Atomistic Characterization of Healthy and Damaged Hair Surfaces: A Molecular Dynamics Simulation Study of Fatty Acids on Protein Layer.

Amid the bourgeoning demand for in-silico designed, environmentally sustainable, and highly effective hair care formulations, a growing interest is evident in the exploration of realistic computational model for the hair surface. In this work, we present an atomistic model for the outermost layer of the hair surface derived through molecular dynamics simulations, which comprises 18-Methyleicosanoic acid (18-MEA) fatty acid chains covalently bound onto the keratin-associated protein 10-4 (KAP10-4) at a spacing distance of ~1 nm. Remarkably, this hair surface model facilitates the inclusion of free fatty acids (free 18-MEA) into the gaps between chemically bound 18-MEA chains, up to a maximum number that results in a packing density of 0.22 nm2 per fatty acid molecule, consistent with the optimal spacing identified through free energy analysis. Atomistic insights are provided for the organization of fatty acid chains, structural features, and interaction energies on protein-inclusive hair surface models with varying amounts of free 18-MEA (FMEA) depletion, as well as varying degrees of anionic cysteic acid from damaged bound 18-MEA (BMEA), under both dry and wet conditions. In the presence of FMEA and water, the fatty acid chains in a pristine hair surface prefers to adopt a thermodynamically favored extended chain conformation, forming a thicker protective layer (~3 nm) on the protein surface. Our simulation results reveal that, while the depletion of FMEA can induce a pronounced impact on the thickness, tilt angle, and order parameters of fatty acid chains, the removal of BMEA has a marked effect on water penetration. There is a "sweet spot" spacing between the 18-MEA whereby damaged hair surface properties can be reinstated by replenishing FMEA. Through the incorporation of the protein layer and free fatty acids, the hair surface models presented in this study enables a realistic representation of the intricate details within the hair epicuticle, facilitating a molecular scale assessment of surface properties during the formulation design process.

Interactions between poloxamer, PEOx-PPOy-PEOx, and non-ionic surfactant, sucrose monolaurate: A study on potential allergenic effect using model phospholipid membrane.

Sugar-based surfactants are involved in skin related allergy cases in the past decade. Skin irritation starts with the interaction of the surfactant with the skin lipids leading to lipid emulsification and eventual barrier damage. Polymers or co-surfactants can be used to mitigate the allergenic effect but the mechanism of formulation mildness on skin remains unclear. We have used the quartz crystal microbalance (QCM) together with dissipative particle dynamics (DPD) simulation, small angle x-ray scattering (SAXS) as well as cell viability tests to decipher the interactions between poloxamers and sucrose monolaurate (SML), and how these interactions could prevent the disruption of a model supported phospholipid bilayer (SLB). Poloxamer addition to the SML solution can delay or totally prevent the disruption of the SLB depending on poloxamer type and concentration. Poloxamer P407 (Pluronic® F127) delays the onset of disruption while poloxamer P188 (Pluronic® F68) does not preserve the bilayer integrity even at high concentration of up to 15% w/w. Preservation of the SLB is likely due to the differences in the aggregates formation between SML-F127 and SML-F68 mixtures with corresponding retarded motion of SML micelles through the SML-F127 polymer matrix that improved cell viability.

Elucidating the Role of Interfacial Hydrogen Bonds on Glass Transition Temperature Change in a Poly(Vinyl Alcohol)/SiO2 Polymer-Nanocomposite by Noncovalent Interaction Characterization and Atomistic Molecular Dynamics Simulations.

A thorough experimental investigation of polymer-glass transition temperature (Tg ) is performed on poly(vinyl alcohol) (PVA) and fumed silica nanoparticle (SiNP) composite. This is done together with atomistic molecular dynamics simulations of PVA systems in contact with bare and fully hydroxylated silica. Experimentally, PVA-SiNP composites are prepared by simple solution casting from aqueous solutions followed by its characterization using Fourier-transform infrared spectroscopy (FTIR), dynamic mechanical analysis (DMA), and dynamic scanning calorimetry (DSC). Both theoretical and experimentally deduced Tg are correlated with the presence of hydrogen bonding interactions involving OH functionality present on the surface of SiNP and along PVA polymer backbone. Further deconvolution of FTIR data show that inter-molecular hydrogen bonding present between PVA and SiNP surface is directly responsible for the increase in Tg . SiNP filler and PVA matrix ratio is also optimized for a desired Tg increase. An optimal loading of SiNP exists, in order to yield the maximum Tg increase arising from the competition between hydrogen bonding and crowding effect of SiNP.

Interfacial Properties and Monolayer Collapse of Alkyl Benzenesulfonate Surfactant Monolayers at the Decane-Water Interface from Molecular Dynamics Simulations.

The molecular structure of a surfactant molecule is known to have a great effect on the interfacial properties and the type of nanostructures formed. In this work, we have performed molecular dynamics simulations on six isomers of an alkyl benzenesulfonate surfactant to investigate the effect of the degree and position of aromatic substitution on the interfacial properties and on the collapse of the surfactant monolayer at a decane-water interface. The surface pressure of the monolayers was shown to increase with increasing surface coverage, until some of the monolayers become mechanically unstable and form large undulations. Shifting the primary alkyl chain of the surfactant from the para to the meta position was found to significantly affect the orientation of the surfactant head groups, while the attachment position of the benzene ring along the primary alkyl chain plays a greater role in the orientation of the surfactant tails. In general, to the extent considered in this work, our results suggest that additional alkyl substitution and meta substitution of the primary alkyl chains increase both the effectiveness and efficiency of the surfactants, and accelerate the onset of monolayer collapse. The interface was found to consist of an inner Helmholtz layer of partially dehydrated counterions in contact with the surfactant head groups, an outer Helmholtz layer of hydrated counterions, and a diffuse layer. The di- and trisubstituted surfactants formed nearly spherical swollen micelles encapsulating pure decane, which effectively solubilizes decane in water as a microemulsion. The monosubstituted surfactants formed elongated buds that protrude from the interface, but did not detach from the monolayer. To our knowledge, the role of aromatic substitution on interfacial properties has not been investigated by molecular simulations previously. The results from this work could provide insights to design improved surfactants by exploiting aromatic substitution to encapsulate material for drug delivery and other applications.

Bimodal magmatism produced by progressively inhibited crustal assimilation.

The origin of bimodal (mafic-felsic) rock suites is a fundamental question in volcanology. Here we use major and trace elements, high-resolution Sr, Nd and Pb isotope analyses, experimental petrology and thermodynamic modelling to investigate bimodal magmatism at the iconic Carlingford Igneous Centre, Ireland. We show that early microgranites are the result of extensive assimilation of trace element-enriched partial melts of local metasiltstones into mafic parent magmas. Melting experiments reveal the crust is very fusible, but thermodynamic modelling indicates repeated heating events rapidly lower its melt-production capacity. Granite generation ceased once enriched partial melts could no longer form and subsequent magmatism incorporated less fertile restite compositions only, producing mafic intrusions and a pronounced compositional gap. Considering the frequency of bimodal magma suites in the North Atlantic Igneous Province, and the ubiquity of suitable crustal compositions, we propose 'progressively inhibited crustal assimilation' (PICA) as a major cause of bimodality in continental volcanism.

Comparison of 2 assays for diagnosing rotavirus and evaluating vaccine effectiveness in children with gastroenteritis.

We compared rotavirus detection rates in children with acute gastroenteritis (AGE) and in healthy controls using enzyme immunoassays (EIAs) and semiquantitative real-time reverse transcription PCR (qRT-PCR). We calculated rotavirus vaccine effectiveness using different laboratory-based case definitions to determine which best identified the proportion of disease that was vaccine preventable. Of 648 AGE patients, 158 (24%) were EIA positive, and 157 were also qRT-PCR positive. An additional 65 (10%) were qRT-PCR positive but EIA negative. Of 500 healthy controls, 1 was EIA positive and 24 (5%) were qRT-PCR positive. Rotavirus vaccine was highly effective (84% [95% CI 71%-91%]) in EIA-positive children but offered no significant protection (14% [95% CI -105% to 64%]) in EIA-negative children for whom virus was detected by qRT-PCR alone. Children with rotavirus detected by qRT-PCR but not by EIA were not protected by vaccination, suggesting that rotavirus detected by qRT-PCR alone might not be causally associated with AGE in all patients.

Insights into the structure of covalently bound fatty acid monolayers on a simplified model of the hair epicuticle from molecular dynamics simulations.

The epicuticle is the outermost layer of the human hair, and consists of a monolayer of fatty acids that is predominantly 18-methyleicosanoic acid (18-MEA) covalently bound to a protein matrix. Surprisingly, despite the clear scientific and industrial importance, the detailed molecular structure of this fatty acid layer is still poorly understood. In this work, we aim to gain insight into the structure of this so-called F-layer by performing molecular dynamics simulations on a simplified hair surface model consisting of a monolayer of 18-MEA covalently attached to graphene sheets at various separation distances. The relative free energy of the fatty acid layer was calculated as a function of separation distance in order to obtain the optimal packing density of the fatty acids. Conformational properties such as the thickness, tilt angle, and order parameter of the fatty acid layers were also calculated to characterize the structure of the F-layer. Simulations of the structurally similar eicosanoic acid (EA) were also performed as a comparison and to investigate the role of the anteiso-methyl side chain at the 18th position of 18-MEA. The degree of water penetration into the fatty acid layer at the various separation distances was also investigated. Our simulations suggest that the optimal spacing for the fatty acids is between 0.492 and 0.651 nm, in contrast to the generally accepted literature value of around 0.9-1.0 nm. This results in a packing density of between 0.21 and 0.37 nm(2) per fatty acid molecule and a thickness of around 2.01-2.64 nm. We also show that, at larger separation distances, the 18-MEA fatty acid provides a slightly better hydrophobic layer than the EA fatty acid, suggesting that the 18-MEA fatty acid may have been naturally selected to provide better protection for the hair when it loses some of the fatty acids due to daily wear and tear. To our knowledge, this is the first attempt to systematically investigate the hair surface structure and properties with molecular simulations.

Biomass gasification and in-bed contaminants removal: performance of iron enriched olivine and bauxite in a process of steam/O2 gasification.

A modified Olivine, enriched in iron content (10% Fe/Olivine), and a natural bauxite, were tested in the in-bed reduction of tar and alkali halides (NaCl and KCl) released in a process of biomass steam/O(2) gasification. The tests were carried out at an ICBFB bench scale reactor under the operating conditions of: 855-890 °C, atmospheric pressure, 0.5 steam/biomass and 0.33 ER ratios. From the use of the two materials, a reduction in the contaminant contents of the fuel gas produced was found. For the alkali halides, a decrease up to 70%(wt) was observed for the potassium concentration, while for sodium, the reduction was found to be quite poor. For the organic content, compared to unmodified Olivine, the chromatographically determined total tar quantity showed a removal efficiency of 38%(wt). Moreover, regarding the particulate content a rough doubling in the fuel gas revealed a certain brittleness of the new bed material.

Reversing hypoxic cell chemoresistance in vitro using genetic and small molecule approaches targeting hypoxia inducible factor-1.

The resistance of hypoxic cells to conventional chemotherapy is well documented. Using both adenovirus-mediated gene delivery and small molecules targeting hypoxia-inducible factor-1 (HIF-1), we evaluated the impact of HIF-1 inhibition on the sensitivity of hypoxic tumor cells to etoposide. The genetic therapy exploited a truncated HIF-1alpha protein that acts as a dominant-negative HIF-1alpha (HIF-1alpha-no-TAD). Its functionality was validated in six human tumor cell lines using HIF-1 reporter assays. An EGFP-fused protein demonstrated that the dominant-negative HIF-1alpha was nucleus-localized and constitutively expressed irrespective of oxygen tension. The small molecules studied were quinocarmycin monocitrate (KW2152), its analog 7-cyanoquinocarcinol (DX-52-1), and topotecan. DX-52-1 and topotecan have been previously established as HIF-1 inhibitors. HT1080 and HCT116 cells were treated with either AdHIF-1alpha-no-TAD or nontoxic concentrations (0.1 microM;

Dual responsive promoters to target therapeutic gene expression to radiation-resistant hypoxic tumor cells.

PURPOSE: Tumor hypoxia is unequivocally linked to poor radiotherapy outcome. This study aimed to identify enhancer sequences that respond maximally to a combination of radiation and hypoxia for use in genetic radiotherapy approaches. METHODS AND MATERIALS: The influence of radiation (5 Gy) and hypoxia (1% O2) on reporter-gene expression driven by hypoxia (HRE) and radiation (Egr-1) responsive elements was evaluated in tumor cells grown as monolayers or multicellular spheroids. Hypoxia-inducible factor-1alpha (HIF-1alpha) and HIF-2alpha protein expression was monitored in parallel. RESULTS: Of the sequences tested, an HRE from the phosphoglycerate kinase-1 gene (PGK-18[5+]) was maximally induced in response to hypoxia plus radiation in all 5 cell lines tested. The additional radiation treatment afforded a significant increase in the induction of PGK-18[5+] compared with hypoxia alone in 3 cell lines. HIF-1alpha/2alpha were induced by radiation but combined hypoxia/radiation treatment did not yield a further increase. The dual responsive nature of HREs was maintained when spheroids were irradiated after delivery of HRE constructs in a replication-deficient adenovirus. CONCLUSIONS: Hypoxia-responsive enhancer element sequences are dually responsive to combined radiation and hypoxic treatment. Their use in genetic radiotherapy in vivo could maximize expression in the most radio-resistant population at the time of radiation and also exploit microenvironmental changes after radiotherapy to yield additional switch-on.

Hypoxia targeted gene therapy to increase the efficacy of tirapazamine as an adjuvant to radiotherapy: reversing tumor radioresistance and effecting cure.

Solid tumors are characterized by regions of hypoxia that are inherently resistant to both radiotherapy and some chemotherapy. To target this resistant population, bioreductive drugs that are preferentially toxic to tumor cells in a hypoxic environment are being evaluated in clinical trials; the lead compound, tirapazamine (TPZ), is being used in combination with cisplatin and/or with radiotherapy. Crucially, tumor response to TPZ is also dependent on the cellular complement of reductases. In particular, NADPH:cytochrome P450 reductase (P450R) plays a major role in the metabolic activation of TPZ. In a gene-directed enzyme prodrug therapy (GDEPT) approach using adenoviral delivery, we have overexpressed human P450R specifically within hypoxic cells in tumors, with the aim of harnessing hypoxia as a trigger for both enzyme expression and drug metabolism. The adenovirus used incorporates the hypoxia-responsive element (HRE) from the lactate dehydrogenase gene in a minimal SV40 promoter context upstream of the cDNA for P450R. In a human tumor model in which TPZ alone does not potentiate radiotherapeutic outcome (HT1080 fibrosarcoma), we witnessed complete tumor regression when tumors were virally transduced before treatment.

The binding of polyamines and of ethidium bromide to tRNA.

The binding of spermidine and ethidium bromide to mixed tRNA and phenylalanine tRNA has been studied under equilibrium conditions. The numbers and classes of binding sites obtained have been compared to those found in complexes isolated by gel filtration a low ionic strength. The latter complexes contain 10-11 moles of either spermidine or ethidium per mole of tRNA; either cation is completely displaceable by the other. In ethidium complexes, the first 2-3 moles are bound in fluorescent binding sites; the remaining 7-8 molecules bind in non-fluorescent form. At least one of the binding sites for spermidine appears similar to a binding site for fluorescent ethidium. Similar results are found with E. coli formylmethionine tRNA. Spermine, in excess of 18-20 moles per mole tRNA, causes precipitation of the complex. Putrescine does not form isolable complexes with yeast tRNA and displaces ethidium less readily from preformed ethidium-tRNA complexes. Under equilibrium conditions, in the absence of Mg++, there are 16-17 moles of spermidine bound per mole of tRNA as determined by equilibrium dialysis. Of these, 2-3 bind with a Ksence of 9 mM Mg++, the total number of binding sites is decreased slightly and there appears to be only one class of sites with a Ka = 600 M(-1). Quantitatively similar results are obtained for the binding of spermidine to yeast phenylalanine tRNA. When the interaction between ethidium bromide and mixed tRNA is studied by equilibrium dialysis or spectrophotometric titration, two classes of binding sites are obtained: 2-3 molecules bind with an average Ka = 6.6 x 10(5) M(-1) and 14-15 molecules bind with an average Ka = 4.1 x 10(4) M(-1). Spermidine, spermine, and Mg++ compete effectively for both classes of ethidium sites and have the effect of reducing the apparent binding constants for ethidium. When the binding of ethidium is studied by fluorometry, there are 3-4 highly fluorescent sites per tRNA. These sites are also affected by spermidine, spermine and Mg++. Putrescine has little effect on any of the classes of binding sites. These data are consistent with those found under non-equilibrium conditions. They suggest that polyamines bind to fairly specific regions of tRNA and may be involved in the maintenance of certain structural features of tRNA.

System of double infection between vaccinia virus and mengovirus.

When L cells are simultaneously infected with vaccinia virus and mengovirus, double interference in the replication of both viruses is observed. Superinfection of vaccinia virus-infected cells by mengovirus during the first 5 hr of infection reduces vaccinia virus yields to between 1 and 3% of controls. The yields of mengovirus are reduced to between 1 and 16% of controls, depending upon the time of superinfection. The replication of vaccinia deoxyribonucleic acid is not inhibited by mengovirus; it is only delayed. On the other hand, vaccinia multiplication severely hinders the replication of mengovirus ribonucleic acid. The double-infected system, at early times, synthesizes proteins that resemble those synthesized in the vaccinia virus-infected cells. Later in infection, however, the pattern is switched to proteins synthesized by mengovirus-infected cells. Possible mechanisms for this double interference in multiplication are discussed.

T6r+-induced proteins and nucleic acids in Escherichia coli infected in the presence of streptomycin.

Streptomycin does not strongly inhibit T-even phage multiplication in the streptomycin-susceptible polyauxotroph, Escherichia coli strain T(-)H(-)U(-). The relatively slight inhibition, observed earlier, on production of late proteins has now been studied further. The phage-induced ribonucleic acid, synthesized in T6 phage infection in the presence of streptomycin, has been characterized by its base composition, size distribution, and behavior in hybridization tests. Comparison of these properties to those of control samples, taken during either early or late periods of infection, have not shown any significant differences. Phage-induced proteins, synthesized at different times during infection, were studied by disc-gel electrophoresis. Staining and autoradiography of the patterns of pulse-labeled proteins, formed in the absence and presence of the antibiotic showed only slight quantitative changes in the appearance of early proteins. More marked quantitative effects were detected later in infection. Nevertheless, changes in the mobilities of the different proteins were not observed in the streptomycin-treated cultures at any time after infection, suggesting the absence of gross misreading sufficiently great to alter the distinctive electrophoretic patterns of the extracts. Cells infected and incubated in the presence of the antibiotic were found to contain intact virus particles, as shown by electron microscopy. Such infected cells contained extensive deoxyribonucleic acid pools and did not develop the rounded nucleoids with enclosed dense bodies characteristic of the lethal action of the antibiotic. On the other hand, infected bacteria previously exposed to lethal concentrations of streptomycin were unable to synthesize the early enzymes, deoxycytidylate (dCMP) hydroxymethylase and dihydrofolate reductase, or to make phage deoxyribonucleic acid and phage. Such previously killed cells contained the rounded and clotted nucleoids and were unable to unravel this pathological structure after phage infection.