Resveratrol nanoparticles induce apoptosis in oral cancer stem cells by disrupting the interaction between ß-catenin and GLI-1 through p53-independent activation of p21.

Cancer stem cells (CSCs) are mainly responsible for tumorigenesis, chemoresistance, and cancer recurrence. CSCs growth and progression are regulated by multiple signaling cascades including Wnt/ß-catenin and Hh/GLI-1, which acts independently or via crosstalk. Targeting the crosstalk of signaling pathways would be an effective approach to control the CSC population. Both Wnt/ß-catenin and Hh/GLI-1 signaling cascades are known to be regulated by p53/p21-dependent mechanism. However, it is interesting to delineate whether p21 can induce apoptosis in a p53-independent manner. Therefore, utilizing various subtypes of oral CSCs (SCC9-PEMT p53+/+p21+/+, SCC9-PEMT p53-/-p21+/+, SCC9-PEMT p53+/+p21-/- and SCC9-PEMT p53-/-p21-/-), we have examined the distinct roles of p53 and p21 in Resveratrol nanoparticle (Res-Nano)-mediated apoptosis. It is interesting to see that, besides the p53/p21-mediated mechanism, Res-Nano exposure also significantly induced apoptosis in oral CSCs through a p53-independent activation of p21. Additionally, Res-Nano-induced p21-activation deregulated the ß-catenin-GLI-1 complex and consequently reduced the TCF/LEF and GLI-1 reporter activities. In agreement with in vitro data, similar experimental results were obtained in in vivo mice xenograft model.

Molecular editing of NSC-666719 enabling discovery of benzodithiazinedioxide-guanidines as anticancer agents.

DNA polymerase ß (Polß) is crucial for the base excision repair (BER) pathway of DNA damage repair and is an attractive target for suppressing tumorigenesis as well as chemotherapeutic intervention of cancer. In this study, a unique strategy of scaffold-hopping-based molecular editing of a bioactive agent NSC-666719 was investigated, which led to the development of new molecular motifs with Polß inhibitory activity. NSC compound and its analogs (two series) were prepared, focusing on pharmacophore-based molecular diversity. Most compounds showed higher activities than the parent NSC-666719 and exhibited effects on apoptosis. The inhibitory activity of Polß was evaluated in both in vitro reconstituted and in vivo intact cell systems. Compound 10e demonstrated significant Polß interaction and inhibition characteristics, including direct, non-covalent, reversible, and comparable binding affinity. The investigated approach is useful, and the discovered novel analogs have a high potential for developing as anticancer therapeutics.

Near infrared-responsive quinacrine-gold hybrid nanoparticles deregulate HSP-70/P300-mediated H3K14 acetylation in ER/PR+ breast cancer stem cells.

Aim: This study aimed to determine if quinacrine-gold hybrid nanoparticles (QAuNPs) + near-infrared (NIR) deregulate HSP-70/P300 complex-mediated H3K14 acetylation in estrogen receptor/progesterone receptor (ER/PR+) breast cancer stem cells (CSCs). Materials & methods: Various cells and mouse-based systems were used as models. Results: QAuNP + NIR treatment reduced the nuclear translocation of HSP-70, affected the histone acetyltransferase activity of P300 and specifically decreased H3K14 acetylation in ER/PR+ breast CSCs. Finally, HSP-70 knockdown showed a reduction in P300 histone acetyltransferase activity, decreased H3K14 acetylation and inhibited activation of the TGF-ß gene. Conclusion: This study revealed that QAuNP + NIR irradiation inhibits oncogenic activation of the TGF-ß gene by decreasing H3K14 acetylation mediated through the HSP-70/P300 nuclear complex in ER/PR+ breast CSCs.

Combination of Resveratrol and PARP inhibitor Olaparib efficiently deregulates homologous recombination repair pathway in breast cancer cells through inhibition of TIP60-mediated chromatin relaxation.

Recently, we reported that a combination of a natural, bioactive compound Resveratrol (RES) and a PARP inhibitor Olaparib (OLA) deregulated the homologous recombination (HR) pathway, and enhanced apoptosis in BRCA1-wild-type, HR-proficient breast cancer cells. Upon DNA damage, chromatin relaxation takes place, which allows the DNA repair proteins to access the DNA lesion. But whether chromatin remodeling has any role in RES + OLA-mediated HR inhibition is not known. By using in vitro and ex vivo model systems of breast cancer, we have investigated whether RES + OLA inhibits chromatin relaxation and thereby blocks the HR pathway. It was found that RES + OLA inhibited PARP1 activity, terminated PARP1-BRCA1 interaction, and deregulated the HR pathway only in the chromatin fraction of MCF-7 cells. DR-GFP reporter plasmid-based HR assay demonstrated marked reduction in HR efficiency in I-SceI endonuclease-transfected cells treated with OLA. RES + OLA efficiently trapped PARP1 at the DNA damage site in the chromatin of MCF-7 cells. Unaltered expressions of HR proteins were found in the chromatin of PARP1-silenced MCF-7 cells, which confirmed that RES + OLA-mediated DNA damage response was PARP1-dependent. Histone Acetyltransferase (HAT) activity and histone H4 acetylation assays showed reduction in HAT activity and H4 acetylation in RES + OLA-treated chromatin fraction of cells. Western blot analysis showed that the HAT enzyme TIP60, P400 and acetylated H4 were downregulated after RES + OLA exposure. In the co-immunoprecipitation assay, it was observed that RES + OLA caused abolition of PARP1-TIP60-BRCA1 interaction, which suggested the PARP1-dependent TIP60-BRCA1 association. Unaltered expressions of PAR, BRCA1, P400, and acetylated H4 in the chromatin of TIP60-silenced MCF-7 cells further confirmed the role of TIP60 in PARP1-mediated HR activation in the chromatin. Similar results were obtained in ex vivo patient-derived primary breast cancer cells. Thus, the present study revealed that RES + OLA treatment inhibited PARP1 activity in the chromatin, and blocked TIP60-mediated chromatin relaxation, which, in turn, affected PARP1-dependent TIP60-BRCA1 association, resulting in deregulation of HR pathway in breast cancer cells.

Talazoparib enhances the quinacrine-mediated apoptosis in patient-derived oral mucosa CSCs by inhibiting BER pathway through the modulation of GCN5 and P300.

The presence of cancer stem cells (CSCs) in the tumor microenvironment (TME) is majorly responsible for the development and recurrence of cancer. Earlier reports suggested that upon DNA damage, poly-(ADP-ribose) polymerase-1 (PARP-1) helps in chromatin modulation and DNA repair process, thereby promoting CSC survival. But whether a combination of DNA damaging agents along with PARP inhibitors can modulate chromatin assembly, inhibit DNA repair processes, and subsequently target CSCs is not known. Hence, we have investigated the effect of nontoxic bioactive compound quinacrine (QC) and a potent PARP inhibitor Talazoparib in patient-derived oral mucosa CSCs (OM-CSCs) and in vivo xenograft mice preclinical model systems. Data showed that QC + Talazoparib inhibited the PARP-1-mediated chromatin remodelers' recruitment and deregulated HAT activity of GCN5 (general control nonderepressible-5) and P300 at DNA damage site, thereby preventing the access of repair proteins to the damaged DNA. Additionally, this combination treatment inhibited topoisomerase activity, induced topological stress, and induced apoptosis in OM-CSCs. Similar results were observed in an in vivo xenograft mice model system. Collectively, the data suggested that QC + Talazoparib treatment inhibited BER pathway, induced genomic instability and triggered apoptosis in OM-CSCs through the deregulation of PARP-1-mediated chromatin remodelers (GCN5 and P300) activity. Schematic representation of QC + Talazoparib-induced apoptosis in oral mucosa CSCs. (1) Induction of DNA damage takes place after QC treatment (2) PARP1-mediated PARylation at the site of DNA damage, which recruits multiple chromatin remodelers (3) Acetylation at the histone tails relax the structure of chromatin and recruits the BER pathway proteins at the site of DNA damage. (4) BER pathway activated at the site of DNA damage. (5) CSCs survive after successful repair of DNA damage. (6) Treatment of QC-treated CSCs with PARP inhibitor Talazoparib (7) Inhibition of PARylation results in failure of chromatin remodelers to interact with PARP1. (8) Inhibition of acetylation status leads to chromatin compaction. (9) BER pathway proteins are not recruited at the site of DNA damage, resulting in inhibition of BER pathway and accumulation of unrepaired DNA damage, leading to apoptosis and cell death.

Quinacrine inhibits HIF-1α/VEGF-A mediated angiogenesis by disrupting the interaction between cMET and ABCG2 in patient-derived breast cancer stem cells.

BACKGROUND: Breast cancer stem cells (BCSCs) have a critical role in progression of breast cancer by inducing angiogenesis. Several therapeutic strategies have been designed for the treatment of breast cancer by specifically preventing angiogenesis. But there is a dearth of study regarding the treatment procedure which can specifically target and kill the BCSCs and cause lesser harm to healthy cells of the body. A plant-based bioactive compound Quinacrine (QC) specifically kills cancer stem cells (CSCs) without harming healthy cells and also inhibits cancer angiogenesis but the detailed mechanistic study of its anti-CSCs and anti-angiogenic activity is yet to explore. HYPOTHESIS: Earlier report showed that both cMET and ABCG2 play an essential role in cancer angiogenesis. Both are present on the cell surface of CSCs and share an identical ATP-binding domain. Interestingly, QC a plant based and bioactive compound which was found to inhibit the function of CSCs marker cMET and ABCG2. These relevant evidence led us to hypothesize that cMET and ABCG2 may interact with each other and induce the production of angiogenic factors, resulting in activation of cancer angiogenesis and QC might disrupt the interaction between them to stop this phenomena. METHODS: Co-immunoprecipitation assay, immunofluorescence assay, and western blotting were performed by using ex vivo patient-derived breast cancer-stem-cells (PDBCSCs) and human umbilical vein endothelial cells (HUVECs). In silico study was carried out to check the interaction between cMET and ABCG2 in presence or absence of QC. Tube formation assay using HUVECs and in ovo Chorioallantoic membrane (CAM) assay using chick fertilized eggs were performed to monitor angiogenesis. In vivo patient-derived xenograft (PDX) mice model was used to validate in silico and ex vivo results. RESULTS: Data revealed that in a hypoxic tumor microenvironment (TME), cMET and ABCG2 interact with each other and upregulate HIF-1α/VEGF-A axis to induce breast cancer angiogenesis. In silico and ex vivo study showed that QC disrupted the interaction between cMET and ABCG2 to inhibit the angiogenic response in endothelial cells by reducing the secretion of VEGF-A from PDBCSCs within the TME. Knockdown of cMET, ABCG2 or both, significantly downregulated the expression of HIF-1α and reduced the secretion of pro-angiogenic factor VEGF-A in the TME of PDBCSCs. Additionally, when PDBCSCs were treated with QC, similar experimental results were obtained. CONCLUSION: In silico, in ovo, ex vivo and in vivo data confirmed that QC inhibited the HIF-1α/VEGF-A mediated angiogenesis in breast cancer by disrupting the interaction between cMET and ABCG2.

Near-infrared enhances antiangiogenic potentiality of quinacrine-gold hybrid nanoparticles in breast cancer stem cells via deregulation of HSP-70/TGF-ß.

Aim: This study aimed to explore the antiangiogenic mechanism of quinacrine-gold hybrid nanoparticle (QAuNP) and near-infrared (NIR) radiation in patient-derived primary breast cancer stem cells. Materials & methods: Various cell-based in ovo angiogenesis and in vivo patient-derived xenograft mouse systems were used as models for the study. Results: The experimental results showed that QAuNP + NIR treatment deregulated the HSP-70/TGF-ß physical interaction in primary breast cancer stem cells. Reduced TGF-ß secretion in the tumor microenvironment inhibited angiogenesis activation in endothelial cells by deregulating the TGF-ß-mediated PI3K/AKT/mTOR cascade. Conclusion: This study revealed that QAuNP + NIR irradiation downregulated HSP-70 expression, inhibited the HSP-70/TGF-ß interaction, reduced the secretion of TGF-ß in the tumor microenvironment and ultimately inhibited TGF-ß-mediated angiogenesis.

This study discovered that the formation of blood vessels in breast cancer is significantly reduced when hybrid nanoparticles and infrared laser therapy are used to treat breast cancer stem cells. The secretory cytokines in the tumor microenvironment primarily responsible for developing blood vessels in the tumor are dramatically reduced by treatment. As a result, the tumor's blood vessel growth is reduced, making it difficult for the cancer cells to get the nutrients and oxygen they need to survive.

Quinacrine and Curcumin in combination decreased the breast cancer angiogenesis by modulating ABCG2 via VEGF A.

Cancer stem cells (CSCs) cause drug resistance in cancer due to its extensive drug efflux, DNA repair and self-renewal capability. ATP binding cassette subfamily G member 2 (ABCG2) efflux pump afford protection to CSCs in tumors, shielding them from the adverse effects of chemotherapy. Although the role of ABCG2 in cancer progression, invasiveness, recurrence are known but its role in metastasis and angiogenesis are not clear. Here, using in vitro (CSCs enriched side population [SP] cells), ex vivo (patient derived primary cells), in ovo (fertilized egg embryo) and in vivo (patient derived primary tissue mediated xenograft (PDX)) system, we have systematically studied the role of ABCG2 in angiogenesis and the regulation of the process by Curcumin (Cur) and Quinacrine (QC). Cur + QC inhibited the proliferation, invasion, migration and expression of representative markers of metastasis and angiogenesis. Following hypoxia, ABCG2 enriched cells released angiogenic factor vascular endothelial growth factor A (VEGF A) and induced the angiogenesis via PI3K-Akt-eNOS cascade. Cur + QC inhibited the ABCG2 expression and thus reduced the angiogenesis. Interestingly, overexpression of ABCG2 in SP cells and incubation of purified ABCG2 protein in media induced the angiogenesis but knockdown of ABCG2 decreased the vascularization. In agreement with in vitro results, ex vivo data showed similar phenomena. An induction of vascularization was noticed in PDX mice but reduction of vascularization was also observed after treatment of Cur + QC. Thus, data suggested that in hypoxia, ABCG2 enhances the production of angiogenesis factor VEGF A which in turn induced angiogenesis and Cur + QC inhibited the process by inhibiting ABCG2 in breast cancer.

Anticipatory Heart Rate Before Moderate- and Vigorous-Intensity Exercise Among Sedentary and Physically Active Young Adult Males.

Background Anticipatory heart rate (HR) refers to an increase in HR that occurs in anticipation of a future event or activity. The anticipatory heart rate (HR) response before exercise is an important physiological indicator of exercise readiness. This study aimed to compare the anticipatory HR changes between sedentary and physically active young adult males during moderate- and vigorous-intensity exercise. Understanding these anticipatory heart rate patterns can provide insights into the physiological adaptations and cardiovascular health of individuals with varying physical activity levels. Materials and methods A total of 60 young adult males, comprising sedentary (n = 30) and physically active individuals (n = 30), participated in this study. A brisk walking for a distance of 50 m was considered moderate intensity and one minute of spot jogging at maximum effort with verbal encouragement was considered vigorous intensity exercise. The HR was recorded at baseline, just before the exercise, and on each minute up to 5 minutes after the exercise. Results The study involved 30 physically active young adult males (mean age 20.23 ± 1.43 years) and 30 sedentary adult males (mean age 20.07 ± 1.17 years). In physically active young adults, the resting HR was 76.4±10.89 bpm and just before starting moderate-intensity exercise, it was 78.83±12.98 bpm, paired t-test P = 0.22. The HR just before vigorous-intensity exercise was 80.83±11.18 bpm (paired t-test P = 0.03). In sedentary young adults, the resting HR was 82.23±12.69 bpm and just before starting moderate-intensity exercise, it was 90.13±18.69 bpm, paired t-test P = 0.0008. The HR just before vigorous-intensity exercise was 91.7±15.04 bpm (paired t-test P <0.0001). Conclusion Physically active young adults did not exhibit a significant increase in anticipatory HR before moderate-intensity exercise. However, sedentary individuals exhibit a significant anticipatory HR response. Before vigorous-intensity exercise, both exhibited significant increments in HR. The result highlights the importance of considering the anticipatory HR response as a potential marker of cardiovascular health and exercise readiness.

Olaparib enhances the Resveratrol-mediated apoptosis in breast cancer cells by inhibiting the homologous recombination repair pathway.

Although sensitization of BRCA-mutated, homologous recombination (HR)-deficient breast cancer cells through PARP inhibitor is widely studied, not much is known about the treatment of BRCA-wild-type, HR-proficient breast cancer. Here, we aim to investigate whether a bioactive compound, Resveratrol (RES), can induce DNA double-strand breaks in HR-proficient breast cancer cells and Olaparib (OLA), a PARP inhibitor, can enhance the RES-mediated apoptosis by deregulating the HR repair pathway. The detailed mechanism of anti-cancer action of RES + OLA combination in breast cancer has been evaluated using in vitro, ex vivo, and in vivo preclinical model systems. OLA increased RES-mediated DNA damage, downregulated the HR pathway proteins, caused a late S/G2 cell cycle arrest, enhanced apoptosis and cell death in RES pre-treated breast cancer cells at much lower concentrations than their individual treatments. Direct measurement of HR pathway activity using a GFP plasmid-based assay demonstrated reduced HR efficiency in I-SceI endonuclease-transfected cells treated with OLA. Moreover, RES + OLA treatment also caused significant reduction in PARP1-mediated PARylation and efficiently trapped PARP1 at the DNA damage site. Upon RES treatment, PARylated PARP1 was found to interact with BRCA1, which then activated other HR pathway proteins. But after addition of OLA in RES pre-treated cells, PARP1 could not interact with BRCA1 due to inhibition of PARylation. This resulted in deregulation of HR pathway. To further confirm the role of BRCA1 in PARP1-mediated HR pathway activation, BRCA1 was knocked down that caused complete inhibition of HR pathway activity, and further enhanced apoptosis after RES + OLA treatment in BRCA1-silenced cells. In agreement with in vitro data, similar experimental results were obtained in ex vivo patient-derived breast cancer cells and in vivo xenograft mice. Thus, RES + OLA combination treatment enhanced breast cancer cell death by causing excessive DNA damage and also simultaneously inhibiting the HR pathway.

Organocatalyzed umpolung addition for synthesis of heterocyclic-fused arylidene-imidazolones as anticancer agents.

A strategy of "Nature-to-new" with iterative scaffold-hopping was considered for investigation of privileged ring/functional motif-elaborated analogs of natural aurones. An organocatalyzed umpolung chemistry based method was established for molecular-diversity feasible synthesis of title class of chemotypes i.e. (Z)-2-Arylideneimidazo[1,2-a]pyridinones and (Z)-2-Arylidenebenzo[d]imidazo[2,1-b]thiazol-3-ones. Various biophysical experiments indicated their important biological properties. The analogs showed characteristic anticancer activities with efficiency more than an anticancer drug. The compounds induced apoptosis with arrest in the S phase of the cell cycle regulation. The compounds' significant effect in up/down-regulation of various apoptotic proteins, an apoptosis cascade, and the inhibition of topoisomerases-mediated DNA relaxation process was identified. The analysis of the structure-activity relationship, interference with biological events and the drug-likeness physicochemical properties of the compounds in the acceptable window indicated distinctive medicinal molecule-to-properties of the investigated chemotypes.

PolySTRAND Model of Flow-Induced Nucleation in Polymers.

We develop a thermodynamic continuum-level model, polySTRAND, for flow-induced nucleation in polymers suitable for use in computational process modeling. The model's molecular origins ensure that it accounts properly for flow and nucleation dynamics of polydisperse systems and can be extended to include effects of exhaustion of highly deformed chains and nucleus roughness. It captures variations with the key processing parameters, flow rate, temperature, and molecular weight distribution. Under strong flow, long chains are over-represented within the nucleus, leading to superexponential nucleation rate growth with shear rate as seen in experiments.

The physics of stratum corneum lipid membranes.

The stratum corneum (SC), the outermost layer of skin, comprises rigid corneocytes (keratin-filled dead cells) in a specialized lipid matrix. The continuous lipid matrix provides the main barrier against uncontrolled water loss and invasion of external pathogens. Unlike all other biological lipid membranes (such as intracellular organelles and plasma membranes), molecules in the SC lipid matrix show small hydrophilic groups and large variability in the length of the alkyl tails and in the numbers and positions of groups that are capable of forming hydrogen bonds. Molecular simulations provide a route for systematically probing the effects of each of these differences separately. In this article, we present the results from atomistic molecular dynamics of selected lipid bilayers and multi-layers to probe the effect of these polydispersities. We address the nature of the tail packing in the gel-like phase, the hydrogen bond network among head groups, the bending moduli expected for leaflets comprising SC lipids and the conformation of very long ceramide lipids in multi-bilayer lipid assemblies.This article is part of the themed issue 'Soft interfacial materials: from fundamentals to formulation'.

Effect of monoglycerides and fatty acids on a ceramide bilayer.

Monoglycerides and unsaturated fatty acids, naturally present in trace amounts in the stratum corneum (top layer of skin) lipid matrix, are commonly used in pharmaceutical, cosmetic and health care formulations. However, a detailed molecular understanding of how the oil additives get incorporated into the skin lipids from topical application and, once incorporated, how they affect the properties and integrity of the lipid matrix remains unexplored. Using ceramide 2 bilayers as skin lipid surrogates, we use a series of molecular dynamics simulations with six different natural oil ingredients at multiple concentrations to investigate the effect of the oils on the properties and stability of the bilayers. The six oils: monoolein, monostearin, monoelaidin, oleic acid, stearic acid and linoleic acid - all having the same length of the alkyl chain, C18, but a varying degree of saturation, allow us to systematically address the effect of unsaturation in the additives. Our results show that at low oil concentration (∼5%) the mixed bilayers containing any of the oils and ceramide 2 (CER2) become more rigid than pure CER2 bilayers due to more efficient lipid packing. Better packing also results in the formation of larger numbers of hydrogen bonds between the lipids, which occurs at the expense of the hydrogen bonds between lipids and water. The mixed bilayers with saturated or trans-unsaturated oils remain stable over the whole range of oil concentration. In contrast, the presence of the oils with at least one cis-double bond leads to bilayer instability and complete loss of bilayer structure at the oil content of about 50-65%. Two cis-double bonds in the lipid tail induce bilayer disruption at even lower concentration (∼30%). The mixed bilayers remain in the gel phase (without melting to a fluid phase) until the phase transition to a non-bilayer phase occurs. We also demonstrate that the stability of the bilayer strongly correlates with the order parameter of the lipid tails.

Fast cholesterol flip-flop and lack of swelling in skin lipid multilayers.

Atomistic simulations were performed on hydrated model lipid multilayers that are representative of the lipid matrix in the outer skin (stratum corneum). We find that cholesterol transfers easily between adjacent leaflets belonging to the same bilayer via fast orientational diffusion (tumbling) in the inter-leaflet disordered region, while at the same time there is a large free energy cost against swelling. This fast flip-flop may play an important role in accommodating the variety of curvatures that would be required in the three dimensional arrangement of the lipid multilayers in skin, and for enabling mechanical or hydration induced strains without large curvature elastic costs.

Lamellar and inverse micellar structures of skin lipids: effect of templating.

The outermost layer of skin comprises rigid nonviable cells (corneocytes) in a layered lipid matrix. Using atomistic simulations we find that the equilibrium phase of the skin lipids is inverse micellar. A model of the corneocyte is used to demonstrate that lamellar layering is induced by the patterned corneocyte wall. The inverse micellar phase is consistent with in vivo observations in regions where corneocyte walls are well separated (lacunar spaces) and in the inner layers of skin, and suggests a functional role in the lipid synthesis pathway in vivo.

In Silico Molecular Design, Synthesis, Characterization, and Rheology of Dendritically Branched Polymers: Closing the Design Loop.

It has been a long held ambition of both industry and academia to understand the relationship between the often complex molecular architecture of polymer chains and their melt flow properties, with the goal of building robust theoretical models to predict their rheology. The established key to this is the use of well-defined, model polymers, homogeneous in chain length and architecture. We describe here for the first time, the in silico design, synthesis, and characterization of an architecturally complex, branched polymer with the optimal rheological properties for such structure-property correlation studies. Moreover, we demonstrate unequivocally the need for accurate characterization using temperature gradient interaction chromatography (TGIC), which reveals the presence of heterogeneities in the molecular structure that are undetectable by size exclusion chromatography (SEC). Experimental rheology exposes the rich pattern of relaxation dynamics associated with branched polymers, but the ultimate test is, of course, did the theoretical (design) model accurately predict the rheological properties of the synthesized model branched polymer? Rarely, if ever before, has such a combination of theory, synthesis, characterization, and analysis resulted in a "yes", expressed without doubt or qualification.

Linking models of polymerization and dynamics to predict branched polymer structure and flow.

We present a predictive scheme connecting the topological structure of highly branched entangled polymers, with industrial-level complexity, to the emergent viscoelasticity of the polymer melt. The scheme is able to calculate the linear and nonlinear viscoelasticity of a stochastically branched "high-pressure free radical" polymer melt as a function of the chemical kinetics of its formation. The method combines numerical simulation of polymerization with the tube/entanglement physics of polymer dynamics extended to fully nonlinear response. We compare calculations for a series of low-density polyethylenes with experiments on structural and viscoelastic properties. The method provides a window onto the molecular processes responsible for the optimized rheology of these melts, connecting fundamental science to process in complex flow, and opens up the in silico design of new materials.

Nanoscale mechanical probing of supported lipid bilayers with atomic force microscopy.

We present theory and experiments for the force-distance curve F(z(0)) of an atomic force microscope (AFM) tip (radius R) indenting a supported fluid bilayer (thickness 2d). For realistic conditions the force is dominated by the area compressibility modulus κ(A) of the bilayer and, to an excellent approximation, given by F=πκ(A)Rz(0)(2)/(2d-z(0))(2). The experimental AFM force curves from coexisting liquid ordered and liquid disordered domains in three-component lipid bilayers are well described by our model, which provides κ(A) in agreement with literature values. The liquid ordered phase has a yieldlike response that we model as due to the breaking of hydrogen bonds.