Terminal Group Effect on Two-Dimensional Self-Assembly of Fluorenone-Based Liquid Crystals at the Solid/Liquid Interface.

Self-assemblies of two fluorenone-based derivatives (FE and FEC) consisting of a central 2,7-diphenyl-9-fluorenone polar moiety but differing in the flexible terminal groups were investigated by scanning tunneling microscopy (STM) at the 1-octanoic acid/HOPG interface under different concentrations and density functional theory calculation (DFT). STM results reveal a concentration-dependent polymorphic self-assembly behavior for FE, but without the presence of co-adsorbed solvents. As the concentration decreases, the dimer, bracket-like, and ribbon-like self-assembled structures were observed. On the contrary, FEC molecules assemble into only a type of oval-shaped morphology by the intermolecular N···H-O hydrogen bonds with the solvent molecules. Combined with DFT calculations, it can be deduced that the intermolecular van der Waals forces, dipole-dipole interactions, and hydrogen bonding are the main driving forces to stabilize the molecular packing of fluorenone-based polycatenars with strong polarity. Our work is of significance at the molecular level to further clarify the intermolecular interactions and conformational effects on the formation of molecular packing structures with liquid crystal property.

From Intercalation to External Binding: Ru(II) Complexes with a Spiro Ligand for TAR RNA Selective Binding and HIV-1 Reverse Transcriptase Inhibition.

As a typical RNA virus, the genetic information on HIV-1 is entirely stored in RNA. The reverse transcription activity of HIV-1 reverse transcriptase (RT) plays a crucial role in the replication and transmission of the virus. Non-nucleoside RT inhibitors (NNRTIs) block the function of RT by binding to the RNA binding site on RT, with very few targeting viral RNA. In this study, by transforming planar conjugated ligands into a spiro structure, we convert classical Ru(II) DNA intercalators into a nonintercalator. This enables selective binding to HIV-1 transactivation response (TAR) RNA on the outer side of nucleic acids through dual interactions involving hydrogen bonds and electrostatic attraction, effectively inhibiting HIV-1 RT and serving as a selective fluorescence probe for TAR RNA.

Thermotropic "Plumber's Nightmare" - A Tight Liquid Organic Double Framework.

Gyroid, double diamond and the body-centred "Plumber's nightmare" are the three most common bicontinuous cubic phases in lyotropic liquid crystals and block copolymers. While the first two are also present in solvent-free thermotropics, the latter had never been found. Containing six-fold junctions, it was unlikely to form in the more common phases with rod-like cores normal to the network columns, where a maximum of four branches can join at a junction. The solution has therefore been sought in side-branched mesogens that lie in axial bundles joined at their ends by flexible "hinges". But for the tightly packed double framework, geometric models predicted that the side-chains should be very short. The true Plumber's nightmare reported here, using fluorescent dithienofluorenone rod-like mesogen, has been achieved with, indeed, no side chains at all, but with 6 flexible end-chains. Such molecules normally form columnar phases, but the key to converting a complex helical column-forming mesogen into a framework-forming one was the addition of just one methyl group to each pendant chain. A geometry-based explanation is given.

Applications of laser technology in the manipulation of human spermatozoa.

The application of laser technology in the field of assisted reproductive technology (ART) has experienced rapid growth over the past decades owing to revolutionary techniques such as intracytoplasmic sperm injection (ICSI), preimplantation genetic testing (PGT), and in vitro manipulation of gametes and embryos. For male gametes, in vitro manipulation techniques include spermatozoa selection, sorting, immobilization, and quality assessment. A number of studies have been conducted to investigate the application of different laser technologies in the manipulation of human spermatozoa. However, there is a lack of a unified understanding of laser application in the in vitro manipulation of sperm and safety considerations in ART and, subsequently, the inability to make clear and accurate decisions on the clinical value of these laser technologies. This review summarizes the advancements and improvements of laser technologies in the manipulation of human spermatozoa, such as photobiomodulation therapy, laser trap systems for sperm analysis and sorting, laser-assisted selection of immotile sperm and laser-assisted immobilization of sperm prior to ICSI. The safety of those technologies used in ART is also discussed. This review will provide helpful and comprehensive insight into the applications of laser technology in the manipulation of human spermatozoa.

Acylhydrazone Functionalized Triphenylamine-Based Fluorescent Probe for Cu2+: Tunable Structures of Conjugated Bridge and Its Practical Application.

Novel fluorescent probes were constructed for the convenient and rapid analysis of Cu2+ ions, taking advantages of the the triphenylamine backbone as chromophore and acylhydrazone group as the Cu2+ recognition site. Especially, probe T2 could act as a dual-channel probe towards Cu2+ through both fluorescent and colorimetric method. Through the fluorescent method, the detection limit of probe T2 was calculated to be as low as 90 nmol/L and there was a good linear relationship between the intensity change and the concentration of Cu2+ ions. By virtue of the two-phase liquid-liquid extraction method, probe T2 could be successfully applied in practical extraction and separation of Cu2+. Furthermore, by applying a "turn-off-turn-on" circle, compound T2 could act as a sensitive probe towards S2- anions through the indirect approach and the detection limit of complex T2-Cu2+ for S2- anion was found to be 110 nmol/L.

Development of an UHPLC-MS/MS method to determine cutaneous biodistribution of cannabidiol after topical application of cannabidiol gel assisted by iontophoresis.

Cannabidiol has potential for use in skin disease therapy, so it is important to know the cutaneous biodistribution of cannabidiol after topical application of cannabidiol formulations. However, currently existing quantification methods for the investigation of cannabidiol skin distribution are not optimal. This study aimed to establish a method for the determination of cannabidiol in skin samples by UHPLC-MS/MS. A BEH C18 (50.0 × 2.1 mm, 2.5 µm) column was used; the mobile phase consisted of acetonitrile-0.1% formic acid (70:30, v/v), the flow rate was 0.2 µl·min-1 and the column temperature was 30°C. Positive-ion mode with multiple reaction monitoring detection was used to quantify cannabidiol (m/z 315.1 → 193.1) while diphenhydramine (m/z 256.3 → 167.08) served as the internal standard. Good linearity was shown in the range of 1-200 ng·ml-1 for cannabidiol with correlation coefficients of >0.999. The LLOQ was 1 ng·ml-1 . The intra-day and inter-day RSDs of cannabidiol were all <2%. A cryo-sectioning technique combined with the UHPLC-MS/MS method was used to successfully determine cannabidiol levels in a series of very thin skin layers.

Fluorene Thiophene α-Cyanostilbene Hexacatenar-Generating LCs with Hexagonal Columnar Phases and Gels with Helical Morphologies as Well as a Light-Emitting LC Display.

Two series of novel synthesized hexacatenars, O/n and M/n, containing two thiophene-cyanostilbene units interconnected by central fluorene units (fluorenone or dicyanovinyl fluorene) using a donor-acceptor-acceptor-donor (A-D-A-D-A) rigid core, with three alkoxy chains at each end, can self-assemble into hexagonal columnar mesophases with wide liquid crystal (LC) ranges and aggregate into organogels with flowerlike and helical cylinder morphologies, as revealed via POM, DSC, XRD and SEM investigation. Furthermore, these compounds were observed to emit yellow luminescence in both solution and solid states which can be adopted to manufacture a light-emitting liquid crystal display (LE-LCD) by doping with commercially available nematic LC.

Chain-Length- and Concentration-Dependent Isomerization of Bithiophenyl-Based Diaminotriazine Derivatives in Two-Dimensional Polymorphic Self-Assembly§.

Bithiophenyl-based diaminotriazine derivatives (2TDT-n, n = 10, 12, 16, and 18) with different chain lengths display colhex/p6mm mesophases. Their supramolecular self-assembled mechanism is investigated using scanning tunneling microscopy (STM) at the 1-octanoic acid/graphite interface at various concentrations. The chain length effect on the two-dimensional adlayers is observed in this system, and 2TDT-n molecules show a structural phase transition from the four-leaf arrangement to the two-row linear nanostructure accompanied by the emergence of molecular isomerization with the increase of the side-chain length. The self-assembled structure of 2TDT-10 is composed of a four-leaf pattern with uniform s-cis conformers. In 2TDT-12, three kinds of nanostructures (bamboo-like, two-row linear pattern-I, and flower-like) are observed. These nanostructures are randomly constituted by cis and trans conformers, and the ratios of the s-cis conformer in three kinds of patterns are 55.7, 42.3, and 62.5%, respectively. Furthermore, when n = 16 and 18, the ratio of the s-cis conformer further decreases to 19.0 and 4.3%, respectively. Those molecules mainly form linear nanostructures consisting of s-trans conformers. Therefore, it is reasonable to conclude that the side-chain length has a great effect on the self-assembled patterns and the molecular conformation of bithiophenyl-based diaminotriazine derivatives. Density functional theory calculations are applied to optimize molecular conformers and assess their single-point energies, showing that the s-cis conformation has higher energy than the s-trans conformer. We speculate that the ratio of two conformers in nanostructures might be similar to that of the liquid crystalline phase.

Novel ratiometric fluorescent probe based on internal reference and its detection of hydrazine.

In this work, dual-emissive ratiometric fluorescent system was constructed by the introduction of an ideal internal reference. By virtue of its unique alkalinity, N2H4 could undergo a hydrazinolysis reaction with the ester group of F1, inducing remarkable fluorescence enhancement while the blue fluorescence of the internal reference DPA remained constant. Consequently, the fluorescence intensity ratios (I540/I440) were proportional to the concentrations of N2H4, which was beneficial for the exactly quantitative detection. The skillful strategy granted the sensing system advantages such as relative good solubility in aqueous media, easy-to-design, simple synthesis, large emission shift, good ratiometric response, as well as the successful application in real water samples and cell imaging.

Liquid Organic Frameworks: The Single-Network "Plumber's Nightmare" Bicontinuous Cubic Liquid Crystal.

Novel bolapolyphiles, built of a p-terphenyl or bistolane core with polar glycerol end-groups and two laterally attached n-alkyl or semiperfluoroalkyl chains, form the first "single plumber's nightmare network", the simplest soft-matter cubic phase (Pm3̅m). Its cage-like grid comprises bundles of aromatic rods lying along the cubic unit cell edges, connected by six-way hydrogen-bonded junctions. Side-chains fill the remaining volume of this unique noninterpenetrating liquid-crystalline organic framework.

Frustration between two- and three-dimensional smectic ordering leads to a biaxial nematic phase.

The bola-amphiphilic, T-shaped mesogen CT2 has an aromatic, biphenyl core terminated on both ends by hydrophilic groups and a semi-perfluorinated, aliphatic side chain. Upon cooling from the isotropic phase, the fluorinated tails and the polar, rod-like cores nanophase-segregate to form a fluid lamellar phase. At high temperatures, the biphenyl cores are orientationally disordered in two dimensions (2D) in the lamellar planes but on further cooling the cores order orientationally, giving a biaxial lamellar phase with 2D nematic in-plane ordering. At lower temperature, the aromatic and hydrophilic parts of the cores nanosegregate within the lamellae and 2D smectic correlations of the head groups develop. X-ray diffraction shows that this 2D smectic ordering is incompatible with the initial lamellar structure, with both structures becoming short-ranged, resulting in a 3D biaxial nematic phase with macroscopic orthorhombic symmetry featuring strong smectic correlations in two orthogonal spatial dimensions. Freeze-fracture transmission electron microscopy enables direct visualization of the resulting short-ranged periodic structures.

Protocol for a prospective, cluster randomized trial to evaluate routine and deferred dialysis initiation (RADDI) in Chinese population.

BACKGROUND: The timing of when to initiate dialysis for progressive chronic kidney disease (CKD) patients has not been well established. There has been a strong trend for early dialysis initiation for these patients over the past decades. However, the perceived survival advantage of early dialysis has been questioned by a series of recent observational studies. The only randomized controlled trial (RCT) research on this issue found the all-cause mortality, comorbidities, and quality of life showed no difference between early and late dialysis starters. To better understand optimal timing for dialysis initiation, our research will evaluate the efficacy and safety of deferred dialysis initiation in a large Chinese population. METHODS: The trial adopts a multicenter, cluster randomized, single-blind (outcomes assessor), and endpoint-driven design. Eligible participants are 18-80 years old, in stable CKD stages 4-5 (eGFR > 7 ml/min /1.73 m2), and with good heart function (NYHA grade I or II). Participants will be randomized into a routine or deferred dialysis group. The reference eGFR at initiating dialysis for asymptomatic patients is 7 ml/min /1.73 m2 (routine dialysis group) and 5 ml/min/1.73 m2 or less (deferred dialysis group) in each group. The primary endpoint will be the difference of all-cause mortality and acute nonfatal cerebro-cardiovascular events between the two groups. The secondary outcomes include hospitalization rate and other safety indices. The primary and secondary outcomes will be analyzed by appropriate statistical methods. DISCUSSION: This study protocol represents a large, cluster randomized study evaluating deferred and routine dialysis intervention for an advanced CKD population. The reference eGFR to initiate dialysis for both treatment groups is targeted at less than 7 ml/min/1.73m2. With this design, we aim to eliminate lead-time and survivor bias and avoid selection bias and confounding factors. We acknowledge that the study has limitations. Even so, given the low-targeted eGFR values of both arms, this study still has potential economic, health, and scientific implications. This research is unique in that such a low targeted eGFR value has never been studied in a clinical trial. TRIAL REGISTRATION: The trial has been approved by ClinicalTrials.gov (Trial registration ID NCT02423655). The date of registration was April 22, 2015.

The influence of environmental factors on clinical pathological changes of patients with immunoglobulin A nephropathy from different areas of China.

OBJECTIVES: The effects of regional characteristics of IgAN patients in different areas of China were investigated. METHODS: Patients who were identified to have primary IgAN by renal biopsy diagnosis were recruited both from Shaanxi province hospital of traditional Chinese medicine and Guangdong province hospital of traditional Chinese medicine. Besides renal histopathology data, a number of clinical and laboratory data were collected. RESULTS: It was shown that the frequency of the patients with no mucosal infection in the urinary tract was higher in the Guangzhou group, while the frequencies of upper respiratory tract and biliary infections were lower when compared with those in the Xi'an group. Serum uric acid, alexin C3, creatinine and serum cholesterol concentrations were increased in the Guangzhou group, while triglyceride, glomerular filtration rate, and urine red blood cell count level decreased. IgA + IgM + C3 and IgA + IgG + IgM + C3 were found in most patients of the Xi'an group, whereas IgA + C3, IgA + IgM + C3 and IgA were more frequent in the Guangzhou group. CONCLUSION: It was found that differential environment, life habits and patterns in the two investigated areas obviously may influence the variable characteristics of IgAN patients.

Coumarin-Based Fluorescent Probe for Hypochlorites and Real Application in Tap Water.

Taking advantages of both the oxidation property of hypochlorite and different coordination properties of Cu+ and Cu2+ ions, we developed a new fluorescent probe for hypochlorite anion, namely, compound C1. In the presence of ClO-, the sensing system displayed extraordinary fluorescence quenching, which was beneficial to the production of a high signal output during detection process. By virtue of its special oxidation property, the probe displayed high selectivity for ClO- over other anions. Moreover, this novel sensing system could be used for the analysis of ClO- levels in tap water and potentially in environmental samples.

Carbamodithioate-based fluorescent chemosensor for Hg(II): a staged response approach and investigation into the sensing mechanism.

Carbamodithioate-based compound C1 was designed and synthesized as a new fluorescent probe for Hg2+ ions. Upon the addition of Hg2+ ions, it displayed a rare staged response: the emission spectra of C1 first showed an apparent red-shift, followed by a dramatic decrease. To investigate the sensing mechanism, control compounds C2 with the same phenanthroimidazole unit and C3 with the same carbamodithioate functionality were synthesized. On comparison, the first step sensing process was ascribed to decreasing photoinduced electron transfer on the coordination of Hg2+ with the lone pair electrons of the nitrogen atom on the phenanthroimidazole ring. The affinity of Hg2+ and the carbamodithioate unit with four sulfur atoms then induced changes in intramolecular charge transfer efficiency and the second step fluorescent response.

Reaction-based probe for hydrogen sulfite: dual-channel and good ratiometric response.

We designed and synthesized a new series of intramolecular charge transfer (ICT) molecules (compounds T1, T2 and T3) by attaching various electron-donating thiophene groups to the triphenylamine backbone with aldehyde group as the electron acceptor. Based on the nucleophilic addition reaction between hydrogen sulfite and aldehyde, all compounds could act as ratiometric optical probe for hydrogen sulfite and displayed efficient chromogenic and fluorogenic signaling. Upon the addition of hydrogen sulfite anions, probe T3 displayed apparent fluorescent color changes from yellowish-green to blue, with a large emission wavelength shift (Δλ = 120 nm). T3 responded to hydrogen sulfite with high sensitivity and the detection limit was determined to be as low as 0.9 µM. At the same time, apparent changes in UV-vis spectra could also be observed. By virtue of the special nucleophilic addition reaction with aldehyde, T3 displayed high selectivity over other anions. Copyright © 2016 John Wiley & Sons, Ltd.

Hydroxylated tropolones inhibit hepatitis B virus replication by blocking viral ribonuclease H activity.

Hepatitis B virus (HBV) remains a major human pathogen despite the development of both antiviral drugs and a vaccine, in part because the current therapies do not suppress HBV replication far enough to eradicate the virus. Here, we screened 51 troponoid compounds for their ability to suppress HBV RNaseH activity and HBV replication based on the activities of α-hydroxytropolones against HIV RNaseH, with the goal of determining whether the tropolone pharmacophore may be a promising scaffold for anti-HBV drug development. Thirteen compounds inhibited HBV RNaseH, with the best 50% inhibitory concentration (IC50) being 2.3 µM. Similar inhibition patterns were observed against HBV genotype D and C RNaseHs, implying limited genotype specificity. Six of 10 compounds tested against HBV replication in culture suppressed replication via blocking of viral RNaseH activity, with the best 50% effective concentration (EC50) being 0.34 µM. Eighteen compounds inhibited recombinant human RNaseH1, and moderate cytotoxicity was observed for all compounds (50% cytotoxic concentration [CC50]=25 to 79 µM). Therapeutic indexes ranged from 3.8 to 94. Efficient inhibition required an intact α-hydroxytropolone moiety plus one or more short appendages on the tropolone ring, but a wide variety of constituents were permissible. These data indicate that troponoids and specifically α-hydroxytropolones are promising lead candidates for development as anti-HBV drugs, providing that toxicity can be minimized. Potential anti-RNaseH drugs are envisioned to be employed in combination with the existing nucleos(t)ide analogs to suppress HBV replication far enough to block genomic maintenance, with the goal of eradicating infection.

The hepatitis B virus ribonuclease H is sensitive to inhibitors of the human immunodeficiency virus ribonuclease H and integrase enzymes.

Nucleos(t)ide analog therapy blocks DNA synthesis by the hepatitis B virus (HBV) reverse transcriptase and can control the infection, but treatment is life-long and has high costs and unpredictable long-term side effects. The profound suppression of HBV by the nucleos(t)ide analogs and their ability to cure some patients indicates that they can push HBV to the brink of extinction. Consequently, more patients could be cured by suppressing HBV replication further using a new drug in combination with the nucleos(t)ide analogs. The HBV ribonuclease H (RNAseH) is a logical drug target because it is the second of only two viral enzymes that are essential for viral replication, but it has not been exploited, primarily because it is very difficult to produce active enzyme. To address this difficulty, we expressed HBV genotype D and H RNAseHs in E. coli and enriched the enzymes by nickel-affinity chromatography. HBV RNAseH activity in the enriched lysates was characterized in preparation for drug screening. Twenty-one candidate HBV RNAseH inhibitors were identified using chemical structure-activity analyses based on inhibitors of the HIV RNAseH and integrase. Twelve anti-RNAseH and anti-integrase compounds inhibited the HBV RNAseH at 10 µM, the best compounds had low micromolar IC(50) values against the RNAseH, and one compound inhibited HBV replication in tissue culture at 10 µM. Recombinant HBV genotype D RNAseH was more sensitive to inhibition than genotype H. This study demonstrates that recombinant HBV RNAseH suitable for low-throughput antiviral drug screening has been produced. The high percentage of compounds developed against the HIV RNAseH and integrase that were active against the HBV RNAseH indicates that the extensive drug design efforts against these HIV enzymes can guide anti-HBV RNAseH drug discovery. Finally, differential inhibition of HBV genotype D and H RNAseHs indicates that viral genetic variability will be a factor during drug development.

Inhibitors of nucleotidyltransferase superfamily enzymes suppress herpes simplex virus replication.

Herpesviruses are large double-stranded DNA viruses that cause serious human diseases. Herpesvirus DNA replication depends on multiple processes typically catalyzed by nucleotidyltransferase superfamily (NTS) enzymes. Therefore, we investigated whether inhibitors of NTS enzymes would suppress replication of herpes simplex virus 1 (HSV-1) and HSV-2. Eight of 42 NTS inhibitors suppressed HSV-1 and/or HSV-2 replication by >10-fold at 5 µM, with suppression at 50 µM reaching ∼1 million-fold. Five compounds in two chemical families inhibited HSV replication in Vero and human foreskin fibroblast cells as well as the approved drug acyclovir did. The compounds had 50% effective concentration values as low as 0.22 µM with negligible cytotoxicity in the assays employed. The inhibitors suppressed accumulation of viral genomes and infectious particles and blocked events in the viral replication cycle before and during viral DNA replication. Acyclovir-resistant mutants of HSV-1 and HSV-2 remained highly sensitive to the NTS inhibitors. Five of six NTS inhibitors of the HSVs also blocked replication of another herpesvirus pathogen, human cytomegalovirus. Therefore, NTS enzyme inhibitors are promising candidates for new herpesvirus treatments that may have broad efficacy against members of the herpesvirus family.

Carbamodithioate-based dual functional fluorescent probe for Hg(2+) and S(2-).

Carbamodithioate-based compound T1 was designed and synthesized as a dual-functional probe for Hg(2+) ions and S(2-) anions. The underlying signaling mechanism was intramolecular charge transfer (ICT). It could serve as a direct probe towards Hg(2+) ions through "on-off" fluorescence changes and an indirect probe towards S(2-) anions through "on-off-on" fluorescence changes.