A ratiometric fluorescent probe based on a novel fluorophore with high selectivity for imaging cysteine in living cells.

As a biothiol, cysteine (Cys) is essential to both physiological and pathological processes and has been associated with many diseases, including neurological disorders, rheumatoid arthritis, and renal dysfunction. Therefore, the development of a high-performance probe for detecting Cys levels can help prevent and diagnose disease. In this study, a ratiometric fluorescent probe based on a novel fluorophore was developed for detecting Cys, and it showed high specificity and a rapid response time toward Cys. This probe demonstrates excellent biocompatibility and has been utilized effectively for the imaging of Cys in living cells.

Comparative study on the thermal runaway characteristics of Li(NixCoyMnz)O2 batteries.

Lithium-ion batteries (LIBs) generate substantial gas during the thermal runaway (TR) process, presenting serious risks to electrochemical energy storage systems in case of ignition or explosions. Previous studies were mainly focused on investigating the TR characteristics of Li(NixCoyMnz)O2 batteries with different cathode materials, but they were conducted in isolation. In this study, the thermal runaway characteristics of prismatic cells that use Li(NixCoyMnz)O2 (with x ranging from 0.33 to 0.9) cathode materials in an inert environment, which are commonly used or proposed for energy storage applications, are examined. The findings of this research show that the normalized gas generation rate remains consistent, regardless of the battery capacity or experimental chamber volume, with a value of 0.1 ± 0.03 mol∙Ah⁻1. High-capacity cells have short jetting durations, and a high nickel content leads to increased mass loss rates. The flammability limits of the gases expelled during thermal runaway, represented by the lower flammability limit (LFL), remain stable at 8 ± 1.8 % with minimal variations. However, the upper flammability limit (UFL) varies significantly, ranging from 30 % to 60 %. Increasing the battery capacity or reducing the experimental chamber volume increases the explosion index. The explosive, combustibility, and jetting duration characteristics of the emitted gases from five different battery chemical compositions provide valuable insights for risk assessment in future electrochemical energy storage systems.

A near-infrared fluorescent probe for detecting hydrazine metabolized from isoniazid in living cells.

Isoniazid is a drug for treating tuberculosis, but hydrazine (N2 H4 ), the major metabolite of isoniazid, can cause hepatotoxicity. Therefore, monitoring the content of N2 H4 in time is of great significance for studying the hepatotoxicity induced by isoniazid. In this study, a near-infrared fluorescent probe (BC-N) was designed and synthesized based on the specific reaction of acetyl ester with N2 H4 . BC-N exhibits excellent selectivity, sensitivity, and biocompatibility. In addition, BC-N is applied in the visualization of N2 H4 produced from isoniazid in living cells and is a potential tool for monitoring hepatotoxicity induced by isoniazid.

Genetic architecture of ear traits based on association mapping and co-expression networks in maize inbred lines and hybrids.

Ear traits are key contributors to grain yield in maize; therefore, exploring their genetic basis facilitates the improvement of grain yield. However, the underlying molecular mechanisms of ear traits remain obscure in both inbred lines and hybrids. Here, two association panels, respectively, comprising 203 inbred lines (IP) and 246 F1 hybrids (HP) were employed to identify candidate genes for six ear traits. The IP showed higher phenotypic variation and lower phenotypic mean than the HP for all traits, except ear tip-barrenness length. By conducting a genome-wide association study (GWAS) across multiple environments, 101 and 228 significant single-nucleotide polymorphisms (SNPs) associated with six ear traits were identified in the IP and HP, respectively. Of these significant SNPs identified in the HP, most showed complete-incomplete dominance and over-dominance effects for each ear trait. Combining a gene co-expression network with GWAS results, 186 and 440 candidate genes were predicted in the IP and HP, respectively, including known ear development genes ids1 and sid1. Of these, nine candidate genes were detected in both populations and expressed in maize ear and spikelet tissues. Furthermore, two key shared genes (GRMZM2G143330 and GRMZM2G171139) in both populations were found to be significantly associated with ear traits in the maize Goodman diversity panel with high-density variations. These findings advance our knowledge of the genetic architecture of ear traits between inbred lines and hybrids and provide a valuable resource for the genetic improvement of ear traits in maize. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-023-01426-9.

Inhibition of cutaneous heat-sensitive Ca2+ -permeable transient receptor potential vanilloid 3 channels alleviates UVB-induced skin lesions in mice.

Ultraviolet B (UVB) radiation causes skin injury by trigging excessive calcium influx and signaling cascades in the skin keratinocytes. The heat-sensitive Ca2+ -permeable transient receptor potential vanilloid 3 (TRPV3) channels robustly expressed in the keratinocytes play an important role in skin barrier formation and wound healing. Here, we report that inhibition of cutaneous TRPV3 alleviates UVB radiation-induced skin lesions. In mouse models of ear swelling and dorsal skin injury induced by a single exposure of weak UVB radiation, TRPV3 genes and proteins were upregulated in quantitative real-time PCR and Western blot assays. In accompany with TRPV3 upregulations, the expressions of proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were also increased. Knockout of the TRPV3 gene alleviates UVB-induced ear swelling and dorsal skin inflammation. Furthermore, topical applications of two selective TRPV3 inhibitors, osthole and verbascoside, resulted in a dose-dependent attenuation of skin inflammation and lesions. Taken together, our findings demonstrate the causative role of overactive TRPV3 channel function in the development of UVB-induced skin injury. Therefore, topical inhibition of TRPV3 may hold potential therapy or prevention of UVB radiation-induced skin injury.

Characterization of the Isocitrate Dehydrogenase Gene Family and Their Response to Drought Stress in Maize.

Isocitrate dehydrogenase (IDH) is a key rate-limiting enzyme in the tricarboxylic acid cycle and acts in glutamine synthesis. IDH also participates in plant growth and development and in response to abiotic stresses. We identified 11 maize IDH genes (ZmIDH) and classified these genes into ZmNAD-IDH and ZmNADP-IDH groups based on their different coenzymes (NAD+ or NADP+). The ZmNAD-IDH group was further divided into two subgroups according to their catalytic and non-catalytic subunits, as in Arabidopsis. The ZmIDHs significantly differed in physicochemical properties, gene structure, conserved motifs, and protein tertiary structure. Promoter prediction analysis revealed that the promoters of these ZmIDHs contain cis-acting elements associated with light response, abscisic acid, phytohormones, and abiotic stresses. ZmIDH is predicted to interact with proteins involved in development and stress resistance. Expression analysis of public data revealed that most ZmIDHs are specifically expressed in anthers. Different types of ZmIDHs responded to abiotic stresses with different expression patterns, but all exhibited responses to abiotic stresses to some extent. In addition, analysis of the public sequence from transcription data in an association panel suggested that natural variation in ZmIDH1.4 will be associated with drought tolerance in maize. These results suggested that ZmIDHs respond differently and/or redundantly to abiotic stresses during plant growth and development, and this analysis provides a foundation to understand how ZmIDHs respond to drought stress in maize.

A novel near-infrared fluorescent probe for visualization of intracellular hydrogen peroxide.

Hydrogen peroxide (H2O2) as a crucial reactive oxygen species (ROS) plays a crucial role in redox signaling in physiological and pathological processes of living cells. Its normal production is closely related to signal transduction of living cells. Overproduction of H2O2 in vivo has been proved to be related to many diseases. Some were developed to reveal the roles of H2O2. However, current fluorescent probes for the detection of H2O2 are restricted in their short emission wavelengths and small Stokes shifts that significantly decrease the sensitivity of detection and cellular visualization. In this work, a novel fluorescent probe BC-B was designed and synthesized with pinacol phenylboronic acid ester as a recognition group and near-infrared fluorophore BC-OH as a reporter group. BC-B probe exhibits a large Stokes shift (122 nm) and near-infrared emission (672 nm), showing an excellent selectivity and sensitivity in detection of H2O2 with the limit of 0.003 µmol/L. Confocal fluorescence imaging further demonstrates that BC-B can be used for detecting endogenous H2O2 in living cells.

A super sensitive fluorescent probe for imaging endogenous hydrogen sulfide in living cells.

Hydrogen sulfide (H2S) that typically performs biphasic biological functions in organisms plays an opposite role at the concentrations above or below normal level of the organism. Therefore, it is significant to develop a fluorescent probe with high sensitivity and selectivity and rapid response for the detection of hydrogen sulfide in vivo. The work describes the design and biological applications of a novel turn-on fluorescence probe SS-N3 in which the quinoline quaternary ammonium salt derivative is introduced as the fluorescent skeleton and azide is employed as the detection group of H2S. The probe SS-N3 shows strong fluorescence at 610 nm, as the azide group is reduced to an amino group by H2S. The probe SS-N3 shows high selectivity to H2S than other anions and some biological mercaptans, and strong anti-interference capacity. In addition, the probe SS-N3 exhibits little cytotoxicity, improved photostability and large Stokes shift (135 nm), as well as can be effectively used as an indicator of H2S level in living cells.

Discovery, synthesis, and optimization of teixobactin, a novel antibiotic without detectable bacterial resistance.

Discovering new antibiotics with novel chemical scaffolds and antibacterial mechanisms presents a challenge for medicinal scientists worldwide as the ever-increasing bacterial resistance poses a serious threat to human health. A new cyclic peptide-based antibiotic termed teixobactin was discovered from a screen of uncultured soil bacteria through iChip technology in 2015. Teixobactin exhibits excellent antibacterial activity against all the tested gram-positive pathogens and Mycobacterium tuberculosis, including drug-resistant strains. Given that teixobactin targets the highly conserved lipid II and lipid III, which induces the simultaneous inhibition of both peptidoglycan and teichoic acid synthesis, the emergence of resistance is considered to be rather difficult. The novel structure, potent antibacterial activity, and highly conservative targets make teixobactin a promising lead compound for further antibiotic development. This review provides a comprehensive treatise on the advances of teixobactin in the areas of discovery processes, antibacterial activity, mechanisms of action, chemical synthesis, and structural optimizations. The synthetic methods for the key building block l-allo-End, natural teixobactin, representative teixobactin analogs, as well as the structure-activity relationship studies will be highlighted and discussed in details. Finally, some insights into new trends for the generation of novel teixobactin analogs and tips for future work and directions will be commented.

Molecular docking and molecular dynamics simulations studies on the protective and pathogenic roles of the amyloid-ß peptide between herpesvirus infection and Alzheimer's disease.

The protective innate immune response of ß-amyloid peptide (Aß) has been indicated as a risk factor for Alzheimer's disease (AD) due to the rapid amyloidosis. In order to obtain molecular-level insights into the protective and pathogenic roles of Aß, the binding modes between Aß1-42 and the envelop glycoprotein D (gD) of Herpes simplex virus-1 (HSV-1)/Aß1-42 were theoretically investigated by using molecular docking, molecular dynamics (MD) simulations and binding free energy decomposition methods in the present study. The Aß1-42 stably binds to the envelop gD via intermolecular hydrogen bonds and van der Waals (vdW) interactions. The Aß1-42 acquires its equilibrium with higher fluctuation amplitude and a better structured C-terminal in the HSV-1 gD-Aß1-42 complex comparing to that in the Aß1-42-Aß1-42 complex. The amino acid residues of Aß1-42 involved in the formation of the Aß1-42 dimer are fully free and accessible in the HSV-1 gD-Aß1-42 complex. It is favorable for the Aß1-42 monomer to interact with the HSV-1 gD-Aß1-42 complex. It may be responsible for the rapid amyloidosis which entraps the herpesvirus as well as causing AD.

The Mpro structure-based modifications of ebselen derivatives for improved antiviral activity against SARS-CoV-2 virus.

The main protease (Mpro or 3CLpro) of SARS-CoV-2 virus is a cysteine enzyme critical for viral replication and transcription, thus indicating a potential target for antiviral therapy. A recent repurposing effort has identified ebselen, a multifunctional drug candidate as an inhibitor of Mpro. Our docking of ebselen to the binding pocket of Mpro crystal structure suggests a noncovalent interaction for improvement of potency, antiviral activity and selectivity. To test this hypothesis, we designed and synthesized ebselen derivatives aimed at enhancing their non-covalent bonds within Mpro. The inhibition of Mpro by ebselen derivatives (0.3 µM) was screened in both HPLC and FRET assays. Nine ebselen derivatives (EBs) exhibited stronger inhibitory effect on Mpro with IC50 of 0.07-0.38 µM. Further evaluation of three derivatives showed that EB2-7 exhibited the most potent inhibition of SARS-CoV-2 viral replication with an IC50 value of 4.08 µM in HPAepiC cells, as compared to the prototype ebselen at 24.61 µM. Mechanistically, EB2-7 functions as a noncovalent Mpro inhibitor in LC-MS/MS assay. Taken together, our identification of ebselen derivatives with improved antiviral activity may lead to developmental potential for treatment of COVID-19 and SARS-CoV-2 infection.

Antagonistic Mechanism of α-Conotoxin BuIA toward the Human α3ß2 Nicotinic Acetylcholine Receptor.

Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels that are abundantly expressed in the central and peripheral nervous systems, playing an important role in mediating neurotransmitter release and inter-synaptic signaling. Dysfunctional nAChRs are associated with neurological disorders, and studying the structure and function of nAChRs is essential for development of drugs or strategies for treatment of related diseases. α-Conotoxins are selective antagonists of the nAChR and are an important class of drug leads. So far, the antagonistic mechanism of α-conotoxins toward the nAChRs is still unclear. In this study, we built an α3ß2 nAChR homology model and investigated its conformational transition mechanism upon binding with a highly potent inhibitor, α-conotoxin BuIA, through µs molecular dynamic simulations and site-directed mutagenesis studies. The results suggested that the α3ß2 nAChR underwent global conformational transitions and was stabilized into a closed state with three hydrophobic gates present in the transmembrane domain by BuIA. Finally, the probable antagonistic mechanism of BuIA was proposed. Overall, the closed-state model of the α3ß2 nAChR bound with BuIA is not only essential for understanding the antagonistic mechanism of α-conotoxins but also particularly valuable for development of therapeutic inhibitors in future.

Plant Nutrient Contents Rather Than Physical Traits Are Coordinated Between Leaves and Roots in a Desert Shrubland.

Although leaf economics spectrum (LES) has been extensively tested with regional and global datasets, the correlation among functional traits of desert plants remains largely unclear. Moreover, examinations on whether and how leaf and root traits are coordinated have yielded mixed results. We investigated variations in leaf and fine-root traits across 48 species in a desert community of northern China to test the hypotheses that (1) the leaf-trait syndrome of plant species in desert shrublands follows the predictions of the global LES, and is paralleled by a similar root-trait syndrome, (2) functional traits related to nutrient contents and resource uptake are tightly coordinated between leaves and fine roots in desert ecosystems where plant growth is limited primarily by dry and nutrient-poor conditions, and (3) traits as well as their relationships vary among functional groups. Our results partially supported the LES theory. Specific leaf area (SLA) was correlated with leaf tissue density, phosphorus content, and carbon-to-nitrogen ratio, but not with leaf nitrogen content. Specific root length (SRL) was not correlated with other fine-root traits, and fine-root traits were largely independent of each other. Therefore, fine-root traits did not mirror the leaf-trait syndrome. Fine-root nitrogen and phosphorus contents, nitrogen-to-phosphorous ratio, and carbon-to-nitrogen ratio all increased with analogous leaf traits, whereas SRL was not correlated with SLA. After phylogenetic effects were considered, nutrient contents and their ratios still displayed stronger coordination between leaves and fine roots than did SRL and SLA. The overall pattern of trait variations and relationships suggested differentiation among functional groups. Our results suggest that despite the absence of a root-trait syndrome, fine-root functions in the studied desert community were probably coordinated with leaf functions with respect to nutrient allocation and use.

Photosensitive and Photoswitchable TRPA1 Agonists Optically Control Pain through Channel Desensitization.

Transient receptor potential ankyrin 1 (TRPA1) channel, as a nonselective ligand-gated cation channel robustly in dorsal root ganglion sensory neurons, is implicated in sensing noxious stimuli and nociceptive signaling. However, small-molecule tools targeting TRPA1 lack temporal and spatial resolution, limiting their use for validation of TRPA1 as a therapeutic target for pain. In our previous work, we found that 4,4'-(diazene-1,2-diyl)dianiline (AB1) is a photoswitchable TRPA1 agonist, but the poor water solubility and activity hinder its further development. Here, we report a series of specific and potent azobenzene-derived photoswitchable TRPA1 agonists (series 1 and 2) that enable optical control of the TRPA1 channel. Two representative compounds 1g and 2c can alleviate capsaicin-induced pain in the cheek model of mice through channel desensitization but not in TRPA1 knockout mice. Taken together, our findings demonstrate that photoswitchable TRPA1 agonists can be used as pharmacological tools for study of pain signaling.

Synthesis and Biological Evaluation of Novel Triazine Derivatives as Positive Allosteric Modulators of α7 Nicotinic Acetylcholine Receptors.

Enhancing neuronal α7 nicotinic acetylcholine receptor (α7 nAChR) function can alleviate cognitive deficits. Here, we report the design, synthesis, and evaluation of N-(4-(trifluoromethoxy)phenyl)-1,3,5-triazin-2-amine derivatives 8-10 as a series of novel α7 nAChR positive allosteric modulators (PAMs). The representative compound 10e functions as a type I PAM with an EC50 of 3.0 µM and approximately 38-fold enhancement of α7 current in the presence of agonist acetylcholine (100 µM). It specifically enhances α7 current with high selectivity. Compound 10e shows good pharmacokinetic property in mice. Intraperitoneal injection of 10e (3 mg/kg) exhibits sufficient blood-brain barrier penetration in mice. Furthermore, 10e can also rescue the auditory gating deficit in mice with schizophrenia-like behavior. Molecular docking of 10e with homopentameric α7 nAChR reveals a new mode of action. These results support the potential of 10e for treatment for schizophrenia and Alzheimer's disease.

Partitioning of evapotranspiration and the influencing factors of evapotranspiration components in a shrub ecosystem dominated by Artemisia ordosica and Hedysarum fruticosum var. mongolicum in the Mu Us Desert, Northwest China.

Evapotranspiration (ET) is an important part of water cycle and energy flow in ecosystem. Accurate estimation of ET and its components is critical for understanding the impacts of ecophysiological processes on ecosystem water balance and plant water use strategy. Using the eddy-covariance technique and the micro-lysimeter, we measured ET, evaporation (E), transpiration (T) of the Artemisia ordosica-Hedysarum fruticosum var. mongolicum shrubland in the Mu Us Desert during May 20 to September 15, 2019, quantified the ET components, and analyzed the seasonal characteristics and influencing factors of ET and its components. The results showed that T was the main component of ET in the growing season, with a T/ET of 53.1%. T/ET increased and E/ET decreased as precipitation decreased. The partitioning of evapotranspiration was regulated by precipi-tation. At the seasonal scale, the value of E was positively correlated with soil water content at 10 cm depth (SWC10) and net radiation (Rn), while SWC10 was the main factor influencing E. The value of T increased with the increases of Rn and leaf area index (LAI), and increased first and then decreased with the increases of soil water content at 30 cm layer (SWC30). T was affected by SWC30, Rn and LAI. Moisture was the main influencing factor of ET. The ET/P in the growing season was 109.2% and was 250.5% in May, indicating that the water consumption of ET in early growing season was partly from the precipitation in non-growing season.

Identification of Ear Morphology Genes in Maize (Zea mays L.) Using Selective Sweeps and Association Mapping.

The performance of maize hybrids largely depend on two parental inbred lines. Improving inbred lines using artificial selection is a key task in breeding programs. However, it is important to elucidate the effects of this selection on inbred lines. Altogether, 208 inbred lines from two maize heterosis groups, named Shaan A and Shaan B, were sequenced by the genotype-by-sequencing to detect genomic changes under selection pressures. In addition, we completed genome-wide association analysis in 121 inbred lines to identify candidate genes for ear morphology related traits. In a genome-wide selection scan, the inbred lines from Shaan A and Shaan B groups showed obvious population divergences and different selective signals distributed in 337 regions harboring 772 genes. Meanwhile, functional enrichment analysis showed those selected genes are mainly involved in regulating cell development. Interestingly, some ear morphology related traits showed significant differentiation between the inbred lines from the two heterosis groups. The genome-wide association analysis of ear morphology related traits showed that four associated genes were co-localized in the selected regions with high linkage disequilibrium. Our spatiotemporal pattern and gene interaction network results for the four genes further contribute to our understanding of the mechanisms behind ear and fruit length development. This study provides a novel insight into digging a candidate gene for complex traits using breeding materials. Our findings in relation to ear morphology will help accelerate future maize improvement.

Identification of two natural coumarin enantiomers for selective inhibition of TRPV2 channels.

Thermosensitive transient receptor potential vanilloid 2 (thermoTRPV2) is a nonselective Ca2+ -permeable cation channel broadly expressed, and is implicated in the pathology of diseases such as diabetes and pancreatitis. However, the physiological and pharmacological functions of TRPV2 channels have not been extensively investigated because of the absence of specific modulators. In this study, we report a pair of natural coumarin derivative enantiomers (-)-murraxocin (B304-1) and (+)-murraxocin (B304-2) from Murraya exotica for their selective inhibition of TRPV2 channels expressed in HEK293 cells and native TRPV2 currents in differentiated brown adipocytes. Whole-cell patch clamp recordings confirmed the enantiomers B304-1 and B304-2 could selectively inhibit the agonist mediated activation of TRPV2 current with IC50 values of 22.2 ± 7.8 µM and 3.7 ± 0.7 µM, respectively. Molecular docking and site-directed mutagenesis revealed a key residue I600 of TRPV2 critical for the binding of the enantiomers. Furthermore, B304-1 and B304-2 significantly reversed TRPV2 agonist-induced inhibition of mouse brown adipocyte differentiation. Taken together, our identification of two natural coumarin enantiomers provides valuable tools and chemical leads for further elucidation of TRPV2 channel function, and pharmacological modulation of thermoTRPV2 in brown adipocytes may represent a new therapeutic strategy for treatment of energy imbalance or metabolic disorders.

Highly Efficient Cell Membrane Tracker Based on a Solvatochromic Dye with Near-Infrared Emission.

The cell membrane is composed of a phospholipid bilayer with embedded proteins and maintains cell homeostasis through dynamic changes. An abnormal cell membrane shape could be a sign of unhealthy cells. Probes for subcellular fluorescence imaging that can identify the abnormal plasma membrane and record the dynamic changes are needed. Based on a solvatochromic dye with a near-infrared emission strategy, the amphipathic molecule (E)-2,2'-((4-(2-(4-(dicyanomethylene)-4H-chromen-2-yl)vinyl)phenyl)azanediyl)bis(ethane-1-sulfonic acid) (MRL) contained a hydrophilic sulfo group and a hydrophobic chromone group, which was designed and synthesized for staining the cell membrane and monitoring the morphology of the membranes under different conditions. MRL exhibited an excellent photostability and low cytotoxicity; when cells were incubated with MRL, cell membranes were specifically labeled. MRL is capable of long-term monitoring of the morphological changes of cell membrane.

Synthesis and biological activity study of the retro-isomer of RhTx against TRPV1.

TRPV1 is a ligand-gated ion channel and plays an important role in detecting noxious heat and pain with an unknown mechanism. RhTx from Chinese red-headed centipede activates the TRPV1 channel through the heat activation pathway by binding to the outer pore region, and causes extreme pain. Here, we synthesized RhTx and its retro-isomer RL-RhTx. Their structures were investigated by their circular dichroic spectra and NMR spectra. The effect of RhTx and RL-RhTx on the currents of wild-type and mutants of TRPV1 indicated that RL-RhTx have comparable TRPV1 activation responses to RhTx. A mutagenesis study showed that four TRPV1 residues, including Leu461, Asp602, Tyr632 and Thr634, significantly contributed to the activation effects of RL-RhTx and RhTx, and both peptides probably bind with TRPV1 in similar binding modes. As a novel TRPV1 activator, RL-RhTx provides an essential powerful tool for the investigation of activation mechanisms of TRPV1.