a potent, orally active, second-generation HIV-1 maturation inhibitor (MI) that advanced through phase IIb clinical trials. The careful design, selection, and evaluation of substituents appended to the C-3 and C-17 positions of the natural product betulinic acid (3) was critical in attaining a molecule with the desired virological and pharmacokinetic profile. Herein, we highlight the key insights made in the discovery program and detail the evolution of the structure-activity relationships (SARs) that led to the design of the specific C-17 amine moiety in 1.

Optimal information transfer in enzymatic networks: A field theoretic formulation.

Signaling in enzymatic networks is typically triggered by environmental fluctuations, resulting in a series of stochastic chemical reactions, leading to corruption of the signal by noise. For example, information flow is initiated by binding of extracellular ligands to receptors, which is transmitted through a cascade involving kinase-phosphatase stochastic chemical reactions. For a class of such networks, we develop a general field-theoretic approach to calculate the error in signal transmission as a function of an appropriate control variable.

Protein collapse is encoded in the folded state architecture.

Folded states of single domain globular proteins are compact with high packing density. The radius of gyration, R, of both the folded and unfolded states increase as N where N is the number of amino acids in the protein. The values of the Flory exponent ν are, respectively, ≈⅓ and ≈0.

Discovery of BMS-955176, a Second Generation HIV-1 Maturation Inhibitor with Broad Spectrum Antiviral Activity.

HIV-1 maturation inhibition (MI) has been clinically validated as an approach to the control of HIV-1 infection. However, identifying an MI with both broad polymorphic spectrum coverage and good oral exposure has been challenging. Herein, we describe the design, synthesis, and preclinical characterization of a potent, orally active, second generation HIV-1 MI, BMS-955176 (2), which is currently in Phase IIb clinical trials as part of a combination antiretroviral regimen.

Identification and Characterization of BMS-955176, a Second-Generation HIV-1 Maturation Inhibitor with Improved Potency, Antiviral Spectrum, and Gag Polymorphic Coverage.

BMS-955176 is a second-generation human immunodeficiency virus type 1 (HIV-1) maturation inhibitor (MI). A first-generation MI, bevirimat, showed clinical efficacy in early-phase studies, but ∼50% of subjects had viruses with reduced susceptibility associated with naturally occurring polymorphisms in Gag near the site of MI action. MI potency was optimized using a panel of engineered reporter viruses containing site-directed polymorphic changes in Gag that reduce susceptibility to bevirimat (including V362I, V370A/M/Δ, and T371A/Δ), leading incrementally to the identification of BMS-955176.

C-3 benzoic acid derivatives of C-3 deoxybetulinic acid and deoxybetulin as HIV-1 maturation inhibitors.

A series of C-3 phenyl- and heterocycle-substituted derivatives of C-3 deoxybetulinic acid and C-3 deoxybetulin was designed and synthesized as HIV-1 maturation inhibitors (MIs) and evaluated for their antiviral activity and cytotoxicity in cell culture. A 4-subsituted benzoic acid moiety was identified as an advantageous replacement for the 3'3'-dimethylsuccinate moiety present in previously disclosed MIs that illuminates new aspects of the topography of the pharmacophore. The new analogs exhibit excellent in vitro antiviral activity against wild-type (wt) virus and a lower serum shift when compared with the prototypical HIV-1 MI bevirimat (1, BVM), the first MI to be evaluated in clinical studies.

On noise induced Poincaré-Andronov-Hopf bifurcation.

It has been numerically seen that noise introduces stable well-defined oscillatory state in a system with unstable limit cycles resulting from subcritical Poincaré-Andronov-Hopf (or simply Hopf) bifurcation. This phenomenon is analogous to the well known stochastic resonance in the sense that it effectively converts noise into useful energy. Herein, we clearly explain how noise induced imperfection in the bifurcation is a generic reason for such a phenomenon to occur and provide explicit analytical calculations in order to explain the typical square-root dependence of the oscillations' amplitude on the noise level below a certain threshold value.

Controlled release of tinidazole and theophylline from chitosan based composite hydrogels.

Several composite hydrogels were synthesized by free radical crosslink copolymerization of acrylic acid (AA) and N' methylene bis-acrylamide (MBA) in the presence of chitosan (CS). During polymerization CS was incorporated in situ in the crosslinked polyacrylic acid gel to produce composite hydrogels. The structure and properties of the hydrogels were characterized by FTIR, (13)C NMR, DTA-TGA, XRD, swelling and diffusion characteristic and also network parameters.

Synthesis, characterization, swelling and drug release behavior of semi-interpenetrating network hydrogels of sodium alginate and polyacrylamide.

Several semi interpenetrating network (SIPN) type hydrogels were synthesized by in-situ free radical crosslink copolymerization of acrylamide and crosslinker N,N'-methylene bisacrylamide (MBA) in aqueous solution of sodium alginate (SA).These SIPN hydrogels were characterized by FTIR, NMR SEM, DTA-TGA, XRD, PZC and also by swelling characteristics and network parameters. Adsorption (loading) and release of acetaminophen drug were studied with these hydrogels.

Exact solution of the Zwanzig-Lauritzen model of polymer crystallization under tension.

We solve a two-dimensional model for polymer chain folding in the presence of mechanical pulling force (f) exactly using equilibrium statistical mechanics. Using analytically derived expression for the partition function we determine the phase diagram for the model in the f-temperature (T) plane. A square root singularity in the susceptibility indicates a second order phase transition from a folded to an unfolded state at a critical force (fc) in the thermodynamic limit of infinitely long polymer chain.

The terminal (catalytic) adenosine of the HIV LTR controls the kinetics of binding and dissociation of HIV integrase strand transfer inhibitors.

Specific HIV integrase strand transfer inhibitors are thought to bind to the integrase active site, positioned to coordinate with two catalytic magnesium atoms in a pocket flanked by the end of the viral LTR. A structural role for the 3' terminus of the viral LTR in the inhibitor-bound state has not previously been examined. This study describes the kinetics of binding of a specific strand transfer inhibitor to integrase variants assembled with systematic changes to the terminal 3' adenosine.

Biochemical analysis of HIV-1 integrase variants resistant to strand transfer inhibitors.

In this study, eight different HIV-1 integrase proteins containing mutations observed in strand transfer inhibitor-resistant viruses were expressed, purified, and used for detailed enzymatic analyses. All the variants examined were impaired for strand transfer activity compared with the wild type enzyme, with relative catalytic efficiencies (k(p)/K(m)) ranging from 0.6 to 50% of wild type.

Changes to the HIV long terminal repeat and to HIV integrase differentially impact HIV integrase assembly, activity, and the binding of strand transfer inhibitors.

Human immunodeficiency virus (HIV) integrase enzyme is required for the integration of viral DNA into the host cell chromosome. Integrase complex assembly and subsequent strand transfer catalysis are mediated by specific interactions between integrase and bases at the end of the viral long terminal repeat (LTR). The strand transfer reaction can be blocked by the action of small molecule inhibitors, thought to bind in the vicinity of the viral LTR termini.

Benzyl amide-ketoacid inhibitors of HIV-integrase.

Integrase is one of three enzymes expressed by HIV and represents a validated target for therapy. Previous reports have demonstrated that the diketoacid-based chemotype is a useful starting point for the design of inhibitors of this enzyme. In this study, one of the ketone groups is replaced by a benzylamide resulting in a new potent chemotype.

Exploration of the diketoacid integrase inhibitor chemotype leading to the discovery of the anilide-ketoacids chemotype.

Integrase is one of three enzymes expressed by HIV and represents a validated target for therapy. A previous study of the diketoacid-based chemotype suggested that there are two aryl-binding domains on integrase. In this study, modifications to the indole-based diketoacid chemotype are explored.