High-throughput diagnostic markers for foliar fungal disease resistance and high oleic acid content in groundnut.

BACKGROUND: Foliar diseases namely late leaf spot (LLS) and leaf rust (LR) reduce yield and deteriorate fodder quality in groundnut. Also the high oleic acid content has emerged as one of the most important traits for industries and consumers due to its increased shelf life and health benefits. RESULTS: Genetic mapping combined with pooled sequencing approaches identified candidate resistance genes (LLSR1 and LLSR2 for LLS and LR1 for LR) for both foliar fungal diseases. The LLS-A02 locus housed LLSR1 gene for LLS resistance, while, LLS-A03 housed LLSR2 and LR1 genes for LLS and LR resistance, respectively. A total of 49 KASPs markers were developed from the genomic regions of important disease resistance genes, such as NBS-LRR, purple acid phosphatase, pentatricopeptide repeat-containing protein, and serine/threonine-protein phosphatase. Among the 49 KASP markers, 41 KASPs were validated successfully on a validation panel of contrasting germplasm and breeding lines. Of the 41 validated KASPs, 39 KASPs were designed for rust and LLS resistance, while two KASPs were developed using fatty acid desaturase (FAD) genes to control high oleic acid levels. These validated KASP markers have been extensively used by various groundnut breeding programs across the world which led to development of thousands of advanced breeding lines and few of them also released for commercial cultivation. CONCLUSION: In this study, high-throughput and cost-effective KASP assays were developed, validated and successfully deployed to improve the resistance against foliar fungal diseases and oleic acid in groundnut. So far deployment of allele-specific and KASP diagnostic markers facilitated development and release of two rust- and LLS-resistant varieties and five high-oleic acid groundnut varieties in India. These validated markers provide opportunities for routine deployment in groundnut breeding programs.

Reversible Reactions of Nitric Oxide with a Binuclear Iron(III) Nitrophorin Mimic.

Construction of functional synthetic systems that can reversibly bind and transport the most biologically important gaseous molecules, oxygen and nitric oxide (NO), remains a contemporary challenge. Myoglobin and nitrophorin perform these respective tasks employing a protein-embedded heme center where one axial iron site is occupied by a histidine residue and the other is available for small molecule ligation, structural features that are extremely difficult to mimic in protein-free environments. Indeed, the hitherto reported designs rely on sophisticated multistep syntheses for limiting access to one of the two axial coordination sites in small molecules. We have shown previously that binuclear Ga(III) and Al(III) corroles have available axial sites, and now report a redox-active binuclear Fe(III) corrole, (1-Fe)2 , in which each (corrolato)Fe(III) center is 5-coordinate, with one axial site occupied by an imidazole from the other corrole. The binuclear structure is further stabilized by attractive forces between the corrole π systems. Reaction of NO with (1-Fe)2 affords mononuclear iron nitrosyls, and of functional relevance, the reaction is reversible: nitric oxide is released upon purging the nitrosyls with inert gases, thereby restoring (1-Fe)2 in solutions or films.

Characterization of serotonin-5-HTR1E signaling pathways and its role in cell survival.

5-Hydroxytryptamine receptor 1E (5-HTR1E) is reported to activate cyclic AMP (cAMP) and extracellular-signal related kinases (ERK) pathways via its ligands and binding partners, but the detailed mechanism underlying the serotonin-induced 5-HTR1E signaling is still not known. In the present study, we determined the cellular regulators of ERK and cAMP signaling pathways in response to serotonin-induced 5-HTR1E activation in 5-HTR1E overexpressing HEK293 cells. We found that Pertussis Toxin (PTX) treatment completely reversed the effect of serotonin-5-HTR1E mediated signaling on cAMP and ERK pathways, confirming the involvement of a Gαi-linked cascade. We also observed that Gßγ and Gq were not associated with 5-HTR1E activation, while blocking protein kinase A (PKA) inhibited ERK signaling only, and had no effect on cAMP. Additionally, serotonin-stimulated ERK1/2 phosphorylation was similar in 5-HTR1E overexpressing, ß-arrestin-deficient HEK293 cells and is solely dependent on G protein signaling. siRNA mediated gene knockdown studies in SH-SY5Y cells revealed that the inhibition of 5-HTR1E reduced the expression of cMyc, Cyclin D1, Cyclin E and BCL2 genes which are related to cell cycle regulation and survival. MTT assays showed that 5-HTR1E knockdown in SHSY-5Y and U118 cells inhibited cell survival significantly. In addition to the signaling mechanism, we also performed RNA-seq analysis in 5-HTR1E overexpressing HEK293 cells and found that 5-HTR1E can regulate the expression of Receptor activity modifying protein 1 (RAMP1), Nuclear receptor 1 (NR4A1) and other Cyclin genes. These findings indicate that serotonin interaction with 5-HTR1E receptor simultaneously activates cAMP and ERK pathway in HEK293 cells and its expression is important for cell survival.

Hippocampal delivery of neurotrophic factor-α1/carboxypeptidase E gene prevents neurodegeneration, amyloidosis, memory loss in Alzheimer's Disease male mice.

Alzheimer's Disease (AD) is a prevalent neurodegenerative disease characterized by tau hyperphosphorylation, Aß1-42 aggregation and cognitive dysfunction. Therapeutic agents directed at mitigating tau aggregation and clearing Aß1-42, and delivery of growth factor genes (BDNF, FGF2), have ameliorated cognitive deficits, but these approaches did not prevent or stop AD progression. Here we report that viral-(AAV) delivery of Neurotrophic Factor-α1/Carboxypeptidase E (NF-α1/CPE) gene in hippocampus at an early age prevented later development of cognitive deficits as assessed by Morris water maze and novel object recognition assays, neurodegeneration, and tau hyperphosphorylation in male 3xTg-AD mice. Additionally, amyloid precursor protein (APP) expression was reduced to near non-AD levels, and insoluble Aß1-42 was reduced significantly. Pro-survival proteins: mitochondrial Bcl2 and Serpina3g were increased; and mitophagy inhibitor Plin4 and pro-inflammatory protein Card14 were decreased in AAV-NF-α1/CPE treated versus untreated AD mice. Thus NF-α1/CPE gene therapy targets many regulatory components to prevent cognitive deficits in 3xTg-AD mice and has implications as a new therapy to prevent AD progression by promoting cell survival, inhibiting APP overexpression and tau hyperphosphorylation.

Hallmarks of anticancer and antimicrobial activities of corroles.

Corroles provide a remarkable opportunity for the development of cancer theranostic agents among other porphyrinoids. While most transition metal corrole complexes are only therapeutic, post-transition metallocorroles also find their applications in bioimaging. Moreover, corroles exhibit excellent photo-physicochemical properties, which can be harnessed for antitumor and antimicrobial interventions. Nevertheless, these intriguing, yet distinct properties of corroles, have not attained sufficient momentum in cancer research. The current review provides a comprehensive summary of various cancer-relevant features of corroles ranging from their structural and photophysical properties, chelation, protein/corrole interactions, to DNA intercalation. Another aspect of the paper deals with the studies of corroles conducted in vitro and in vivo with an emphasis on medical imaging (optical and magnetic resonance), photo/sonodynamic therapies, and photodynamic inactivation. Special attention is also given to a most recent finding that shows the development of pH-responsive phosphorus corrole as a potent antitumor drug for organelle selective antitumor cytotoxicity in preclinical studies. Another biomedical application of corroles is also highlighted, signifying the application of water-soluble and completely lipophilic corroles in the photodynamic inactivation of microorganisms. We strongly believe that future studies will offer a greater possibility of utilizing advanced corroles for selective tumor targeting and antitumor cytotoxicity. In the line with future developments, an ideal pipeline is envisioned on grounds of cancer targeting nanoparticle systems upon decoration with tumor-specific ligands. Hence, we envision that a bright future lies ahead of corrole anticancer research and therapeutics.

Thiacalixarene Appended Azo-based Supramolecular Systems: Self-assembly and Photo Tuning Reversible Liquid Crystalline Properties.

Four new azo-based supramolecular materials containing thiacalixarene core substituted by variable alkoxy groups (TFA1 -TFA4 ) have been designed and synthesized for the mesomorphic and photoswitching properties. The liquid crystalline behavior were accomplished by using DSC, POM, and XRD studies. All azo-based thiacalixarene based materials with short and higher chain length display columnar hexagonal mesophase with broad temperature range. The thermal behavior of all the materials was investigated by DSC and TGA study. The structural and conformational study of the lower rim functionalized materials was confirmed by using different techniques. These thiacalixarene moulded liquid crystalline compounds shows columnar self-assembly type behavior and higher thermal stability. The introduction of bi-substituted azo-ester network towards the lower rim of thiacalixarene core has impact on the electron delocalization and liquid crystalline properties. The photoswitching properties suggested cis and trans azo-isomerization under radiation of UV light and higher thermal back relaxation time. The mesogenic behaviour of compound TFA2 and TFA4 were demolished by the influence of cis and trans isomerization. The structure-property correlation is studied to understand the variation in mesogenic properties with the substitution of variable alkoxy side chain.

A New Conformationally Symmetrical Calix[4]pyrrole Based Supramolecular System for Liquid Crystalline and Window Layer Solar Cell Applications.

The newly symmetrical liquid crystalline compounds (CPB1 -CPB4 ) based on calix[4]pyrrole as central rigid core are synthesized via esterification reaction. All the four functionalized compounds exhibit columnar hexagonal phase (Colh ) over a higher mesophase temperature range and further stabilized mesophase upto room temperature. The thermal behavior and optical texture are identified by using differential scanning calorimetry (DSC), Polarizing optical microscopy (POM) while the molecular organization of compound in mesogenic state by X-ray diffraction technique. The molecular system based on calix[4]pyrrole core with symmetrical nature exhibited columnar type self-assembly at room temperature. All these four supramolecules with different side spacer show higher thermal stability. Based upon the optimization, compound CPB2 has been further tested to implicate as optical window layer in thin films solar cell devices. The calix[4]pyrrole functionalized supramolecular liquid crystalline compound based thin films showed suitable transmittance, optical energy band gap together with absorbance and extinction coefficient. The linear dependence of current on the voltage demonstrated Ohmic behavior of the CPB2 films. The surface morphology to the developed samples designated nearly uniform deposition of the CPB2 thin films together with grain growth. The findings warrant suitability of the films to implicate these as an eco-friendly optical window layer in thin films based solar cells.

The discovery, structure, and function of 5-HTR1E serotonin receptor.

Serotonin (5-hydroxytryptamine, 5-HT) is a unique neurotransmitter which can regulate various biological processes by activating thirteen different receptors. These serotonin receptors are divided into seven different classes based on their structure and functions. Since these receptors co-express in various tissue and cell types and share the same ligand (5-HT), it has been a challenge for the researchers to define specific pathway and separate physiological role for each of these serotonin receptors. Though the evidence of operational diversity of these receptors is continuously emerging, much work remains to be done. 5-HTR1E is a member of 5-HT1 receptor family which belongs to G-protein coupled receptors (GPCRs). Even after three decades since its discovery, 5-HTR1E remains the least explored serotonin receptor. Very high similarity with another family member (5-HTR1F) and its non-existence in mice or rats makes 5-HTR1E a difficult target to study. Despite these challenges, recent findings on the role of 5-HTR1E in neuroprotection and diseases such as cancer, have excited many researchers to explore this receptor in detail. Here, we provide the first review of 5-HTR1E, since its discovery in 1989 to 2023. We highlight the structural and functional characteristics of this important serotonin receptor in detail and propose future directions in developing 5-HTR1E as a drug target. Video Abstract.

Visible light mediated synthesis of 1,3-diarylated imidazo[1,5-a]pyridines via oxidative amination of C-H catalyzed by graphitic carbon nitride.

Graphitic carbon nitride (g-C3N4) as a novel heterogeneous catalyst is employed for the visible light-mediated synthesis of the imidazo[1,5-a]pyridines via the oxidative amination of C-H bond at room temperature without the need for any additional solvent. Extensive characterization of the catalyst was performed using techniques such as FT-IR, PXRD, TGA, SEM and EDX analysis. The optimized conditions enabled the successful and expeditious conversion of a wide range of substrates to imidazo[1,5-a]pyridines in good yields; a notable advantage of this catalyst being recyclability, as it can be reused for up to five cycles without significant loss of activity. This feature makes it suitable for gram-scale synthesis of imidazo[1,5-a]pyridines. Additionally, this approach offers several benefits from a green chemistry perspective as affirmed by its favorable green chemistry metrics (GCM), including low process mass intensity (PMI), low E-factor, high atom economy (AE), and good reaction mass efficiency (RME) relative to existing protocols. In addition, chemical yield (CY), mass intensity (MI), mass productivity (MP) and optimum efficiency were also calculated. This environmentally friendly method offers multiple advantages and represents a significant advancement in the synthesis of imidazo[1,5-a]pyridines.

Genetic analysis for detection of genes associated to drought tolerance in rice accessions belonging to north east India.

INTRODUCTION: The North East (NE) India is rich in biodiversity and also considered as the secondary centre for origin of rice. The NE rice accessions was characterized previously using genetic markers and morphological traits. Simultaneously, genome-wide association studies (GWAS) reveal significant marker-trait associations for the drought tolerance traits. METHODS AND RESULTS: The genetic diversity and population structure of 296 NE rice accessions were studied using 96,712 single nucleotide polymorphism (SNP) markers distributed across 12 chromosomes. The accessions were clustered into two major sub-groups (SG). A total of 91 accessions were assembled as SG1 and 114 accessions as SG2, while the remaining 91 were admixture genotypes. A total of 200 genotypes belonging to different groups were phenotyped for yield component traits under drought and control conditions. The GWAS was performed to identify significant marker-trait associations (MTAs). Consequently, 47 MTAs were detected under drought, exhibiting 0.02-9.95% of phenotypic variance (P.V.). Whereas 58 MTAs were discovered under control conditions, showing a 0.01-9.74% contribution to the phenotype. Through in-silico mining of QTLs, 2999 genes were identified. Among these; only 22 genes were directly associated with stress response. CONCLUSION: These QTLs/genes may be deployed for marker-assisted pyramiding to improve drought tolerance in popular drought susceptible rice varieties.

Molecular mapping of drought-responsive QTLs during the reproductive stage of rice using a GBS (genotyping-by-sequencing) based SNP linkage map.

BACKGROUND: In rice, drought stress at reproductive stage drastically reduces yield, which in turn hampers farmer's efforts towards crop production. The majority of the rice varieties have resistance genes against several abiotic and biotic stresses. Therefore, the traditional landraces were studied to identify QTLs/candidate genes associated with drought tolerance. METHODS AND RESULTS: A high-density SNP-based genetic map was constructed using a Genotyping-by-sequencing (GBS) approach. The recombinant inbred lines (RILs) derived from crossing 'Banglami × Ranjit' were used for QTL analysis. A total map length of 1306.424 cM was constructed, which had an average inter-marker distance of 0.281 cM. The phenotypic evaluation of F6 and F7 RILs were performed under drought stress and control conditions. A total of 42 QTLs were identified under drought stress and control conditions for yield component traits explaining 1.95-13.36% of the total phenotypic variance (PVE). Among these, 19 QTLs were identified under drought stress conditions, whereas 23 QTLs were located under control conditions. A total of 4 QTLs explained a PVE ≥ 10% which are considered as the major QTLs. Moreover, bioinformatics analysis revealed the presence of 6 candidate genes, which showed differential expression under drought and control conditions. CONCLUSION: These QTLs/genes may be deployed for marker-assisted pyramiding to improve drought tolerance in the existing rice varieties.

Novel combination approaches to locoregional and systemic therapy in the management of primary and metastatic liver tumors.

Several pathways and mutations must develop or be in place for the onset of cancer. Therefore, therapies should ideally target as many of these pathways as possible to improve outcomes. Combining several agents has proven to be more effective than the use of monotherapy in the treatment of renal cell carcinoma, hepatocellular carcinoma, and other cancers. Combination therapy can also include locoregional therapies such as ablation and embolization with systemic agents for synergistic effects. This review article discusses the current literature and clinical trials covering these multifactorial combination therapies in primary and metastatic liver tumors.

Protocol for developing a dashboard for interactive cohort analysis of oral health-related data.

INTRODUCTION: A working knowledge of data analytics is becoming increasingly important in the digital health era. Interactive dashboards are a useful, accessible format for presenting and disseminating health-related information to a wide audience. However, many oral health researchers receive minimal data visualisation and programming skills. OBJECTIVES: The objective of this protocols paper is to demonstrate the development of an analytical, interactive dashboard, using oral health-related data from multiple national cohort surveys. METHODS: The flexdashboard package was used within the R Studio framework to create the structure-elements of the dashboard and interactivity was added with the Shiny package. Data sources derived from the national longitudinal study of children in Ireland and the national children's food survey. Variables for input were selected based on their known associations with oral health. The data were aggregated using tidyverse packages such as dplyr and summarised using ggplot2 and kableExtra with specific functions created to generate bar-plots and tables. RESULTS: The dashboard layout is structured by the YAML (YAML Ain't Markup Language) metadata in the R Markdown document and the syntax from Flexdashboard. Survey type, wave of survey and variable selector were set as filter options. Shiny's render functions were used to change input to automatically render code and update output. The deployed dashboard is openly accessible at https://dduh.shinyapps.io/dduh/ . Examples of how to interact with the dashboard for selected oral health variables are illustrated. CONCLUSION: Visualisation of national child cohort data in an interactive dashboard allows viewers to dynamically explore oral health data without requiring multiple plots and tables and sharing of extensive documentation. Dashboard development requires minimal non-standard R coding and can be quickly created with open-source software.

DNA Coil Dynamics and Hydrodynamic Gating of Pressure-Biased Nanopores.

Nanopores are ideally suited for the analysis of long DNA fragments including chromosomal DNA and synthetic DNA with applications in genome sequencing and DNA data storage, respectively. Hydrodynamic fluid flow has been shown to slow down DNA transit time within the pore, however other influences of hydrodynamic forces have yet to be explored. In this report, a broad analysis of pressure-biased nanopores and the impact of hydrodynamics on DNA transit time, capture rate, current blockade depth, and DNA folding are conducted. Using a 10 nm pore, it is shown that hydrodynamic flow inhibits the early stages of linearization of DNA and produces predominately folded events which are initiated by folded DNA (2-strands) entering the pore. Furthermore, utilizing larger pores (30 nm) leads to unique DNA gating behavior in which DNA events can be switched on and off with the application of pressure. A computational model, based on combining electrophoretic drift velocities with fluid velocities, accurately predicts the pore size required to observe DNA gating. Hydrodynamic fluid flow generated by a pressure bias, or potentially more generally by other mechanisms like electroosmotic flow, is shown to have significant effects on DNA sensing and can be useful for DNA sensing technologies.

Exploring the molecular interaction of pheniramine with Enterococcus faecalis homoserine kinase: In-silico studies.

Infections caused by the bacteria Enterococcus faecalis (also known as E. faecalis) are common in hospitals. This bacterium is resistant to a wide range of medicines and causes a variety of nosocomial infections. An increase in the number of infections caused by multidrug-resistant (MDR) bacteria is causing substantial economic and health issues around the world. Consequently, new therapeutic techniques to tackle the growing threat of E. faecalis infections must be developed as soon as possible. In this regard, we have targeted a protein that is regarded to be critical for the survival of bacteria in this experiment. Homoserine kinase (HSK) is a threonine metabolism enzyme that belongs to the GHMP kinase superfamily. It is a crucial enzyme in threonine metabolism. This enzyme is responsible for a critical step in the threonine biosynthesis pathway. Given the important function that E. faecalis Homoserine Kinase (ESK) plays in bacterial metabolism, we report here cloning, expression, purification and structural studies of E. faecalis HSK using homology modelling. In addition, we have reported on the model's molecular docking and Molecular Dynamic Stimulation (MD Stimulation) investigations to validate the results of the docking experiments. The results were promising. In silico investigations came up with the conclusion: pheniramine has good binding affinity for the E. faecalis HSK.

Metastable 1T'-phase group VIB transition metal dichalcogenide crystals.

Metastable 1T'-phase transition metal dichalcogenides (1T'-TMDs) with semi-metallic natures have attracted increasing interest owing to their uniquely distorted structures and fascinating phase-dependent physicochemical properties. However, the synthesis of high-quality metastable 1T'-TMD crystals, especially for the group VIB TMDs, remains a challenge. Here, we report a general synthetic method for the large-scale preparation of metastable 1T'-phase group VIB TMDs, including WS2, WSe2, MoS2, MoSe2, WS2xSe2(1-x) and MoS2xSe2(1-x). We solve the crystal structures of 1T'-WS2, -WSe2, -MoS2 and -MoSe2 with single-crystal X-ray diffraction. The as-prepared 1T'-WS2 exhibits thickness-dependent intrinsic superconductivity, showing critical transition temperatures of 8.6 K for the thickness of 90.1 nm and 5.7 K for the single layer, which we attribute to the high intrinsic carrier concentration and the semi-metallic nature of 1T'-WS2. This synthesis method will allow a more systematic investigation of the intrinsic properties of metastable TMDs.

GWAS to spot candidate genes associated with grain quality traits in diverse rice accessions of North East India.

INTRODUCTION: North East (NE) India is the second centre for the origin of rice and is enriched with a diverse collection of traditional rice accessions. These genotypes possess unique traits of breeding interest and are rich in grain nutritional and cooking qualities. Therefore, quantitative trait loci (QTLs)/genes associated with the various quality traits may be identified through genome-wide association studies (GWAS) and used in crop improvement programmes. METHODS AND RESULTS: A pool of 526 unique rice accessions from Assam, North East (NE) India were characterized by using 9 grain-quality traits and grouped into 16 clusters. Among these, the highest number of 156 (29.65%) genotypes belongs to diverse phenotypic classes; Sali, Lahi, and Chokuwa were grouped into cluster 6. The first three principal components showed 54.76% of morphological variability with Eigenvalue >1. Genome-wide association studies (GWAS) was performed in 103 rice accessions using 42,446 SNP markers. A total of 11 significant marker-trait associations were detected for 5 grain-quality traits, explaining 0.22-8.86% of phenotypic variation (PV). In-silico mining of QTLs detected 'candidate genes' associated with the quality traits. CONCLUSIONS: The phenotypic diversity among the 526 rice accessions of NE India was studied using grain quality traits and grouped into 16 significantly different clusters. The QTLs, or candidate genes identified for various grain quality traits, may be used in breeding programmes for the development of improved rice varieties.

Identification and characterization of genes for drought tolerance in upland rice cultivar 'Banglami' of North East India.

INTRODUCTION: Rice is a major crop in Assam, North East (NE) India. The rice accessions belonging to NE India possess unique traits of breeder's interest, i.e., tolerant to biotic and abiotic stresses. In the present research programme, the stress responsive genes were identified within the QTLs associated with drought tolerance. The differential expression profiling of genes were performed under drought stress and control conditions. Thus, the 'candidate genes' associated with drought tolerance were recognised and may be deployed in a breeding programme. METHODS AND RESULTS: A drought-tolerant traditional rice cultivar, Banglami, was crossed with a high-yielding, drought-susceptible variety, Ranjit. The mapping population (F4) was raised through the single seed descent (SSD) method and used in QTL analysis. Under drought stress, a total of 4752 genes were identified through in-silico mining of QTLs. Among these, only 21 genes primarily associated with the stress response. The maximum of four stress-responsive genes were located within the QTLs, qNOG12.1 and qGY1.1. However, under control conditions, 2088 genes were identified, out of which, only 15 were categorised as the major stress responsive genes. The functional characterization of genes recognized 24 different types of proteins. Among these, peroxidase and heat shock proteins (Hsp) are the principal proteins encoded during stress. In addition to that, OsbZIP23, inorganic pyrophosphatase, universal stress protein, serine threonine kinase, NADPH oxidoreductase, and proteins belonging to the ABC1 family were also produced during stress condition. The differential expression profiling showed a profound expression pattern of three candidate genes under drought stress condition, i.e., OsI_32199 (Ascorbate peroxidase), OsI_37694 (Universal stress protein) and OsI_32167 (Heat shock protein 81 - 1). CONCLUSION: The novel candidate genes identified for drought tolerance, may be used in the breeding programme for the development of 'climate smart rice varieties'.

Heteroleptic Cu(I) bis-diimine complexes as sensitizers in dye-sensitized solar cells (DSSCs): on some factors affecting intramolecular charge transfer.

A set of eight heteroleptic bis-diimine copper dye complexes with two different ancillary ligands (functionalised 2,9-dimethyl-1,10-phenanthroline (dmp) and functionalised 6,6'-diphenyl-2,2'-bipyridine (dpbpy)) are investigated for their potential use as sensitizers in dye-sensitized solar cells (DSSCs), using first principles density functional theory (DFT) and time dependent DFT (TDDFT). A detailed analysis of the structural properties, projected density of electronic states and Kohn-Sham energy levels, and optical absorption spectra in the UV-visible region reveals that substituting the thiophene group in the ancillary ligand, and enhancing conjugation in the anchoring ligand, lead to increase in the light harvesting efficiency (LHE). However, a natural transition orbital (NTO) analysis, shows that the nature of charge transfer depends mainly on the nature of the parent ancillary group and is not significantly affected by the structural modifications. Importantly, the lower energy excitations lead to favourable mixed metal to ligand charge transfer (MLCT) and ligand to ligand charge transfer (LLCT), as well as good electron injection. The best charge transfer directionality is found in the dmp-based dyes, particularly thiophene substituted dyes, thus making these the more effective sensitizers in DSSCs.

Novel interaction between neurotrophic factor-α1/carboxypeptidase E and serotonin receptor, 5-HTR1E, protects human neurons against oxidative/neuroexcitotoxic stress via ß-arrestin/ERK signaling.

Protecting neurons from death during oxidative and neuroexcitotoxic stress is key for preventing cognitive dysfunction. We uncovered a novel neuroprotective mechanism involving interaction between neurotrophic factor-α1 (NF-α1/carboxypeptidase E, CPE) and human 5-HTR1E, a G protein-coupled serotonin receptor with no previously known neurological function. Co-immunoprecipitation and pull-down assays confirmed interaction between NFα1/CPE and 5-HTR1E and 125I NF-α1/CPE-binding studies demonstrated saturable, high-affinity binding to 5-HTR1E in stably transfected HEK293 cells (Kd = 13.82 nM). Treatment of 5-HTR1E stable cells with NF-α1/CPE increased pERK 1/2 and pCREB levels which prevented a decrease in pro-survival protein, BCL2, during H2O2-induced oxidative stress. Cell survival assay in ß-arrestin Knockout HEK293 cells showed that the NF-α1/CPE-5-HTR1E-mediated protection against oxidative stress was ß-arrestin-dependent. Molecular dynamics studies revealed that NF-α1/CPE interacts with 5-HTR1E via 3 salt bridges, stabilized by several hydrogen bonds, independent of the serotonin pocket. Furthermore, after phosphorylating the C-terminal tail and intracellular loop 3 (ICL3) of NF-α1/CPE-5-HTR1E, it recruited ß-arrestin1 by forming numerous salt bridges and hydrogen bonds to ICL2 and ICL3, leading to activation of ß-arrestin1. Immunofluorescence studies showed 5-HTR1E and NF-α1/CPE are highly expressed and co-localized on cell surface of human hippocampal neurons. Importantly, knock-down of 5-HTR1E in human primary neurons diminished the NF-α1/CPE-mediated protection of these neurons against oxidative stress and glutamate neurotoxicity-induced cell death. Thus, NF-α1/CPE uniquely interacts with serotonin receptor 5-HTR1E to activate the ß-arrestin/ERK/CREB/BCL2 pathway to mediate stress-induced neuroprotection.