Motor neurons generate pose-targeted movements via proprioceptive sculpting.

Motor neurons are the final common pathway1 through which the brain controls movement of the body, forming the basic elements from which all movement is composed. Yet how a single motor neuron contributes to control during natural movement remains unclear. Here we anatomically and functionally characterize the individual roles of the motor neurons that control head movement in the fly, Drosophila melanogaster. Counterintuitively, we find that activity in a single motor neuron rotates the head in different directions, depending on the starting posture of the head, such that the head converges towards a pose determined by the identity of the stimulated motor neuron. A feedback model predicts that this convergent behaviour results from motor neuron drive interacting with proprioceptive feedback. We identify and genetically2 suppress a single class of proprioceptive neuron3 that changes the motor neuron-induced convergence as predicted by the feedback model. These data suggest a framework for how the brain controls movements: instead of directly generating movement in a given direction by activating a fixed set of motor neurons, the brain controls movements by adding bias to a continuing proprioceptive-motor loop.

Synaptic gradients transform object location to action.

To survive, animals must convert sensory information into appropriate behaviours1,2. Vision is a common sense for locating ethologically relevant stimuli and guiding motor responses3-5. How circuitry converts object location in retinal coordinates to movement direction in body coordinates remains largely unknown. Here we show through behaviour, physiology, anatomy and connectomics in Drosophila that visuomotor transformation occurs by conversion of topographic maps formed by the dendrites of feature-detecting visual projection neurons (VPNs)6,7 into synaptic weight gradients of VPN outputs onto central brain neurons. We demonstrate how this gradient motif transforms the anteroposterior location of a visual looming stimulus into the fly's directional escape. Specifically, we discover that two neurons postsynaptic to a looming-responsive VPN type promote opposite takeoff directions. Opposite synaptic weight gradients onto these neurons from looming VPNs in different visual field regions convert localized looming threats into correctly oriented escapes. For a second looming-responsive VPN type, we demonstrate graded responses along the dorsoventral axis. We show that this synaptic gradient motif generalizes across all 20 primary VPN cell types and most often arises without VPN axon topography. Synaptic gradients may thus be a general mechanism for conveying spatial features of sensory information into directed motor outputs.

Graphynes and Graphdiynes for Energy Storage and Catalytic Utilization: Theoretical Insights into Recent Advances.

Carbon allotropes have contributed to all aspects of people's lives throughout human history. As emerging carbon-based low-dimensional materials, graphyne family members (GYF), represented by graphdiyne, have a wide range potential applications due to their superior physical and chemical properties. In particular, graphdiyne (GDY), as the leader of the graphyne family, has been practically applied to various research fields since it was first successfully synthesized. GYF have a large surface area, both sp and sp2 hybridization, and a certain band gap, which was considered to originate from the overlap of carbon 2pz orbitals and the inhomogeneous π-bonds of carbon atoms in different hybridization forms. These properties mean GYF-based materials still have many potential applications to be developed, especially in energy storage and catalytic utilization. Since most of the GYF have yet to be synthesized and applications of successfully synthesized GYF have not been developed for a long time, theoretical results in various application fields should be shared to experimentalists to attract more intentions. In this Review, we summarized and discussed the synthesis, structural properties, and applications of GYF-based materials from the theoretical insights, hoping to provide different viewpoints and comments.

Platelet-fibrin clot strength and platelet reactivity predicting cardiovascular events after percutaneous coronary interventions.

BACKGROUND AND AIMS: Platelet-fibrin clot strength (PFCS) is linked to major adverse cardiovascular event (MACE) risk. However, the association between PFCS and platelet reactivity and their prognostic implication remains uncertain in patients undergoing percutaneous coronary intervention (PCI). METHODS: In PCI-treated patients (n = 2512) from registry data from January 2010 to November 2018 in South Korea, PFCS using thromboelastography and platelet reactivity using VerifyNow were measured. High PFCS (PFCSHigh) was defined as thromboelastography maximal amplitude ≥ 68 mm, and high platelet reactivity (HPR) was defined as >208 P2Y12 reaction units. Patients were stratified into four groups according to maximal amplitude and P2Y12 reaction unit levels: (i) normal platelet reactivity (NPR)-PFCSNormal (31.8%), (ii) HPR-PFCSNormal (29.0%), (iii) NPR-PFCSHigh (18.1%), and (iv) HPR-PFCSHigh (21.1%). Major adverse cardiovascular event (all-cause death, myocardial infarction, or stroke) and major bleeding were followed up to 4 years. RESULTS: High platelet reactivity and PFCSHigh showed an additive effect for clinical outcomes (log-rank test, P < .001). Individuals with NPR-PFCSNormal, NPR-PFCSHigh, HPR-PFCSNormal, and HPR-PFCSHigh demonstrated MACE incidences of 7.5%, 12.6%, 13.4%, and 19.3%, respectively. The HPR-PFCSHigh group showed significantly higher risks of MACE compared with the NPR-PFCSNormal group [adjusted hazard ratio (HRadj) 1.89; 95% confidence interval (CI) 1.23-2.91; P = .004] and the HPR-PFCSNormal group (HRadj 1.60; 95% CI 1.12-2.27; P = .009). Similar results were observed for all-cause death. Compared with HPR-PFCSNormal phenotype, NPR-PFCSNormal phenotype was associated with a higher risk of major bleeding (HRadj 3.12; 95% CI 1.30-7.69; P = .010). CONCLUSIONS: In PCI patients, PFCS and platelet reactivity demonstrated important relationships in predicting clinical prognosis. Their combined assessment may enhance post-PCI risk stratification for personalized antithrombotic therapy.

A comparative full-length transcriptomic resource provides insight into the perennial monocarpic mass flowering.

Perennial monocarpic mass flowering represents as a key developmental innovation in flowering time diversity in several biological and economical essential families, such as the woody bamboos and the shrubby Strobilanthes. However, molecular and genetic mechanisms underlying this important biodiversity remain poorly investigated. Here, we generated a full-length transcriptome resource incorporated into the BlueOmics database (http://blueomics.iflora.cn) for two Strobilanthes species, which feature contrasting flowering time behaviors. Using about 112 and 104 Gb Iso-seq reads together with ~185 and ~75 Gb strand-specific RNA seq data, we annotated 80 971 and 79 985 non-redundant full-length transcripts for the perennial polycarpic Strobilanthes tetrasperma and the perennial monocarpic Strobilanthes biocullata, respectively. In S. tetrasperma, we identified 8794 transcripts showing spatiotemporal expression in nine tissues. In leaves and shoot apical meristems at two developmental stages, 977 and 1121 transcripts were differentially accumulated in S. tetrasperma and S. biocullata, respectively. Interestingly, among the 33 transcription factors showing differential expression in S. tetrasperma but without differential expression in S. biocullata, three were involved potentially in the photoperiod and circadian-clock pathway of flowering time regulation (FAR1 RELATED SEQUENCE 12, FRS12; NUCLEAR FACTOR Y A1, NFYA1; PSEUDO-RESPONSE REGULATOR 5, PRR5), hence provides an important clue in deciphering the flowering diversity mechanisms. Our data serve as a key resource for further dissection of molecular and genetic mechanisms underpinning key biological innovations, here, the perennial monocarpic mass flowering.

Evolution of myxozoan mitochondrial genomes: insights from myxobolids.

BACKGROUND: Myxozoa is a class of cnidarian parasites that encompasses over 2,400 species. Phylogenetic relationships among myxozoans remain highly debated, owing to both a lack of informative morphological characters and a shortage of molecular markers. Mitochondrial (mt) genomes are a common marker in phylogeny and biogeography. However, only five complete myxozoan mt genomes have been sequenced: four belonging to two closely related genera, Enteromyxum and Kudoa, and one from the genus Myxobolus. Interestingly, while cytochrome oxidase genes could be identified in Enteromyxum and Kudoa, no such genes were found in Myxobolus squamalis, and another member of the Myxobolidae (Henneguya salminicola) was found to have lost its entire mt genome. To evaluate the utility of mt genomes to reconstruct myxozoan relationships and to understand if the loss of cytochrome oxidase genes is a characteristic of myxobolids, we sequenced the mt genome of five myxozoans (Myxobolus wulii, M. honghuensis, M. shantungensis, Thelohanellus kitauei and, Sphaeromyxa zaharoni) using Illumina and Oxford Nanopore platforms. RESULTS: Unlike Enteromyxum, which possesses a partitioned mt genome, the five mt genomes were encoded on single circular chromosomes. An mt plasmid was found in M. wulii, as described previously in Kudoa iwatai. In all new myxozoan genomes, five protein-coding genes (cob, cox1, cox2, nad1, and nad5) and two rRNAs (rnl and rns) were recognized, but no tRNA. We found that Myxobolus and Thelohanellus species shared unidentified reading frames, supporting the view that these mt open reading frames are functional. Our phylogenetic reconstructions based on the five conserved mt genes agree with previously published trees based on the 18S rRNA gene. CONCLUSIONS: Our results suggest that the loss of cytochrome oxidase genes is not a characteristic of all myxobolids, the ancestral myxozoan mt genome was likely encoded on a single circular chromosome, and mt plasmids exist in a few lineages. Our findings indicate that myxozoan mt sequences are poor markers for reconstructing myxozoan phylogenetic relationships because of their fast-evolutionary rates and the abundance of repeated elements, which complicates assembly.

Lutetium Texaphyrin-Celecoxib Conjugate as a Potential Immuno-Photodynamic Therapy Agent.

Immuno-photodynamic therapy (IPDT) has emerged as a new modality for cancer treatment. Novel photosensitizers can help achieve the promise inherent in IPDT, namely, the complete eradication of a tumor without recurrence. We report here a small molecule photosensitizer conjugate, LuCXB. This IPDT agent integrates a celecoxib (cyclooxygenase-2 inhibitor) moiety with a near-infrared absorbing lutetium texaphyrin photocatalytic core. In aqueous environments, the two components of LuCXB are self-associated through inferred donor-acceptor interactions. A consequence of this intramolecular association is that upon photoirradiation with 730 nm light, LuCXB produces superoxide radicals (O2-•) via a type I photodynamic pathway; this provides a first line of defense against the tumor while promoting IPDT. For in vivo therapeutic applications, we prepared a CD133-targeting, aptamer-functionalized exosome-based nanophotosensitizer (Ex-apt@LuCXB) designed to target cancer stem cells. Ex-apt@LuCXB was found to display good photosensitivity, acceptable biocompatibility, and robust tumor targetability. Under conditions of photoirradiation, Ex-apt@LuCXB acts to amplify IPDT while exerting a significant antitumor effect in both liver and breast cancer mouse models. The observed therapeutic effects are attributed to a synergistic mechanism that combines antiangiogenesis and photoinduced cancer immunotherapy.

Identification of NET formation and the renoprotective effect of degraded NETs in lupus nephritis.

To explore molecular biomarkers associated with the pathophysiology and therapy of lupus nephritis (LN), we conducted a joint analysis of transcriptomic data from 40 peripheral blood mononuclear cells (PBMCs) (GSE81622) and 21 kidney samples (GSE112943) from the Gene Expression Omnibus database using bioinformatics. A total of 976 and 2,427 differentially expressed genes (DEGs) were identified in PBMCs and renal tissues. Seven and two functional modules closely related to LN were identified. Further enrichment analysis revealed that the neutrophil activation pathway was highly active in both PBMCs and the kidney. Subsequently, 16 core genes closely associated with LN were verified by protein-protein interaction screening and quantitative PCR. In vitro cell models and MRL/lpr mouse models confirmed that the abnormal expression of these core genes was closely linked to neutrophil extracellular traps (NETs) generated by neutrophil activation, while degradation of NETs led to downregulation of core gene expression, thereby improving pathological symptoms of LN. Therefore, identification of patients with systemic lupus erythematosus exhibiting abnormal expression patterns for these core genes may serve as a useful indicator for kidney involvement. In addition, targeting neutrophils to modulate their activation levels and inhibit aberrant expression of these genes represents a potential therapeutic strategy for treating LN. NEW & NOTEWORTHY The mechanisms by which immune cells cause kidney injury in lupus nephritis are poorly understood. We integrated and analyzed the transcriptomic features of PBMCs and renal tissues from the GEO database to identify key molecular markers associated with neutrophil activation. We confirmed that neutrophil extracellular traps (NETs) formed by neutrophil activation promoted the upregulation of key genes in cell and animal models. Targeted degradation of NETs significantly ameliorated kidney injury in MRL/lpr mice.

Wafer-Scale Semitransparent MoS2/WS2 Heterojunction Catalyst on a Silicon Photocathode for Efficient Hydrogen Evolution.

The development of catalysts that are optically transparent, electrically charge-transferable, and capable of protecting underlying photoactive semiconductors is crucial for efficient photoelectrochemical (PEC) hydrogen production. However, meeting all these requirements simultaneously poses significant challenges. In this study, the fabrication of a wafer-scale transparent bilayer MoS2/WS2 catalyst is presented with a staggered heterojunction, optimized for photon absorption, extraction of photogenerated charge carriers, and surface passivation of p-Si photocathode. The MoS2 and WS2 monolayers are grown via metal-organic chemical vapor deposition, followed by sequential transfer and stacking onto the p-Si photocathode. The resulting type-II heterojunction film establishes a strong built-in electric field for rapid charge carrier transport and effectively protects the Si surface from oxidation and corrosion. The fabricated MoS2/WS2/p-Si photocathode demonstrates outstanding PEC performance, achieving a high photocurrent density of -25 mA cm-2 at 0 V versus reversible hydrogen electrode, along with enhanced stability compared to monolayer MoS2/p-Si. This work provides promising strategies for developing optically transparent, electrically active, and protective catalysts for practical PEC energy conversion systems.

Timing of fractional flow reserve-guided complete revascularization in patients with ST-segment elevation myocardial infarction with multivessel disease: Rationale and design of the OPTION-STEMI trial.

BACKGROUND: Current guidelines recommend complete revascularization (CR) in hemodynamically stable patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease (MVD). With regard to the timing of percutaneous coronary intervention (PCI) for non-infarct-related artery (non-IRA), recent randomized clinical trials have revealed that immediate CR was non-inferior to staged CR. However, the optimal timing of CR remains uncertain. The OPTION-STEMI trial compared immediate CR and in-hospital staged CR guided by fractional flow reserve (FFR) for intermediate stenosis of the non-IRA. METHODS: The OPTION-STEMI is a multicenter, investigator-initiated, prospective, open-label, non-inferiority randomized clinical trial. The study included patients with at least 1 non-IRA lesion with ≥50% stenosis by visual estimation. Patients fulfilling the inclusion criteria were randomized into 2 groups at a 1:1 ratio: immediate CR (i.e., PCI for the non-IRA performed during primary angioplasty) or in-hospital staged CR. In the in-hospital staged CR group, PCI for non-IRA lesions was performed on another day during the index hospitalization. Non-IRA lesions with 50%-69% stenosis by visual estimation were evaluated by FFR, whereas those with ≥70% stenosis was revascularized without FFR. The primary endpoint was the composite of all-cause death, non-fatal myocardial infarction, and all unplanned revascularization at 1 year after randomization. Enrolment began in December 2019 and was completed in January 2024. The follow-up for the primary endpoint will be completed in January 2025, and primary results will be available in the middle of 2025. CONCLUSIONS: The OPTION-STEMI is a multicenter, non-inferiority, randomized trial that evaluated the timing of in-hospital CR with the aid of FFR in patients with STEMI and MVD. TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov. Unique identifier: NCT04626882; and URL: https://cris.nih.go.kr. Unique identifier: KCT0004457.

IFIT1 + neutrophil is a causative factor of immunosuppressive features of poorly cohesive carcinoma (PCC).

The importance of the immune microenvironment in poorly cohesive carcinoma (PCC) has been highlighted due to its limited response rate to conventional therapy and emerging treatment resistance. A combination of clinical cohorts, bioinformatics analyses, and functional/molecular experiments revealed that high infiltration of Interferon Induced Protein with Tetratricopeptide Repeats 1 (IFIT1) + tumor-associated neutrophils (TANs) is a distinguishing feature of PCC patients. Upregulation of IFIT1 + TANs promote migration and invasion of gastric cancer (GC) cell lines (MKN45 and MKN74) and stimulates the growth of cell-derived xenograft models. Besides, by promoting macrophage secreted phosphoprotein 1 (SPP1) expression and facilitating cancer-associated fibroblast and endothelial cell recruitment and activation through TANs, IFIT1 promotes a mesenchymal phenotype, which is associated with a poor prognosis. Importantly, compared to non-PCC (NPCC), PCC tumors is more immunosuppressive. Mechanistically, IFIT1 can be stimulated by IFN-γ and contributes to the expression of Programmed Cell Death 1 Ligand (PDL1) in TANs. We demonstrated in mouse models that IFIT1 + PDL1 + TANs can induce acquired resistance to anti-PD-1 immunotherapy, which may be responsible for the difficulty of PCC patients to benefit from immunotherapy. This work highlights the role of IFIT1 + TANs in mediating the remodeling of the tumor immune microenvironment and immunotherapeutic resistance and introduces IFIT1 + TANs as a promising target for precision therapy of PCC.

Spatiotemporal heterogeneity of LMOD1 expression summarizes two modes of cell communication in colorectal cancer.

Cellular communication (CC) influences tumor development by mediating intercellular junctions between cells. However, the role and underlying mechanisms of CC in malignant transformation remain unknown. Here, we investigated the spatiotemporal heterogeneity of CC molecular expression during malignant transformation. It was found that although both tight junctions (TJs) and gap junctions (GJs) were involved in maintaining the tumor microenvironment (TME), they exhibited opposite characteristics. Mechanistically, for epithelial cells (parenchymal component), the expression of TJ molecules consistently decreased during normal-cancer transformation and is a potential oncogenic factor. For fibroblasts (mesenchymal component), the expression of GJs consistently increased during normal-cancer transformation and is a potential oncogenic factor. In addition, the molecular profiles of TJs and GJs were used to stratify colorectal cancer (CRC) patients, where subtypes characterized by high GJ levels and low TJ levels exhibited enhanced mesenchymal signals. Importantly, we propose that leiomodin 1 (LMOD1) is biphasic, with features of both TJs and GJs. LMOD1 not only promotes the activation of cancer-associated fibroblasts (CAFs) but also inhibits the Epithelial-mesenchymal transition (EMT) program in cancer cells. In conclusion, these findings demonstrate the molecular heterogeneity of CC and provide new insights into further understanding of TME heterogeneity.

The SOX2/PDIA6 axis mediates aerobic glycolysis to promote stemness in non-small cell lung cancer cells.

Non-small cell lung cancer (NSCLC) is an aggressive and rapidly expanding lung cancer. Abnormal upregulation or knockdown of PDIA6 expression can predict poor prognosis in various cancers. This study aimed to investigate the biological function of PDIA6 in NSCLC. SOX2 and PDIA6 expression in NSCLC tissues and regulatory relationship between them were analyzed using bioinformatics. GSEA was performed on the enrichment pathway of PDIA6. qRT-PCR was utilized to examine expression of SOX2 and PDIA6 in NSCLC tissues and cells, and dual-luciferase reporter assay and ChIP experiments were performed to validate their regulatory relationship. CCK-8 experiment was conducted to assess cell viability, western blot was to examine levels of stem cell markers and proteins related to aerobic glycolysis pathway in cells. Cell sphere formation assay was used to evaluate efficiency of cell sphere formation. Reagent kits were used to measure glycolysis levels and glycolysis products. High expression of PDIA6 in NSCLC was linked to aerobic glycolysis. Knockdown of PDIA6 reduced cell viability, expression of stem cell surface markers, and cell sphere formation efficiency in NSCLC. Overexpression of PDIA6 could enhance cell viability and promote aerobic glycolysis, but the addition of 2-DG could reverse this result. Bioinformatics predicted the existence of upstream transcription factor SOX2 for PDIA6, and SOX2 was significantly upregulated in NSCLC, and they had a binding relationship. Further experiments revealed that PDIA6 overexpression restored repressive effect of knocking down SOX2 on aerobic glycolysis and cell stemness. This work revealed that the SOX2/PDIA6 axis mediated aerobic glycolysis to promote NSCLC cell stemness, providing new therapeutic strategies for NSCLC.

Comparative single-cell RNA sequencing analysis of immune response to inactivated vaccine and natural SARS-CoV-2 infection.

Uncovering the immune response to an inactivated SARS-CoV-2 vaccine (In-Vac) and natural infection is crucial for comprehending COVID-19 immunology. Here we conducted an integrated analysis of single-cell RNA sequencing (scRNA-seq) data from serial peripheral blood mononuclear cell (PBMC) samples derived from 12 individuals receiving In-Vac compared with those from COVID-19 patients. Our study reveals that In-Vac induces subtle immunological changes in PBMC, including cell proportions and transcriptomes, compared with profound changes for natural infection. In-Vac modestly upregulates IFN-α but downregulates NF-κB pathways, while natural infection triggers hyperactive IFN-α and NF-κB pathways. Both In-Vac and natural infection alter T/B cell receptor repertoires, but COVID-19 has more significant change in preferential VJ gene, indicating a vigorous immune response. Our study reveals distinct patterns of cellular communications, including a selective activation of IL-15RA/IL-15 receptor pathway after In-Vac boost, suggesting its potential role in enhancing In-Vac-induced immunity. Collectively, our study illuminates multifaceted immune responses to In-Vac and natural infection, providing insights for optimizing SARS-CoV-2 vaccine efficacy.

Arabidopsis AGAMOUS-LIKE16 and SUPPRESSOR OF CONSTANS1 regulate the genome-wide expression and flowering time.

Flowering transition is tightly coordinated by complex gene regulatory networks, in which AGAMOUS-LIKE 16 (AGL16) plays important roles. Here, we identified the molecular function and binding properties of AGL16 and demonstrated its partial dependency on the SUPPRESSOR OF CONSTANS 1 (SOC1) function in regulating flowering. AGL16 bound to promoters of more than 2,000 genes via CArG-box motifs with high similarity to that of SOC1 in Arabidopsis (Arabidopsis thaliana). Approximately 70 flowering genes involved in multiple pathways were potential targets of AGL16. AGL16 formed a protein complex with SOC1 and shared a common set of targets. Intriguingly, only a limited number of genes were differentially expressed in the agl16-1 loss-of-function mutant. However, in the soc1-2 knockout background, AGL16 repressed and activated the expression of 375 and 182 genes, respectively, with more than a quarter bound by AGL16. Corroborating these findings, AGL16 repressed the flowering time more strongly in soc1-2 than in the Col-0 background. These data identify a partial inter-dependency between AGL16 and SOC1 in regulating genome-wide gene expression and flowering time, while AGL16 provides a feedback regulation on SOC1 expression. Our study sheds light on the complex background dependency of AGL16 in flowering regulation, thus providing additional insights into the molecular coordination of development and environmental adaptation.

Molecular and genetic regulation of petal number variation.

Floral forms with an increased number of petals, also known as double-flower phenotypes, have been selected and conserved in many domesticated plants, particularly in ornamentals, because of their great economic value. The molecular and genetic mechanisms that control this trait are therefore of great interest, not only for scientists, but also for breeders. In this review, we summarize current knowledge of the gene regulatory networks of flower initiation and development and known mutations that lead to variation of petal number in many species. In addition to the well-accepted miR172/AP2-like module, for which many questions remain unanswered, we also discuss other pathways in which mutations also lead to the formation of extra petals, such as those involved in meristem maintenance, hormone signalling, epigenetic regulation, and responses to environmental signals. We discuss how the concept of 'natural mutants' and recent advances in genomics and genome editing make it possible to explore the molecular mechanisms underlying double-flower formation, and how such knowledge could contribute to the future breeding and selection of this trait in more crops.

Evolution of FLOWERING LOCUS T-like genes in angiosperms: a core Lamiales-specific diversification.

Plant life history is determined by two transitions, germination and flowering time, in which the phosphatidylethanolamine-binding proteins (PEBPs) FLOWERING LOCUS T (FT) and TERMINAL FLOWER1 (TFL1) play key regulatory roles. Compared with the highly conserved TFL1-like genes, FT-like genes vary significantly in copy numbers in gymnosperms, and monocots within the angiosperms, while sporadic duplications can be observed in eudicots. Here, via a systematic analysis of the PEBPs in angiosperms with a special focus on 12 representative species featuring high-quality genomes in the order Lamiales, we identified a successive lineage-specific but systematic expansion of FT-like genes in the families of core Lamiales. The first expansion event generated FT1-like genes mainly via a core Lamiales-specific whole-genome duplication (cL-WGD), while a likely random duplication produced the FT2-like genes in the lineages containing Scrophulariaceae and the rest of the core Lamiales. Both FT1- and FT2-like genes were further amplified tandemly in some families. These expanded FT-like genes featured highly diverged expression patterns and structural variation, indicating functional diversification. Intriguingly, some core Lamiales contained the relict MOTHER OF FT AND TFL1 like 2 (MFT2) that probably expanded in the common ancestor of angiosperms. Our data showcase the highly dynamic lineage-specific expansion of the FT-like genes, and thus provide important and fresh evolutionary insights into the gene regulatory network underpinning flowering time diversity in Lamiales and, more generally, in angiosperms.

Circulating miRNA-4701-3p as a predictive biomarker of cardiovascular disease which induces angiogenesis by inhibition of TOB2.

Angiogenesis is mainly regulated by the delivery of VEGF-dependent signaling to cells. However, the angiogenesis mechanism regulated by VEGF-induced miRNA is still not understood. After VEGF treatment in HUVECs, we screened the changed miRNAs through small-RNA sequencing and found VEGF-induced miR-4701-3p. Furthermore, the GFP reporter gene was used to reveal that TOB2 expression was regulated by miR-4701-3p, and it was found that TOB2 and miR-4701-3p modulation could cause angiogenesis in an in-vitro angiogenic assay. Through the luciferase assay, it was confirmed that the activation of the angiogenic transcription factor MEF2 was regulated by the suppression and overexpression of TOB2 and miR-4701-3p. As a result, MEF2 downstream gene mRNAs that induce angiogenic function were regulated. We used the NCBI GEO datasets to reveal that the expression of TOB2 and MEF2 was significantly changed in cardiovascular disease. Finally, it was confirmed that the expression of circulating miR-4701-3p in the blood of myocardial infarction patients was remarkably increased. In patients with myocardial infarction, circulating miR-4701-3p was increased regardless of age, BMI, and sex, and showed high AUC levels in specificity and sensitivity analysis (AUROC) (AUC = 0.8451, 95 % CI 0.78-0.90). Our data showed TOB2-mediated modulation of MEF2 and its angiogenesis by VEGF-induced miR-4701-3p in vascular endothelial cells. In addition, through bioinformatics analysis using GEO data, changes in TOB2 and MEF2 were revealed in cardiovascular disease. We suggest that circulating miR-4701-3p has high potential as a biomarker for myocardial infarction.

Kamebakaurin Suppresses Antigen-Induced Mast Cell Activation by Inhibition of FcεRI Signaling Pathway.

INTRODUCTION: Kamebakaurin is an active constituent of both Rabdosia japonica and Rabdosia excisa, which are utilized in Chinese traditional medicine for improving symptoms in patients with allergies. We investigated the molecular mechanisms of the anti-allergic effects of kamebakaurin using BMMCs. METHODS: The degranulation ratio, histamine release, and the interleukin (IL)-4, leukotriene B4 (LTB4), and cysteinyl leukotriene productions on antigen-triggered BMMC were investigated. Additionally, the effects of kamebakaurin on signal transduction proteins were examined by Western blot and binding to the Syk and Lyn kinase domain was calculated. The effects of kamebakaurin on antigen-induced hyperpermeability were investigated using mouse model. RESULTS: At 10 µm, kamebakaurin partially inhibited degranulation, histamine release, and IL-4 production. At 30 µm, kamebakaurin partially reduced LTB4 and cysteinyl leukotriene productions and suppressed degranulation, histamine release, and IL-4 production. Phosphorylation of both Syk Y519/520 and its downstream protein, Gab2, was reduced by kamebakaurin, and complete inhibition was observed with 30 µm kamebakaurin. In contrast, phosphorylation of Erk was only partially inhibited, even in the presence of 30 µm kamebakaurin. Syk Y519/520 is known to be auto-phosphorylated via intramolecular ATP present in its own ATP-binding site, and this auto-phosphorylation triggers degranulation, histamine release, and IL-4 production. Docking simulation study indicated kamebakaurin blocked ATP binding to the ATP-binding site in Syk. Therefore, inhibition of Syk auto-phosphorylation by kamebakaurin binding to the Syk ATP-binding site appeared to cause a reduction of histamine release and IL-4 production. Kamebakaurin inhibited antigen-induced vascular hyperpermeability in a dose-dependent fashion but did not reduce histamine-induced vascular hyperpermeability. CONCLUSION: Kamebakaurin ameliorates allergic symptoms via inhibition of Syk phosphorylation; thus, kamebakaurin could be a lead compound for the new anti-allergic drug.

Identification and characterization of endogenous biomarkers for hepatic vectorial transport (OATP1B3-P-gp) function using metabolomics with serum pharmacology.

The organic anion-transporting polypeptide 1B3 and P-glycoprotein (P-gp) provide efficient directional transport (OATP1B3-P-gp) from the blood to the bile that serves as a key determinant of hepatic disposition of the drug. Unfortunately, there is still a lack of effective means to evaluate the disposal ability mediated by transporters. The present study was designed to identify a suitable endogenous biomarker for the assessment of OATP1B3-P-gp function in the liver. We established stably transfected HEK293T-OATP1B3 and HEK293T-P-gp cell lines. Results showed that azelaic acid (AzA) was an endogenous substrate for OATP1B3 and P-gp using serum pharmacology combined with metabolomics. There is a good correlation between the serum concentration of AzA and probe drugs of rOATP1B3 and rP-gp when rats were treated with their inhibitors. Importantly, after 5-fluorouracil-induced rat liver injury, the relative mRNA level and expression of rOATP1B3 and rP-gp were markedly down-regulated in the liver, and the serum concentration of AzA was significantly increased. These observations suggest that AzA is an endogenous substrate of both OATP1B3 and P-gp, and may serve as a potential endogenous biomarker for the assessment of the function of OATP1B3-P-gp for the prediction of changes in the pharmacokinetics of drugs transported by OATP1B3-P-gp in liver disease states.