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.

Identification of a new retigabine derivative with improved photostability for selective activation of neuronal Kv7 channels and antiseizure activity.

OBJECTIVE: Pharmacological activation of neuronal Kv7 channels by the antiepileptic drug retigabine (RTG; ezogabine) has been proven effective in treating partial epilepsy. However, RTG was withdrawn from the market due to the toxicity caused by its phenazinium dimer metabolites, leading to peripheral skin discoloration and retinal abnormalities. To address the undesirable metabolic properties of RTG and prevent the formation of phenazinium dimers, we made chemical modifications to RTG, resulting in a new RTG derivative, 1025c, N,N'-{4-[(4-fluorobenzyl) (prop-2-yn-1-yl)amino]-1,2-phenylene}bis(3,3-dimethylbutanamide). METHODS: Whole-cell recordings were used to evaluate Kv7 channel openers. Site-directed mutagenesis and molecular docking were adopted to investigate the molecular mechanism underlying 1025c and Kv7.2 interactions. Mouse seizure models of maximal electroshock (MES), subcutaneous pentylenetetrazol (scPTZ), and PTZ-induced kindling were utilized to test compound antiepileptic activity. RESULTS: The novel compound 1025c selectively activates whole-cell Kv7.2/7.3 currents in a concentration-dependent manner, with half-maximal effective concentration of .91 ± .17 µmol·L-1. The 1025c compound also causes a leftward shift in Kv7.2/7.3 current activation toward a more hyperpolarized membrane potential, with a shift of the half voltage of maximal activation (ΔV1/2) of -18.6 ± 3.0 mV. Intraperitoneal administration of 1025c demonstrates dose-dependent antiseizure activities in assays of MES, scPTZ, and PTZ-induced kindling models. Moreover, through site-directed mutagenesis combined with molecular docking, a key residue Trp236 has been identified as critical for 1025c-mediated activation of Kv7.2 channels. Photostability experiments further reveal that 1025c is more photostable than RTG and is unable to dimerize. SIGNIFICANCE: Our findings demonstrate that 1025c exhibits potent and selective activation of neuronal Kv7 channels without being metabolized to phenazinium dimers, suggesting its developmental potential as an antiseizure agent for therapy.

Experimental investigation of thermal runaway in 40Ah prismatic lithium batteries at different SOC.

With the evolution of energy storage, Thermal Runaway (TR) stands out as the most critical safety concern for Lithium-Ion Batteries (LIBs). This study employs a prismatic lithium battery with a nominal capacity of 40Ah, featuring Li(Ni0.6Co0.2Mn0.2)O2 as the cathode material. The investigation delves into the thermal runaway characteristics of the battery at 25%, 50%, 75%, and 100% State of Charge (SOC) in a nitrogen environment. The findings indicate: 1) an ascending trend in the highest temperatures at various points within the battery as SOC increases, accompanied by a declining trend in normalized gas production and a non-linear relationship between the heat released during TR and the stored electrochemical energy; 2) the highest temperature point within the battery consistently resides at the surface, offering insights for the temperature monitoring of the Battery Thermal Management System (BTMS); 3) a direct correlation between higher SOC and increased material ejection, with a mass loss rate of 25.8% at 100% SOC, a static total gas production of 2.45 mol, and a maximum explosion index of 0.2886 kPa⋅m⋅s⁻¹.

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.

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.

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.

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.

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.

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.

Visualizing TRPA1 in the Plasma Membrane for Rapidly Screening Optical Control Agonists via a Photochromic Ligand Based Fluorescent Probe.

Fluorescent probes have been used as effective methods for profiling proteins in biological systems because of their high selectivity, sensitivity, and temporal-spatial resolution. A specific fluorescent probe for understanding the function of the transient receptor potential ankyrin 1 (TRPA1) channel that is closely related with various diseases like persistent pain, respiratory, and chronic itch syndromes, however, is still lacking. Here, we report a "turn-on" fluorescent probe (A1CA) for visualizing TRPA1 channels in the plasma membrane of live cells based on a photochromic ligand derived from 4-(phenylazo)benzenamine. Evaluating the specificity and sensitivity of A1CA by electrophysiology and confocal imaging showed that the A1CA probe displays higher affinity and selectivity to TRPA1 channel versus all other ion channels including TRPV1, TRPV3, Nav1.4, Nav1.5, and hERG. Based on the supporting evidence, A1CA has great potential as a molecular imaging probe for high-throughput screening of novel TRPA1 agonists.

Pharmacological characterization of JWX-A0108 as a novel type I positive allosteric modulator of α7 nAChR that can reverse acoustic gating deficits in a mouse prepulse inhibition model.

The α7 nicotinic acetylcholine receptor (α7 nAChR) is a ligand-gated Ca2+-permeable homopentameric ion channel implicated in cognition and neuropsychiatric disorders. Pharmacological enhancement of α7 nAChR function has been suggested for improvement of cognitive deficits. In the present study, we characterized a thiazolyl heterocyclic derivative, 6-(2-chloro-6-methylphenyl)-2-((3-fluoro-4-methylphenyl)amino)thiazolo[4,5-d]pyrimidin-7(6H)-one (JWX-A0108), as a novel type I α7 nAChR positive allosteric modulator (PAM), and evaluated its ability to reverse auditory gating and spatial working memory deficits in mice. In Xenopus oocytes expressing human nAChR channels, application of JWX-A0108 selectively enhanced α7 nAChR-mediated inward current in the presence of the agonist ACh (EC50 value = 4.35 ± 0.12 µM). In hippocampal slices, co-application of ACh and JWX-A0108 (10 µM for each) markedly increased both the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded in pyramidal neurons, but JWX-A0108 did not affect GABA-induced current in oocytes expressing human GABAA receptor α1ß3γ2 and α5ß3γ2 subtypes. In mice with MK-801-induced deficits in auditory gating, administration of JWX-A0108 (1, 3, and 10 mg/kg, i.p.) dose-dependently attenuates MK-801-induced auditory gating deficits in five prepulse intensities (72, 76, 80, 84, and 88 dB). Furthermore, administration of JWX-A0108 (0.03, 0.1, or 0.3 mg/kg, i.p.) significantly reversed MK-801-induced impaired spatial working memory in mice. Our results demonstrate that JWX-A0108 is a novel type I PAM of α7 nAChR, which may be beneficial for improvement of cognitive deficits commonly found in neuropsychiatric disorders such as schizophrenia and Alzheimer's disease.

Antipruritic Effect of Natural Coumarin Osthole through Selective Inhibition of Thermosensitive TRPV3 Channel in the Skin.

Coumarin osthole is a dominant bioactive ingredient of the natural Cnidium monnieri plant commonly used for traditional Chinese herbal medicines for therapies and treatments including antipruritus and antidermatitis. However, the molecular mechanism underlying the action of osthole remains unclear. In this study, we report that osthole exerts an antipruritic effect through selective inhibition of Ca2+-permeable and thermosensitive transient receptor potential vanilloid 3 (TRPV3) cation channels that are primarily expressed in the keratinocytes of the skin. Coumarin osthole was identified as an inhibitor of TRPV3 channels transiently expressed in HEK293 cells in a calcium fluorescent assay. Inhibition of the TRPV3 current by osthole and its selectivity were further confirmed by whole-cell patch clamp recordings of TRPV3-expressing HEK293 cells and mouse primary cultured keratinocytes. Behavioral evaluation demonstrated that inhibition of TRPV3 by osthole or silencing by knockout of the TRPV3 gene significantly reduced the scratching induced by either acetone-ether-water or histamine in localized rostral neck skin in mice. Taken together, our findings provide a molecular basis for use of natural coumarin osthole from the C. monnieri plant in antipruritic or skin care therapy, thus establishing a significant role of the TRPV3 channel in chronic itch signaling or acute histamine-dependent itch sensation.

A pivotal role for the activation of TRPV3 channel in itch sensations induced by the natural skin sensitizer carvacrol.

Itching is an intricate, common symptom of dermatologic and systemic diseases, and both TRPV3 and TRPA1 channels have been suggested to function as downstream effector targets. But the relative contributions of TRPV3 and TRPA1 to itch sensation in vivo remain unclear. To dissect the role of TRPA1 or TRPV3 in the cutaneous sensation of itching, we took the advantage of a natural compound carvacrol from oregano, and examined its effect on the induction of scratching behavior in mice. We showed that the intradermal injection of carvacrol (0.01%, 0.1% and 1%, 50 µL) induced scratching in a concentration-dependent manner. But in TRPV3-knockout mice, the scratching induced by carvacrol (1%, 50 µL) was markedly decreased by approximately 64% (from 275 scratching bouts down to 90) within 60 min. Further analysis revealed that TRPV3-knockout caused a reduction of scratching bouts for approximately 40% in the first 20 min (the initial phase), whereas the scratching bouts were reduced by approximately 90% in the last 40 min (the sustained phase). These results were in consistence with those in our whole-cell recordings in HEK-293T cells expressing either TRPA1 or TRPV3: carvacrol exhibited similar potencies in activating either TRPA1 or TRPV3, but carvacrol-activated TRPA1 current showed a rapid desensitization, which was reduced by approximately 90% within 5 min before a complete washout, whereas carvacrol-induced TRPV3 current showed a slow desensitization that caused less than 30% of current reduction in 10 min and left a significant residual TRPV3 current after washout. Our results demonstrate that carvacrol from plant oregano is a skin sensitizer or allergen; TRPV3 is involved in the initial phase and the sustained phase of pruritus, whereas TRPA1 likely contributes to the initial phase.

Selective Activation of Nociceptor TRPV1 Channel and Reversal of Inflammatory Pain in Mice by a Novel Coumarin Derivative Muralatin L from Murraya alata.

Coumarin and its derivatives are fragrant natural compounds isolated from the genus Murraya that are flowering plants widely distributed in East Asia, Australia, and the Pacific Islands. Murraya plants have been widely used as medicinal herbs for relief of pain, such as headache, rheumatic pain, toothache, and snake bites. However, little is known about their analgesic components and the molecular mechanism underlying pain relief. Here, we report the bioassay-guided fractionation and identification of a novel coumarin derivative, named muralatin L, that can specifically activate the nociceptor transient receptor potential vanilloid 1 (TRPV1) channel and reverse the inflammatory pain in mice through channel desensitization. Muralatin L was identified from the active extract of Murraya alata against TRPV1 transiently expressed in HEK-293T cells in fluorescent calcium FlexStation assay. Activation of TRPV1 current by muralatin L and its selectivity were further confirmed by whole-cell patch clamp recordings of TRPV1-expressing HEK-293T cells and dorsal root ganglion neurons isolated from mice. Furthermore, muralatin L could reverse inflammatory pain induced by formalin and acetic acid in mice but not in TRPV1 knock-out mice. Taken together, our findings show that muralatin L specifically activates TRPV1 and reverses inflammatory pain, thus highlighting the potential of coumarin derivatives from Murraya plants for pharmaceutical and medicinal applications such as pain therapy.

Identification and in vitro pharmacological characterization of a novel and selective α7 nicotinic acetylcholine receptor agonist, Br-IQ17B.

AIM: Alpha7-nicotinic acetylcholine receptor (α7 nAChR) is a ligand-gated Ca(2+)-permeable ion channel implicated in cognition and neuropsychiatric disorders. Activation of α7 nAChR improves learning, memory, and sensory gating in animal models. To identify novel α7 nAChR agonists, we synthesized a series of small molecules and characterized a representative compound, Br-IQ17B, N-[(3R)-1-azabicyclo[2,2,2]oct-3-yl]-5-bromoindolizine-2-carboxamide, which specifically activates α7 nAChR. METHODS: Two-electrode voltage clamp (TEVC) recordings were primarily used for screening in Xenopus oocytes expressing human α7 nAChR. Assays, including radioisotope ligand binding, Western blots, whole-cell recordings of hippocampal culture neurons, and spontaneous IPSC recordings of brain slices, were also utilized to evaluate and confirm the specific activation of α7 nAChR by Br-IQ17B. RESULTS: Br-IQ17B potently activates α7 nAChR with an EC50 of 1.8±0.2 µmol/L. Br-IQ17B is selective over other subtypes such as α4ß2 and α3ß4, but it blocks 5-HT3A receptors. Br-IQ17B displaced binding of the α7 blocker [(3)H]-MLA to hippocampal crude membranes with a Ki of 14.9±3.2 nmol/L. In hippocampal neurons, Br-IQ17B evoked α7-like currents that were inhibited by MLA and enhanced in the presence of the α7 PAM PNU-120596. In brain slice recordings, Br-IQ17B enhanced GABAergic synaptic transmission in CA1 neurons. Mechanistically, Br-IQ17B increased ERK1/2 phosphorylation that was MLA-sensitive. CONCLUSION: We identified the novel, potent, and selective α7 agonist Br-IQ17B, which enhances synaptic transmission. Br-IQ17B may be a helpful tool to understand new aspects of α7 nAChR function, and it also has potential for being developed as therapy for schizophrenia and cognitive deficits.

SABRE: ligand/structure-based virtual screening approach using consensus molecular-shape pattern recognition.

We present an efficient and rational ligand/structure shape-based virtual screening approach combining our previous ligand shape-based similarity SABRE (shape-approach-based routines enhanced) and the 3D shape of the receptor binding site. Our approach exploits the pharmacological preferences of a number of known active ligands to take advantage of the structural diversities and chemical similarities, using a linear combination of weighted molecular shape density. Furthermore, the algorithm generates a consensus molecular-shape pattern recognition that is used to filter and place the candidate structure into the binding pocket. The descriptor pool used to construct the consensus molecular-shape pattern consists of four dimensional (4D) fingerprints generated from the distribution of conformer states available to a molecule and the 3D shapes of a set of active ligands computed using SABRE software. The virtual screening efficiency of SABRE was validated using the Database of Useful Decoys (DUD) and the filtered version (WOMBAT) of 10 DUD targets. The ligand/structure shape-based similarity SABRE algorithm outperforms several other widely used virtual screening methods which uses the data fusion of multiscreening tools (2D and 3D fingerprints) and demonstrates a superior early retrieval rate of active compounds (EF(0.1%) = 69.0% and EF(1%) = 98.7%) from a large size of ligand database (∼95,000 structures). Therefore, our developed similarity approach can be of particular use for identifying active compounds that are similar to reference molecules and predicting activity against other targets (chemogenomics). An academic license of the SABRE program is available on request.

Application of the 4D fingerprint method with a robust scoring function for scaffold-hopping and drug repurposing strategies.

Two factors contribute to the inefficiency associated with screening pharmaceutical library collections as a means of identifying new drugs: [1] the limited success of virtual screening (VS) methods in identifying new scaffolds; [2] the limited accuracy of computational methods in predicting off-target effects. We recently introduced a 3D shape-based similarity algorithm of the SABRE program, which encodes a consensus molecular shape pattern of a set of active ligands into a 4D fingerprint descriptor. Here, we report a mathematical model for shape similarity comparisons and ligand database filtering using this 4D fingerprint method and benchmarked the scoring function HWK (Hamza-Wei-Korotkov), using the 81 targets of the DEKOIS database. Subsequently, we applied our combined 4D fingerprint and HWK scoring function VS approach in scaffold-hopping and drug repurposing using the National Cancer Institute (NCI) and Food and Drug Administration (FDA) databases, and we identified new inhibitors with different scaffolds of MycP1 protease from the mycobacterial ESX-1 secretion system. Experimental evaluation of nine compounds from the NCI database and three from the FDA database displayed IC50 values ranging from 70 to 100 µM against MycP1 and possessed high structural diversity, which provides departure points for further structure-activity relationship (SAR) optimization. In addition, this study demonstrates that the combination of our 4D fingerprint algorithm and the HWK scoring function may provide a means for identifying repurposed drugs for the treatment of infectious diseases and may be used in the drug-target profile strategy.

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 dynamic regulome of shoot-apical-meristem-related homeobox transcription factors modulates plant architecture in maize.

BACKGROUND: The shoot apical meristem (SAM), from which all above-ground tissues of plants are derived, is critical to plant morphology and development. In maize (Zea mays), loss-of-function mutant studies have identified several SAM-related genes, most encoding homeobox transcription factors (TFs), located upstream of hierarchical networks of hundreds of genes. RESULTS: Here, we collect 46 transcriptome and 16 translatome datasets across 62 different tissues or stages from the maize inbred line B73. We construct a dynamic regulome for 27 members of three SAM-related homeobox subfamilies (KNOX, WOX, and ZF-HD) through machine-learning models for the detection of TF targets across different tissues and stages by combining tsCUT&Tag, ATAC-seq, and expression profiling. This dynamic regulome demonstrates the distinct binding specificity and co-factors for these homeobox subfamilies, indicative of functional divergence between and within them. Furthermore, we assemble a SAM dynamic regulome, illustrating potential functional mechanisms associated with plant architecture. Lastly, we generate a wox13a mutant that provides evidence that WOX13A directly regulates Gn1 expression to modulate plant height, validating the regulome of SAM-related homeobox genes. CONCLUSIONS: The SAM-related homeobox transcription-factor regulome presents an unprecedented opportunity to dissect the molecular mechanisms governing SAM maintenance and development, thereby advancing our understanding of maize growth and shoot architecture.

Microscopic Modes and Free Energies for Topoisomerase I-DNA Covalent Complex Binding with Non-campothecin Inhibitors by Molecular Docking and Dynamics Simulations.

Topoisomerase I (Topo1) has been identified as an attractive target for anticancer drug development due to its central role in facilitating the nuclear process of the DNA. It is essential for rational design of novel Topo1 inhibitors to reliably predict the binding structures of the Topo1 inhibitors interacting with the Topo1-DNA complex. The detailed binding structures and binding free energies for the Topo1-DNA complex interacting with typical non-camptothecin (CPT) Topo1 inhibitors have been examined by performing molecular docking, molecular dynamic (MD) simulations, and binding free energy calculations. The computational results provide valuable insights into the binding modes of the inhibitors binding with the Topo1-DNA complex and the key factors affecting the binding affinity. It has been demonstrated that the - stacking interaction with the DNA base pairs and the hydrogen bonding with Topo1 have the pivotal contributions to the binding structures and binding free energies, although the van der Waals and electrostatic interactions also significantly contribute to the stabilization of the binding structures. The calculated binding free energies are in good agreement with the available experiment activity data. The detailed binding modes and the crucial factors affecting the binding free energies obtained from the present computational studies may provide valuable insights for future rational design of novel, more potent Topo1 inhibitors.