Broadband and strong visible-light-absorbing cuprous sensitizers for boosting photosynthesis.

Rational construction of broadband and strong visible-light-absorbing (BSVLA) earth-abundant complexes is of great importance for efficient and sustainable solar energy utilization. Herein, we explore a universal Cu(I) center to couple with multiple strong visible-light-absorbing antennas to break the energy level limitations of the current noble-metal complexes, resulting in the BSVLA nonprecious complex (Cu-3). Systematic investigations demonstrate that double "ping-pong" energy-transfer processes in Cu-3 involving resonance energy transfer and Dexter mechanism enable a BSVLA between 430 and 620 nm and an antenna-localized long-lived triplet state for efficient intermolecular electron/energy transfer. Impressively, Cu-3 exhibited an outstanding performance for both energy- and electron-transfer reactions. Pseudo-first-order rate constant of photooxidation of 1,5-dihydroxynaphthalene with Cu-3 can achieve a record value of 190.8 × 10-3 min-1 among the molecular catalytic systems, over 30 times higher than that with a noble-metal photosensitizer (PS) [Ru(bpy)3]2+. These findings pave the way to develop BSVLA earth-abundant PSs for boosting photosynthesis.

Resolving Ultraviolet-Visible Spectra for Complex Dissolved Mixtures of Multitudinous Organic Matters in Aerosols.

Light-absorbing organic aerosols, referred to as brown carbon (BrC), play a vital role in the global climate and air quality. Due to the complexity of BrC chromophores, the identified absorbing substances in the ambient atmosphere are very limited. However, without comprehensive knowledge of the complex absorbing compounds in BrC, our understanding of its sources, formation, and evolution mechanisms remains superficial, leading to great uncertainty in climatic and atmospheric models. To address this gap, we developed a constrained non-negative matrix factorization (NMF) model to resolve the individual ultraviolet-visible spectrum for each substance in dissolved organic aerosols, with the power of ultrahigh-performance liquid chromatography-diode array detector-ultrahigh-resolution mass spectrometry (UHPLC-DAD-UHRMS). The resolved spectra were validated by selected standard substances and validation samples. Approximately 40,000 light-absorbing substances were recognized at the MS1 level. It turns out that BrC is composed of a vast number of substances rather than a few prominent chromophores in the urban atmosphere. Previous understanding of the absorbing feature of BrC based on a few identified compounds could be biased. Weak-absorbing substances missed previously play an important role in BrC absorption when they are integrated due to their overwhelming number. This model brings the property exploration of complex dissolved organic mixtures to a molecular level, laying a foundation for identifying potentially significant compositions and obtaining a comprehensive chemical picture.

Pterostilbene alleviates MPTP-induced neurotoxicity by targeting neuroinflammation and oxidative stress.

Pterostilbene (PTE), a naturally occurring phenolic compound primarily found in blueberries, demonstrates neuroprotective properties. However, the role of PTE in Parkinson's disease (PD) remains unclear. This study aimed to investigate the neuroprotective role of PTE in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD animal model. Our findings demonstrate that administering PTE effectively reversed the diminished levels of dopamine in the striatum, thereby ameliorating motor impairments in the MPTP model. Moreover, PTE administration mitigated the loss of dopaminergic (DA) neurons and reduced the upregulation of α-synuclein (α-syn) induced by MPTP. Mechanistic analysis revealed that PTE administration inhibited the activation of microglia and astrocytes, as well as pro-inflammatory factors such as TNF-α and IL-1ß in the MPTP model. Additionally, PTE administration decreased MPTP-induced levels of reactive oxygen species (ROS) and malondialdehyde (MDA), while increasing total antioxidant capacity (TAOC) and superoxide dismutase (SOD) activity, thereby attenuating oxidative stress. Collectively, these findings demonstrate that PTE exerts neuroprotective effects in the MPTP mouse model of PD by suppressing neuroinflammation and oxidative stress. Thus, PTE holds promise as a therapeutic agent for PD.

Reinstatement of the fission yeast species Schizosaccharomyces versatilis Wickerham et Duprat, a sibling species of Schizosaccharomyces japonicus.

Schizosaccharomyces japonicus Yukawa et Maki (1931) and Schizosaccharomyces versatilis Wickerham et Duprat (1945) have been treated as varieties of S. japonicus or as conspecific, based on various approaches including mating trials and nDNA/nDNA optical reassociation studies. However, the type strains of S. japonicus and S. versatilis differ by five substitutions (99.15% identity) and one 1-bp indel in the sequences of the D1/D2 domain of the 26S rRNA gene, and 23 substitutions (96.3% identity) and 31-bp indels in the sequences of internal transcribed spacer (ITS) of rRNA, suggesting that they may not be conspecific. To reassess their taxonomic status, we conducted mating trials and whole-genome analyses. Mating trials using the type strains showed a strong but incomplete prezygotic sterility barrier, yielding interspecies mating products at two orders of magnitude lower efficiency than intraspecies matings. These mating products, which were exclusively allodiploid hybrids, were unable to undergo the haplontic life cycle of the parents. We generated chromosome-level gap-less genome assemblies for both type strains. Whole genome sequences yielded an average nucleotide identity (ANI) of 86.4%, indicating clear separation of S. japonicus and S. versatilis. Based on these findings, we propose the reinstatement of S. versatilis as a distinct species (holotype strain: CBS 103T and ex-types: NRRL Y-1026, NBRC 1607, ATCC 9987, PYCC 7100; Mycobank no.: 847838).

Study on the susceptibility of bovine coronavirus to BALB/c mice.

There are no other bovine coronavirus (BCoV) infection models except calves, which makes efficacy evaluation of vaccines and pathogenic mechanism research of BCoV inconvenient owing to their high value and inconvenient operation. This study aimed to establish a mouse model of BCoV infection. BCoV was used to infect 4-week-old male BALB/c mice and the optimal infection conditions were screened, including the following infection routes: gavage, intraperitoneal injection, and tail vein injection at doses of 1 × 108 TCID50, 2 × 108 TCID50 and 4 × 108 TCID50. Using the optimal infection conditions, BALB/c mice were infected with BCoV, and their body weight, blood routine, inflammatory factors, autopsy, virus distribution, and viral load were measured at 1, 3, 5, and 7 days after infection. The results showed that the optimal conditions for infecting BALB/c mice with BCoV HLJ-325 strain were continuous oral gavage for 3 days with a dose of 4 × 108 TCID50. On the 7th day after infection, there was significant extensive consolidation of the lungs and thinning of the colon wall. Significant inflammation was observed in various organs, especially in the colon and alveoli, where a large number of inflammatory cells infiltrate. Both BCoV Ag and nucleic acid are positive in visceral organs. The viral load in the colon and lungs was significantly higher than that in the other organs (p < 0.001). BCoV-infected mice showed a decreasing trend in body weight starting from day 5, and there was a significant difference compared to the control group on days 6 and 7 (p < 0.001). The total number of white blood cells and lymphocytes began to decrease and was significantly lower than that in the control group 24 h after infection (p < 0.001), and gradually returned to the control level. The cytokine TNF-α, IL-1ß, and IL-6 showed an increasing trend, significantly higher than the control group on day 5 and 7 (p < 0.001). These results indicate that the BCoV HLJ-325 strain can infect BALB/c mice and cause inflammatory reactions and tissue lesions. The most significant effect was observed on the seventh day after infection with a dose of 4 × 108 TCID50 and three consecutive gavages. This study established, for the first time, a BALB/c mouse model of BCoV infection, providing a technical means for evaluating the immune efficacy of BCoV vaccines and studying their pathogenic mechanisms.

Review on Layered Manganese-Based Metal Oxides Cathode Materials for Potassium-Ion Batteries: From Preparation to Modification.

Potassium-ion battery is rich in resources and cheap in price, in the era of lithium-ion battery commercialization, potassium-ion battery is the most likely to replace it. Based on the classification and summary of electrode materials for potassium-ion batteries, this paper focuses on the introduction of manganese-based oxide KxMnO2. The layered KxMnO2 has a large layer spacing and can be embedded with large size potassium-ions. This paper focuses on the preparation and doping of manganese-based cathode materials for potassium-ion batteries, summarizes the main challenges of KxMnO2-based cathode materials in the current stage of research and further looks into its future development direction.

Molecular nociceptive mechanisms in migraine: The migraine cascade.

OBJECTIVE: This review will explore the categorization of migraine-provoking molecules, their cellular actions, site of action and potential drug targets based on the migraine cascade model. METHODS: Personal experience and literature. RESULTS: Migraine impacts over 1 billion people worldwide but is underfunded in research. Recent progress, particularly through the human and animal provocation model, has deepened our understanding of its mechanisms. This model have identified endogenous neuropeptides such as calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating peptide (PACAP) that induces controlled migraine-like attacks leading to significant discoveries of their role in migraine. This knowledge led to the development of CGRP-inhibiting drugs; a groundbreaking migraine treatment now accessible globally. Also a PACAP-inhibiting drug was effective in a recent phase II trial. Notably, rodent studies have shed light on pain pathways and the mechanisms of various migraine-inducing substances identifying novel drug targets. This is primarily done by using selective inhibitors that target specific signaling pathways of the known migraine triggers leading to the hypothesized cellular cascade model of migraine. CONCLUSION: The model of migraine presents numerous opportunities for innovative drug development. The future of new migraine treatments is limited only by the investment from pharmaceutical companies.

All-in-one detection of breast cancer-derived exosomal miRNA on a pen-based paper chip.

Exosomal microRNAs (miRNAs) play a pivotal role in intercellular communication, regulating gene expression in target cells, and hold significant promise as cancer biomarkers for early detection and screening. However, achieving precise and viable detection of exosomal miRNAs remains a challenge. This paper proposes an all-in-one detection strategy for breast cancer-derived exosomal miRNA-21 on a pen-based paper chip (PPC). The PPC is constructed using a modified automatic pen and lateral flow assay (LFA), which results in a cost-effective fabrication process. The user only needs to add the sample and trigger the top of the self-contained PPC after a period of time to complete the entire detection process. To enhance the sensitivity of exosomal miRNA testing, an enzyme-free catalyzed hairpin assembly (CHA) is further introduced, enabling highly sensitive detection of miRNA-21 with a limit of detection (LOD) of 25 fmol. Additionally, the detection of miRNAs in differentially-expressed cells and clinical samples has also been successfully achieved with high specificity. Overall, the proposed PPC provides an effective tool for detecting early cancer, monitoring diseases, and establishing point of care testing (POCT).

Stable Mg Single-Atom Solid Base Catalysts Anchored on Metal-Organic Framework-Derived Nitrogen-Doped Carbon.

Solid base catalysts are widely used in the chemical industry owing to their advantages of environmental friendliness and easy separation. However, their application is limited by basic site aggregation and poor stability. In this study, we report the preparation of magnesium (Mg) single-atom catalysts with high activity and stability by a sublimation-trapping strategy. The Mg net was sublimated as Mg vapor at 620 °C, subsequently transported through argon, and finally trapped on the defects of nitrogen-doped carbon derived from metal-organic framework ZIF-8, producing Mg1/NC. Because of the atomically dispersed Mg sites, the obtained Mg1/NC exhibits high catalytic activity and stability for Knoevenagel condensation of benzaldehyde with malononitrile, which is a typical base-catalyzed reaction. The Mg1/NC catalyst achieves a high efficiency with a turnover frequency of 49.6 h-1, which is much better than that of the traditional counterpart MgO/NC (7.7 h-1). In particular, the activity of Mg1/NC shows no decrease after five catalytic cycles, while that of MgO/NC declines due to the instability of basic sites.

A Near-Explicit Reaction Mechanism of Chlorine-Initiated Limonene: Implications for Health Risks Associated with the Concurrent Use of Cleaning Agents and Disinfectants.

Limonene, a key volatile chemical product (VCP) commonly found in personal care and cleaning agents, is emerging as a major indoor air pollutant. Recently, elevated levels of reactive chlorine species during bleach cleaning and disinfection have been reported to increase indoor oxidative capacity. However, incomplete knowledge of the indoor transformation of limonene, especially the missing chlorine chemistry, poses a barrier to evaluating the environmental implications associated with the concurrent use of cleaning agents and disinfectants. Here, we investigated the reaction mechanisms of chlorinated limonene peroxy radicals (Cl-lim-RO2•), key intermediates in determining the chlorine chemistry of limonene, and toxicity of transformation products (TPs) using quantum chemical calculations and toxicology modeling. The results indicate that Cl-lim-RO2• undergoes a concerted autoxidation process modulated by RO2• and alkoxy radicals (RO•), particularly emphasizing the importance of RO• isomerization. Following this generalized autoxidation mechanism, Cl-lim-RO2• can produce low-volatility precursors of secondary organic aerosols. Toxicological findings further indicate that the majority of TPs exhibit increased respiratory toxicity, mutagenicity, and eye/skin irritation compared to limonene, presenting an occupational hazard for indoor occupants. The proposed near-explicit reaction mechanism of chlorine-initiated limonene significantly enhances our current understanding of both RO2• and RO• chemistry while also highlighting the health risks associated with the concurrent use of cleaning agents and disinfectants.

Secondary Organic Aerosol Formation Potential from Vehicular Non-tailpipe Emissions under Real-World Driving Conditions.

Traffic emissions are a dominant source of secondary organic aerosol (SOA) in urban environments. Though tailpipe exhaust has drawn extensive attention, the impact of non-tailpipe emissions on atmospheric SOA has not been well studied. Here, a closure study was performed combining urban tunnel experiments and dynamometer tests using an oxidation flow reactor in situ photo-oxidation. Results show a significant gap between field and laboratory research; the average SOA formation potential from real-world fleet is 639 ± 156 mg kg fuel-1, higher than the reconstructed result (188 mg kg fuel-1) based on dynamometer tests coupled with fleet composition inside the tunnel. Considering the minimal variation of SOA/CO in emission standards, we also reconstruct CO and find the critical role of high-emitting events in the real-world SOA burden. Different profiles of organic gases are detected inside the tunnel than tailpipe exhaust, such as more abundant C6-C9 aromatics, C11-C16 species, and benzothiazoles, denoting contributions from non-tailpipe emissions to SOA formation. Using these surrogate chemical compounds, we roughly estimate that high-emitting, evaporative emission, and asphalt-related and tire sublimation share 14, 20, and 10% of the SOA budget, respectively, partially explaining the gap between field and laboratory research. These experimental results highlight the importance of non-tailpipe emissions to atmospheric SOA.

Second messenger signalling bypasses CGRP receptor blockade to provoke migraine attacks in humans.

There are several endogenous molecules that can trigger migraine attacks when administered to humans. Notably, calcitonin gene-related peptide (CGRP) has been identified as a key player in a signalling cascade involved in migraine attacks, acting through the second messenger cyclic adenosine monophosphate (cAMP) in various cells, including intracranial vascular smooth muscle cells. However, it remains unclear whether intracellular cAMP signalling requires CGRP receptor activation during a migraine attack in humans. To address this question, we conducted a randomized, double-blind, placebo-controlled, parallel trial using a human provocation model involving the administration of CGRP and cilostazol in individuals with migraine pretreated with erenumab or placebo. Our study revealed that migraine attacks can be provoked in patients by cAMP-mediated mechanisms using cilostazol, even when the CGRP receptor is blocked by erenumab. Furthermore, the dilation of cranial arteries induced by cilostazol was not influenced by the CGRP receptor blockade. These findings provide clinical evidence that cAMP-evoked migraine attacks do not require CGRP receptor activation. This discovery opens up new possibilities for the development of mechanism-based drugs for the treatment of migraine.

Anion Photoelectron Spectroscopy and Quantum Chemistry Calculations of Gas-Phase TaSi17Ì and TaSi18Ì Clusters: Structural Determination, Bonding Characteristics, and Multiplicity of Structural Forms.

This study explores the structures and chemical bonding properties of TaSi17̅ and TaSi18̅ clusters by employing anion photoelectron spectroscopy and theoretical computations. Utilizing CALYPSO and ABCluster programs for initial structure prediction, B3LYP hybrid functional for optimization, and CCSD(T)/def2-TZVPPD level for energy calculations, the research identifies the most stable isomers of these clusters. Key findings include the identification of two coexisting low-energy isomers for TaSi17̅, exhibiting Ta-endohedral fullerene-like cage structures, and the lowest-energy structures of TaSi17̅ and TaSi18̅ anions can be considered as derived from the TaSi16̅ superatom cluster. The study enhances the understanding of group 14 element chemistry and guides the design of novel inorganic metallic compounds, potentially impacting materials science.

Effect of long-acting PEGylated growth hormone for catch-up growth in children with idiopathic short stature: a 2-year real-world retrospective cohort study.

Several evidence gaps exist regarding the use of long-acting polyethylene glycol recombinant human growth hormone (PEG-rhGH) in children with idiopathic short stature (ISS), particularly studies conducted in real-world settings, with long-term follow-up, involving varied dosing regimens, and in comparison with daily rhGH. The study aimed to evaluate the effectiveness, safety, and adherence of once-weekly PEG-rhGH for catch-up growth in children with prepubertal ISS compared to daily rhGH. A real-world retrospective cohort study was conducted in prepubertal children with ISS in China. Children who voluntarily received once-weekly PEG-rhGH or daily rhGH were included and were followed up for 2 years. Ninety-five children were included, 47 received PEG-rhGH 0.2-0.3 mg/kg weekly and 48 received daily rhGH. Outcome measures included effectiveness in catch-up growth, adverse events, and treatment adherence. Height velocity increased significantly in both groups during rhGH therapy. In children who received PEG-rhGH treatment, height velocity was 10.59 ± 1.37 cm/year and 8.75 ± 0.86 cm/year in the first and second year, respectively, which were significantly more than those who received daily rhGH (9.80 ± 1.05 cm/year, P = 0.002, and 8.03 ± 0.89 cm/year, P < 0.001). The height standard deviation score improved at the end of the second year for all children (P < 0.001). However, children who received PEG-rhGH showed more excellent improvement than those with daily rhGH (1.65 ± 0.38 vs. 1.50 ± 0.36, P = 0.001). In children who received PEG-rhGH, lower missed doses were observed than those with daily rhGH (0.75 ± 1.06 vs. 4.4 ± 2.0, P < 0.001). No serious adverse events were observed. CONCLUSION: PEG-rhGH demonstrated superior effectiveness and adherence compared to daily rhGH in the treatment of children with ISS. The safety profiles were similar between the two treatments. WHAT IS KNOWN: • Recombinant human growth hormone (rhGH) has been used to increase adult height in children with idiopathic short stature (ISS), and its safety profile is comparable to other indications for growth hormone treatment. • The use of long-acting rhGH in children with ISS is still an area of uncertainty. WHAT IS NEW: • This 2-year real-world study provides new evidence that PEGylated rhGH (PEG-rhGH) is more effective than daily rhGH in promoting catch-up growth in children with ISS. • PEG-rhGH also demonstrated superior treatment adherence compared to daily rhGH in children with ISS. • The safety profiles of PEG-rhGH and daily rhGH were found to be similar.

Assembly and characterization of the complete mitochondrial genome of Ventilago leiocarpa.

KEY MESSAGE: We reported the mitochondrial genome of Ventilago leiocarpa for the first time. Two and one sites lead to the generation of stop and stat codon through editing were verified. Ventilago leiocarpa, a member of the Rhamnaceae family, is frequently utilized in traditional medicine due to the medicinal properties of its roots. In this study, we successfully assembled the mitogenome of V. leiocarpa using both BGI short reads and Nanopore long reads. This mitogenome has a total length of 331,839 bp. The annotated results showed 36 unique protein-coding, 16 tRNA and 3 rRNA genes in this mitogenome. Furthermore, we confirmed the presence of a branched structure through the utilization of long reads mapping, PCR amplification, and Sanger sequencing. Specifically, the ctg1 can form a single circular molecule or combine with ctg4 to form a linear molecule. Likewise, ctg2 can form a single circular molecule or can be connected to ctg4 to form a linear molecule. Subsequently, through a comparative analysis of the mitogenome and cpgenome sequences, we identified ten mitochondrial plastid sequences (MTPTs), including two complete protein-coding genes and five complete tRNA genes. The existence of MTPTs was verified by long reads. Colinear analysis showed that the mitogenomes of Rosales were highly divergent in structure. Finally, we identified 545 RNA editing sites involving 36 protein-coding genes by Deepred-mt. To validate our findings, we conducted PCR amplification and Sanger sequencing, which confirmed the generation of stop codons in atp9-223 and rps10-391, as well as the generation of a start codon in nad4L-2. This project reported the complex structure and RNA editing event of the V. Leiocarpa mitogenome, which will provide valuable information for the study of mitochondrial gene expression.

Molecular strategies of the pygmy grasshopper Eucriotettix oculatus adapting to long-term heavy metal pollution.

To study the heavy metal accumulation and its impact on insect exterior and chromosome morphology, and reveal the molecular mechanism of insects adapting to long-term heavy metal compound pollution habitats, this study, in the Diaojiang river basin, which has been polluted by heavy metals(HMs) for nearly a thousand years, two Eucriotettix oculatus populations was collected from mining and non-mining areas. It was found that the contents of 7 heavy metals (As, Cd, Pb, Zn, Cu, Sn, Sb) in E. oculatus of the mining area were higher than that in the non-mining 1-11 times. The analysis of morphology shows that the external morphology, the hind wing type and the chromosomal morphology of E. oculatus are significant differences between the two populations. Based on the heavy metal accumulation，morphological change, and stable population density, it is inferred that the mining area population has been affected by heavy metals and has adapted to the environment of heavy metals pollution. Then, by analyzing the transcriptome of the two populations, it was found that the digestion, immunity, excretion, endocrine, nerve, circulation, reproductive and other systems and lysosomes, endoplasmic reticulum and other cell structure-related gene expression were suppressed. This shows that the functions of the above-mentioned related systems of E. oculatus are inhibited by heavy metal stress. However, it has also been found that through the significant up-regulation of genes related to the above system, such as ATP2B, pepsin A, ubiquitin, AQP1, ACOX, ATPeV0A, SEC61A, CANX, ALDH7A1, DLD, aceE, Hsp40, and catalase, etc., and the down-regulation of MAPK signalling pathway genes, can enhanced nutrient absorption, improve energy metabolism, repair damaged cells and degrade abnormal proteins, maintain the stability of cells and systems, and resist heavy metal damage so that E. oculatus can adapt to the environment of heavy metal pollution for a long time.

Three new red neutral and ionic iridium(III) complexes based on the same main ligand and auxiliary ligand but with different counterions for solution-processed organic light-emitting diodes.

Three new neutral and ionic phosphorescent iridium(III) complexes were successfully prepared using 1-(6-methoxynaphthalen-2-yl)isoquinoline as the main ligand, while the auxiliary ligand was 2-(2-1H-imidazolyl)pyridine. Three complexes (Ir1, Ir2, Ir3) showed red emission, peaking at 610, 609, and 615 nm, respectively, and they exhibited good solubility and excellent photophysical properties in different solvents, which is suitable to prepare organic light-emitting diodes (OLEDs) by solution method. Among the three OLEDs prepared by iridium(III) complexes using the solution method, the device based on Ir2 possessed better electroluminescent properties, and its maximum brightness, current efficiency (CE), power efficiency (PE), and the maximum external quantum efficiency (EQE) were 507.2 cd m-2 , 0.14 cd A-1 , 0.06 lm W-1 , and 0.14%. respectively, proving that the three complexes have a certain of potential for OLEDs applications and are expected to expand the applications of iridium(III) complexes for OLEDs.

Improved A* Algorithm for Mobile Robots under Rough Terrain Based on Ground Trafficability Model and Ground Ruggedness Model.

Considering that the existing path planning algorithms for mobile robots under rugged terrain do not consider the ground flatness and the lack of optimality, which leads to the instability of the center of mass of the mobile robot, this paper proposes an improved A* algorithm for mobile robots under rugged terrain based on the ground accessibility model and the ground ruggedness model. Firstly, the ground accessibility and ruggedness models are established based on the elevation map, expressing the ground flatness. Secondly, the elevation cost function that can obtain the optimal path is designed based on the two types of models combined with the characteristics of the A* algorithm, and the continuous cost function is established by connecting with the original distance cost function, which avoids the center-of-mass instability caused by the non-optimal path. Finally, the effectiveness of the improved algorithm is verified by simulation and experiment. The results show that compared with the existing commonly used path planning algorithms under rugged terrain, the enhanced algorithm improves the smoothness of paths and the optimization degree of paths in the path planning process under rough terrain.

VPAC1 and VPAC2 receptors mediate tactile hindpaw hypersensitivity and carotid artery dilatation induced by PACAP38 in a migraine relevant mouse model.

BACKGROUND: Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide pivotal in migraine pathophysiology and is considered a promising new migraine drug target. Although intravenous PACAP triggers migraine attacks and a recent phase II trial with a PACAP-inhibiting antibody showed efficacy in migraine prevention, targeting the PACAP receptor PAC1 alone has been unsuccessful. The present study investigated the role of three PACAP receptors (PAC1, VPAC1 and VPAC2) in inducing migraine-relevant hypersensitivity in mice. METHODS: Hindpaw hypersensitivity was induced by repeated PACAP38 injections. Tactile sensitivity responses were quantified using von Frey filaments in three knockout (KO) mouse strains, each lacking one of the PACAP-receptors (Ntotal = 160). Additionally, ex vivo wire myography was used to assess vasoactivity of the carotid artery, and gene expression of PACAP receptors was examined by qPCR. RESULTS: PACAP38 induced hypersensitivity in WT controls (p < 0.01) that was diminished in VPAC1 and VPAC2 KO mice (p < 0.05). In contrast, PAC1 KO mice showed similar responses to WT controls (p > 0.05). Myograph experiments supported these findings showing diminished vasoactivity in VPAC1 and VPAC2 KO mice. We found no upregulation of the non-modified PACAP receptors in KO mice. CONCLUSIONS: This study assessed all three PACAP receptors in a migraine mouse model and suggests a significant role of VPAC receptors in migraine pathophysiology. The lack of hypersensitivity reduction in PAC1 KO mice suggests the involvement of other PACAP receptors or compensatory mechanisms. The results indicate that targeting only individual PACAP receptors may not be an effective migraine treatment.

Identification of Crucial Photosensitizing Factors to Promote CO2 -to-CO Conversion.

The sensitizing ability of a catalytic system is closely related to the visible-light absorption ability, excited-state lifetime, redox potential, and electron-transfer rate of photosensitizers (PSs), however it remains a great challenge to concurrently mediate these factors to boost CO2 photoreduction. Herein, a series of Ir(III)-based PSs (Ir-1-Ir-6) were prepared as molecular platforms to understand the interplay of these factors and identify the primary factors for efficient CO2 photoreduction. Among them, less efficient visible-light absorption capacity results in lower CO yields of Ir-1, Ir-2 or Ir-4. Ir-3 shows the most efficient photocatalytic activity among these mononuclear PSs due to some comprehensive parameters. Although the Kobs of Ir-3 is ≈10 times higher than that of Ir-5, the CO yield of Ir-3 is slightly higher than that of Ir-5 due to the compensation of Ir-5's strong visible-light-absorbing ability. Ir-6 exhibits excellent photocatalytic performance due to the strong visible-light absorption ability, comparable thermodynamic driving force, and electron transfer rate among these PSs. Remarkably, the CO2 photoreduction to CO with Ir-6 can achieve 91.5 µmol, over 54 times higher than Ir-1, and the optimized TONC-1 can reach up to 28160. Various photophysical properties of the PSs were concurrently adjusted by fine ligand modification to promote CO2 photoreduction.