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Background: Through its central role in neurotransmission, the vesicular acetylcholine transporter (VAChT) is an increasingly valuable target for positron emission tomography (PET). VAChT ligands have been mostly derived from the vesamicol structure, but with limitations in available labelling methods and selectivity for VAChT against σ receptors being a common pitfall of such compounds, the development of selective VAChT tracers remains a challenge. Modern labelling techniques, in this case the [¹¹C]MeLi cross-coupling methodology, expands labelling opportunities, allowing to explore novel vesamicol-based structures as potential PET-tracers.

Results: A series of vesamicol derivatives was synthesized and their binding towards VAChT, σ1 and σ2 receptors assessed. Of all compound tested, (-)-2-methylspirobenzovesamicol ((-)-4) was the most promising with a 16 ± 4 nM affinity towards VAChT, a 29-fold weaker affinity for σ1 receptors and negligible binding (> 1 μM) towards σ2 receptors. The radiolabelling was performed from the corresponding bromide using a [¹¹C]MeLi cross-coupling protocol, yielding 2-[¹¹C]methylspirobenzovesamicol in 32-37% RCY. New in vitro binding data is also made available for (-)-FEOBV with human-sourced σ1 receptors, revealing a 300-fold stronger affinity for VAChT compared to σ receptors.

Conclusion: (-)-2-methylspirobenzovesamicol was identified as a potent and selective VAChT ligand, with moderate to low affinity for σ receptors, and its racemate was radiolabeled in good radiochemical yields with Carbon-11. At this stage, [¹¹C]-methyl-2-methylspirobenzovesamicol appears a promising ¹¹C-PET tracer for VAChT imaging.

Identification of O-glycopeptides from tandem mass spectrometry data is complicated by the near complete dissociation of O-glycans from the peptide during collisional activation and by the combinatorial explosion of possible glycoforms when glycans are retained intact in electron-based activation. The recent O-Pair search method provides an elegant solution to these problems, using a collisional activation scan to identify the peptide sequence and total glycan mass, and a follow-up electron-based activation scan to localize the glycosite(s) using a graph-based algorithm in a reduced search space. Our previous O-glycoproteomics methods with MSFragger-Glyco allowed for extremely fast and sensitive identification of O-glycopeptides from collisional activation data but had limited support for site localization of glycans and quantification of glycopeptides. Here, we report an improved pipeline for O-glycoproteomics analysis that provides proteome-wide, site-specific, quantitative results by incorporating the O-Pair method as a module within FragPipe. In addition to improved search speed and sensitivity, we add flexible options for oxonium ion-based filtering of glycans and support for a variety of MS acquisition methods and provide a comparison between all software tools currently capable of O-glycosite localization in proteome-wide searches.

The avidity of cancer cells for iron highlights the potential for iron chelators to be used in cancer therapy. Herein, we designed and synthesized a novel series of 5H-[1,2,4]triazino[5,6-b]indole derivatives bearing a pyridinocycloalkyl moiety using a ring-fusion strategy based on the structure of an iron chelator, VLX600. The antiproliferative activity evaluation against cancer cells and normal cells led to the identification of compound 3k, which displayed the strongest antiproliferative activity in vitro against A549, MCF-7, Hela and HepG-2 with IC₅₀ values of 0.59, 0.86, 1.31 and 0.92 μM, respectively, and had lower cytotoxicity against HEK293 than VLX600. Further investigations revealed that unlike VLX600, compound 3k selectively bound to ferrous ions, but not to ferric ions, and addition of Fe²⁺ abolished the cytotoxicity of 3k. Flow cytometry assays demonstrated that 3k arrested the cell cycle at the G1 phase and induced significant apoptosis in A549 cells in dose and time-dependent manners, corresponding to JC-1 staining assay results. Western blot analysis of Bcl-2, Bax and cleaved caspase-3 proteins further provided evidences that induction of apoptosis by 3k in A549 cells might be at least via the mitochondria pathway. These above results highlight that 3k is a valuable lead compound that deserves further investigation as an iron chelator for the treatment of cancer.

Visceral Leishmaniasis (VL), the second neglected tropical disease caused by various Leishmania species, presents a significant public health challenge due to limited treatment options and the absence of vaccines. The agent responsible for visceral leishmaniasis, also referred to as "black fever" in India, is Leishmania donovani. This study focuses on L. donovani Minichromosome maintenance 10 (LdMcm10), a crucial protein in the DNA replication machinery, as a potential therapeutic target in Leishmania therapy using in silico and in vitro approaches. We employed bioinformatics tools, molecular docking, and molecular dynamics simulations to predict potential inhibitors against the target protein. The research revealed that the target protein lacks homologues in the host, emphasizing its potential as a drug target. Ligands from the DrugBank database were screened against LdMcm10 using PyRx software. The top three compounds, namely suramin, vapreotide, and pasireotide, exhibiting the best docking scores, underwent further investigation through molecular dynamic simulation and in vitro analysis. The observed structural dynamics suggested that LdMcm10-ligand complexes maintained consistent binding throughout the 300 ns simulation period, with minimal variations in their backbone. These findings suggest that these three compounds hold promise as potential lead compounds for developing new drugs against leishmaniasis. In vitro experiments also demonstrated a dose-dependent reduction in L. donovani viability for suramin, vapreotide, and pasireotide, with computed IC₅₀ values providing quantitative metrics of their anti-leishmanial efficacy. The research offers a comprehensive understanding of LdMcm10 as a drug target and provides a foundation for further investigations and clinical exploration, ultimately advancing drug discovery strategies for leishmaniasis treatment.

Mandarin fish (Siniperca chuatsi) is a voracious carnivorous species, usually consuming only live bait fish, but dietary acclimation enables it to accept artificial feed. However, the effects of dietary acclimation on intestinal performance and gene expression in mandarin fish and related mechanisms remain largely unknown. Therefore, this study investigated the effects of artificial feed on intestinal physicochemical and biochemical performance and gene expression in mandarin fish. Mandarin fish were sampled on day 10 after feeding with live dace (LD), at day 40 after subsequent feeding with dead dace plus artificial feed (DD + AF) from day 11 to day 40, and at day 90 after continuous feeding with artificial feed (AF) alone from day 41 to day 90 for transcriptome sequencing. The biochemical analysis results indicated that artificial feed significantly increased the activity of antioxidant enzymes glutathione peroxidase and superoxide dismutase in the intestine, liver, and stomach. Histological analysis demonstrated intestinal damage in mandarin fish fed with artificial feed. The GO and KEGG enrichment analyses indicated that the DEGs in AF vs. DD + AF were significantly enriched in the pentose phosphate pathway, and the DEGs in AF vs. LD were mainly significantly enriched in glycolysis/gluconeogenesis and PPAR signaling pathways. Nineteen feed acclimation-related key genes such as gene pfkfb4a and scd were identified in the intestine and found to exhibit upregulated expressions. These results revealed that artificial feed domestication enhanced the antioxidant capacity of the mandarin fish intestine and reduced hepatic lipid deposition by upregulating the related gene expression of mandarin fish and that the regulation of carbon metabolisms, including sugar, lipid, and steroid metabolisms, might be fundamental mechanisms for mandarin fish to acclimatize to dietary changes. These findings provide novel insights into the feed acclimation mechanism of mandarin fish, holding implications for promoting large-scale artificial feed aquaculture of mandarin fish and improving economic efficiency.

A highly sensitive antibody detection strategy is presented that leverages the rational spatial arrangement of antigens at the sensing interface. Specifically, we employed rigid benzene ring-based coupling agents, carefully controlling their density and orientation on the biosensing interface to establish a well-defined spatial arrangement of receptor molecules, thereby enhancing antibody binding efficiency. Additionally, we utilized Au-decorated MoS₂ nanosheets as an effective electrode modification, which also function as contact points for regulating the coupling agents. By optimizing both the electrode materials and the spatial arrangement of receptor molecules, our strategy enabled the precise and rapid detection of anti-p53 autoantibodies (anti-p53aAbs) in spiked plasma samples, achieving a broad linear range from 0.05 to 10 ng/mL and a low detection limit of 16.67 pg/mL, surpassing the performance of most existing methods. Notably, we introduce a biomimetic strategy for the spatial arrangement of antigens, inspired by the bionic recognition mechanism. This design effectively reduces steric hindrance between antibody molecules, enhances binding efficiency, and provides a novel approach for the rapid and sensitive detection of macromolecules, such as antibodies.

Pulmonary endothelial barrier dysfunction is a hallmark of sepsis-induced acute lung injury (ALI). Ophiopogonin D (OP-D), isolated from the roots of Ophiopogon japonicus, is involved in regulating inflammation, apoptosis and intestinal permeability. However, the role of OP-D in ALI has not been reported and the related mechanisms remain unclear. In this study, cecal ligation and puncture (CLP) was used to establish a septic ALI model in mice. We found that OP-D effectively alleviated lung pathological damage. Moreover, OP-D decreased pulmonary microvascular permeability, restrained the inflammatory response and apoptosis in murine lung tissues and LPS-exposed PMVECs. Specifically, OP-D exerted the beneficial effects via mediating the inactivation of HIF-1α-VEGF pathway, which was partly abrogated by the overexpression of HIF-1α. Collectively, our findings showed that OP-D protected against sepsis-induced ALI through improving pulmonary microvascular endothelial barrier dysfunction via suppressing HIF-1α-VEGF pathway.

The Eastern Himalaya region is highly susceptible to flood and other hydrological hazards due to frizzle geophysical setup, reshaping geomorphology, and heavy annual rainfall (1600-3200 mm). Despite that, anthropogenic activities have been enhancing this susceptibility which increases the intensity and impact of floods in terms of economic loss, human loss, and environmental degradation. Addressing this environmental problem, a geospatial technology-based case study of the Kohima district, Nagaland state (India), a part of the eastern Himalaya is presented here. Various experiential models are available for computing flood hazards; however, the geospatial technique-based analytic hierarchy process (AHP) method was applied in this study due to its robustness and high accuracy level. AHP integrates reclassified GIS layers of hazard-triggering factors and sub-factors by assigning relative weights 1-9 based on their corresponding impacts on flood occurrence. Overlay operation of reclassified GIS layer (causative factors and sub-factors) in ArcMap 10.8 software generated flood spatial variability map which shows four zones, namely low, moderate, high, and very high hazard zones, covers 23%, 35%, 28%, and 14% proportion of total area (978.96 km²), respectively. The study poses a serious concern for the study area as most of the densely populated urban centers fall into moderate to very high flood hazard zones including the state capital city Kohima. So, to avert a worse flood disaster, a flood hazard zone study is the need of the hour. The present study can be used as a decision support system (DSS) for flood disaster risk reduction, infrastructural development, and land use planning in Kohima district.

A hydrazine (HYD) detection method is presented based on molecularly imprinting polymers (MIPs) and cobalt-barium stannate nanoparticles incorporated-functionalized MWCNTs (CBSNPs/f-MWCNTs) nanocomposite. Firstly, co-precipitation and sonication techniques were applied to the preparations of CBSNPs and CBSNPs/f-MWCNTs nanocomposite, respectively. Since waste generation occurs at a minimum level in these techniques, an environmentally friendly nanocomposite was prepared. After the glassy carbon electrode modification with CBSNPs and CBSNPs/f-MWCNTs nanocomposite, HYD imprinted electrodes were fabricated using cyclic voltammetry (CV) with a dispersion containing 100.0 mM pyrrole (Py) monomer and 25.0 mM HYD molecule. The resulting electrochemical sensor demonstrated a detection span of 1.0 × 10^-9 M to 1.0 × 10^-8 M HYD and achieved a detection limit (LOD) of 3.0 × 10^-10 M. Furthermore, the developed electrochemical sensor was used for actual tap water samples, and the obtained values close to 100.00% in recovery experiments showed the high accuracy of the developed sensor in real sample analysis. Finally, the selectivity, stability, and reproducibility of the created electrochemical sensor were investigated, and the developed sensor has been demonstrated to have high stability for at least 7 weeks, high reproducibility with a relative standard deviation (RSD) value of 0.14%, and high selectivity in real samples.

The analysis of the volatile compounds released by biological samples represents a promising approach for the non-invasive diagnosis of a disease. The present study, focused on a population of dogs infected with canine leishmaniasis, aimed to decipher the volatolomic profile associated with this disease in dogs, which represent the main animal reservoir for Leishmania pathogen transmission to humans. The volatiles emitted by the breath and hair of dogs were analysed employing the gas chromatography-mass spectrometry (GC-MS) technique. The acquired chromatograms were investigated using a novel algorithm developed in this study for automated chromatographic peak detection and matching in untargeted GC-MS analysis, which includes various steps that comprise noise reduction, m/z filtering, background subtraction, peak detection, peak matching, and generation of a peak table for compounds identification. The results revealed one tentative breath volatile biomarker and five tentative hair volatile biomarkers for the cutaneous form of the disease, which is characterised by skin ulcerations. Additionally, nine tentative breath volatile biomarkers and four tentative hair volatile biomarkers were found for the visceral form of the disease, which affects internal organs such as spleen, liver and bone marrow. All tentative biomarkers identified in this study were upregulated in cutaneous leishmaniasis, while in visceral leishmaniasis, all tentative biomarkers were upregulated in the breath and only one out of four in the hair. Only one compound (glyceryl monooleate) was identified as tentative volatile biomarker for both forms of the disease, in the hair of dogs.