Molecular electronics describes a field that seeks to implement electronic components made of molecular building blocks. To date, few studies have used conjugated polymers in molecular junctions despite the fact that they potentially transport charge more efficiently than the extensively investigated small-molecular systems. Here we report a novel type of molecular tunnelling junction exploring the use of conjugated polymers, which are self-assembled into ultrathin films in a distinguishable ‘planar' manner from the traditional vertically oriented small-molecule monolayers. Electrical measurements on the junctions reveal molecular-specific characteristics of the polymeric molecules in comparison with less conjugated small molecules. More significantly, we decorate redox-active functionality into polymeric backbones, demonstrating a key role of redox centre in the modulation of charge transport behaviour via energy level engineering and external stimuli, and implying the potential of employing tailor-made polymeric components as alternatives to small molecules for future molecular-scale electronics. To date, conjugated polymers have not yet been used in molecular junctions despite the fact that they transport charge more efficiently than small-molecular systems. Here, Wang et al. showcase the self-assembly of conjugated polymers into ultrathin films in a planar manner for device construction. The visionary idea of molecular electronics has been sketched out for decades23567810112131416181921p-phenylene ethynylene)s (PPEs)2122232427283031Herein, we investigate the self-assembly manner of long CPs on metal surface in comparison with typical vertically aligned small molecules, and thereby introduce a novel type of molecular junction employing CPs as the active charge transport layer. Poly and TTF–PPEs  are chemisorbed on flat Au substrates (root mean squared (r.m.s.) roughness≈0.5 nm) in micropores (4 μm in diameter)Both thioacetyl-end-functionalized PPEs (2) for ease of characterization. The CP-covered surface morphology was imaged by atomic force microscopy , S 2p spectrum showed only one doublet peak with S 2p3/2 at 162 eV attributed to S atom bonding to Au. Limited signals were observed at 164 eV from S to R (R refers to H/Ac/C), indicating that almost no free anchoring groups were present. For TTF–PPEs, S 2p signals were clearly distinguished. In addition to the peaks at 162 eV related to S–Au bonds, much stronger peaks at 164 eV appeared, attributed to S–R bonds in the TTF unitf signal  was utilized to analyse the band spectra of molecular film/Au interface, especially the barrier height for charge injection, which plays a key role for charge transport in molecular tunnelling junctions. The measured UPS spectra of secondary electron cutoff (SEC) region and the HOMO region for PPEs and TTF–PPEs are shown in I–V curves of the CP junctions are non-linear showing semiconducting characteristics, similar to typical SAM junctions. The junctions were very stable and they did not exhibit either current attenuation or short-circuit failure on repeated bias scans  than TTF–PPE junctions, resulting from a joint action of tunnelling length and energy barriers (more discussion in the following sections).On the basis of energy level analysis, both CPs and small molecules were assembled into rGO top-contact test bed for charge transport measurements. rGO-only junctions showed typical ohmic behaviour with resistances orders of magnitude lower than the junctions based on molecular components . Typicalas scans , indicatAs discussed above, the CPs formed a novel type of molecular layer with thickness of 2–3 nm between bottom and top contacts. On this occasion, charge transport in the junctions can be simplified as electron tunnelling through a barrierd is the barrier width, me is the electron effective mass and Φ is the barrier height . A Fowler–Nordheim (F–N) plot of ln (I/V2) versus 1/V can provide further insight into the charge transport process—a method called transition voltage spectroscopy143738394041Vtrans. The transition voltage is related to the energy offset between the electrode Fermi level and the nearest molecular orbital . In particular, Bâldea derived an approximate relation, for a point-like molecule, between Vtrans and the energy level offset Φ: eVtrans≈1.15Φ , which agrees with the fact that alkanes have fairly large energy gaps (up to 7 eV) and, therefore, large charge injection barriersVtrans. Log–log plot showed consistent results . The magnitude of Vtrans scales roughly with the EF–EHOMO energy difference predicted by UPS and corresponds to molecular-specific signatures. The observed lowering of the effective barrier height in transition voltage analysis compared with UPS measured values has been discussed elsewhere1437Wherein  results , inset. In addition to shifting the molecular energy levels, TTF units can act as redox-active centres, and we further investigated how the redox process affects charge transport properties of the junctions. CV characterization in solution and thin-film state both verified that the redox properties were retained after the TTF units were inserted into PPE backbones . On this4)3·6H2O in CP solutions, ultraviolet–vis spectroscopy showed clearly changed absorption spectrum of TTF–PPEs, while that of the PPEs was not affected (4)3·6H2O was used, ascribed to TTF2+–PPE. The ultraviolet–vis spectroscopy did not exhibit a stable radical cation state4445·+–PPE), probably due to the poor stability of the radical cations at our experimental conditions, especially in the dilute solution (10−5 M) suitable for ultraviolet–vis measurement. The radical cations were successfully traced by electron spin-resonance spectroscopy (ESR) analysis with a distinct signal appearing during the addition of oxidant47−3 M tetrahydrofuran (THF) solution (s XPS spectra of PPEs (p spectra see 4)3 solution for 12 h, no visible change on C 1s spectra was observed for PPEs. At the same time, an obvious change of C 1s signal for TTF–PPEs appeared after oxidant treatment: besides the main peak in the spectrum falling at 284.6 eV attributed to unsaturated carbons belonging to the polymer backbone, which resembles that of PPEs, a pronounced shoulder peak at around 286.1 eV appeared. This phenomenon was induced by an upper shift of C–S bonding energy from 285.3 eV  of I(V) characteristics. Experimental evidences confirmed that a modulation of conductance of TTF–PPE junctions was achieved via oxidant treatment on the CP films, which was not observed for non-redox-active PPE junctions. The Rs of TTF2+–PPE junction was on average one order of magnitude higher than that of their neutral state  for 10 min, where a new absorption peak at about 436 nm and an broad absorption around at 1,050 nm  that can be ‘read' by electrical measurements. Furthermore, we demonstrate the potential of tailoring the charge transport behaviours of the polymeric components by synthetic methods. The synthetic tailorability of functional molecules not only enables energy level engineering when they are assembled between contact electrodes, but also modulation of their chemical/physical properties via external stimuli. Our work could lead to more studies and potential applications on incorporating CPs into molecular-scale devices for electrical switches and memories, preferably taking advantages of unique properties of CPs  for a potential alternative to SAMs of small molecules.n∼15 and n∼10) for control experiments to investigate whether there is lateral propagation of electrons within the film. We suppose that if these shorter PPEs are also lying flat on the Au surface, we can, thus, compare their charge transport properties with long PPEs. If the short PPEs exhibit apparently different characteristics compared with the long PPEs, a lateral charge propagation may be involved. However, based on XPS analysis, these shorter PPEs were found to be more inclined to stand up rather than totally lie flat on the Au surface (n∼100) , non-resonant tunnelling would dominate. In this sense, the electron has no real retention time on the CPs  and the junction conductance will be determined only by the height of tunnelling barrier and tunnelling distance (thickness of the CP film). For further confirmation, we synthesized a group of ‘shorter' PPEs  . It woulAnother point worthy of attention is that the electrochemical method appears to be superior to the chemical method for tuning the performance of TTF–PPE junctions. On one hand, cycling oxidation–reduction process can be much easier achieved using an electrochemical method; on the other hand, the encapsulated geometry of the molecular junctions is designed under the consideration of long shelf-life, stable operation and possible scalability. Using chemicals would not be the best choice for the operation of solid-state devices. At the present state, the device performance under electrical oxidation/reduction is not as stable as the reported small-molecule systems, which indicates there is still room for improvement on molecular design and calls for a deeper understanding of specific molecular charateristics for a better device manipulation. More importantly, in addition to redox-active systems, polymeric molecules endowed with more complex functionalities and improved self-assembly ability can be expected for constructing nanoscale electronic switchable devices on various external stimuli.In summary, we study the self-assembly of two kinds of CPs: PPEs and redox-active TTF–PPEs, on Au surface. The long CPs are self-assembled into ultrathin films (2–3 nm) in a distinguishable ‘planar' manner from the vertically oriented SAMs. On this basis, we introduce a novel type of CP junction that exhibits molecular-specific properties of the CPs on electrical measurements in comparison with conventional small molecules. More significantly, it is confirmed that the decoration of TTF units into the PPE backbone not only decreases its energy gap but also achieves a better alignment of energy levels for charge injection. Furthermore, we demonstrate a key role of the TTF redox centre in the modulation of charge transport through CP junctions using both chemical and electrochemical methods, which is not observed for non-redox-active molecular systems. This work proposes the potential of employing CPs as alternatives to typical small-molecule monolayers for device construction in the field of molecular electronics, as well as the possibility of incorporating desirable functionality into polymeric molecules for switchable electronic devices, which are regarded as the basic elements in the blueprint of molecular electronics.3)2Cl2 , CuI  and end-capping reagent of S-4-iodophenyl ethanethioate  were fully mixed, degassed three times and backfilled with N2, and then triethylamine (2 ml) in dry toluene (12 ml) solution was added. After stirring the resulted solution for 30 min at 50 °C, M1 monomer  was added for initiating the cross-coupling reaction and continuously stirring for more 4.5 h. A toluene solution of excessive end-capping reagent of S-4-iodophenyl ethanethiolate  was dissolved and reacted for 40 h. After removing the solvent under reduced pressure, the residue was extracted by THF, precipitated in acetone and filtrated. After purification for several times using THF and acetone, the final PPE orange solids were obtained with a yield of 90%. 1H NMR  δ 7.01 (bs), 4.05–4.02 (m), 2.44 (m), 1.89–1.83 (m), 1.54–1.51 (m), 1.35–1.34 (m), 0.91–0.89 (m).Thioacetyl-end-functionalized PPEs were synthesized according to previously reported methods233)2Cl2  and CuI  were fully mixed in anhydrous THF (40 ml) under N2, and then triethylamine (15 ml) was added. After reaction for about 4 days at 60 °C, appropriate additional catalysts and excess end-capping reagent S-4-iodophenyl ethanethiolate  were added and the reaction mixture was further stirred for another 2 days. After filtration to get rid of the formed precipitate, a red solid was acquired via removing the solvent under rotary evaporation, which was again redissolved with THF as little as possible. TTF–PPE was obtained through reprecipitation separately in 200 ml acetone and 200 ml MeOH, and dried in vacuum. Yield 214 mg, 95%. 1H NMR : δ 7.47 (m), 7.01 (s), 4.01 (t), 2.53 (s), 2.43 (s), 1.80–1.87 (m), 1.34–1.36 (m), 0.83–0.92 (t).Thioacetyl-end-functionalized TTF–PPEs were synthesized and characterized as reported in a previous paperOther chemicals and reagents were purchased from commercial suppliers and used without further purification.−1 in anhydrous THF) were transferred in a quartz flat cell, with the typical spectrometer settings as modulation amplitude of 0.05–0.15 mT, modulation frequency of 100 kHz, microwave power of 12.9 mW, microwave frequency of 9.5 GHz, conversion time of 82 ms, time constant of 164 ms and receiver gain of 104–106.Ultraviolet–vis absorption was conducted on a JASCO V-570 ultraviolet–vis spectrometer. Cyclic voltammetry (CHI 660C electrochemistry station) was performed under inert conditions in a standard three-electrode electrochemical cell that consisted of a glassy carbon working electrode, an Ag/AgCl reference electrode and a Pt wire counter electrode. Spectroelectrochemical experiments (with JASCO V-570 ultraviolet–vis spectrometer and CHI 660C electrochemistry station) were performed at room temperature in an optically transparent thin-layer electrochemical cell equipped with Pt gauze working electrode, Pt wire counter electrode and Ag/AgCl reference electrode with the optical path length of 1.0 mm. Absorption spectra were recorded immediately after the completion of electrochemical oxidation/reduction process. ESR was recorded on a Bruker ESP-300 spectrometer at the X-band. ESR samples (∼1 mg ml−1) and OPE3 (0.4 mg ml−1) were dissolved in anhydrous THF solution containing 25% triethylamine , and C12 was directly dissolved in ethanol (∼2 mM). The Au substrates were then put into the solutions and stored in N2 glove box for 48 h. The samples were then taken out and rinsed with excess solvents. The oxidant treatment was performed by immersing the sample into 10 mM Fe(ClO4)3 in THF. A solution of 10 mM ferrocene was used for reduction treatment.Self-assembled molecular thin films were grown on flat Au substrates by Au–thiol attachment chemistryf7/2 line at 84.0 eV. UPS measurements were taken with the same system with a base pressure >2 × 10−9 torr and He I (h=21.22 eV) as the excitation source. To obtain the SEC, a sample bias of −9 V was applied in the normal emission geometry. For all the UPS spectra, the Fermi level of the system was calibrated by determining the Fermi level edge of a sputtered clean Au film and referenced as the zero-binding energy. Atomic force microscopy characterization was performed on a Nanoscopy IIIa (USA) in a tapping mode.XPS (KRATOS Axis Ultra DLD spectrometer) was conducted with a monochromatized Al Kα X-ray source (1486.6 eV) and an analyser pass energy of 20 eV at takeoff angles of 90°. All samples were energy calibrated using the Au 4−1). The sample was then loaded in a Savannah 100 atomic layer deposition system from Cambridge Nano Tech. The sample was heated to 110 °C and exposed to alternating gasses of water and trimethylaluminium this was repeated 400 times resulting in a ∼30-nm thick layer of Al2O3. The microholes were etched using electron beam lithography followed by a wet etch in an aluminium etching mixture consisting of phosphoric and acetic acid.Devices were fabricated according to the previously reported methods2/Si substrates were prepared by spin-coating method, which were thermally reduced to rGO films at 600 °C in Ar atmosphere (140 ml min−1) for 60 min. The delamination of rGO films from SiO2/Si substrate was achieved by generally used methods. Briefly, sodium hydroxide (NaOH) solution (1 M) was slowly added onto the rGO film until the solution spread over the SiO2/Si wafer. Then, the wafer was submerged into deionized water at a tilt angle, which delaminated the rGO films from the substrate. The floating rGO films on water were transferred onto the bottom electrodes covered by molecular films to act as the top contact. Finally, the unserviceable parts of rGO films were etched away by oxygen plasma using a stripped Au film as mask. I–V characterization was carried out using a Keithley 4,200 SCS system and a Micromanipulator 6150 probe station under ambient conditions.Monolayered graphene oxide sheets were obtained by Hummers' method. Continuous GO films on SiOHow to cite this article: Wang, Z. et al. Role of redox centre in charge transport investigated by novel self-assembled conjugated polymer molecular junctions. Nat. Commun. 6:7478 doi: 10.1038/ncomms8478 (2015).Supplementary Figures 1-16 and Supplementary References


We targeted halorhodopsin (NpHR) specifically to dopamine cells by injecting Cre-inducible virus into ventral tegmental area (VTA) of transgenic rats that expressed Cre recombinase under control of the tyrosine hydroxylase promoter (TH-Cre+ rats). Consistent with previous work, co-administration of cocaine and raclopride led to the generation of dopamine transients in NAc shell. Illumination of VTA with laser strongly suppressed the frequency of transients in NpHR-expressing rats, but not in control rats. Laser did not have any effect on amplitude of transients. Thus, optogenetics can effectively reduce the occurrence of drug-evoked transients and is therefore a suitable approach for studying the functional role of such transients in drug-associated behavior.Brief fluctuations in dopamine concentration (dopamine transients) play a key role in behavior towards rewards, including drugs of abuse. Drug-evoked dopamine transients may result from actions at both dopamine cell bodies and dopamine terminals. Inhibitory opsins can be targeted to dopamine neurons permitting their firing activity to be suppressed. However, as dopamine transients can become uncoupled from firing, it is unknown whether optogenetic hyperpolarization at the level of the soma is able to suppress dopamine transients. Here, we used  All rats used were male and weighed 275–350 g at time of initial surgery. Rats were group-housed until surgery and singly housed thereafter. Standard housing conditions were provided  with ad libitum access to food and water. Animal care and use was in accordance with the National Institutes for Health Guide for the Care and Use of Laboratory Animals, and approved by the Institutional Animal Care and Use Committee at the University of Illinois at Chicago.Transgenic rats (Long-Evans background) expressing Cre recombinase under the control of the 12 particles/mL; serotype AAV5) were purchased from University of North Carolina Vector Core: AAV-EF1a-DIO-eNpHR3.0-EYFP (NpHR); AAV-EF1a-DIO-EYFP (eYFP). TH-Cre+ rats infused with NpHR  were compared to TH-Cre+ rats infused with eYFP or TH-Cre− rats infused with NpHR .The following Cre-dependent viruses  and xylazine hydrochloride , and 2 μL of appropriate virus (see above) was infused using a custom made injector with tips separated 0.8 mm AP and 1 mm DV  and S(−)-raclopride (+)-tartrate salt (Sigma-Aldrich) were dissolved in sterile saline at 10 mg/mL and 1 mg/mL, respectively, before injecting.At the end of recording rats were transcardially perfused. Brains were removed and post-fixed in formalin for 24 h followed by 30% sucrose in 0.1 M phosphate buffer (PB). In a subset of rats, to double-label neurons, anti-TH immunohistochemistry was performed as previously described , as previously described  was used to objectively identify and analyze transients from t-tests were used to compare “laser on” trials to “laser off” trials. MATLAB was used to conduct statistical testing.The epoch used for analysis began 1 s after the laser was turned on and ended when the laser was turned off. This was compared to an equivalent epoch in trials when the laser was never turned on. Paired + rats with Cre-dependent virus led to expression of transgenes in midbrain dopamine neurons. Expression of eYFP reporter was seen throughout the VTA and substantia nigra compacta of TH-Cre+ rats , as expected. Colocalization of eYFP with TH immunoreactivity was observed in the VTA of TH-Cre+ rats infected with Cre-dependent eYFP  = −3.489, p = 0.010). Control rats were defined as TH-Cre+ rats injected with eYFP reporter or TH-Cre− rats injected with NpHR. No difference between “laser on” and “laser off” trials was observed in these rats and they were pooled for analysis  = 1.569, p = 0.192).To analyze the effect of the laser, mean dopamine concentration during the laser epoch was subtracted from mean dopamine concentration during a corresponding baseline epoch that preceded the laser . This value was compared with a similar calculation performed on trials in which the laser was not turned on . Analysis of all NpHR-expressing rats shows a greater suppression of dopamine concentration during “laser on” trials, compared with “laser off” trials  = −2.961, p = 0.031). This reduction in frequency was not seen in control rats (t(3) = 0.397, p = 0.718). Surprisingly, even though transient frequency was reduced during “laser on” trials in NpHR-expressing rats, when transients were detected, their amplitude was not affected by the laser  = −2.014, p = 0.100). No change in transient amplitude was seen in control rats as a result of laser (t(3) = −0.259, p = 0.813).In rats in which dopamine transients were observed, characteristics of transients were further analyzed. One control rat exhibited very low spontaneous activity (<1 transient/min) and was excluded from this analysis. In NpHR-expressing rats, the frequency of transients was reduced during “laser on” trials, compared with corresponding “laser off” trials (Figure in vivo due to its sub-second time resolution, which permits detection of brief release events. This study paves the way for future studies using optogenetics to discern the role of dopamine transients in driving drug reinforcement and drug-seeking behaviors.Here, we show that somatic hyperpolarization using optogenetics is sufficient to suppress drug-evoked phasic dopamine transients. Specifically, by illuminating dopamine neurons that were selectively transfected with the inhibitory opsin NpHR, we robustly attenuated the occurrence of dopamine transients in NAc produced by co-administration of cocaine and raclopride. We used this pharmacological challenge as it is known to potently drive phasic dopamine release (Venton and Wightman, + rats used virus infusion coordinates that targeted medial VTA (Witten et al., In this study we recorded from NAc rostral shell. We chose this region as it exhibits a high degree of spontaneous and drug-evoked transient activity (Aragona et al., + rats, opsin expression has been shown to correlate with behavioral outcome (Witten et al., We observed suppression of dopamine release in all NpHR-expressing rats. This finding is consistent with cocaine and raclopride stimulating burst firing in dopamine neurons (Shi et al., We observed an increase in dopamine concentration and the probability of a dopamine transient immediately after termination of the laser in some rats, which could be characterized as an inhibition-induced rebound in dopamine concentration. This rebound response could reflect either a property of NpHR (e.g., change in chloride reversal potential after sustained channel opening; Raimondo et al., Several studies have assessed the contribution of cell body excitability on dopamine transients monitored in dopamine terminal regions. Sombers et al.  used intin vivo or evoke hyperpolarizing currents in dopamine neurons in an ex vivo slice preparation (Tan et al., A number of studies have used optogenetics to suppress firing of dopamine neurons either by directly targeting dopamine neurons with an inhibitory opsin (Tan et al., Optogenetic inhibition of dopamine cells increased immobility in the tail suspension test and reduced sucrose preference (Tye et al., de novo generation of dopamine transients is a key feature common to all abused drugs (Covey et al., In summary, somatic hyperpolarization of dopamine neurons is sufficient to suppress the occurrence of dopamine transients in terminal regions. As The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


A 43-year-old female patient presented with a swelling of 6-weeks duration on the lower lip . The sweWhat is the etiology of pyogenic granuloma?How does pyogenic granuloma present?What are the treatment options for this patient?What are the differential diagnoses?,2,1,3-2,3Pyogenic granuloma has been classified as a disorder of angiogenesis, although no single unifying hypothesis adequately explains the etiopathogenesis.1,2,5,3,4,7Pyogenic granuloma is relatively common with a worldwide distribution. A higher frequency is however observed in the second and third decade of life, with peak prevalence in women.1Management has 2 goals: diminution of the risk of recurrence and an improved cosmetic appearance. Several detailed reviews have demonstrated the application of the full spectrum of treatment options of which the standard is thought to be excision and primary closure.5,3,7Although pyogenic granuloma has distinct clinical features, the clinical diagnosis may often be difficult, due to lesions that appear similar.1Pyogenic granulomas are benign vascular proliferations commonly seen in young female adults. An exuberant vascular response to minor trauma and hormonal influences has been implicated. Acceptable esthetic result can be achieved with surgical excision, which, if adequate, should not lead to recurrence.


Twenty years after its discovery AIDS-KS lesions are characterized by proliferating KSHV-infected spindle cells, intense angiogenesis with erythrocyte extravasation, and inflammatory cell infiltration Identifying the KS progenitor is complex since KSHV infection causes transcriptional reprogramming and KSHV can infect many cell types due to broad expression of its entry receptors, the α3β5 integrin (ITGA3/ITGB5) and the EphrinA-receptor-2 (EPHA2). Thus, it is difficult to know whether the phenotypic markers of infected KS spindle cells correspond to those of the target cells, or are the consequence of KSHV's ability to reprogram host-cell transcription BCL-2 and A20KSHV encodes for several viral oncogenes, including 14 host homologues that carry the potential to induce all the malignant phenotypic characteristics—cancer hallmarks—of KS KSHV lytic expression includes genes that favor viral replication by affecting the DNA damage response, promoting survival, and evading the immune response. As a consequence, lytic genes can induce the following KS malignant phenotypes: (1) Immune evasion KSHV lytic genes may also favor reinfection of KS progenitors by inducing angiogenesis and inflammation that help to recruit un-infected endothelial-lineage and hematopoietic cells. vGPCR, a constitutively active homolog of the Groα and IL-8 receptors CXCR1/2, activates MAPKs, NFkB, and PI3K-AKT-mTOR pathways, leading to an angiogenic switch and endothelial cell immortalization caused by up-regulation of VEGF and its receptor-2 KDR (VEGFR2) The remarkable oncogenic potential of KSHV conflicts with the fact that KSHV infection culminates in KS in certain epidemiological settings such as HIV infection and AIDS Growth factor signaling pathways mediating KSHV-paracrine oncogenesis are attractive therapeutic targets in AIDS-KS . They caProgress in prevention and treatment of AIDS-KS is the consequence of advances in controlling HIV/AIDS as well as KSHV oncogenesis Advances in the molecular understanding of KS oncogenesis have provided a basis for the development of several targeted interventions  [35]. Ra


Electrospinning is a versatile technique, which can be used to generate nanofibers from a rich variety of materials. We investigate the variation of a zinc oxide (ZnO)-polyvinylpyrrolidone (PVP) composite structure in morphology by electrospinning from a series of mixture solutions of ZnO sol–gel and PVP. Calcination conditions for the crystallization of ZnO nanofibers and removal of the PVP component from the ZnO-PVP composite nanofibers were also studied. The progression of the ZnO-PVP composite structure from grains to nanofibers was observed, and ZnO-PVP nanofibers as thin as 29.9 ± 0.8 nm on average were successfully fabricated. The size of the resultant ZnO-PVP composite nanofibers was considerably affected by two parameters: the concentrations of zinc acetate and PVP in the precursor solution. The concentration of zinc acetate particularly influenced the diameter distribution of the ZnO-PVP nanofibers. The ZnO-PVP nanofibers could be subsequently converted into ZnO nanofibers of a pure wurtzite phase via calcination in air at 500°C for 2 h. One-dimensional zinc oxide (ZnO) nanostructures have attracted considerable attention within the last decade because of unique characteristics such as large aspect ratio, high electron mobility, and electrical and optical anisotropy ,2. TheirElectrospinning is a simple and versatile method along the solution-solid route for producing oxide nanofibers ,7-10. AlMw = 1,300,000, Aldrich, St. Louis, MO, USA) in ethanol was used for electrospinning [3COO)2 · 2H2O was first dissolved in a monoethanolamine (MEA)-2-methoxyethanol solution at room temperature. The molar ratio of MEA to zinc acetate was kept at 1.0, and the concentration of zinc acetate was 0.1 mol/L. The resultant mixture was stirred at 60°C for 30 min to obtain a transparent and homogeneous solution. Then an ethanol solution containing 0.2 g PVP was added to the ZnO sol–gel solution, and the mixture was loaded into a glass capillary with a 100-μm inner diameter at the blunt tip.In this work, a mixture of ZnO sol–gel solution and polyvinylpyrrolidone (PVP)  and applied to the solution through a copper wire in the glass capillary. In addition, an indium tin oxide (ITO)-coated glass substrate (25 mm × 25 mm) was placed perpendicular to the axis of the capillary at a distance of 10 cm from its tip as a counter electrode. This counter electrode was connected to the ground along with the high-voltage power supply.θ ranging from 20° to 80°.Three groups of samples were electrospun at 6.0 kV from the precursor solutions, which contained 0.1, 0.4, and 0.75 M zinc acetate, respectively. PVP solution was added into the precursor solution before electrospinning at concentrations varying from 0.02 to 0.14 g/mL for each group. A portion of the synthesized ZnO nanofibers were treated at 300°C in air for 10 min, and the others were calcined at 500°C in a programmable furnace for 2 h. Scanning electron microscope (SEM) images were taken using a field-emission SEM  operated at an accelerating voltage of 15 kV. The diameters of these fibers were quantitatively evaluated using their high-magnification SEM images. Transmission electron microcopy (TEM) images were taken using a Tecnai G2 20 microscope operated at 200 kV. The X-ray diffraction (XRD) pattern was recorded with a D/MAX Ultima III diffractometer (Cu Kα radiation) at a scanning rate of 0.02°/s in 2Figure Figure In order to analyze the effect of the precursor solution on the size of the resultant nanofibers quantitatively, we measured the diameter of the nanofibers from their high-resolution SEM images and plotted the mean of 50 measurements with a corresponding standard error for each sample Figure . For theIn summary, we have demonstrated that the diameter of electrospun ZnO-PVP composite nanofibers can be controlled in the range from hundreds of nanometers down to less than 30 nm. The effects of two key factors, the molar concentration of zinc acetate in the ZnO sol–gel solution and the concentration of PVP in the precursor solution, on the morphology and diameter of the electrospun fibers were discussed, and the calcination condition for generating pure crystalline ZnO nanofibers was also investigated. Pure wurtzite-phase ZnO nanofibers with a clear lattice image in the TEM observation were formed after calcination at 500°C for 2 h. We hope to apply these results to the manufacture of ultrathin ZnO nanofibers for solar cells with increased contacting area and better charge collection efficiency, which is currently underway in our laboratory. We believe that the diameter control method described here may extend the application of ZnO nanofibers to more diameter-dependent devices.ITO: indium tin oxide; MEA: monoethanolamine; PVP: polyvinylpyrrolidone; SEM: scanning electron microscope; TEM: transmission electron microcopy; XRD: X-ray diffraction; ZnO: zinc oxide.The authors declare that they have no competing interests.YJL fabricated the samples, performed the related characterization, and drafted the manuscript. TF and NK supervised the sample analysis and revised the manuscript. MT carried out the TEM measurement. All authors read and approved the final manuscript.


Aims: Myocardial ischemia can result in marked mitochondrial damage leading to cardiac dysfunction, as such identifying novel mechanisms to limit mitochondrial injury is important. This study investigated the hypothesis that inhibiting soluble epoxide hydrolase (sEH), responsible for converting epoxyeicosatrienoic acids to dihydroxyeicosatrienoic acids protects mitochondrial from injury caused by myocardial infarction.Methods: sEH null and WT littermate mice were subjected to surgical occlusion of the left anterior descending (LAD) artery or sham operation. A parallel group of WT mice received an sEH inhibitor, trans-4-[4-(3-adamantan-1-y1-ureido)-cyclohexyloxy]-benzoic acid  or vehicle in the drinking water 4 days prior and 7 days post-MI. Cardiac function was assessed by echocardiography prior- and 7-days post-surgery. Heart tissues were dissected into infarct, peri-, and non-infarct regions to assess ultrastructure by electron microscopy. Complexes I, II, IV, citrate synthase, PI3K activities, and mitochondrial respiration were assessed in non-infarct regions. Isolated working hearts were used to measure the rates of glucose and palmitate oxidation.Results: Echocardiography revealed that tAUCB treatment or sEH deficiency significantly improved systolic and diastolic function post-MI compared to controls. Reduced infarct expansion and less adverse cardiac remodeling were observed in tAUCB-treated and sEH null groups. EM data demonstrated mitochondrial ultrastructure damage occurred in infarct and peri-infarct regions but not in non-infarct regions. Inhibition of sEH resulted in significant improvements in mitochondrial respiration, ATP content, mitochondrial enzymatic activities and restored insulin sensitivity and PI3K activity.Conclusion: Inhibition or genetic deletion of sEH protects against long-term ischemia by preserving cardiac function and maintaining mitochondrial efficiency. Arachidonic acid (AA) is a polyunsaturated fatty acid found in the phospholipid domain of cell membranes. Activation of cytoplasmic phospholipase A2 and other enzymes trigger the release of AA, which is further metabolized into a vast array of lipid mediators. The predominant enzyme systems that metabolize AA are cyclooxygenase, lipoxygenase, and cytochrome P450 (CYP) monooxygenases generating prostanoids, leukotrienes, epoxidized, and hydrolylated metabolites, respectively  following cellular stress limiting mitochondrial dysfunction  and wild-type (WT) littermates are maintained at the University of Alberta  coronary artery as described . sEH activity was assessed using a soluble epoxide hydrolase assay kit assay .Non-invasive functional assessment was performed by transthoracic echocardiography using a Vevo 770 high-resolution imaging system with a 30 MHz transducer . Isoflurane (0.8% by anesthetic machine) was used to anesthetize the mice during the recordings. To assess changes in cardiac function, echocardiography was carried 1 day prior to MI (baseline) and 7 days post-MI. Left ventricular end-systolic diameter (LVESD) and end-diastolic diameter (LVEDD) were obtained from M-mode images, while left atrial size was obtained by M-mode imaging in the parasternal long axis view  in 0.1M sodium cacodylate buffer, dehydrated in an ethyl alcohol series, embedded with epoxy resin, and thermally polymerized as previously described , using established spectrophotometric techniques . Heart powders were homogenized and centrifuged at 15000 × g for 2 min and the resultant supernatant was assessed for ATP content. Standard curve for ATP and reaction mixture were prepared according the kit manual in a 96-well-plate and optical density (OD) was measured at 570 nm.Mitochondria were freshly isolated from hearts according to established protocols . Statistical significance was determined by one-way ANOVA with Bonferroni Baseline heart function in WT, tAUCB treated, and sEH null mice was similar among all groups Figure ; Table 1sEH protein expression was not altered following tAUCB treatment in either sham or post-MI hearts, while no expression was detected in sEH null hearts Figure . BaselinTo visualize the effect of ischemia on mitochondrial ultrastructure we assessed baseline and post-MI hearts using electron microscopy. Healthy and intact mitochondria were observed in the sham groups with no differences between WT, tAUCB, or sEH null mice. Seven days post-MI, we dissected the left ventricle into infarct, peri-, and non-infarct regions. EM images demonstrate that the mitochondrial ultrastructure of the infarct region in the sEH null group was significantly more preserved than the infarct regions of the WT and tAUCB treated groups. In the peri-infarct region, the mitochondrial content was more preserved than the infarct region in all the groups, moreover, mitochondrial damage was attenuated in tAUCB and sEH null mice compared to the WT group. The mitochondrial ultrastructure was not impacted in the non-infarct region of the three groups Figure .In order to maintain cardiac contractility and function, the heart needs a healthy pool of mitochondria to supply it with the energy required for contraction. We first quantified the abundance of key mitochondrial proteins in the non-infarct region where mitochondrial ultrastructure was preserved. Consistent with EM images, there was no significant difference in the protein content between any of the groups in either sham or post-MI for citrate synthase, succinate dehydrogenase or cytochrome C oxidase expression Figure . These oEnzymatic activities of the mitochondrial respiratory chain were assessed in non-infarcted regions of the heart where no damage in the mitochondrial ultrastructure was observed. No significant differences were observed in the enzymatic activities between sham WT, tAUCB, or sEH null groups Figure . HoweverConsidering sEH inhibition attenuated the loss of catalytic activity of key enzymes involved in ATP production, we next measured respiration in isolated mitochondria. To ensure respiration rates were not attributed to low substrate availability, malate, and glutamate were used to support basal respiration. WT post-MI groups showed a significant decrease in ADP-simulated respiration that was attenuated by inhibiting sEH with tAUCB or deletion in sEH null mice, which is reflected in the preserved respiratory control ratio (RCR). Enhancement in RCR was seen in the post-MI tAUCB and sEH null groups compared to WT mice Figure . ConsistEx vivo working hearts were used to investigate the effect of sEH inhibition on energy metabolism following MI. In the absence of insulin, the rates of glucose oxidation were similar between the experimental groups  and promoted cell survival  myocardium. Furthermore, inhibiting sEH preserved insulin sensitivity in post-MI hearts reflecting more optimal functioning cardiac metabolism thereby indicating activation of physiological recovery from ischemic insult.All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.This work was supported by an operating grant from the Canadian Institutes of Health Research (JS MOP115037). KJ and AT are supported by graduate studentship awards from Alberta Innovates Health Solutions . Partial support was provided by NIEHS RO1 ES002710 (BH).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


We demonstrate that metastable molecular assemblies transform into differently ordered structures either due to additional energy provided by thermal annealing or when the influence of intermolecular forces is increased by the enlarged amount of deposited molecules. Proper adjustment of molecular coverage and substrate temperature during deposition allows for fabrication of desired assemblies. Differences between PTCDA/TiO2(110) and PTCDA/TiO2(011) systems obtained through identical experimental procedures are discussed.Transformations of molecular structures formed by perylene-3,4,9,10-tetracarboxylic dianhydride (PTCDA) molecules on a rutile TiO Molecular self-assembly appears to be a very powerful and versatile tool for the formation of molecular structures and devices at the nanoscale. Thus, it continuously attracts much attention in the field of nanoscience and nanotechnology –7. An inAmong many different substrates that are used as templates for molecular growth, metal oxides are currently regarded as very promising supports. For example, titanium dioxide surfaces are exceptionally useful in various applications, including the catalysis, solar energy conversion, gas sensing and others –15. Merg2  crystallographic direction, i.e., surface rows, by a multiple of a surface unit cell dimension. The shifting distance seems to be accidental, and no correlation between the shifts of neighbouring molecular pairs is observed. Hence, the lines have a meandering distorted appearance. Nevertheless, along such a meandering line, one may distinguish pairs, triples and (rarely) larger numbers of molecules that locally form a straight line, adapting to a preferred crystallographic direction . The experiments demonstrated that the molecular structures could be changed by thermal annealing of the system and also by the amount of molecules. At low coverage, the molecules adsorb mainly as single entities at surface steps and surface defects at terraces. At moderate coverage, the molecules deposited at room temperature form meandering molecular lines, which are transformed into the ordered molecular layer either by mild thermal annealing (approx. 100 °C) or by increasing the amount of molecules (>0.85 ML). The ordered layer is destroyed by annealing at higher temperatures (ca. 150 °C) resulting in a completely disordered phase.We have performed STM measurements of molecular structures formed by PTCDA molecules on the surface of rutile TiOIn the analysed case, the self-assembly process is steered by thermal annealing, which provides additional energy, enabling equilibration. The method allows for switching from the formation of meandering, not well-organized chains to a well-ordered phase. Deposition of the molecules on a substrate maintained at an elevated temperature leads to the formation of similar structures. The likeness of these results indicates that the obtained structures are formed due to the equilibration of the system and not through kinetic trapping. At this point, it is worth comparing the behaviour of the molecules on the (110) surface with the other stable face of rutile titania, namely, the (011) surface. On the latter surface, post-deposition annealing does not lead at all to the formation of any ordered structures. The ordering is observed only if the molecules are deposited at the surface kept at a temperature of approximately 100 °C. Moreover, the temperature window is very narrow, and the deviation of the temperature by 20 °C leads to structure destruction. The ordered assemblies are obtained only for low coverages, where the formation of quasi-one-dimensional chains is observed . For lar2(110) surface and unordered structures on the (011) face. Additionally, molecules belonging to a different family of large polycyclic molecules, i.e., phthalocyanines (Pc), exhibit remarkably different behaviour on the two faces. The experiments showed that copper phthalocyanines (CuPc) form ordered layers on the (011) face and completely unordered assemblies on the (110) surface [Similar results were obtained for other small  molecules , which f surface . All of −10 mbar range. The preparation of samples was performed by the application of the standard procedure containing sputtering with argon ions and thermal annealing [The measurements were performed in an ultra-high vacuum (UHV) system containing preparation, analytical, radial distribution and microscope chambers. In the experiments, a commercially available variable-temperature STM (VT-STM), manufactured by Omicron Nanotechnology GmbH, was used. The base pressure in the UHV system was in the low 10nnealing . To obtannealing .


Energetic levels of C60 hybrids are resolved by in situ scanning tunnelling spectroscopy with an energy resolution in the order of 0.1 eV at room-temperature. An ultra-thin organic spacer layer serves to limit contact metal-molecule energy overlap. The measured molecular conductance gap spread is statistically benchmarked against first principles electronic structure calculations and used to quantify the diversity in electronic species within a standard population of molecules. These findings provide important progress towards understanding conduction mechanisms at a single-molecular level and in serving as useful guidelines for rational design of robust nanoscale devices based on functional organic molecules.Predicting the electronic framework of an organic molecule under practical conditions is essential if the molecules are to be wired in a realistic circuit. This demands a clear description of the molecular energy levels and dynamics as it adapts to the feedback from its evolving chemical environment and the surface topology. Here, we address this issue by monitoring in real-time the structural stability and intrinsic molecular resonance states of fullerene (C These arguments are valid in the case of relatively simple and short-length molecules60) have been actively explored as molecular anchor groups20222460 based complexes have helped understand the charge transport process in these systems. However, the experimental and theoretical studies on C60 dimers (C60—linker—bridge—linker—C60) report on structurally stable molecules and do not take into account the possibility of mixed electronic species, which has limited the interpretation of measured conductance values and charge propagation modes.To decipher the conductance spectrum of molecules requires an in-depth knowledge of molecular binding geometry, intermolecular interactions and access to unperturbed molecular energy levels. Bonding geometries in metal-molecule-metal junctions1234678116in situ (within the liquid medium) scanning tunnelling microscope (in situ STM)/spectroscope (in situ STS) setup3560 dimers in liquids is mainly because this class of molecular complexes is not compatible with vapor-phase deposition and by performing such measurements in a wide range of solvents, the role of the encompassing solvent on the molecular electronic structure and molecular structural stability can be verified. From real-space and time-elapsed STM studies we observe that in addition to the expected regular dimers there exists a small population of new molecular species of individual C60 components with a strikingly different electronic structure (verified using STS) in comparison to the regular dimer counterparts. This observation of a non-homogenous distribution of molecular electronic structures can explain the spread in the previously reported conductance values of fullerene anchor based molecular complexes21Previously, the structure of molecules and metal adatoms within an organic matrix has been visualized26272829303260 dimer molecules  surface by controlled deposition inside a liquid-cell. Previously, we demonstrated the application of an alkane (n-C30H62) molecular layer to electronically decouple adsorbed low-dimensional organics from the underlying metal surfacen-C14H30 spacer layer (for fabrication see Regular Cn-C14H30 adsorbed on Au(111). The mean molecular length and intermolecular spacing between the side by side packed n-C14H30 units is (1.5 ± 0.1) nm and ~0.4 nm, respectively, in good agreement with previous reports60 dimers (solublised in n-tetradecane solvent) were directly deposited onto a clean Au(111) surface also resulted in partial ordering of the alkanes. However, the alkane layer was not continuous over large sections (verified using in situ STM) as the alkanes enter into a direct energetic competition with the C60 dimers for adsorption onto the Au(111) surface. This justifies the deposition of C60 dimers onto a pre-formed rigid and homogeneous spacer layer  (−10 molecules/cm2) and molecule-gold adsorption energy of (−2.3 ± 0.3) eV/molecule is calculated, indicating a strongly adsorbed and tightly packed monolayer. The regular C60 dimer is well-resolved from the high-resolution in situ STM image . The mean molecular length value obtained from the in situ STM data is close to previous STM measurements taken in dry conditions (solvent evaporated after molecular deposition) on related C60 dimers on Au (111)Au (111) , an inteTM image  recordedTM image  when mea60 dimers adsorbed on n-C14H30 spacer layer coated Au(111) in a liquid medium. The local electronic interaction between a monolayer of n-C14H30 and Au(111) in liquids has been previously discussedn-tetradecane has been demonstrated to serve as a reliable liquid sheath model system in which tunnelling spectroscopic measurements can be performed on organic complexes without any electrical interference from the encompassing liquid304060 dimer is located (60 lobe and the feedback loop is opened at a fixed height above the molecule and the voltage is swept (−1 V to +1 V) while the current is recorded. The STM tip drift rate is ~1 nm/min in n-tetradecane solvent, with the feedback loop re-initiated between acquiring spectral data to ensure that the structure and position of the molecule remains unchanged after each spectroscopic reading at the different points marked as blue spheres in n-tetradecane solvent medium . These individual molecules were observed to form clusters with neighboring molecules for a short-period of time, after which they disentangle. The bottom most molecular configuration in 60 molecules in close proximity, confirmed by their intercage separation of ~1 nm when the actual intercage separation for regular C60 dimers is ~2.5 nm. In addition, the individual C60 units observed in several in situ STM images structurally resemble pristine C60 molecules but were observed to have contrasting electronic signatures  coated Au(111) surface which we measured previouslyInterestingly, imaging on separate regions within the same sample revealed the presence of isolated, single Cgnatures  when com60 anchors and are not actually pristine C60. Complementary standard chemical purity analytical tests also indicate that pristine, unfunctionalised C60 units are not present in the as-synthesized material . The possibility of the molecular backbone rupture during the landing of the molecules from liquid-phase onto solid surfaces, cannot be totally ignored. Such cracking of molecular backbone has been previously reported for large macromolecules and attributed to variations in the local interactions of the different segments of the molecule with the underlying surfaceBased on experimental evidence and control measurements see , we sugg60 dimers is also shown in the same panel (green histogram) for direct comparison between the different molecular species. We derive a mean conductance gap value (0.8 ± 0.2) eV for the individual molecules which is lower than the mean conductance gap of (1.1 ± 0.1) eV for the regular C60 dimers, and in agreement with the DFT computed HOMO-LUMO gaps.From the local point probe spectroscopic approach we observe a clear distinction between the electronic signatures for the regular dimers  and monoin situ profiling of the electronic structure, molecular structural stability and intermolecular interaction events occurring in the presence of liquid at room-temperature. The impact of such mixed electronic species warrants consideration when interpreting the information content from single channel peaks in molecular conductance histograms589101620Although cooperative effects between molecules has been suggested as a possibility when interpreting line shapes in conductance histogramsHow to cite this article: Nirmalraj, P. et al. Fingerprinting Electronic Molecular Complexes in Liquid. Sci. Rep.6, 19009; doi: 10.1038/srep19009 (2016).


Kaposi’s sarcoma (KS), an endothelial neoplasm, is associated with human herpes virus (HHV) -8 infection. KS has four clinical sub-types: Mediterranean/classic, African/endemic, human immunodeficiency virus (HIV) -associated/epidemic, and transplantation-related/iatrogenic. Immunosuppression is an important cofactor in KS process. Classic KS (CKS) is exceedingly rare in children and when occurs, it is much more disseminated than adults. The epidemic, HIV-associated and the iatrogenic forms of childhood KS are a result of a profound and acquired T-cell deficiency. To our knowledge, this is the first paediatric KS case report from Iraq. Our patient was showing an unusual aggressive course of the disease while receiving Valproic acid (VPA) of the potential immune-suppressive effect.A six-year-old Iraqi boy, who had cerebral palsy (CP) and epilepsy since the age of 9-months, had received VPA to control his seizures. He developed skin discoloration followed by nodules that disseminated proximally from the lower extremities to the groin, face, ears and oral cavity, and then he died from severe respiratory distress after 110 days from the disease evolution. KS diagnosis was proved by a skin biopsy. As the patient was of Arab-Asian ethnicity and was HIV-seronegative status, accordingly, his condition best fitted the classic form of KS. However, recent studies showed the link of VPA with the reactivation of HHV-8. Moreover, accumulated experimental and clinical data elucidated that VPA induces T-cell suppression. Given that there was a lack of facilities to perform the laboratory immunological diagnostic tests in Iraq, the VPA-induced effect on immunity in our case (iatrogenic KS) could not be evaluated.Our report demonstrates a rare, rapidly progressing paediatric KS case and highlights the possible role of the 5-years’ administration of VPA and its challenging effect on cellular immunity based on recent studies. Thus, VPA could have promoted the development of the KS in our patient. This report also recalls the need of paediatricians to consider KS especially when the skin lesion appears at the child’s foot even in countries outside the geographical map of the disease.The online version of this article (doi:10.1186/s12887-016-0653-3) contains supplementary material, which is available to authorized users. Kaposi’s sarcoma (KS), an endothelial neoplasm, was first reported by Moritz Kaposi in 1872 , 4. ClasOf note, KS is >100 times more common in immunosuppressed individuals. Loss of T-cell-mediated immune control allows HHV-8-infected cells to proliferate unchecked and thus the tumours to develop .The prevalence of HHV-8 varies geographically; with a seropositivity level exceeds 40 % in parts of Africa and South America, ranges from 30 %–40 % in the Mediterranean Basin, and drops to 20 % in non-endemic areas such as North America, Northern Europe, and most of Asia. However, the vast majority of HHV-8 infected individuals  do not develop KS. The epidemiology of HHV-8 infection and development of iatrogenic KS in the paediatric population has not been fully elucidated yet . UnfortuThe following is a paediatric KS case from Iraq who was showing an unusual aggressive course of the disease while receiving Valproic acid (VPA) of the potential immune-suppressive effect. To our knowledge this is the first paediatric KS case report from Iraq.A 6-year-old Iraqi boy of Arab-Asian ethnicity who had developed cerebral palsy (CP) with mental retardation and epilepsy after encephalitis at the age of 9 months. Since that time, he had been treated with oral VPA  to control the seizures. His family history was unremarkable apart from that his next older brother had acute lymphoblastic leukaemia and died due to severe infection a year and a half before the birth of this case of KS. Our patient was the youngest among 4 siblings of healthy second-cousin parents. The other 2 older siblings are healthy. Our patient suffered from recurrent respiratory tract infections and was hospitalized twice. The latest episode was on December 1st, 2013 when he was 6 years-old. Although he had middle lobe atelectasis, he responded well to a 1-week treatment with non-specific antibiotic and his chest roentgenogram showed improvement.One week after being discharged from the hospital, painless skin lesions appeared in the form of a bluish-purple plaque (blue-violet to black hue) on the middle and little toes of his left foot and extended to the upper lateral sole area Fig. . PhysicaIn January 2014, palpable bluish-purple nodules appeared on the left leg and then on the right leg. The skin discoloration extended to the plantar surface, and edema of the left foot became obvious Fig. , but perThe skin biopsy material was re-evaluated in Japan because of the lack of facilities for HHV-8 detection in Iraq. The results are presented in Fig. Given the accessible published literatures since 1960 excluding African, iatrogenic and HIV-associated KS, there were 36 paediatric KS cases of 15 years of age or younger including our case were identified. Of them, 32 had skin lesions and 4 had no skin lesion , 16–31. KS was diagnosed on the basis of skin biopsies demonstrating the presence of spindle cells in 90 % of cases. HIV was negative in all 26 examined cases, and HHV-8 was positive in 87.5 % of the examined cases. Within the collected series, 16 (64 %) of 25 cases with known outcome were reported as survivors, including two cases rescued by Hematopoietic stem cell transplantation, and five of the 16 survivors had coexisted identified immunodeficiency. The remaining 9 cases were reported dead, eight of them had visceral involvement and five of them died within < 6 months of the onset of the disease.In our patient, KS was suspected by the evolution from a macular stage, with characteristic colour, multifocal distribution and the presence of lesions on the toes. The diagnosis was made by the characteristic skin biopsy findings along with immunohistochemical detection of HHV-8.Regarding the risk factors in our patient, it is well known that the development of KS is a multifactorial process in which HHV-8 infection is a prerequisite and an immunosuppression is an important cofactor , 32, 33.CKS has been reported in two isolated studies among Iraqi adults: a 21-patient report over a 10 year period (1974–1984) and a more aggressive 20-case report over a shorter period (1999–2001) with a predilection for younger age . Taken tFinally, despite the scarcity of the KS and the shortage of the diagnostic tools in Iraq, diagnosis of KS was possible with multiple consultations and cooperation from inside and outside Iraq and then it was proved in Japan. In reference to KS subtype, our patient was of Arab-Asian ethnicity, and was HIV-seronegative, accordingly, his condition could be categorized as a classic form of KS; however, the iatrogenic VPA-induced-KS could not be excluded.Our report demonstrates one of the rare, rapidly progressing paediatric KS and highlights the possible role of the 5-years’ administration of VPA and its challenging effect on cellular immunity based on recent studies. Thus, VPA could have promoted the development of the KS in our patient. This report also recalls the need of paediatricians to consider KS especially when the skin lesion appears at the child’s foot even in countries outside the geographical map of the disease.CKS, Classic Kaposi’s sarcoma; CP, cerebral palsy; DU, depleted uranium; HHV-8, human herpes virus −8; HIV, human immunodeficiency virus; IFN-ɤ, Interferon-gamma; KS, Kaposi’s sarcoma; VPA, valproic acid


Molecular crowding plays a significant role in regulating molecular conformation in cellular environments. It is also likely to be important wherever high molecular densities are required, for example in surface-phase studies, in which molecular densities generally far exceed those observed in solution. Using on-surface circular dichroism (CD) spectroscopy, we have investigated the structure of a synthetic peptide assembled into a highly packed monolayer. The immobilized peptide undergoes a structural transition between α-helical and random coil conformation upon changes in pH and ionic concentration, but critically the threshold for conformational change is altered dramatically by molecular crowding within the peptide monolayer. This study highlights the often overlooked role molecular crowding plays in regulating molecular structure and function in surface-phase studies of biological molecules. Molecular crowding plays an essential role in the assembly and stability of many macromolecular complexes, for example, α-synuclein fibrils and the 14 molecules per cm2, –18 16–18In conclusion, surface-immobilized systems can provide unique insights into the effect of molecular crowding on the conformation of peptides and proteins in high-molecular-density environments, and biophysical tools are today available for measuring molecular conformation on-surface. Here, we used on-surface CD to study an immobilized exemplar peptide and show that molecular crowding, which results directly from immobilization, dramatically shifts the pH and ionic strength at which the peptides undergo a structural transition between random coil and α-helical conformation. Although the kinetics and thermodynamics governing the interaction between an immobilized protein and a ligand in solution are well established, our results show that interactions between proteins in an immobilized layer can also strongly influence molecular conformation and need to be considered, for example, using on-surface CD or complementary tools such as IR spectroscopy, in the design and interpretation of experimental studies involving immobilized molecular systems.


L-DOPA-induced dyskinesias (LID) remain a major problem of long-term therapy of Parkinson's disease. Levetiracetam, a new antiepileptic drug, has been shown to reduce LID, but the mechanisms underlying its effects are unknown. In this study, we assessed the effect of levetiracetam on key mediators of LID in rats with 6-hydroxydopamine (6-OHDA) lesions. Following chronic administration of L-DOPA , rats developed abnormal involuntary movements (AIMs), but co-administration of levetiracetam  with equivalent L-DOPA dosing significantly reduced AIMs scores in a dose dependent manner. The effects of levetiracetam were associated with changes in striatal expression of ΔFosB, phosphorylated extracellular signal-regulated kinases 1 and 2 (p-ERK1/2), and phosphorylated cAMP-regulated phosphoprotein of 32 kDa (p-DARPP-32). These data support that levetiracetam acts at multiple sites in the pathogenetic cascade of LID, and that further understanding of these actions of antiepileptics may contribute to developing new LID therapies. Dopamine replacement therapy with L-3,4-dihydroxyphenylalanine (L-DOPA), still the most effective treatment for Parkinson's disease (PD), is commonly associated with disabling long-term motor complications, including response fluctuations and L-DOPA-induced dyskinesias (LID) . LID are1 receptor-mediated responses in the direct striatal output pathway leading to imbalance of striatal outputs -DARPP-32 were found to correlate with the severity of dyskinesia in rodents [The exact pathogenetic mechanisms underlying LID are still unclear; however, the evidence indicates that exogenous L-DOPA given with a pulsatile regimen is converted to dopamine irregularly in the remaining dopamine terminals and neighbor cells leading to nonphysiologic dopamine release in the striatum and thereby fluctuating stimulation on postsynaptic dopamine receptors –21. This pathway , 22. D1  rodents , and del rodents , 8. Foll rodents . Other i rodents . Striata rodents , 13, 25. rodents .Our data showed that levetiracetam had specific effects on striatal ΔFosB, p-DARPP-32, and p-ERK1/2, and these molecular effects were parallel to the LID changes. Also both the molecular and behavioral effects were dose-dependent. Levetiracetam is a new type of antiepileptic drug, which binds to ion channels and specifically to the presynaptic vesicle protein SV2A participating in neurotransmitter release. It has been proved efficient as adjunctive therapy in patients with partial seizures . In mechSeveral open-label clinical trials have confirmed efficacy of levetiracetam for the management of levodopa-induced dyskinesias in PD , 31. In In summary, we have demonstrated that Levetiracetam can attenuate AIMs dose-dependently in 6-hydroxydopamine lesioned rats. Levetiracetam reverses the striatal ΔFosB overexpression and reduces the striatal levels of phosphorylated ERK1/2 and DARPP-32, associated with the improvement of LID. This study supports that levetiracetam acts at multiple sites in the pathogenetic cascade of LID and that further understanding of these actions of antiepileptics may contribute to develop new LID therapies.


The influence of the applied voltage on these three types of coaxial nozzles was studied. Specific surface area, pore size diameter, crystallinity, and degree of graphitization of the hollow and mesoporous structures of carbon nanofibers obtained after carbonization of the as spun PMMA/PAN nanofibers were characterized by BET analyses, X-ray diffraction, and Raman spectroscopy in addition to the conductivity measurements. It was found that specific surface area, crystallinity, and graphitization degree of the HCNFs affect the electrical conductivity of the carbon nanofibers.Hollow carbon nanofibers (HCNFs) were prepared by electrospinning method with several coaxial nozzles, in which the level of the inner nozzle-end is adjustable. Core/shell nanofibers were prepared from poly(methyl methacrylate) (PMMA) as a pyrolytic core and polyacrylonitrile (PAN) as a carbon shell with three types of normal (viz Carbon nanofibers (CNFs) have attracted considerable attention in recent years because they have superior mechanical strength and excellent electronic properties , 2 due tSome researchers studied the method to increase the specific surface area by fabrication of the nanofibers with a hollow structure –16 or inMany studies have been focused on the enhancement of the surface area or the improvement of the morphology of the electrospun nanofibers by improving production process , treatmeMany researchers paid effort to clarify the influence of the electrospinning voltage on the properties of the obtained fibers. However, the affection of the applied voltages on the diameter of electrospun nanofibers is a little controversial. Several researchers found that a higher voltage could facilitate an increment of fiber diameters, which may be caused by the faster extraction rate , 29. SomFor the coaxial electrospinning, the effect of applied voltage might align in the same trend. Many research groups demonstrated that when the applied voltage is increased, the diameter of the fibers was decreased. In the meanwhile, the core diameter of electrospun core/shell fibers was also decreased , 36. VinMw: 996,000 g mol−1, Sigma-Aldrich) and poly(acrylonitrile)  were used as thermally degradable core precursor and carbonizing shell precursor, respectively. The polymers were dissolved separately in N,N-dimethylformamide , where the concentration of PMMA and PAN were 10 and 12 wt%, respectively. Composite nanofibers of PMMA/PAN were prepared by in-house designed coaxial nozzle electrospinning which adjustable inner nozzle-end for 1 mm inward and outward direction compared to the outer nozzle. To study the influence of inner/outer nozzle-end level, the inner nozzle was set to three levels as shown in Fig. −1, respectively. The applied voltage was varied from 10 to 25 kV to study its effect on the morphologies of the obtained PMMA/PAN composite nanofibers, as spun PMMA/PAN composite nanofibers were thermally treated for oxidative stabilization for 30 min after increasing temperature to 250 °C at a rate of 5 °C min−1 in air, carbonized for 1 h at 800 °C in nitrogen, and finally heated at 1000 °C in nitrogen for another hour to obtain the HCNFs. For comparison, the normal CNFs were also prepared by electrospinning of PAN solution (12 wt%) using single nozzle  with a flow rate of 1.0 mL h−1 under the same electrospinning conditions. The stabilization and carbonization process was also carried out under the same conditions as the HCNFs.Poly(methyl methacrylate) . The Brunauer-Emmet-Teller (BET) method was used to determine the specific surface area (SSA), the pore volume and the pore size of the HCNFs and CNFs. The crystallinity and the degree of graphitization were investigated by X-ray diffraction analysis  and Raman spectroscopy . From C(002) peak of XRD spectra, we can calculate the interlayer spacing (c/2) of the carbon nanofiber by Bragg’s law and the crystallite size along the c-axis (Lc) by Scherrer’s equation. The graphitization degree of the carbon nanofiber was determined by Id/Ig ratio, which is the ratio between the peak intensity of the disordered carbon (1355 cm−1) and graphitic carbon (1575 cm−1) from Raman spectrum [a-axis (La) then were calculated from Id/Ig ratio.The morphologies of the samples were observed by field emission scanning electron microscopy . High-resolution images were obtained from transmission electron microscopy  operated at 200 kV. The physical adsorption properties were determined by Nspectrum , the cryMw: 7300∼9300, Wako) into 0.6 mL of ethanol/water. The HCNF paste was spread on an ITO-coated glass substrate  by the doctor-blade technique using adhesive tape masking to control the thickness. The concise layer thickness was measured by cross-sectional SEM images. An aluminium electrode (thickness 100 nm) was thermally evaporated on the samples, and then the current density-voltage (J-V) characteristic  is measured to obtain the conductance  values. Then the conductance value was used to calculate the electrical conductivity of the samples.The conductivity measurement was carried out using two-electrode cells. A paste of grinded carbon nanofibers were prepared by mixing 0.1 g of HCNFs and 0.04 g of polyethylene glycol  were obtained from the coaxial nozzle electrospinning at 15 kV. At a lower applied voltage of 10 kV, the injection was occurred after an electrospinning solution was agglomerated at the end of the nozzle, retarded for a while until the electrostatic force was strong enough to inject the solution jet. The initial agglomerated shape may cause some difficulties for the solution jet to form the continuous compound of Taylor’s cone at the end of the nozzle. Therefore, the obtained nanofibers show a non-uniform beaded fiber morphologies and some nanofibers were fused together as a bundle of fibers. For the coaxial electrospinning at higher voltage of 15–25 kV, composite nanofibers with no beads and more uniform morphologies were obtained. However, when the applied voltage was increased greater than 20 kV, the extraction rate of the precursor solution was too high and the solution was collected and accumulated at the collector before the evaporation of the solvent. Therefore, wet nanofibers were fused onto the aluminium foil collector or fused together resulting in the bundle morphologies. From the obtained results, we used the applied voltage at 15 kV for further experiment.For comparison, the morphologies of as spun PAN nanofibers from single nozzle electrospinning were also observed by SEM as shown in Fig. The TEM images of the as spun PMMA/PAN composite nanofibers obtained from coaxial electrospinning with different inner nozzle-end levels were shown in Fig. After electrospinning, the as spun nanofibers were stabilized and carbonized to obtain the carbon nanofibers. In this process, the as spun nanofibers were stabilized in oxygen atmosphere for a greater stability to sustain at higher temperature . When inThe SEM images of the surface of the CNFs and the HCNFs after the stabilization and carbonization process show some rough surface as shown in Fig. The hollow morphologies were observed clearer in the TEM images as shown in Fig. 2 adsorption measurement.As shown in Table 2 adsorption isotherms . The BET surface area, total pore volume and average pore diameter of the HCNFs and CNFs are summarized in Table 2 g−1, which is 1.69 times larger than that of the CNFs from single nozzle electrospinning. This value is also larger than those of the hollow carbon nanofibers fabricated by the same bi-component system of PMMA and PAN reported previously [The Nrms Fig.  show thaeviously .Fig. 6N2θ around 24–26° indicate graphitic ordered structure of carbon. All samples show very board C(002) peak as well as large interlayer distance (c/2) than graphitic carbon (0.335 nm) and turbostratic carbon (0.344 nm) [Figure .344 nm) . This su.344 nm)  since itId/Ig ratio and the increase in crystallite size (both Lc and La). Increase of the graphitization degree and crystallite size of the HCNFs from normal coaxial nozzle may arise from the smoother flow of both core and shell polymer solutions, which were pulled out from the same comparative levels of nozzle-end configuration.Among all samples, the HCNFs from normal coaxial nozzle show the higher C(002) peak intensity, 2.11 and 1.21 times than that of the HCNFs from inward and outward coaxial nozzle, respectively. The increase of C(002) peak intensity of the HCNFs from normal coaxial nozzle suggests the better orientation of the graphitic plane as compared to the HCNFs from inward and outward coaxial nozzle. Decrease of C(002) peak broadening (FWHM) is reflected by the decrease of The electrical conductivity of the obtained HCNFs and CNFs are shown in Table −1, respectively) almost two orders of magnitude than that of the HCNFs produced from the inward coaxial nozzle system (376 S m−1). The high electrical conductivity of the HCNFs produced from the outward and normal coaxial nozzle may be ascribed to different reasons. For the HCNFs produced from the outward coaxial nozzle, the major contribution is its high specific surface area to volume ratio  are quite lower as compared to the previously reported results. For examples, Sebastian et al. [−1. The higher electrical conductivity is mainly influenced by its higher orientation of the graphitic planes, which they suggested to be increased by an increment of synthesis temperature of the carbon nanofibers. The great effect of graphitic plane orientation also reported by Maita et al. [Ig/Id). Based on the abovementioned facts, we can imply that an increase of the electrical conductivity comes from the mixed contribution of the graphitic plane orientation and the surface area or the porosity of the HCNFs.Among the hollow nanofibers, the HCNFs produced from the outward and normal coaxial nozzle show higher electrical conductivity (675 and 648 S me system 76 S m−1.n et al.  reporteda et al.  that the2 g−1, which is 1.69 times larger than that of the CNFs from single nozzle electrospinning. The XRD peaks and Raman spectrum of the HCNFs produced from normal coaxial nozzle electrospinning exhibit much higher crystallinity and graphitization degree as compared to the inward and outward coaxial nozzle systems. The high electrical conductivity of the HCNFs obtained from the outward and normal coaxial nozzle systems confirm that the electrical conductivity were affected by both of the porosity and the graphitization degree of the nanofibers.We have clarified the influence of the applied voltage on the coaxial electrospinning of the PMMA/PAN composite nanofibers with different levels of inner nozzle-end and studied the effect of the levels of inner nozzle-end on the morphologies and physical properties of the obtained HCNFs. By using the outward coaxial nozzle system, we could produce the HCNFs with highest specific surface area of 278.56 m


Caenorhabditis elegans, the dopamine transporter DAT-1 regulates synaptic dopamine (DA) signaling by controlling extracellular DA levels. In dat-1(ok157) animals, DA is not taken back up presynaptically but instead reaches extrasynpatic sites, where it activates the dopamine receptor DOP-3 on choligeneric motor neurons and causes animals to become paralyzed in water. This phenotype is called swimming-induced paralysis (SWIP) and is dependent on dat-1 and dop-3. Upstream regulators of dat-1 and dop-3 have yet to be described in C. elegans. In our previous studies, we defined a role for HLH-17 during dopamine response through its regulation of the dopamine receptors. Here we continue our characterization of the effects of HLH-17 on dopamine signaling. Our results suggest that HLH-17 acts downstream of dopamine synthesis to regulate the expression of dop-3 and dat-1. First, we show that hlh-17 animals display a SWIP phenotype that is consistent with its regulation of dop-3 and dat-1. Second, we show that this behavior is enhanced by treatment with the dopamine reuptake inhibitor, bupropion, in both hlh-17 and dat-1 animals, a result suggesting that SWIP behavior is regulated via a mechanism that is both dependent on and independent of DAT-1. Third, and finally, we show that although the SWIP phenotype of hlh-17 animals is unresponsive to the dopamine agonist, reserpine, and to the antidepressant, fluoxetine, hlh-17 animals are not defective in acetylcholine signaling. Taken together, our work suggests that HLH-17 is required to maintain normal levels of dopamine in the synaptic cleft through its regulation of dop-3 and dat-1.In  Caenorhabditis elegans and other multicellular organisms, basic helix-loop-helix (bHLH) proteins coordinate a number of developmental events, including myogenesis  and D-2 like receptors (DOP-2 and DOP-3) that are positioned either pre-, post-, or extra-synaptically. Unbound dopamine is taken back up into the presynaptic cell via reuptake by the dopamine transporter DAT-1.In vertebrates and invertebrates, dopamine signaling is associated with motivation, recognition and reward, memory and adaptation, hormonal regulation, and motor control. In humans, imbalances in dopamine signaling are associated with many neurological diseases, including Parkinson disease, Alzheimer disease, ADHD, and substance abuse  animals to endogenous and exogenous dopamine. The hlh-17(ns204) animals also have reduced levels of the dop-3 and dop-1 mRNAs and phenocopy dop-3 hypomorhs  animals. Furthermore, hlh-17(ns204) animals display swimming-induced paralysis (SWIP) behavior in water that is an intermediate between the behavior in dat-1 animals and in wild-type animals and that is enhanced by treatment with the dopamine reuptake inhibitor, bupropion. We show that a null allele of dop-3 completely suppresses the SWIP phenotype of hlh-17 animals, supporting previous data that HLH-17 acts upstream of DOP-3. Surprisingly, the SWIP phenotype of hlh-17 animals is unaffected by treatment with the VMAT inhibitor reserpine or with the serotonin reuptake inhibitor, fluoxetine; however, this unresponsiveness is not due to reduced acetylcholine signaling. Taken together, our results suggest that HLH-17 influences extracellular dopamine levels in C. elegans, in part by its regulation of the dopamine receptors and the dopamine transporter.Here we continue our characterization of the role of N2); RM2702 [dat-1(ok157)]; OS2649: [hlh-17(ns204)]; and LX705 [dop-1 (vs100dop-3 (vs106)) ]. OS2649 was a gift from Dr. S. Shaham. The strains CMJ2003  and CMJ2004  were generated using traditional crossing techniques and the genotypes were confirmed by PCR. To generate CMJ2004, hlh-17(ns204) males were crossed with dop-1(vs100) dop-3(vs106) hermaphrodites, and the F1 males were backcrossed to dop-1(vs100) dop-3(vs106). F2 hermaphrodites were separately cloned, and their progeny were genotyped by PCR. The strain CMJ2005  was generated by crossing CMJ2003 males with CMJ2004. F1 hermaphrodites were separately cloned, and their progeny were genotyped by PCR for hlh-17 and dat-1. The progeny of hermaphrodites that were confirmed to be homozygous for both hlh-17 and dat-1 were then subcloned and their progeny were screened for homozygosity for dop-3 by PCR and for rescue of SWIP behavior.The following strains were used in this study: wild-type: Bristol strain , and 850 bp of the sequences coding for green fluorescent protein (GFP). The GFP sequences were amplified from pPD95.67 (a gift from A. Fire) using serial overlap PCR. Transgenic lines to rescue loss of hlh-17 were produced by microinjecting the final PCR product (cmjEx22) into hlh-17(ns204) animals, along with the pCFJ90 [Pmyo-2::mCherry::unc-54utr] co-injection marker, using standard microinjection techniques(hlh-17(ns204); cmjEX22, pCFJ90(Pmyo-2::mCherry::unc54utr)].The transgene, cmjEx22, is a 6.2-kb genomic fragment consisting of 2 kbp upstream of the SWIP, basal slowing response, and dopamine paralysis. All three lines were able to at least partially rescue each of the phenotypes tested; however, the degree of rescue for each line was specific to the phenotype tested.Three separate lines  were tested for rescue of OP50 at 20° using standard methods and synchronized cultures were prepared by hypochlorite treatment of gravid adults, as previously described  containing escribed . The folgpd-3) (Ce02616909_gH) as the endogenous control. The probe sets used were: hlh-17(Ce02616669_m1); dat-1(Ce02450896_g1); cat-1(Ce02495610_m1); mod-5 (Ce02415245_m1); dop-1 (Ce02494345_m1); dop-2 (Ce02479824_m1) dop-3(Ce02496462_m1); lev-8 (Ce02501240_g1); and unc-43 (Ce02458977_m1). Gene expression assays were performed in triplicate for at least three biological replicates.Synchronized populations were collected at the L4 stage, pelleted, and frozen at −80°. Total RNA, cDNA synthesis, and real-time PCR were performed as previously described , except SWIP, approximately 10 L4-stage animals were placed in 150 µL of water in a single well of 48-well tissue culture plate . After 20 min, animals were categorized as paralyzed if they failed to exert the normal thrashing behavior within a 20-sec time frame , fluoxetine , and bupropion ] and then analyzed in water. All inhibitors were obtained from Selleckchem. Aldicarb-induced paralysis and levamisole-induced paralysis assays were conducted using standard protocols  animals and that hlh-17(ns204) animals phenocopy those carrying loss-of-function alleles of dop-3 (hlh-17(ns204) and dop-3(vs106) animals than wild-type animals were paralyzed after 40 min of exposure to 10 mM of exogenous DA, and both well-fed hlh-17(ns204) animals and well-fed dop-3(vs106) animals failed to exhibit the basal slowing response (BSR) when encountering a bacterial lawn. In this study, we used an extragenic, translational reporter for hlh-17 to rescue the dopamine paralysis and basal slowing phenotypes of transgenic hlh-17(ns204) animals. This reporter was able to restore dopamine sensitivity and to enhance BSR, showing that the previously reported phenotypes are indeed a result of loss of HLH-17 ; dop-3(vs106) are not significantly different from the resistance and slowing response phenotypes of dop-3(vs106) and hlh-17(ns204) animals . Additionally, dopamine receptor genes are expressed in mammalian glial cells  and the aromatic amino acid decarboxylase (bas-1), were not affected by loss of hlh-17. This suggested that the presynaptic synthesis of dopamine is not compromised in hlh-17(ns204) animals. Additionally, exogenous dopamine failed to repress egg-laying in naive hlh-17(ns204) animals; however, exogenous dopamine was able to repress the stimulation of egg-laying by the neurotransmitter, serotonin (hlh-17(ns204) animals, this result suggested that some ability of hlh-17(ns204) animals to respond to exogenous dopamine may be mediated by the binding of the neurotransmitter to other non-dopaminergic receptors. For example, dopamine can bind with low affinity to a number of the neurotransmitter receptors involved in serotonin-stimulated egg-laying, including MOD-1, SER-1, SER-2, and SER-7 , cat-1, and the dopamine reuptake transporter, dat-1, in hlh-17(ns204) animals. As shown in dat-1, but not cat-1, mRNA levels, are decreased in hlh-17(ns204) animals. We also found that the mRNA levels for the dopamine receptor genes, dop-1, dop-2, and dop-3, are downregulated in L4-stage animals, confirming that the decreased levels previously reported in L1-stage animals  animals synthesize and release normal levels of dopamine, but produce less DAT-1, then they would be less efficient than wild-type animals at clearing extrasynpatic dopamine from the synaptic cleft. To test this hypothesis, we conducted SWIP assays with wild-type, hlh-17(ns204), and dat-1(ok157) animals. As reported previously (dat-1(ok157) animals, but not wild-type animals, have a strong SWIP response after 20 min in water. The SWIP response of hlh-17(ns204) animals was an intermediate response, with approximately 40% of the animals becoming paralyzed after 20 min in water. This phenotype was rescued by transgenic expression of HLH-17. The result suggests that loss of HLH-17 compromises the ability of mutant animals to clear dopamine from the synaptic cleft and could be interpreted as representing a slight, rather than complete, loss of dat-1 activity.Like the mammalian VMATs, SWIP phenotype seen in dat-1 animals is completely rescued by loss of DOP-3 (SWIP response of hlh-17(ns204) animals, which is an intermediate of the responses of wild-type and dat-1 animals, may be the result of having decreased levels of both dop-3 and dat-1. To test this hypothesis, we compared the SWIP phenotypes of hlh-17(ns204); dat-1(ok157) animals and of hlh-17(ns204); dop-3(vs106) animals with those of dat-1(ok157) and dop-3(vs106) animals, respectively. As shown in dat-1 activity enhanced the SWIP response of hlh-17(ns204) animals, whereas complete loss of dop-3 activity significantly decreased the SWIP response. Furthermore, the SWIP phenotypes of hlh-17(ns204); dop-3(vs106) animals and hlh-17(ns204); dop-3(vs106); dat-1(ok157) animals were not significantly different from that of dop-3(vs106) animals . Interestingly, loss of hlh-17 and dat-1 appears to be an additive effect: a comparison of the differences of the means shows that the difference for wild-type hlh-17vs. ; dat-1 is equal to the sum of the differences for wild-type hlh-17vs.  and wild-type dat-1vs. . These results underscore the dependence of the SWIP phenotype on DOP-3. Furthermore, the results suggest that the SWIP response is not mediated solely through dat-1, and that hlh-17 may affect the SWIP phenotype through both dat-1-dependent and dat-1-independent mechanisms. A dat-1-independent, dop-3-dependent mechanism for the SWIP phenotype is consistent with the results of a previously reported forward genetics screen  animals are less sensitive to exogenous dopamine, a result that is consistent with reduced dop-3 activity. The results from assays for BSR and SWIP, both of which rely on normal synthesis and release of endogenous dopamine from presynaptic neurons, suggest that hlh-17(ns204) animals produce normal amounts of dopamine but are deficient in the ability to transport the dopamine. This result is also consistent with reduced dop-3 activity. Likewise, a failure in the ability to transport dopamine from the synaptic cleft is consistent with reduced dat-1 activity, as is the SWIP phenotype of hlh-17(ns204) animals. From these results, we conclude that HLH-17 functions to control extrasynpatic dopamine levels, in part by its regulation of dop-3 and dat-1.Our results from the dopamine paralysis assays and the egg-laying assays suggest that SWIP behavior of hlh-17(ns204) animals occurs because these animals still produce a small amount of functional DAT-1, and that treatment with bupropion would increase SWIP in hlh-17(ns204) animals. As expected, pretreatment of hlh-17(ns204) animals with bupropion increased their SWIP response to that of untreated dat-1(ok157) animals (dat-1 expression is reduced but not completely eliminated in hlh-17(ns204) animals. It has been shown previously that SWIP can be rescued in dat-1(ok157) animals by pretreatment with the dopamine antagonist reserpine (SWIP responses of dat-1(ok157) animals but did not affect SWIP in wild-type animals or in hlh-17(ns204) animals. This result was unexpected because cat-1 mRNA levels are not affected in hlh-17(ns204) animals; however, others have reported reserpine insensitive mutants that show SWIP behavior in a dat-1-dependent manner (SWIP in dat-1(ok157) animals, hlh-17(ns204); dat-1(ok157) animals, and hlh-17(ns204); dat-1(ok157); dop-3(vs106) animals , and dat-1(ok157) animals after exposure to fluoxetine. Fluoxetine blocks the function of SERT/MOD-5, the serotonin (5HT) reuptake transporter  animals. These results can be explained by the action of fluoxetine, which is known to increase extracellular concentrations of dopamine  animals were insensitive to fluoxetine, although they have normal levels of mod-5 mRNA  animals.To test the possibility that the mRNA see  and respmRNA see . FluoxetSWIP response of hlh-17(ns204) animals is insensitive to both reserpine and fluoxetine because HLH-17 influences the activity of C. elegans biogenic amines in a manner that, with the exception of dopamine, does not involve the regulation of genes directly involved in neurotransmitter synthesis, packaging, or transport. A more attractive, alternative possibility is that HLH-17 influences acetylcholine release, as the phenotypic effects of both reserpine  animals (It is possible that the hlh-17(ns204) animals. Aldicarb is an acetylcholinesterase inhibitor and thereby increases the concentration of acetylcholine in the neuromuscular junction. Animals with reduced acetylcholine release are resistant to aldicarb-induced paralysis, whereas those with increased acetylcholine release are more sensitive (hlh-17(ns204) animals are more sensitive to aldicarb than wild-type and dat-1(ok157) animals . This result is consistent with the weak effects of the dop-3(v106) mutation on aldicarb sensitivity that was previously reported, and suggests that acetylcholine release is otherwise normal in hlh-17(ns204) animals. We also found that hlh-17(ns204) animals are more sensitive to levamisole (P = 0.0002), a cholinergic agonist that binds selectively to acetylcholine receptors in body-wall muscles  animals. Interestingly, our microarray data indicated that the gene encoding the calcium/calmodulin-dependent protein kinase UNC-43 is also upregulated. Mutants carrying gain-of-function alleles of unc-43 have previously been reported to have increased resistance to fluoxetine. As shown in unc-43 and lev-8 are increased in hlh-17 animals, whereas the level of mod-5, a gene that was not differentially affected in our microarray analysis, remained unaffected. To our knowledge, loss of dopamine receptor activity, in particular dop-3, has not been tested; however, animals that are defective in dopamine synthesis display normal sensitivity to levamisole (hlh-17(ns204) animals, and that the resistance to reserpine and fluoxetine may be mediated through other genes in the HLH-17 transcriptional network.We used aldicarb and levamisole sensitivity assays to examine acetylcholine release and acetylcholine reception, respectively, in ensitive . As show muscles . We are vamisole . Taken tC. elegans, HLH-17 is an Olig homolog that is expressed in sheath cells of the dopaminergic neurons; however, this protein has no known role in glial cell specification, neurite extension, or axon guidance  animals have reduced mRNA levels for dat-1, dop-3, dop-2, and dop-1 but maintain normal levels of cat-1 and cat-2. Second, the SWIP response of hlh-17(ns204) animals is consistent with reduced levels of dat-1 and dop-3 and is rescued when dop-3 activity is completely eliminated. Third, hlh-17(ns204) animals are not defective in acetylcholine release and, in fact, show an increased sensitivity to aldicarb that is consistent with the increased acetylcholine release that occurs in animals with reduced dop-3 activity.The Olig sub-family of bHLH transcription factors influences the specification of oligodendrocytes, myelin formation, and axon pathfinding of motor neurons in both invertebrates and vertebrates . In C. eDrosophila, for example, the bHLH gene, lethal of scute, is required for cell-specific transcription of the dopaminergic H-cell neuron of the ventral nerve cord and for specification of the non-midline dopaminergic neurons  animals is enhanced by pre-treatment with bupropion, an antidepressant and DAT inhibitor that is used to treat ADHD in adults and children (hlh-17(ns204) for this purpose.Interestingly, the


We study charge and energy transfer in two-site molecular electronic junctions in which electron transport is assisted by a vibrational mode. To understand the role of mode harmonicity/anharmonicity in transport behavior, we consider two limiting situations: (i) the mode is assumed harmonic, (ii) we truncate the mode spectrum to include only two levels, to represent an anharmonic mode. Based on the cumulant generating functions of the models, we analyze the linear-response and nonlinear performance of these junctions and demonstrate that while the electrical and thermal conductances are sensitive to whether the mode is harmonic/anharmonic, the Seebeck coefficient, the thermoelectric figure-of-merit, and the thermoelectric efficiency beyond linear response, conceal this information. Molecular electronic junctions offer a rich playground for exploring basic and practical questions in quantum transport, such as the interplay between electronic and nuclear dynamics in nonequilibrium situations. Theoretical and computational efforts based on minimal model Hamiltonians are largely focused on the Anderson impurity dot model which consists a single molecular electronic orbital directly coupled to biased metal leads, as well as to a particular vibrational mode . Since tIn this work, we focus on a different class of molecular junctions as depicted in This model is related to the original Aviram–Ratner construction for a donor–acceptor molecular rectifier . Thus, wRecently, Erpenbeck et al. had provided a thorough computational study of transport characteristics with nondiagonal  as well as diagonal  electron–vibration interactions . Here, iMeasurements of charge current and electrical conductance in single molecules hand over detailed energetic and dynamical information . ComplemWhat information can linear and nonlinear thermoelectric transport coefficients reveal on molecular junctions? Specifically, can they expose the underlying electron–phonon interactions and the characteristics of the vibrational modes participating in the process? Focusing on the challenge of efficient thermoelectric systems, how should we tune molecular parameters to improve heat to work conversion efficiency? These questions were examined in recent studies, a non-exhaustive list includes –1425–36.14We focus here on the effect of vibrational anharmonicity on thermoelectric transport within the D–A model. To explore this issue, two limiting variants of the basic construction are examined, as displayed in The complete information over transport behavior is contained in the respective cumulant generating functions, which we provide here for the HO and the AH models, valid under the approximation of weak electron–vibration interactions. From the CGFs, we derive expressions for charge and heat currents, and study the linear and nonlinear thermoelectric performance of the junctions. Focusing on the role of vibrational anharmonicity, we find that while it significantly influences the electrical and thermal conductances, nevertheless in the present model it does not affect heat-to-work conversion efficiency. and , respectively) is assisted by a vibrational mode. The total Hamiltonian is written asWe consider a two-site junction, where electron hopping between the D and A electronic states  is a fermionic creation (annihilation) operator. The electronic Hamiltonian (Hvib+ Hel−vib) can be diagonalized and expressed in terms of new fermionic operators al and ar,The molecular electronic states of energies εThe molecular operators can be expanded in the new basis as,l,r coefficients satisfy −1 is the Fermi–Dirac distribution function of the ν = L,R lead. The properties of the molecular junction are embedded within the spectral density functions, peaked around the molecular electronic energies εd,a with the broadening ΓL,R satisfying, e.g., ,The rates d,a 14] we de