Molecular Domains Research Articles

Identification of Novel Allosteric Modulators of Glutamate Transporter EAAT2.

Dysfunction of excitatory amino acid transporters (EAATs) has been implicated in the pathogenesis of various neurological disorders, such as stroke, brain trauma, epilepsy, and neurodegenerative diseases, among others. EAAT2 is the main subtype responsible for glutamate clearance in the brain, having a key role in regulating transmission and preventing excitotoxicity. Therefore, compounds that increase the expression or activity of EAAT2 have therapeutic potential for neuroprotection. Previous studies identified molecular determinants for EAAT2 transport stimulation in a structural domain that lies at the interface of the rigid trimerization domain and the central substrate binding transport domain. In this work, a hybrid structure based approach was applied, based on this molecular domain, to create a high-resolution pharmacophore. Subsequently, virtual screening of a library of small molecules was performed, identifying 10 hit molecules that interact at the proposed domain. Among these, three compounds were determined to be activators, four were inhibitors, and three had no effect on EAAT2-mediated transport in vitro. Further characterization of the two best ranking EAAT2 activators for efficacy, potency, and selectivity for glutamate over monoamine transporters subtypes and NMDA receptors and for efficacy in cultured astrocytes is demonstrated. Mutagenesis studies suggest that the EAAT2 activators interact with residues forming the interface between the trimerization and transport domains. These compounds enhance the glutamate translocation rate, with no effect on substrate interaction, suggesting an allosteric mechanism. The identification of these novel positive allosteric modulators of EAAT2 offers an innovative approach for the development of therapies based on glutamate transport enhancement.

Assembly of PCBM and tn-ZnPc Molecular Domains and Phase Separation of Molecular Mixtures from Liquid Solution on Si(111).

We present the results of investigations aimed at understanding the mechanisms by which small, mutually immiscible organic molecules self-assemble into domains during phase separation from liquid solutions in the presence of a solid substrate. As an example system, we investigated molecular mixtures of tetranitro zinc-phthalocyanine (tn-ZnPc), an electron donor, and [6,6]-phenyl-C61-butyric acid methyl ester (PCBM), an electron acceptor, in chloroform solution, deposited onto native oxide-covered Si(111) substrates. We found qualitatively different behavior in the formation of domains of the two types of molecules, seemingly because of a large difference in their solubilities in the solvent. The morphology of PCBM molecule domains varies widely depending on the solvent evaporation rate, the presence/absence of tn-ZnPc molecules in the solution, solvent annealing conditions, and seemingly the presence/absence of trace impurities. By contrast, we find evidence that the shape of the tn-ZnPc domains is insensitive to evaporation; these form while in liquid suspension, and the assembly of domains into clusters varies according to the rate and mode of solvent evaporation.

Regulation and dysregulation of axon infrastructure by myelinating glia.

Axon loss and neurodegeneration constitute clinically debilitating sequelae in demyelinating diseases such as multiple sclerosis, but the underlying mechanisms of secondary degeneration are not well understood. Myelinating glia play a fundamental role in promoting the maturation of the axon cytoskeleton, regulating axon trafficking parameters, and imposing architectural rearrangements such as the nodes of Ranvier and their associated molecular domains. In the setting of demyelination, these changes may be reversed or persist as maladaptive features, leading to axon degeneration. In this review, we consider recent insights into axon-glial interactions during development and disease to propose that disruption of the cytoskeleton, nodal architecture, and other components of axon infrastructure is a potential mediator of pathophysiological damage after demyelination.

Chemometric Evaluation of THz Spectral Similarity for the Selection of Early Drug Candidates

In this paper we discuss the link between the domain of physical parameters – molecular descriptors of a drug, and terahertz (THz) spectra. We measured the derivatives of the well-known anti-inflammatory drug Piroxicam using THz spectroscopy and employed Principal Component Analysis to build similarity maps in the molecular descriptor and spectral domains. We observed, that the spatial neighborhood on the molecular descriptors map is highly correlated with the spectral neighbourhood within a group of structurally-similar molecules. We built a Partial Least Squares (PLS) predictive model to quantify the relationship between the spectra and the melting point, which can guide the selection of early drug candidates.

Enzymatic Catalysis at Nanoscale: Enzyme-Coated Nanoparticles as Colloidal Biocatalysts for Polymerization Reactions.

Enzyme-catalyzed controlled radical polymerization represents a powerful approach for the polymerization of a wide variety of water-soluble monomers. However, in such an enzyme-based polymerization system, the macromolecular catalyst (i.e., enzyme) has to be separated from the polymer product. Here, we present a compelling approach for the separation of the two macromolecular species, by taking the catalyst out of the molecular domain and locating it in the colloidal domain, ensuring quasi-homogeneous catalysis as well as easy separation of precious biocatalysts. We report on gold nanoparticles coated with horseradish peroxidase that can catalyze the polymerization of various monomers (e.g., N-isopropylacrylamide), yielding thermoresponsive polymers. Strikingly, these biocatalyst-coated nanoparticles can be recovered completely and reused in more than three independent polymerization cycles, without significant loss of their catalytic activity.

Editorial: Conceptual Density Functional Theory: Its Grand Application to Atomic and Molecular Domain

Editorial: Conceptual Density Functional Theory: Its Grand Application to Atomic and Molecular Domain

On the Application of Conceptual Density Functional Theory to Atomic and Molecular Domain

On the Application of Conceptual Density Functional Theory to Atomic and Molecular Domain

Paolo Samorì

Angewandte Chemie International EditionVolume 56, Issue 49 p. 15498-15498 Author ProfileFree Access Paolo Samorì First published: 17 August 2017 https://doi.org/10.1002/anie.201707626Citations: 4AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Graphical Abstract “My science “hero” is Richard Feynman. The most important thing I learned from my students is innocent curiosity ...” This and more about Paolo Samorì can be found on page 15498. Paolo Samorì The author presented on this page has recently published his 10th article in Angewandte Chemie in the last 10 years: “Ultrafast Delamination of Graphite into High-Quality Graphene Using Alternating Currents”: S. Yang et al., Angew. Chem. Int. Ed. 2017, 56, 6669; Angew. Chem. 2017, 129, 6770. The work of P. Samorì has been featured on the cover of Angewandte Chemie: “Dynamers at the Solid–Liquid Interface: Controlling the Reversible Assembly/Reassembly Process between Two Highly Ordered Supramolecular Guanine Motifs”: A. Ciesielski, S. Lena, S. Masiero, G. P. Spada, P. Samorì, Angew. Chem. Int. Ed. 2010, 49, 1963; Angew. Chem. 2010, 122, 2007. Date of birth: May 3, 1971 Position: Distinguished Professor, Université de Strasbourg, and Director, Institut de Science et d'Ingénierie Supramoléculaires (ISIS), Strasbourg E-mail: samori@unistra.fr Homepage: www.nanochemistry.fr ORCID: 0000-0001-6256-8281 Education: 1995 Laurea, University of Bologna 2000 PhD, Humboldt Universität zu Berlin Awards: 2010 Junior member of the Institut Universitaire de France (IUF); 2011 Fellow of the Royal Society of Chemistry; 2012 CNRS Silver Medal; 2014 Fellow of the European Academy of Sciences; 2014 Member of the Academia Europaea; 2017 Grignard–Wittig Lecture (GDCh); 2017 Catalan–Sabatier Prize (RSEQ) Current research interests: Multifunctional nanomaterials for electronics, energy, and sensing applications; two-dimensional materials; organic electronics; supramolecular chemistry; nanoscience Hobbies: Nature, fishing, hunting My science “hero” is Richard Feynman. The most important thing I learned from my students is innocent curiosity. The secret of being a successful scientist is openness, passion, and perseverance: never give up! If I had one year of paid leave I would make a world tour with my family. The principal aspect of my personality is that I am always willing to learn from anyone I meet. My favorite musician is David Bowie. The biggest challenge facing scientists is finding a solution to energy and environmental problems. Looking back over my career, I am happy to be a chemist! My favorite drink is red wine – spicy and berry-flavored (Grenache and/or Syrah). If I were a car I would be a red Ferrari (with paint based on a diketopyrrolopyrrole dye). My biggest inspiration is Nature – any living matter around me. I advise my students to keep their eyes fully open when they are doing an experiment to catch any unexpected behavior or result. My 5 top papers: 1“Cooperative light-induced molecular movements of highly ordered azobenzene SAMs”: G. Pace, V. Ferri, C. Grave, M. Elbing, M. Zharnikov, M. Mayor, M. A. Rampi, P. Samorì, Proc. Natl. Acad. Sci. USA. 2007, 104, 9937. (Photochemical switching can occur over entire molecular 2D crystalline domains.) 2“Molecular Tectonics on Surfaces: Bottom-Up Fabrication of 1D Coordination Networks that Form 1D and 2D Arrays on Graphite”: M. Surin, P. Samorì, A. Jouaiti, N. Kyritsakas, M. W. Hosseini, Angew. Chem. Int. Ed. 2007, 46, 245; Angew. Chem. 2007, 119, 249. (Nanopatterning of 1D or 2D multifunctional arrays on surfaces with sub-nanometer precision.) 3“Self-assembly of an Amphiphilic π-Conjugated Dyad into Fibers: Ultrafast and Ultrasensitive Humidity Sensor”: M. A. Squillaci, L. Ferlauto, Y. Zagranyarski, S. Milita, K. Müllen, P. Samorì, Adv. Mater. 2015, 27, 3170. (The self-assembly of electroactive π–π stacked fibrillar structures can be triggered by irradiation with visible light.) 4“Light-enhanced liquid-phase exfoliation and photoswitching current in graphene–azobenzene composites”: M. Döbbelin et al., Nat. Commun. 2016, 7, 11090. (Reversible photomodulated current was observed in two-terminal devices based on these composites.) 5“Flexible non-volatile optical memory thin-film transistor device with over 256 distinct levels based on an organic bicomponent blend”: T. Leydecker, M. Herder, E. Pavlica, G. Bratina, S. Hecht, E. Orgiu, P. Samorì, Nat. Nanotech 2016, 11, 769. (A blend of a reference polymer semiconductor and a photochromic diarylethene that can be switched with ultraviolet and green light irradiation.) Citing Literature Volume56, Issue49December 4, 2017Pages 15498-15498 ReferencesRelatedInformation

Linearization of evaporative light scattering detector signal

ABSTRACTRecent advances in nebulizer technology of the evaporative light scattering detector (ELSD) allow the evaporation of trichlorobenzene (TCB) at much lower temperatures than the previous instruments, thus avoiding the sample loss in the lower molecular weight domain. Therefore, the new ELSD opens the possibility to correctly evaluate the molecular weight distribution (MWD) of polymers by gel permeation chromatography, after linearizing the ELSD signal intensity in function of concentration. To find the correct exponent parameter for linearization, it is necessary to take into account not only the peak area, but each point of the chromatogram. The evaluation method for this exponent parameter, found to be 1.61 for the analysis in TCB of polyolefin and polystyrene samples, is presented in this study. This value was verified by the excellent correlation found between the obtained MWD of a high-density polyethylene both with the ELSD and with the traditional differential refractive index detector.

Zebrafish earns its stripes for in vivo ASC speck dynamics.

Assembly of the ASC speck is critical for signaling by the inflammasome. In this issue, Kuri et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201703103) use live microscopy to track fluorescently tagged endogenous ASC in the zebrafish, describing the molecular domains driving ASC speck assembly and identifying a key role for macrophages in ASC speck removal in vivo.

Proteomics and metabolomics in ageing research: from biomarkers to systems biology.

Age is the single greatest risk factor for a wide range of diseases, and as the mean age of human populations grows steadily older, the impact of this risk factor grows as well. Laboratory studies on the basic biology of ageing have shed light on numerous genetic pathways that have strong effects on lifespan. However, we still do not know the degree to which the pathways that affect ageing in the lab also influence variation in rates of ageing and age-related disease in human populations. Similarly, despite considerable effort, we have yet to identify reliable and reproducible 'biomarkers', which are predictors of one's biological as opposed to chronological age. One challenge lies in the enormous mechanistic distance between genotype and downstream ageing phenotypes. Here, we consider the power of studying 'endophenotypes' in the context of ageing. Endophenotypes are the various molecular domains that exist at intermediate levels of organization between the genotype and phenotype. We focus our attention specifically on proteins and metabolites. Proteomic and metabolomic profiling has the potential to help identify the underlying causal mechanisms that link genotype to phenotype. We present a brief review of proteomics and metabolomics in ageing research with a focus on the potential of a systems biology and network-centric perspective in geroscience. While network analyses to study ageing utilizing proteomics and metabolomics are in their infancy, they may be the powerful model needed to discover underlying biological processes that influence natural variation in ageing, age-related disease, and longevity.

Self-Phase-Stabilized Heterodyne Vibrational Sum Frequency Generation Microscopy

Vibrational sum frequency generation (VSFG) spectroscopy has been a powerful technique to probe molecular structures in non-centrosymmetric media. Recently developed heterodyne (HD) detection can further reveal spectral phase and molecular orientations. Adding imaging capability to an HD VSFG signal can bring spatial visualization capability into this nonlinear optical technique. However, it has been a challenge to build an HD VSFG microscope that is easy to align and has good spectral phase stability, two necessary criteria for the broad application of this technique to various areas of science. Here, we report a fully collinear HD VSFG microscope, which meets both phase stability and optical alignment requirements, that can spatially resolve images of molecular interfaces and domains, with chemical and structural sensitivities. The phase stability is more than 9 times better than a Michelson interferometric HD VSFG microscope. Using this HD VSFG microscope, we study the structures of molecular self-assembly films. Because of the superior phase sensitivity, we successfully identify two molecular domains with different molecular orientations, which we show is not possible to extract from an ensemble-averaged VSFG spectrum or homodyne-detected VSFG image.

ATS drugs molecular structure representation using refined 3D geometric moment invariants

The campaign against drug abuse is fought by all countries, most notably on ATS drugs. The identification process of ATS drugs depends heavily on its molecular structure. However, the process becomes more unreliable due to the introduction of new, sophisticated, and increasingly complex ATS molecular structures. Therefore, distinctive features of ATS drug molecular structure need to be accurately obtained. In this paper, two variants of refined 3D geometric moment invariants for ATS drug molecular structure representation are discussed. This paper is also meant for comparing the performance of these two variants. The comparison was conducted using drug chemical structures obtained from Isomer Design’s PiHKaL.info database for the ATS drugs, while non-ATS drugs are obtained randomly from ChemSpider database. The assessment highlights the best technique which is suitable to be further explored and improved in the future studies so that it is wholly attuned with ATS drug molecular similarity search domain.

Tricyclic Spirolactones as Modular TRPV1 Synthetic Agonists.

TRPV1 is a prominent signal integrator of the pain system, known to be activated by vanilloids, a family of endogenous and exogenous pain-evoking molecules, through the vanilloid-binding site (VBS). The extensive preclinical profiling of small molecule inhibitors provides intriguing evidence that TRPV1 inhibition can be a useful therapeutic approach. However, the dissimilarity of chemical species that activate TRPV1 creates a major obstacle to understanding the molecular mechanism of pain induction, which is viewed as a pivotal trait of the somatosensory system. Here, we establish the existence of a unique family of synthetic agonists that interface with TRPV1 through the VBS, containing none of the molecular domains previously believed to be required for this interaction. The overarching value obtained from our inquiry is the novel advancement of the existing TRPV1 activation model. These findings uncover new potential in the area of pain treatment, providing a novel synthetic platform.

SHADOW study: Comparison of conventional clinical follow-up with clinician led video follow-up in newly diagnosed patients with intermediate and high grade glioma receiving adjuvant temozolomide therapy.

2024 Background: In patients with gliomas, nurse led telephonic follow-up was associated with high satisfaction rates and was a valid alternative approach to conventional hospital based follow-up. However, other alternative forms of follow-up have not been studied in patients on active treatment. Methods: SHADOW was a prospective, randomized trial (CTRI/2017/01/007626). Adult intermediate to high grade glioma patients on adjuvant temozolomide with facilities for live video call were invited. After their consent, patients underwent a video follow-up (VF) 4 days prior to clinical follow-up (CF). The decisions taken during the VF and CF were noted in 5 domains, relating to temozolomide decisions (primary endpoint), concurrent medications, need for imaging, molecular testing and rehabilitation. Clinicians performing VF or CF were randomly assigned and were blinded for the other arm decisions. Patients satisfaction and costs incurred in each type of follow-up was documented. The planned sample size was 65, assuming an alpha of 0.05, a kappa coefficient of 0.9 with a one sided CI for lower limit of 0.6 and assuming a 20% lost to follow up rate. Agreement analysis was performed for calculation of Cohen's kappa coefficient. Results: 112 patients were screened and 65 were accrued. All patients underwent both VF and CCF. The concurrence in decision of administering temozolomide between VF and CCF was 100% (Cohen kappa = 1.0, 95%CI 1.0-1.0, p < 0.00). In concurrent medication domain (k = 0.66,95% CI 0.04 -1, p < 0.00), imaging domain (k = 1.0, 95%CI 1.0-1.0, p < 0.00), rehabilitation domain (k = 1.0, 95%CI 1.0-1.0, p < 0.00) and molecular testing domain (k = 0.65, 95% CI 0.20-1, p < 0.00), the agreement was substantial. The satisfaction rate was 100% post video follow up and was 98.5 % post clinical follow up. The median cost incurred in VF was 58.15 USD (IQR 43.38-91.69) while that incurred in CCF was 131.23 USD (IQR 68.8-256 (p < 0.00)). Conclusions: The decisions taken regarding administration of adjuvant TMZ were similar between VF and CCF. Hence, it's practical and economical to substitute CCF with VF during adjuvant TMZ administration. Clinical trial information: CTRI/2017/01/007626.

Constraints on interstellar dust models from extinction and spectro-polarimetry

We present polarisation spectra of seven stars in the lines-of-sight towards the Sco OB1 association. Our spectra were obtained within the framework of the Large Interstellar Polarization Survey carried out with the FORS instrument of the ESO VLT. We have modelled the wavelength-dependence of extinction and linear polarisation with a dust model for the diffuse interstellar medium which consists of a mixture of particles with size ranging from the molecular domain of 0.5 nm up to 350 nm. We have included stochastically heated small dust grains with radii between 0.5 and 6 nm made of graphite and silicate, as well as polycyclic aromatic hydrocarbon molecules (PAHs), and we have assumed that larger particles are prolate spheroids made of amorphous carbon and silicate. Overall, a dust model with eight free parameters best reproduces the observations, and is in agreement with cosmic abundance constraints. Reducing the number of free parameters leads to results that are inconsistent with the cosmic abundances of silicate and carbon. We found that aligned silicates are the dominant contributor to the observed polarisation, and that the polarisation spectra are best-fit by a lower limit of the equivolume sphere radius of aligned grains of 70–200 nm.

Computational perspectives on structure, dynamics, gas sorption, and bio-interactions in deep eutectic solvents

We present a snapshot of the current status of understanding structure, dynamics, and molecular interactions within deep eutectic solvents (DESs) gained from a computational perspective. The simulations reported thus far have been largely aimed at unravelling the relationship between the molecular features within a DES and the depressed melting temperature at its eutectic composition. Computational efforts consistently reveal that the addition of hydrogen bond donors significantly disrupts long-range ordering of the cation–anion arrangement in choline chloride, resulting in significant moderation of the interaction energies between the components of the DES. These studies paint a picture of DES formation being accompanied by hydrogen-bond directed charge transfer processes yielding transient cage-like formation and nanoscale ordering entailing segregation of the ionic and molecular domains. Computational insights further uncover how unique solvation features present within DESs may lead to enhanced biomolecular (e.g., protein, nucleic acid, polysaccharide) stability and/or activity while also offering advantages as environmentally-responsible gas sorbents.

Steering On‐Surface Reactions by a Self‐Assembly Approach

Abstract4,4′‐Bis(2,6‐difluoropyridin‐4‐yl)‐1,1′:4′,1′′‐terphenyl (BDFPTP) molecules underwent dehydrocyclization and covalent coupling reactions on Au(111) according to scanning tunneling microscopy (STM) measurements and density functional theory (DFT) calculations. Self‐assembly of the reactants in well‐defined molecular domains prior to reaction could greatly enhance the regioselectivity of the dehydrocyclization reaction and suppress defluorinated coupling, demonstrating that self‐assembly can efficiently steer on‐surface reactions. Such a strategy could be of great importance in surface chemistry and widely applied to control on‐surface reactions.

Steering On-Surface Reactions by a Self-Assembly Approach.

4,4'-Bis(2,6-difluoropyridin-4-yl)-1,1':4',1''-terphenyl (BDFPTP) molecules underwent dehydrocyclization and covalent coupling reactions on Au(111) according to scanning tunneling microscopy (STM) measurements and density functional theory (DFT) calculations. Self-assembly of the reactants in well-defined molecular domains prior to reaction could greatly enhance the regioselectivity of the dehydrocyclization reaction and suppress defluorinated coupling, demonstrating that self-assembly can efficiently steer on-surface reactions. Such a strategy could be of great importance in surface chemistry and widely applied to control on-surface reactions.

Plasticity, elasticity, and adhesion energy of plant cell walls: nanometrology of lignin loss using atomic force microscopy

The complex organic polymer, lignin, abundant in plants, prevents the efficient extraction of sugars from the cell walls that is required for large scale biofuel production. Because lignin removal is crucial in overcoming this challenge, the question of how the nanoscale properties of the plant cell ultrastructure correlate with delignification processes is important. Here, we report how distinct molecular domains can be identified and how physical quantities of adhesion energy, elasticity, and plasticity undergo changes, and whether such quantitative observations can be used to characterize delignification. By chemically processing biomass, and employing nanometrology, the various stages of lignin removal are shown to be distinguished through the observed morphochemical and nanomechanical variations. Such spatially resolved correlations between chemistry and nanomechanics during deconstruction not only provide a better understanding of the cell wall architecture but also is vital for devising optimum chemical treatments.