GRAS transcription factor PINNATE-LIKE PENTAFOLIATA2 controls compound leaf morphogenesis in Medicago truncatula.

The milestone of compound leaf development is the generation of separate leaflet primordia during the early stages, which involves two linked but distinct morphogenetic events: leaflet initiation and boundary establishment for leaflet separation. Although some progress in understanding the regulatory pathways for each event have been made, it is unclear how they are intrinsically coordinated. Here, we identify the PINNATE-LIKE PENTAFOLIATA2 (PINNA2) gene encoding a newly identified GRAS transcription factor in Medicago truncatula. PINNA2 transcripts are preferentially detected at organ boundaries. Its loss-of-function mutations convert trifoliate leaves into a pinnate pentafoliate pattern. PINNA2 directly binds to the promoter region of the LEAFY orthologue SINGLE LEAFLET1 (SGL1), which encodes a key positive regulator of leaflet initiation, and downregulates its expression. Further analysis revealed that PINNA2 synergizes with two other repressors of SGL1 expression, the BEL1-like homeodomain protein PINNA1 and the C2H2 zinc finger protein PALMATE-LIKE PENTAFOLIATA1 (PALM1), to precisely define the spatiotemporal expression of SGL1 in compound leaf primordia, thereby maintaining a proper pattern of leaflet initiation. Moreover, we showed that the enriched expression of PINNA2 at the leaflet-to-leaflet boundaries is positively regulated by the boundary-specific gene MtNAM, which is essential for leaflet boundary formation. Together, these results unveil a pivotal role of the boundary-expressed transcription factor PINNA2 in regulating leaflet initiation, providing molecular insights into the coordination of intricate developmental processes underlying compound leaf pattern formation.

Enhancement of in situ detection and imaging of phytohormones in plant tissues by MALDI-MSI using 2,4-dihydroxy-5-nitrobenzoic acid as a novel matrix.

Phytohormones possess unique chemical structures, and their physiological effects are regulated through intricate interactions or crosstalk among multiple phytohormones. MALDI-MSI enables the simultaneous detection and imaging of multiple hormones. However, its application for tracing phytohormones is currently restricted by low abundance of hormone in plant and suboptimal matrix selection. 2,4-Dihydroxy-5-nitrobenzoic acid (DHNBA) was reported as a new MALDI matrix for the enhanced detection and imaging of multiple phytohormones in plant tissues. DHNBA demonstrates remarkable sensitivity improvement when compared to the commonly used matrix, 2,5-dihydroxybenzoic acid (DHB), in the detection of isoprenoid cytokinins (trans-zeatin (tZ), dihy-drozeatin (DHZ), meta-topolin (mT), and N6-(Δ2-isopentenyl) adenine (iP)), jasmonic acid (JA), abscisic acid (ABA), and 1-aminocyclo-propane-1-carboxylic acid (ACC) standards. The distinctive properties of DHNBA (i.e. robust UV absorption, uniform matrix deposition, negligible background interference, and high ionization efficiency of phytohormones) make it as an ideal matrix for enhanced detection and imaging of phytohormones, including tZ, DHZ, ABA, indole-3-acetic acid (IAA), and ACC, by MALDI-MSI in various plant tissues, for example germinating seeds, primary/lateral roots, and nodules. Employing DHNBA significantly enhances our capability to concurrently track complex phytohormone biosynthesis pathways while providing precise differentiation of the specific roles played by individual phytohormones within the same category. This will propel forward the comprehensive exploration of phytohormonal functions in plant science.

Phase State Regulates Photochemical HONO Production from NaNO3/Dicarboxylic Acid Mixtures.

Field observations of daytime HONO source strengths have not been well explained by laboratory measurements and model predictions up until now. More efforts are urgently needed to fill the knowledge gaps concerning how environmental factors, especially relative humidity (RH), affect particulate nitrate photolysis. In this work, two critical attributes for atmospheric particles, i.e., phase state and bulk-phase acidity, both influenced by ambient RH, were focused to illuminate the key regulators for reactive nitrogen production from typical internally mixed systems, i.e., NaNO3 and dicarboxylic acid (DCA) mixtures. The dissolution of only few oxalic acid (OA) crystals resulted in a remarkable 50-fold increase in HONO production compared to pure nitrate photolysis at 85% RH. Furthermore, the HONO production rates (PHONO) increased by about 1 order of magnitude as RH rose from <5% to 95%, initially exhibiting an almost linear dependence on the amount of surface absorbed water and subsequently showing a substantial increase in PHONO once nitrate deliquescence occurred at approximately 75% RH. NaNO3/malonic acid (MA) and NaNO3/succinic acid (SA) mixtures exhibited similar phase state effects on the photochemical HONO production. These results offer a new perspective on how aerosol physicochemical properties influence particulate nitrate photolysis in the atmosphere.

The Relationship Between Ureaplasma Species and Male Infertility: Pathogenicity, Biology, Diagnosis, and Treatment.

Objective: Ureaplasma spp. comprise a group of mycoplasmas containing two human-associated species, namely, Ureaplasma urealyticum (UUR) and Ureaplasma parvum (UPA). The characterization of Ureaplasma species as pathogens contributing to male infertility remains a subject of considerable controversy. While numerous authors have proposed a relationship between UUR and changes in fertility, there is limited evidence supporting the involvement of UPA in this context. There has been an increased focus on Ureaplasma spp. and its potential role in the development of male infertility, especially over the past few years. The review aims to clarify the relationship between Ureaplasma species and male infertility. Methods: Firstly, we introduce a background of the appropriate biology including growth characteristics, the divided biovars, and the transmission pathways. Secondly, we examine the studies that support a causal role for Ureaplasma spp. in the development of infertility in the last 30 years. Finally, the diagnosed method, antimicrobial susceptibility, and potential therapeutic considerations are evaluated. Results: UPA and UUR can impair semen motility. The species of Ureaplasma spp., the sexual history of the patient, the number of sexual partners, the load of Ureaplasma, and antimicrobial resistance are expected to constitute key risk factors in the development of male infertility. In terms of treatment, Doxycycline remains the drug of first choice for ureaplasmal infections. Conclusion: Ureaplasma spp. are not simply "innocent bystanders" in infertility and may indeed be an "underestimated enemy of human reproduction". Ureaplasma spp. can be considered an etiological agent in unexplained infertility and a useful marker.

Effect of liquid level monitor gas injection point size on information source amplitude-frequency characteristics.

In order to analyse the effect of the injection point size of the CBM (Coalbed Methane) well level monitor on the amplitude and frequency of pressure pulsations in the wellhead manifold, numerical simulations and experiments were carried out to investigate the effect of different injection point sizes on the amplitude and frequency of pressure pulsations downstream of the sudden expansion structure. Using compressed air as the fluid and the size of the injection point as the variable, the amplitude and frequency of pressure pulsations at different locations downstream of the sudden expansion structure were tested. The results show that the pressure pulsation amplitude is affected by the size of the injection point, and the larger the injection point is, the larger the pressure pulsation amplitude is; the size of the injection point has less influence on the pressure pulsation frequency downstream of the protruding and expanding structure, and the pressure pulsation frequency at 0.5 m and 1 m downstream of the protruding and expanding structure is in the vicinity of 76 Hz. Therefore, the echo signal processing should be filtered around this frequency to obtain accurate liquid level echo signals, so as to improve the accuracy of liquid level monitoring and realise the efficient development of coalbed methane wells.

Mo Doping to Modify Lattice and Morphology of the LiNi0.9Co0.05Mn0.05O2 Cathode toward High-Efficient Lithium-Ion Storage.

The Ni-rich Co-poor layered cathode (LiNixCoyMn1-x-yO2, x ≥ 0.9) is a candidate for the next-generation lithium-ion batteries due to its high specific capacity and low cost. However, the inherent structural instability and slow kinetics of Li+ migration hinder their large-scale application. Mo doping is proposed to enhance the crystal structure stability of LiNi0.9Co0.05Mn0.05O2 and to ensure the preservation of the spherical secondary particles after the cycle. The characterization results indicate that Mo doping not only significantly relieves the lattice strain accompanied by H2 → H3 phase transition but also alleviates particle stress accumulation to avoid pulverization. The Mo-modification allows the generation of uniform fine primary particulates and further agglomeration into the smooth secondary particles to inhibit electrolyte penetration. Hence, the Mo-modified sample NCM90-1%Mo displays an excellent capacity retention of 85.9% after 200 cycles at 0.5 C current density, which is 23.8% higher than that of the pristine NCM90. In addition, with the expansion of the Li slab to accelerate Li+ diffusion and the fine primary particles to shorten the Li+ pathway, the NCM90-1%Mo sample exhibits a high discharge capacity of 150 mAh g-1 at 5 C current density. This work provides a new thought for the design and construction of high-capacity cathode materials for the next-generation lithium-ion batteries.

Visual and refractive outcomes of opposite clear corneal incision combined with rotationally asymmetric multifocal intraocular lens implantation.

Purpose: To evaluate the visual and refractive outcomes of astigmatic cataract patients following opposite clear corneal incision (OCCI) combined with rotationally asymmetric multifocal intraocular lens (IOL) implantation. Setting: Department of Ophthalmology, Zhongshan Hospital (Xiamen), Fudan University, People's Republic of China. Design: Retrospective cohort study. Methods: This study comprised 58 cataract eyes of 54 patients with corneal astigmatism who underwent phacoemulsification and rotationally asymmetric multifocal IOL implantation which received either OCCI (OCCI group) or a single clear corneal incision (SCCI group). The follow-up period was 3 months after surgery. Distance, intermediate and near visual acuity, refractive outcomes, and corneal anterior keratometry were compared between the two groups. Vector analysis was used to evaluate astigmatism correction. Results: Three months after surgery, the distance, intermediate and near visual acuity, and sphere remained comparable between the two groups, but a significant difference was detected in residual astigmatism and anterior corneal keratometric astigmatism. In the OCCI group, the residual astigmatism and keratometric astigmatism were -0.60 ± 0.29 D and 0.59 ± 0.28 D, respectively, which were lower than those in SCCI groups (-1.18 ± 0.47 D and 1.15 ± 0.45 D, both p < 0.05). In vector analysis, the difference vector (DV), angle of error (AoE), absolute AoE, index of success (IoS) and correction index (CI) were statistically significantly different between the two groups (p < 0.05). Conclusion: OCCI combined with rotationally asymmetric multifocal intraocular lens implantation showed predictable and desirable efficacy in treating cataract patients with astigmatism.

Fibrinogen and tumors.

Elevated plasma fibrinogen (Fg) levels consistently correlate with an unfavorable prognosis in various tumor patient cohorts. Within the tumor microenvironment, aberrant deposition and expression of Fg have been consistently observed, interacting with multiple cellular receptors and thereby accentuating its role as a regulator of inflammatory processes. Specifically, Fg serves to stimulate and recruit immune cells and pro-inflammatory cytokines, thereby contributing to the promotion of tumor progression. Additionally, Fg and its fragments exhibit dichotomous effects on tumor angiogenesis. Notably, Fg also facilitates tumor migration through both platelet-dependent and platelet-independent mechanisms. Recent studies have illuminated several tumor-related signaling pathways influenced by Fg. This review provides a comprehensive summary of the intricate involvement of Fg in tumor biology, elucidating its multifaceted role and the underlying mechanisms.

Lupiwighteone as an Antitumor Agent Reverses Multidrug Resistance in K562/ADR Cells by Regulating Cellular Prion Protein-Oct4 Axis.

INTRODUCTION: One of the many reasons for cancer treatment failure and recurrence is acquired Multidrug Resistance (MDR). Overcoming cancer drug resistance has been the focus of researchers' studies. Cellular prion protein (PrPC) is a glycophosphatidylinositol-anchored cell-surface glycoprotein that has been implicated in tumor behavior, including proliferation, apoptosis, invasion, metastasis, and chemoresistance. >Method: Lupiwighteone (Lup), a natural isoflavone found in the root of Glycyrrhiza glabra, has anticancer activity against prostate cancer cells, neuroblastoma cells, and human breast cancer cells. However, its pharmacological effects and mechanisms in drug-resistant cancer cells have not been reported. In this study, we used an adriamycin- resistant leukemia K562 cell model, and for the first time, we investigated the reversal effect of Lup on its MDR and the potential mechanism. RESULT: The results indicated that Lup could induce apoptosis through the mitochondrial pathway while upregulating the expression of related apoptotic proteins, such as Bax, Cyto C, Caspase-3, and PARP1. Autophagy is commonly recognized as a protective mechanism that mediates MDR during treatment. We found that Lup induced cellular autophagy while upregulating the expression of related autophagy proteins such as Beclin 1 and LC3 II. CONCLUSION: In addition, when Lup was combined with adriamycin, Lup decreased the IC50 of K562/ADR cells; moreover, Lup can downregulate the expression of drug-resistant proteins, suggesting that Lup can reverse drug resistance. Further studies have shown that Lup can downregulate the expression of PrPC-PI3K-Akt axis proteins and PrPC-Oct4 axis proteins. This study demonstrated that Lup has the potential to inhibit the proliferation of K562/ADR cells by targeting PrPC, and further study of the signaling pathway associated with PrPC may provide the experimental basis for the treatment of drug-resistant leukemia.

Pongamol Prevents Neurotoxicity via the Activation of MAPKs/Nrf2 Signaling Pathway in H2O2-Induced Neuronal PC12 Cells and Prolongs the Lifespan of Caenorhabditis elegans.

Despite tremendous advances in modern medicine, effective prevention or therapeutic strategies for age-related neurodegenerative diseases such as Alzheimer's disease (AD) remain limited. Growing evidence now suggests that oxidative stress and apoptosis are increasingly associated with AD as promising therapeutic targets. Pongamol, a flavonoid, is the main constituent of pongamia pinnata and possesses a variety of pharmacological activities such as antioxidant, anti-aging and anti-inflammatory. In the present study, we investigated the antioxidant effects and mechanisms of pongamol in H2O2-induced PC12 cells and Caenorhabditis elegans (C. elegans). Our findings revealed that pongamol reduced cellular damage and apoptosis in H2O2-induced PC12 cells. Furthermore, pongamol reduced levels of apoptosis-related proteins Bax, Cyto C, Cleaved Caspase-3, and Cleaved PARP1, and increased the level of anti-apoptotic protein Bcl-2. Pongamol also effectively attenuated the level of oxidative stress markers such as glutathione (GSH) and reactive oxygen species (ROS) in H2O2-induced PC12 cells. Additionally, pongamol possessed antioxidant activity in H2O2-induced PC12 cells through the MAPKs/Nrf2 signaling pathway. Furthermore, pongamol exerted neuroprotective and anti-aging effects in C. elegans. All together, these results suggested that pongamol has a potential neuroprotective effect through the modulation of MAPKs/Nrf2 signaling pathway.

Pongamol Alleviates Neuroinflammation and Promotes Autophagy in Alzheimer's Disease by Regulating the Akt/mTOR Signaling Pathway.

Alzheimer's disease (AD), one of the neurodegenerative disorders, is highly correlated with the abnormal hyperphosphorylation of Tau and aggregation of ß-amyloid (Aß). Oxidative stress, neuroinflammation, and abnormal autophagy are key drivers of AD and how they contribute to neuropathology remains largely unknown. The flavonoid compound pongamol is reported to possess a variety of pharmacological activities, such as antioxidant, antibacterial, and anti-inflammatory. This study investigated the neuroprotective effect and its mechanisms of pongamol in lipopolysaccharide (LPS)-induced BV2 cells, d-galactose/sodium nitrite/aluminum chloride (d-gal/NaNO2/AlCl3)-induced AD mice, and Caenorhabditis elegans models. Our research revealed that pongamol reduced the release of inflammatory factors IL-1ß, TNF-α, COX-2, and iNOS in LPS-induced BV2 cells. Pongamol also protected neurons and significantly restored memory function, inhibited Tau phosphorylation, downregulated Aß aggregation, and increased oxidoreductase activity in the hippocampus of AD mice. In addition, pongamol reversed the nuclear transfer of NF-κB and increased the levels of Beclin 1 and LC3 II/LC3 I. Most importantly, the anti-inflammatory and promoter autophagy effects of pongamol may be related to the regulation of the Akt/mTOR signaling pathway. In summary, these results showed that pongamol has a potential neuroprotective effect, which greatly enriched the research on the pharmacological activity of pongamol for improving AD.

Dual-Barb Microneedle with JAK/STAT Inhibitor-Loaded Nanovesicles Encapsulation for Tendinopathy.

Tendon stem/progenitor cells (TSPCs) are crucial for tendon repair, regeneration, and homeostasis. Dysfunction of TSPCs, due to aberrant activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, contributes to tendinopathy. Unfortunately, the effectiveness of conventional subcutaneous injection targeting at suppressing JAK/STAT signaling pathway is limited due to the passive diffusion of drugs away from the injury site. Herein, a novel poly-gamma-glutamic acid (γ-PGA) dual-barb microneedle (MN) path loaded with TSPCs-derived nanovesicles (NVs) containing JAK/STAT inhibitor WP1066 (MN-WP1066-NVs) for tendinopathy treatment is designed. The dual-barb design of the MN ensures firm adhesion to the skin, allowing for sustained and prolonged release of WP1066-NVs, facilitating enhanced TSPCs self-renewal, migration, and stemness in tendinopathy. In vitro and in vivo experiments demonstrate that the degradation of γ-PGA patch tips facilitates the gradual release of WP1066-NVs at the lesion site. This release alleviates inflammation, suppresses extracellular matrix degradation, and restores normal tendon histological structure by inhibiting the JAK/STAT pathway. These findings suggest that the multifunctional dual-barb MN patch offers a novel and effective therapeutic strategy for tendinopathy treatment.

5-Aza-2'-Deoxycytidine Ameliorates Choroidal Neovascularization by Inhibiting the Wnt/ß-Catenin Signaling Pathway.

Purpose: Choroidal neovascularization (CNV) can constitute the final pathology of many ocular diseases and result in severe vision loss. Studies have demonstrated that DNA methylation is critical in retinal development, aging, and disorders. The current work investigated the effects and underlying mechanism of 5-Aza-2'-deoxycytidine (5-aza-dC), a suppressor of DNA methylation, in the pathological progression of CNV. Methods: The DNA methylation profiles of retinal pigment epithelial (RPE)/choroidal complexes in normal and laser-induced CNV mice were assessed by Arraystar Mouse RefSeq Promoter Arrays. The CNV area and blood flow density and intensity were observed by optical coherence tomography angiography, and fluorescence leakage was examined by fundus fluorescein angiography in CNV mice with systemic administration of 5-aza-dC. The effects of 5-aza-dC on the biological functions of bEnd.3 cells were estimated by related assays. Notum gene promoter methylation was measured using bisulfite sequencing PCR. Methyltransferases and Wnt signaling-related genes were detected in animal and cell culture experiments by real-time PCR and immunoblot. Results: Methyltransferases were upregulated, but Notum (a secretion inhibitor of Wnt signaling) was downregulated in the RPE/choroidal complexes of mice with experimental CNV. Intraperitoneal injection of 5-aza-dC inactivated the Wnt pathway and ameliorated the lesion area and the intensity and density of blood flow, as well as the degree of leakage in CNV. In vitro, vascular endothelial growth factor A (VEGFA) stimulation promoted methyltransferases expression and suppressed Notum expression, consequently activating Wnt signaling, whereas exogenous 5-aza-dC reversed VEGFA-induced hyperpermeability, proliferation, migration, and tube formation in bEnd.3 cells via demethylation of Notum promoter. Conclusions: We observed that 5-aza-dC attenuates the growth of CNV by inhibiting the Wnt signaling pathway via promoter demethylation of the Wnt antagonist Notum. These findings provide a theoretical basis for methylation-based treatment with the Notum gene as a potential target for CNV treatment.

Endoplasmic reticulum aminopeptidase 2 regulates CD4+ T cells pyroptosis in rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease with a complex pathogenesis that has not yet been fully elucidated, and T-cell pyroptosis is an important pathogenetic factor in RA. This study aimed to investigate the role of endoplasmic reticulum aminopeptidase 2 (ERAP2) in the pyroptosis of CD4+ T cells in RA and the specific molecular mechanism. METHODS: Peripheral venous blood was collected from human subjects, and CD4+ T cells were isolated and activated to measure the level of pyroptosis and ERAP2 expression. Pyroptosis levels were assessed using immunofluorescence, flow cytometry, qRT-PCR, and Western blotting. Changes in pyroptosis levels were observed upon knockdown or overexpression of ERAP2. To detect activated Caspase-1 in tissues, chimeric mice were engrafted with human synovial tissue and reconstituted with human CD4+ T cells. CD4 + T cells were treated with GLI1 antagonists and SMO receptor agonists to detect changes in pyroptosis levels. RESULTS: CD4+ T cell levels undergoing pyroptosis were found to be elevated in the blood and synovium of RA patients. The gene and protein expression of ERAP2 were significantly higher in CD4+ T cells from RA patients. Deletion of ERAP2 suppressed pyroptosis of these cells, attenuated the activation of Caspase-1 in tissue T cells, and reduced tissue inflammatory responses. Reciprocally, overexpression of ERAP2 triggered inflammasome assembly, activated Caspase-1, and induced pyroptosis in CD4+ T cells. Mechanistically, ERAP2 inhibits the Hedgehog signaling pathway and upregulates the expression of nucleotide-binding oligomerization segment-like receptor family 3(NLRP3), cleaved Caspase-1, and Gasdermin D to promote pyroptosis in CD4+ T cells. CONCLUSIONS: Taken together, our results identify a novel mechanism by which ERAP2 regulates RA development and document the effect of the ERAP2/Hedgehog signaling axis on pyroptosis of CD4+ T cells from RA patients.

ALOX5 drives the pyroptosis of CD4+ T cells and tissue inflammation in rheumatoid arthritis.

Pyroptosis, an inflammatory form of programmed cell death, is linked to the pathology of rheumatoid arthritis (RA). Here, we investigated the molecular mechanism underlying pyroptosis in T cells isolated from patients with RA. Compared with healthy individuals, patients with RA had more pyroptotic CD4+ T cells in blood and synovia, which correlated with clinical measures of disease activity. Moreover, the mRNA expression and protein abundance of arachidonate 5-lipoxygenase (ALOX5), which converts arachidonic acid to leukotriene A4 (LTA4), were increased in CD4+ T cells from patients with RA and, among patients with RA, were lowest in those in clinical remission. Knockdown or pharmacological inhibition of ALOX5 suppressed CD4+ T cell pyroptosis and improved symptoms in two rodent models of RA. Mechanistically, the increase in ALOX5 activity in RA CD4+ T cells enhanced the production of the LTA4 derivative LTB4, which stimulated Ca2+ influx through ORAI3 channels, leading to the activation of NLRP3 inflammasomes and pyroptosis. Our findings reveal a role for ALOX5 in RA and provide a molecular basis for further exploring the clinical utility of ALOX5 inhibition in RA and for using ALOX5 as a biomarker to distinguish active disease and remission in RA.