A Circle Has No End: Role of Cyclic Topology and Accompanying Structural Reorganization on the Hole Distribution in Cyclic and Linear Poly‑p‑phenylene Molecular Wires

π-Conjugated organic oligomers/polymers hold great promise as long-range charge-transfer materials for modern photovoltaic applications. However, a set of criteria for the rational design of functional materials is not yet available, in part because of a lack of understanding of charge distribution in extended π-conjugated systems of different topologies, and concomitant effects on redox and optical properties. Herein we demonstrate the role of cyclic versus linear topology in controlling the redox/optical properties and hole distribution in poly-p-phenylenes (PPs) with the aid of experiment, computation, and our recently developed multistate parabolic model (MPM). It is unequivocally shown that the hole distribution in both cyclic and linear poly-p-phenylene (n ≥ 7) cation radicals is limited to seven p-phenylene units, despite the very different topologies. However, the effect of topology is evidenced in the very different trends in oxidation potentials of cyclic versus linear PPs, which are shown to originate largely from the geometrical distortion of individual p-phenylene units in cyclic PPs. The presence of additional pairwise electronic coupling element in cyclic PPs, absent in linear PPs, plays a significant role only in smaller cyclic PP5 and PP6. This study provides a detailed conceptual description of cyclic and linear poly-p-phenylene cation radicals and demonstrates the versatility and predictive power of MPM, an important new tool for the design and synthesis of novel and efficient charge-transfer materials for molecular electronics and photovoltaic applications, an area of widespread interest

Can Structural Differences between SARS-CoV and SARS-CoV-2 explain Differences in Drug Efficacy?

The severe acute respiratory syndrome corona virus (SARS-CoV)and severe acute respiratory syndrome corona virus-2 (SARS-CoV-2), both virus spike proteins are recognized by the cell surface receptors, human angiotensin converting enzyme-2 (ACE-2).These viruses gain access into the host cell through ACE-2receptors.The main aim of the current study was to elaborate on the structural differences in the receptor binding domain (RBD) of spike glycoprotein in SARS-CoV and SARS-CoV-2 that bind at the same active binding site. The crystal structures of receptor bound spikes of SARS-CoV and SARS-CoV-2 were compared using UCSF Chimera and pyMOL software which revealed significant differences in the receptor binding domain of the spikes with variation in the amino acid residues. It was also observed that conformational changes occurred in the amino acid residues at the binding site on ACE-2 receptor. These conformational changes in ACE-2 binding site of SARS-CoV-2 were attributed to a greater number of contacts forming between RBD and active binding site when compared to that of SARS-CoV and could explain any differences in the effectiveness of drugs against SARS-CoV and SARS-CoV-2. In addition, using Autodock vina software, drugs that were found to be effective in SARS-COV treatment were docked at active binding site on ACE-2.Antivirals, ACE-2 inhibitors and corticosteroids were docked at the active binding site domains of ACE-2 receptor in SARS-CoV andSARS-CoV-2.Antivirals such as Oseltamivir, Umifenovir, Favipiravir, Remdesivir and antibiotics such as Moxifloxacin and Azithromycin, Ace-2. Antivirals inhibitors such as Losartan and steroids such as Dexamethasone have shown a greater negative docking score (indicating more binding affinity) in and SARS-CoV-2 when compared to that of SARS-CoV. This kind of preliminary analysis using computational techniques could help in screening and repurposing the existing drugs that are potential in treating new diseases such as CoVID-19

Synthesis, Characterization, and Theory of [9]-, [12]-, and [18]Cycloparaphenylene: Carbon Nanohoop Structures

The first synthesis and characterization of [9]-, [12]-, and [18]cycloparaphenylene was demonstrated utilizing a novel aromatization reaction. We refer to these fascinating structures as "carbon nanohoops" due to their structural similarity to carbon nanotubes. Additionally, we have utilized computational methods to understand the unique properties of these fully conjugated macrocycles

Rational Design of Peptide Ligands Based on Knob−Socket Protein Packing Model Using CD13 as a Prototype Receptor

Structure-based computational peptide design methods have gained significant interest in recent years owing to the availability of structural insights into protein–protein interactions obtained from the crystal structures. The majority of these approaches design new peptide ligands by connecting the crucial amino acid residues from the protein interface and are generally not based on any predicted receptor–ligand interaction. In this work, a peptide design method based on the Knob–Socket model was used to identify the specific ligand residues packed into the receptor interface. This method enables peptide ligands to be designed rationally by predicting amino acid residues that will fit best at the binding site of the receptor protein. In this, specific peptide ligands were designed for the model receptor CD13, overexpression of which has been observed in several cancer types. From the initial library of designed peptides, three potential candidates were selected based on simulated energies in the CD13 binding site using the programs molecular operating environment and AutoDock Vina. In the CD13 enzymatic activity inhibition assay, the three identified peptides exhibited 2.7–7.4 times lower IC50 values (GYPAY, 227 μM; GFPAY, 463 μM; GYPAVYLF, 170 μM) as compared to the known peptide ligand CNGRC (C1–C5) (1260 μM). The apparent binding affinities of the peptides (GYPAY, Ki = 54.0 μM; GFPAY, Ki = 74.3 μM; GYPAVYLF, Ki = 38.8 μM) were 10–20 times higher than that of CNGRC (C1–C5) (Ki = 773 μM). The double reciprocal plots from the steady-state enzyme kinetic assays confirmed the binding of the peptides to the intended active site of CD13. The cell binding and confocal microscopy assays showed that the designed peptides selectively bind to the CD13 on the cell surface. Our study demonstrates the feasibility of a Knob–Socket-based rational design of novel peptide ligands in improving the identification of specific binding versus current more labor-intensive methods

Use of polyethyleneimine polymer in cell culture as attachment factor and lipofection enhancer

BACKGROUND: Several cell lines and primary cultures benefit from the use of positively charged extracellular matrix proteins or polymers that enhance their ability to attach to culture plates. Polyethyleneimine is a positively charged polymer that has gained recent attention as a transfection reagent. A less known use of this cationic polymer as an attachment factor was explored with several cell lines. RESULTS: Polyethyleneimine compared favorably to traditional attachment factors such as collagen and polylysine. PC-12 and HEK-293 cells plated on dishes coated with polyethyleneimine showed a homogeneous distribution of cells in the plate, demonstrating strong cell adhesion that survived washing procedures. The polymer could also be used to enhance the adherence and allow axonal outgrowth from zebrafish retinal explants. The effects of this coating agent on the transfection of loosely attaching cell lines were studied. Pre-coating with polyethyleneimine had the effect of enhancing the transfection yield in procedures using lipofection reagents. CONCLUSION: Polyethyleneimine is an effective attachment factor for weakly anchoring cell lines and primary cells. Its use in lipofection protocols makes the procedures more reliable and increases the yield of expressed products with commonly used cell lines such as PC-12 and HEK-293 cells

BINGE EATING DISORDERS; UPDATED AND EMERGING APPROACHES

Objective: Binge eating disorders (BED) recently become a global health care issue for clinicians with detrimental effects on all organ systems. A multidisciplinary strategy including pharmacotherapy is required for its management. Methods: This review is intended to comparatively evaluate the relative efficacy of different pharmacological agents in BED treatment with new therapeutic approaches, focusing on the clinical evidence and on Phase III randomized controlled trials. Results: Data suggest that certain treatments have advantages over placebos to reduce binge eating features; however, the small duration of such research with the lack of adequately sized trials was the major limitation in interpreting these findings. Furthermore, these medications are mostly not greatly efficient for BED associated with obesity except for topiramate, which markedly improves the features of binge episodes with weight loss. Till now, lisdexamfetamine is still the only drug with regulatory permission for BED therapy; however, its weight loss efficacy has not been established. Conclusion: Drugs alone or in combination approaches may be useful pharmacotherapies to yield promising outcomes acutely and over longer-term follow-up in the treatment of BED

TRANSETHOSOMES AS BREAKTHROUGH TOOL FOR CONTROLLED TRANSDERMAL DELIVERY OF DEXKETOPROFEN TROMETAMOL: DESIGN, FABRICATION, STATISTICAL OPTIMIZATION, IN VITRO, AND EX VIVO CHARACTERIZATION

Objective: Transethosomes (TEs) have introduced an emerging avenue of interest in vesicular research for transdermal delivery of drugs and can be a proper delivery system for painkillers like NSAIDS. This study aimed to formulate and characterize the potential of TE to enhance the transdermal transport of Dexketoprofen trometamol (DKT) to achieve controlled pain management compared to DKT solution. Methods: Factorial design (23) was adopted to appraise the influence of independent variables, namely, Lipoid S100 and surfactant concentrations and surfactant type (X3) on the % solubilization efficiency (% SE), vesicle size (VS), and % release efficiency (% RE). Thin film hydration was the preferred approach for preparing TEs where vesicle size, zeta potential, polydispersity index, %SE and %RE were investigated. The optimized formula was nominated and subjected to several studies. For the permeation study, optimum TE was incorporated into carbapol gel base for comparison with DKT solution. Also, an accelerated stability study was assessed for optimized formula. Results: All the prepared DKT-loaded TEs revealed acceptable VS, PDI, and ZP. The highest %SE (86.08±1.05 %) and lowest %RE (44.62±1.36 %) were observed in case of F1. The optimized formula (F1) displayed VS of 133.2±1.62 nm, PDI of 0.342±0.03 and ZP of-21.6±2.45 mV. F1 revealed enhanced skin permeation of a 2.6-fold increase compared with DKT solution. Moreover, F1 was stable upon storage and a non-significant change (P>0.05) was observed. Conclusion: DKT was successfully incorporated into vesicle carrier and can signify an alternative option for providing this therapy, bypassing the poor bioavailability and considerable adverse consequences of using the oral route besides improved patient compliance

Self-trapping of excitons, violation of condon approximation, and efficient fluorescence in conjugated cycloparaphenylenes

Cycloparaphenylenes, the simplest structural unit of armchair carbon nanotubes, have unique optoelectronic properties counterintuitive in the class of conjugated organic materials. Our time-dependent density functional theory study and excited state dynamics simulations of cycloparaphenylene chromophores provide a simple and conceptually appealing physical picture explaining experimentally observed trends in optical properties in this family of molecules. Fully delocalized degenerate second and third excitonic states define linear absorption spectra. Self-trapping of the lowest excitonic state due to electron-phonon coupling leads to the formation of spatially localized excitation in large cycloparaphenylenes within 100 fs. This invalidates the commonly used Condon approximation and breaks optical selection rules, making these materials superior fluorophores. This process does not occur in the small molecules, which remain inefficient emitters. A complex interplay of symmetry, π-conjugation, conformational distortion and bending strain controls all photophysics of cycloparaphenylenes.Fil: Adamska, Lyudmyla. Los Alamos National Laboratory. Los Alamos; Estados UnidosFil: Nayyar, Iffat. Los Alamos National Laboratory. Los Alamos; Estados UnidosFil: Chen, Hang. Boston University; Estados UnidosFil: Swan, Anna K.. Boston University; Estados UnidosFil: Oldani, Andres Nicolas. Universidad Nacional de Quilmes; ArgentinaFil: Fernández Alberti, Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; ArgentinaFil: Golder, Matthew R.. University of Oregon; Estados UnidosFil: Jasti, Ramesh. University of Oregon; Estados UnidosFil: Doorn, Stephen K.. Los Alamos National Laboratory. Los Alamos; Estados UnidosFil: Tretiak, Sergei. Los Alamos National Laboratory. Los Alamos; Estados Unido

Targeting Phosphopeptide Recognition by the Human BRCA1 Tandem BRCT Domain to Interrupt BRCA1-Dependent Signaling.

Intracellular signals triggered by DNA breakage flow through proteins containing BRCT (BRCA1 C-terminal) domains. This family, comprising 23 conserved phosphopeptide-binding modules in man, is inaccessible to small-molecule chemical inhibitors. Here, we develop Bractoppin, a drug-like inhibitor of phosphopeptide recognition by the human BRCA1 tandem (t)BRCT domain, which selectively inhibits substrate binding with nanomolar potency in vitro. Structure-activity exploration suggests that Bractoppin engages BRCA1 tBRCT residues recognizing pSer in the consensus motif, pSer-Pro-Thr-Phe, plus an abutting hydrophobic pocket that is distinct in structurally related BRCT domains, conferring selectivity. In cells, Bractoppin inhibits substrate recognition detected by Förster resonance energy transfer, and diminishes BRCA1 recruitment to DNA breaks, in turn suppressing damage-induced G2 arrest and assembly of the recombinase, RAD51. But damage-induced MDC1 recruitment, single-stranded DNA (ssDNA) generation, and TOPBP1 recruitment remain unaffected. Thus, an inhibitor of phosphopeptide recognition selectively interrupts BRCA1 tBRCT-dependent signals evoked by DNA damage