N-substituted-4-(pyridin-4-ylalkyl)piperazine-1-carboxamides and related compounds as Leishmania CYP51 and CYP5122A1 inhibitors.

CYP5122A1, an enzyme involved in sterol biosynthesis in Leishmania, was recently characterized as a sterol C4-methyl oxidase. Screening of a library of compounds against CYP5122A1 and CYP51 from Leishmania resulted in the identification of two structurally related classes of inhibitors of these enzymes. Analogs of screening hit N-(3,5-dimethylphenyl)-4-(pyridin-4-ylmethyl)piperazine-1-carboxamide (4a) were generally strong inhibitors of CYP51 but were less potent against CYP5122A1 and typically displayed weak inhibition of L. donovani promastigote growth. Analogs of screening hit N-(4-(benzyloxy)phenyl)-4-(2-(pyridin-4-yl)ethyl)piperazine-1-carboxamide (18a) were stronger inhibitors of both CYP5122A1 and L. donovani promastigote proliferation but also remained selective for inhibition of CYP51. Two compounds in this series, N-(4-((3,5-bis(trifluoromethyl)benzyl)oxy)phenyl)-4-(2-(pyridin-4-yl)ethyl)piperazine-1-carboxamide (18e) and N-(4-((3,5-di-tert-butylbenzyl)oxy)phenyl)-4-(2-(pyridin-4-yl)ethyl)piperazine-1-carboxamide (18i) showed modest selectivity for inhibiting L. donovani promastigote proliferation compared to J774 macrophages and were effective against intracellular L. donovani with EC50 values in the low micromolar range. Replacement of the 4-pyridyl ring present in 18e with imidazole resulted in a compound (4-(2-(1H-imidazol-1-yl)ethyl)-N-(4-((3,5-bis(trifluoromethyl)benzyl)oxy)phenyl)piperazine-1-carboxamide, 18p) with approximately fourfold selectivity for CYP5122A1 over CYP51 that inhibited both enzymes with IC50 values ≤ 1 µM, although selective potency against L. donovani promastigotes was lost. Compound 18p also inhibited the proliferation of L. major promastigotes and caused the accumulation of 4-methylated sterols in L. major membranes, indicating that this compound blocks sterol demethylation at the 4-position in Leishmania parasites. The molecules described here may therefore be useful for the future identification of dual inhibitors of CYP51 and CYP5122A1 as potential antileishmanial drug candidates and as probes to shed further light on sterol biosynthesis in Leishmania and related parasites.

Optimizing the Agrobacterium tumefaciens-mediated transformation conditions in Colletotrichum lindemuthianum: a step forward to unravel the functions of pathogenicity arsenals.

Colletotrichum lindemuthianum is a hemibiotrophic fungal pathogen that causes bean anthracnose and it is rated among the top 10 important diseases infecting beans. Currently our knowledge on molecular mechanisms underlying C. lindemuthianum pathogenesis is limited. About five pathogenicity genes have been identified in C. lindemuthianum using Restricted Enzyme Mediated Integration and the transformation using Agroinfection has not been optimized. In this study, a series of experiments were conducted to optimize the key parameters affecting the Agrobacterium tumefaciens-mediated transformation for C. lindemuthianum. The transformation efficiency increased with increase in spore concentration and co-cultivation time. However, the optimum conditions that yielded significant number of transformants were 106 ml-1 spore concentration, co-cultivation time of 72 h, incubation at 25°C and using a cellulose membrane filter for the co-cultivation. The optimized protocol resulted in establishment of large mutant library (2400). A few mutants were melanin deficient and a few were unable to produce conidia. To determine the altered pathogenicity, two new approaches such as detached leaf and twig techniques proved reliable and require fewer resources to screen the large mutant libraries in a short time. Among the 1200 transformants tested for virulence, 90% transformants were pathogenically similar to wild type (race 2047), 96 and 24 were reduced and impaired, respectively. The altered avirulent transformants can prove vital for understanding the missing link between growth and developmental stages of pathogen with virulence. This platform will help to develop strategies to determine the potential pathogenicity genes and to decipher molecular mechanisms of host-pathogen interactions in more detail.

Surfactant free synthesis of cationic nano-vesicles: A safe triple drug loaded vehicle for the topical treatment of cutaneous leishmaniasis.

The basic aim of the study was to develop and evaluate the triple drug loaded cationic nano-vesicles (cNVs), where miltefosine was used as a replacement of surfactant (apart from its anti-leishmanial role), in addition to meglumine antimoniate (MAM) and imiquimod (Imq), as a combination therapy for the topical treatment of cutaneous leishmaniasis (CL). The optimized formulation was nano-sized (86.2 ±â€¯2.7 nm) with high entrapment efficiency (63.8 ±â€¯2.1% (MAM) and 81.4 ±â€¯2.3% (Imq)). In-vivo skin irritation assay showed reduced irritation potential and a decrease in the cytotoxicity of cNVs as compared to conventional NVs (having sodium deoxycholate as a surfactant). A synergistic interaction between drugs was observed against intracellular amastigotes, whereas the in-vivo antileishmanial study presented a significant reduction in the parasitic burden. The results suggested the potential of surfactant free, triple drug loaded cNVs as an efficient vehicle for the safe topical treatment of CL.

Influence of domestication on specialized metabolic pathways in fruit crops.

MAIN CONCLUSION: During the process of plant domestication, the selection and traditional breeding for desired characters such as flavor, juiciness and nutritional value of fruits, probably have resulted in gain or loss of specialized metabolites contributing to these traits. Their appearance in fruits is likely due to the acquisition of novel and specialized metabolic pathways and their regulation, driven by systematic molecular evolutionary events facilitated by traditional breeding. Plants change their armory of specialized metabolism to adapt and survive in diverse ecosystems. This may occur through molecular evolutionary events, such as single nucleotide polymorphism, gene duplication and transposition, leading to convergent or divergent evolution of biosynthetic pathways producing such specialized metabolites. Breeding and selection for improved specific and desired traits (fruit size, color, taste, flavor, etc.) in fruit crops through conventional breeding approaches may further alter content and profile of specialized metabolites. Biosynthetic routes of these metabolites have been studied in various plants. Here, we explore the influence of plant domestication and breeding processes on the selection of biosynthetic pathways of favorable specialized metabolites in fruit crops. An orderly clustered arrangement of genes associated with their production is observed in many fruit crops. We further analyzed selection-based acquisition of specialized metabolic pathways comparing first the metabolic profiles and genes involved in their biosynthesis, followed by the genomic organization of such genes between wild and domesticated horticultural crops. Domestication of crop plants favored the acquisition and retention of metabolic pathways that enhanced the fruit value while eliminated those which produced toxic or unfavorable metabolites. Interestingly, unintentional reorganization of complex metabolic pathways by selection and traditional breeding processes has endowed us with flavorful, juicy and nutritionally rich fruits.

Molecular phylogeny, pathogenic variability and phytohormone production of Fusarium species associated with bakanae disease of rice in temperate agro-ecosystems.

Bakanae is the emerging disease threating the rice cultivation globally. Yield reduction of 4-70% is recorded in different parts of the world. A total of 119 Fusarium isolates were collected from rice plants at different geographical locations and seeds of different rice cultivars. The isolates were evaluated for morphological, biochemical and pathogenic diversity. The amplification of TEF-1α gene was carried out for exploring the species spectrum associated with the cultivated and pre-released rice varieties. The production of gibberellin varied from 0.53 to 2.26 µg/25 ml, while as that of Indole acetic acid varied from 0.60 to 3.15 µg/25 ml among the Fusarium isolates. The phylogenetic analysis identified 5 different species of the genus Fusarium viz. Fusarium fujikuroi, F. proliferatum, F. equiseti, F.oxysporum and F. persicinum after nucleotide blasting in NCBI. Only two Fusarium spp. F. fujikuroi and F. proliferatum were found to be pathogenic under virulence assays of the isolates. The isolates showed a considerable variation in morphological and pathogenic characters. The isolates were divided into different groups based on morphology and pathogenicity tests. The isolates showed a considerable variation in morphology, phytohormone profile and virulence indicative of population diversity. Three species F. equiseti, F.oxysporum and F. persicinum which have not been reported as pathogens of rice in India were found to be associated with bakanae disease of rice, however their pathogenicity could not be established.

Population structure of Venturia inaequalis, a hemibiotrophic fungus, under different host resistance specificities in the Kashmir valley.

Venturia inaequalis is a notorious fungal pathogen and show classical gene for gene interaction with its apple host. Neutral markers provide clues about history, evolutionary potential, genetic diversity and population structure of V. inaequalis. The genetic diversity and population structure of fungus indicates that the pathogen is highly diverse with the capacity to breach the scab resistance genes. In the present study, we collected 108 V. inaequalis isolates from three apple cultivars differing in Rvi1 resistance gene. Based on the AMOVA, the variation was mostly distributed among the isolates, providing evidence of non-existence of subpopulation in orchards thus founder population is difficult to arise in Kashmir apple orchards. Pair wise genetic differentiation is less due to regular occurrence of gene flow between the populations residing on different orchard as infected material is transported without stringent quarantine measures. Based on principal coordinate analysis and clustering algorithm as implemented in STRUCTURE, we observed admixture between the two subpopulations, which is quite low, suggesting the existence of pre-zygotic and post-zygotic barriers to gene flow and we cannot rule out the existence of other structures shared by accessions belonging to different varieties. Due to the continuous increase in introduction and monoculture of apple varieties, mixed orchard with different host resistance specificities are more suitable for managing the apple scab in Kashmir valley.

Bifunctional Organic Spacers for Formamidinium-Based Hybrid Dion-Jacobson Two-Dimensional Perovskite Solar Cells.

Three-dimensional (3D) perovskite materials display remarkable potential in photovoltaics owing to their superior solar-to-electric power conversion efficiency, with current efforts focused on improving stability. Two-dimensional (2D) perovskite analogues feature greater stability toward environmental factors, such as moisture, owing to a hydrophobic organic cation that acts as a spacer between the inorganic layers, which offers a significant advantage over their comparatively less stable 3D analogues. Here, we demonstrate the first example of a formamidinium (FA) containing Dion-Jacobson 2D perovskite material characterized by the BFA n-1Pb nI3 n+1 formulation through employing a novel bifunctional organic spacer (B), namely 1,4-phenylenedimethanammonium (PDMA). We achieve remarkable efficiencies exceeding 7% for (PDMA)FA2Pb3I10 based 2D perovskite solar cells resisting degradation when exposed to humid ambient air, which opens up new avenues in the design of stable perovskite materials.

Stabilization of Highly Efficient and Stable Phase-Pure FAPbI3 Perovskite Solar Cells by Molecularly Tailored 2D-Overlayers.

As a result of their attractive optoelectronic properties, metal halide APbI3 perovskites employing formamidinium (FA+ ) as the A cation are the focus of research. The superior chemical and thermal stability of FA+ cations makes α-FAPbI3 more suitable for solar-cell applications than methylammonium lead iodide (MAPbI3 ). However, its spontaneous conversion into the yellow non-perovskite phase (δ-FAPbI3 ) under ambient conditions poses a serious challenge for practical applications. Herein, we report on the stabilization of the desired α-FAPbI3 perovskite phase by protecting it with a two-dimensional (2D) IBA2 FAPb2 I7 (IBA=iso-butylammonium overlayer, formed via stepwise annealing. The α-FAPbI3 /IBA2 FAPb2 I7 based perovskite solar cell (PSC) reached a high power conversion efficiency (PCE) of close to 23 %. In addition, it showed excellent operational stability, retaining around 85 % of its initial efficiency under severe combined heat and light stress, that is, simultaneous exposure with maximum power tracking to full simulated sunlight at 80 °C over 500 h.

Low-Cost and Highly Efficient Carbon-Based Perovskite Solar Cells Exhibiting Excellent Long-Term Operational and UV Stability.

Today's perovskite solar cells (PSCs) mostly use components, such as organic hole conductors or noble metal back contacts, that are very expensive or cause degradation of their photovoltaic performance. For future large-scale deployment of PSCs, these components need to be replaced with cost-effective and robust ones that maintain high efficiency while ascertaining long-term operational stability. Here, a simple and low-cost PSC architecture employing dopant-free TiO2 and CuSCN as the electron and hole conductor, respectively, is introduced while a graphitic carbon layer deposited at room temperature serves as the back electrical contact. The resulting PSCs show efficiencies exceeding 18% under standard AM 1.5 solar illumination and retain ≈95% of their initial efficiencies for >2000 h at the maximum power point under full-sun illumination at 60 °C. In addition, the CuSCN/carbon-based PSCs exhibit remarkable stability under ultraviolet irradiance for >1000 h while under similar conditions, the standard spiro-MeOTAD/Au based devices degrade severely.

Insights about the Absence of Rb Cation from the 3D Perovskite Lattice: Effect on the Structural, Morphological, and Photophysical Properties and Photovoltaic Performance.

Efficiencies >20% are obtained from the perovskite solar cells (PSCs) employing Cs+ and Rb+ based perovskite compositions; therefore, it is important to understand the effect of these inorganic cations specifically Rb+ on the properties of perovskite structures. Here the influence of Cs+ and Rb+ is elucidated on the structural, morphological, and photophysical properties of perovskite structures and the photovoltaic performances of resulting PSCs. Structural, photoluminescence (PL), and external quantum efficiency studies establish the incorporation of Cs+ (x < 10%) but amply rule out the possibility of Rb-incorporation into the MAPbI3 (MA = CH3 NH3+ ) lattice. Moreover, morphological studies and time-resolved PL show that both Cs+ and Rb+ detrimentally affect the surface coverage of MAPbI3 layers and charge-carrier dynamics, respectively, by influencing nucleation density and by inducing nonradiative recombination. In addition, differential scanning calorimetry shows that the transition from orthorhombic to tetragonal phase occurring around 160 K requires more thermal energy for the Cs-containing MAPbI3 systems compared to the pristine MAPbI3 . Investigation including mixed halide (I/Br) and mixed cation A-cation based compositions further confirms the absence of Rb+ from the 3D-perovskite lattice. The fundamental insights gained through this work will be of great significance to further understand highly promising perovskite compositions.

Electron-Affinity-Triggered Variations on the Optical and Electrical Properties of Dye Molecules Enabling Highly Efficient Dye-Sensitized Solar Cells.

The synthesis, characterization, and photovoltaic performance of a series of indacenodithiophene (IDT)-based D-π-A organic dyes with varying electron-accepting units is presented. By control of the electron affinity, perfectly matching energy levels were achieved with a copper(I/II)-based redox electrolyte, reaching a high open-circuit voltage (>1.1 V) while harvesting a large fraction of solar photons at the same time. Besides achieving high power conversion efficiencies (PCEs) for dye-sensitized solar cells (DSCs), that is, 11.2 % under standard AM 1.5 G sunlight, and 28.4 % under a 1000 lux fluorescent light tube, this work provides a possible method for the design and fabrication of low-cost highly efficient DSCs.

Surfactant-assisted synthesis of polythiophene/Ni0.5Zn0.5Fe2-xCexO4 ferrite composites: study of structural, dielectric and magnetic properties for EMI-shielding applications.

This work reports the exploitation of nanocrystalline Ni0.5Zn0.5Fe2-xCexO4 ferrite for potential application by designing quasi-spherical shaped polythiophene (PTH) composites via in situ emulsion polymerization. The structural, electronic, dielectric, magnetic, and electromagnetic interference (EMI) shielding properties of PTH/Ni0.5Zn0.5Fe2-xCexO4 composites were investigated. Our results suggest that these properties could be optimized by modulating the concentration of x (composition) in the polymer matrix. Higher values of ε' and ε'' were obtained on composite formation, and could be due to the heterogeneity developed in the material. An enhancement in the value of saturation magnetization (123 emu g-1 for x = 0.04) and Curie temperature was obtained with Ce concentration, which is useful for high density recording purposes. A low value of saturation magnetization was obtained for the PTH/Ni0.5Zn0.5Fe2-xCexO4 composite (36 emu g-1 for x = 0.04). This could be attributed to the non-magnetic nature of the polymer. A total shielding effectiveness (SET = SEA + SER) up to 34 dB (≈99.9% attenuation) was recorded for PTH/Ni0.5Zn0.5Fe2-xCexO4 composites (x = 0.04) in a frequency range of 8.2-12.4 GHz (X-band), which surpasses the shielding criteria of SET > 30 dB for commercial purposes. Such a material with high SE identifies its potential for making electromagnetic shields. The effect of Ce substitution on the microstructure, dielectric, impedance and magnetic properties of PTH/Ni0.5Zn0.5Fe2-xCexO4 ferrite composites was also investigated. X-ray diffraction analysis confirmed cubic spinel phase formation, and the broad reflection peaks indicated the formation of smaller sized particles. The smaller energy band gap (2.53 eV) of the composite indicated that this material could be used for photocatalysis in the visible region. Dielectric and impedance measurements were carried out in a frequency range of 8.2-12.4 GHz. Dielectric properties were improved considerably by the substitution of Ce3+ ions in PTH/Ni0.5Zn0.5Fe2-xCexO4 composites. Impedance spectroscopy was used to study the effect of grain and grain boundaries on the electrical properties of PTH/Ni0.5Zn0.5Fe2-xCexO4 composites. Cole-Cole plots showed the formation of single semi-circles for all samples in the measured frequency range. This showed that the composite material was composed of good conducting grains and poorly conducting grain boundaries.

Intrinsic and Extrinsic Stability of Formamidinium Lead Bromide Perovskite Solar Cells Yielding High Photovoltage.

We report on both the intrinsic and the extrinsic stability of a formamidinium lead bromide [CH(NH2)2PbBr3 = FAPbBr3] perovskite solar cell that yields a high photovoltage. The fabrication of FAPbBr3 devices, displaying an outstanding photovoltage of 1.53 V and a power conversion efficiency of over 8%, was realized by modifying the mesoporous TiO2-FAPbBr3 interface using lithium treatment. Reasons for improved photovoltaic performance were revealed by a combination of techniques, including photothermal deflection absorption spectroscopy (PDS), transient-photovoltage and charge-extraction analysis, and time-integrated and time-resolved photoluminescence. With lithium-treated TiO2 films, PDS reveals that the TiO2-FAPbBr3 interface exhibits low energetic disorder, and the emission dynamics showed that electron injection from the conduction band of FAPbBr3 into that of mesoporous TiO2 is faster than for the untreated scaffold. Moreover, compared to the device with pristine TiO2, the charge carrier recombination rate within a device based on lithium-treated TiO2 film is 1 order of magnitude lower. Importantly, the operational stability of perovskites solar cells examined at a maximum power point revealed that the FAPbBr3 material is intrinsically (under nitrogen) as well as extrinsically (in ambient conditions) stable, as the unsealed devices retained over 95% of the initial efficiency under continuous full sun illumination for 150 h in nitrogen and dry air and 80% in 60% relative humidity (T = ∼60 °C). The demonstration of high photovoltage, a record for FAPbBr3, together with robust stability renders our work of practical significance.

Triazatruxene-Based Hole Transporting Materials for Highly Efficient Perovskite Solar Cells.

Four center symmetrical star-shaped hole transporting materials (HTMs) comprising planar triazatruxene core and electron-rich methoxy-engineered side arms have been synthesized and successfully employed in (FAPbI3)0.85(MAPbBr3)0.15 perovskite solar cells. These HTMs are obtained from relatively cheap starting materials by adopting facile preparation procedure, without using expensive and complicated purification techniques. Developed compounds have suitable highest occupied molecular orbitals (HOMO) with respect to the valence band level of the perovskite, and time-resolved photoluminescence indicates that hole injection from the valence band of perovskite into the HOMO of triazatruxene-based HTMs is relatively more efficient as compared to that of well-studied spiro-OMeTAD. Remarkable power conversion efficiency over 18% was achieved using 5,10,15-trihexyl-3,8,13-tris(4-methoxyphenyl)-10,15-dihydro-5H-diindolo[3,2-a:3',2'-c]carbazole (KR131) with compositive perovskite absorber. This result demonstrates triazatruxene-based compounds as a new class of HTM for the fabrication of highly efficient perovskite solar cells.

Stable and Efficient Perovskite Solar Cells Based on Titania Nanotube Arrays.

Highly ordered 1D TiO2 nanotube arrays are fabricated and applied as nanocontainers and electron transporting material in CH3 NH3 PbI3 perovskite solar cells. The optimized device shows a power conversion efficiency of 14.8%, and improved stability under an illumination of 100 mW cm(-2). This is the best result based on 1D TiO2 nanostructures so far.

Ethanol-Induced Cerebellar Ataxia: Cellular and Molecular Mechanisms.

The cerebellum is an important target of ethanol toxicity given that cerebellar ataxia is the most consistent physical manifestation of acute ethanol consumption. Despite the significance of the cerebellum in ethanol-induced cerebellar ataxia (EICA), the cellular and molecular mechanisms underlying EICA are incompletely understood. However, two important findings have shed greater light on this phenomenon. First, ethanol-induced blockade of cerebellar adenosine uptake in rodent models points to a role for adenosinergic A1 modulation of EICA. Second, the consistent observation that intracerebellar administration of nicotine in mice leads to antagonism of EICA provides evidence for a critical role of cerebellar nitric oxide (NO) in EICA reversal. Based on these two important findings, this review discusses the potential molecular events at two key synaptic sites (mossy fiber-granule cell-Golgi cell (MGG synaptic site) and granule cell parallel fiber-Purkinje cell (GPP synaptic site) that lead to EICA. Specifically, ethanol-induced neuronal NOS inhibition at the MGG synaptic site acts as a critical trigger for Golgi cell activation which leads to granule cell deafferentation. Concurrently, ethanol-induced inhibition of adenosine uptake at the GPP synaptic site produces adenosine accumulation which decreases glutamate release and leads to the profound activation of Purkinje cells (PCs). These molecular events at the MGG and GPP synaptic sites are mutually reinforcing and lead to cerebellar dysfunction, decreased excitatory output of deep cerebellar nuclei, and EICA. The critical importance of PCs as the sole output of the cerebellar cortex suggests normalization of PC function could have important therapeutic implications.

Investigation regarding the role of chloride in organic-inorganic halide perovskites obtained from chloride containing precursors.

As the photovoltaic performance of a device is strongly influenced by the morphology of perovskite, achieving precise control over the crystal formation of organic-inorganic halide perovskites synthesized in the ambience of chloride ions has garnered much attention. Although the resulting morphology dictates the performance of the device considerably, the understanding of the role of chloride ions has been scant. To unravel this mystery, we investigated three different organic-inorganic halide perovskite materials grown from the chloride-containing precursors under different but optimized conditions. Despite the presence of chloride ions in the reaction mixture, scanning transmission electron microscopy- energy dispersive spectroscopy (STEM-EDS) reveals that the CH3NH3PbI3 perovskites formed are chloride-free. Moreover bright field transmission electron microscopy indicates that chloride ions effect the growth of the CH3NH3PbI3.

Quantum-confined ZnO nanoshell photoanodes for mesoscopic solar cells.

We present a photoanode for dye-sensitized solar cell (DSC) based on ZnO nanoshell deposited by atomic layer deposition at 150 °C on a mesoporous insulating template. An ultrathin layer of ZnO between 3 and 6 nm, which exhibits quantum confinement effect, is found to be sufficient to transport the photogenerated electrons to the external contacts and exhibits near-unity collection efficiency. A 6 nm ZnO nanoshell on a 2.5 µm mesoporous nanoparticle Al2O3 template yields photovoltaic power conversion efficiency (PCE) of 4.2% in liquid DSC. Perovskite absorber (CH3NH3PbI3) based solid state solar cells made with similar ZnO nanostructures lead to a high PCE of 7%.

Perovskite solar cells with 12.8% efficiency by using conjugated quinolizino acridine based hole transporting material.

A low band gap quinolizino acridine based molecule was designed and synthesized as new hole transporting material for organic-inorganic hybrid lead halide perovskite solar cells. The functionalized quinolizino acridine compound showed an effective hole mobility in the same range of the state-of-the-art spiro-MeOTAD and an appropriate oxidation potential of 5.23 eV vs the vacuum level. The device based on this new hole transporting material achieved high power conversion efficiency of 12.8% under the illumination of 98.8 mW cm(-2), which was better than the well-known spiro-MeOTAD under the same conditions. Moreover, this molecule could work alone without any additives, thus making it to be a promising candidate for solid-state photovoltaic application.