ALLENE OXIDE SYNTHASE (AOS) induces petal senescence through a novel JA-associated regulatory pathway in Arabidopsis.

Flowers are crucial for the reproduction of flowering plants and their senescence has drastic effects on plant-animal interactions as well as pollination. Petal senescence is the final phase of flower development which is regulated by hormones and genes. Among these, jasmonic acid (JA) has emerged as a major contributor to petal senescence, but its molecular mechanisms remain elusive. Here, the role of JA in petal senescence in Arabidopsis was investigated. We showed that petal senescence in aos mutant was significantly delayed, which also affected petal cell size and proliferation. Similar significant delays in petal senescence were observed in dad1 and coi1 mutants. However, MYB21/24 and MYC2/3/4, known downstream regulators of JA in flower development, played no role in petal senescence. This indicated that JA regulates petal senescence by modulating other unknown transcription factors. Transcriptomic analysis revealed that AOS altered the expression of 3681 genes associated, and identified groups of differentially expressed transcription factors, highlighting the potential involvement of AP-2, WRKY and NAC. Furthermore, bHLH13, bHLH17 and URH2 were identified as potential new regulators of JA-mediated petal senescence. In conclusion, our findings suggest a novel genetic pathway through which JA regulates petal senescence in Arabidopsis. This pathway operates independently of stamen development and leaf senescence, suggesting the evolution of specialized mechanisms for petal senescence. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-024-01425-w.

Prospects and challenges of CAR-T cell therapy combined with ICIs.

Immune checkpoint molecules are a group of molecules expressed on the surface of immune cells that primarily regulate their immune homeostasis. Chimeric antigen receptor (CAR) T cell therapy is an immunotherapeutic technology that realizes tumor-targeted killing by constructing synthetic T cells expressing specific antigens through biotechnology. Currently, CAR-T cell therapy has achieved good efficacy in non-solid tumors, but its treatment of solid tumors has not yielded the desired results. Immune checkpoint inhibitors (ICIs) combined with CAR-T cell therapy is a novel combination therapy with high expectations to defeat solid tumors. This review addresses the challenges and expectations of this combination therapy in the treatment of solid tumors.

Elevated arsenic level in fasting serum via ingestion of fish meat increased the risk of hypertension in humans and mice.

Aims: There has been a shortage of human studies to elucidate the association between serum arsenic levels and the prevalence of hypertension. This study multidirectionally investigated associations among arsenic exposure, dietary ingestion, and the risk of hypertension by combined human epidemiological and mouse experimental studies. Methods and results: This study focused on the total arsenic level in fasting serum, a biomarker of arsenic exposure. Associations among ingestion frequencies of 54 diet items of Japanese food separated into six categories, total arsenic level in fasting serum, and the prevalence of hypertension were investigated in 2709 general people in Japan. Logistic regression analysis demonstrated a dose-dependent association between serum arsenic level and hypertension and a positive association between the ingestion of fish meat and hypertension. Further analysis showed that the latter association was fully mediated by increased fasting serum arsenic levels in humans. Similarly, oral exposure to the putative human-equivalent dose of arsenic species mixture with the same ratios in a common fish meat in Japan increased systolic blood pressure and arsenic levels in fasting serum in mice. Conclusion: This interdisciplinary approach suggests that fish-meat ingestion is a potential risk factor for arsenic-mediated hypertension. Because the increased consumption of fish meat is a recent global trend, health risks of the increased ingestion of arsenic via fish meat should be further investigated.

miR-100-5p Is a Novel Biomarker That Suppresses the Proliferation, Migration, and Invasion in Skin Cutaneous Melanoma.

Objective: To better understand the role and underlying mechanisms of SKCM, we conducted bioinformatics analysis and in vivo experiments. Results: We found its role as a tumor suppressor gene in SKCM and its effect on prognosis. In addition, this study found that miR-100-5p had a bidirectional effect on SKCM microenvironment. After exploring the relationship between the two, it was found that tumors with intermediate miR-100-5p expression had the highest level of immune cell infiltration. In addition, the value of miR-100-5p was assessed by survival analysis, univariate Cox regression analysis, and nomogram prognostic prediction. Finally, we constructed a regulatory network to illustrate the regulatory relationship of miR-100-5p. Conclusions: In conclusion, the antitumor effect of miR-100-5p is revealed, and the present study is followed by a discussion of its molecular regulatory network, followed by novel insights into SKCM therapy.

Vascular endothelium as a target tissue for short-term exposure to low-frequency noise that increases cutaneous blood flow.

Harmful health effects of exposure to low-frequency noise (LFN) defined as noise with frequencies at ≤100 Hz on the circulatory system have been a concern. However, there has been no study on the effects of exposure to LFN on the circulatory system with consideration of its frequencies and decibels. In this study, the effects of short-term exposure to broad-band LFNs and their pure-tone components (pure-tone LFNs) on cutaneous blood flow in the extremities including the hands were investigated. In our fieldwork study, we first sampled some kinds of common broad-band LFNs. Our human study then showed that broad-band LFN with a narrower frequency range more strongly increased cutaneous blood flow than did broad-band LFN with a wider frequency range. Pure-tone LFNs of 70-100 Hz at ≤85 dB(Z), but not pure-tone LFNs exceeding 100 Hz, further increased levels of cutaneous blood flow. Our wavelet-transform spectrum analysis of cutaneous blood flow next revealed that the nitric oxide (NO)-dependent and -independent vascular activities of the vascular endothelium were specifically increased by exposure to pure-tone LFN. Our animal study again indicated that exposure to pure-tone LFN increased cutaneous blood flow in mice with impairments of bilateral inner ears as well as cutaneous blood flow in control mice, suggesting a limited effect of inner ear function on the LFN-mediated increase in cutaneous blood flow. The NO-dependent suppressive effect of pure-tone LFN on cutaneous blood flow was confirmed by inhibition of vascular endothelial activity through intravenous injection of an NO inhibitor in wild-type mice. Taken together, the results of this study demonstrated that the vascular endothelium is a target tissue of LFN and that NO is an effector of the LFN-mediated increase in cutaneous blood flow. Since improvement of peripheral circulation could generally promote human health, short-term exposure to LFN may be beneficial for health.

Exportin 4 depletion leads to nuclear accumulation of a subset of circular RNAs.

Numerous RNAs are exported from the nucleus, abnormalities of which lead to cellular complications and diseases. How thousands of circular RNAs (circRNAs) are exported from the nucleus remains elusive. Here, we provide lines of evidence to demonstrate a link between the conserved Exportin 4 (XPO4) and nuclear export of a subset of circRNAs in metazoans. Exonic circRNAs (ecircRNAs) with higher expression levels, larger length, and lower GC content are more sensitive to XPO4 deficiency. Cellular insufficiency of XPO4 leads to nuclear circRNA accumulation, circRNA:DNA (ciR-loop) formation, linear RNA:DNA (liR-loop) buildup, and DNA damage. DDX39 known to modulate circRNA export can resolve ciR-loop, and splicing factors involved in the biogenesis of circRNAs can also affect the levels of ciR-loop. Testis and brain are two organs with high abundance of circRNAs, and insufficient XPO4 levels are detrimental, as Xpo4 heterozygous mice display male infertility and neural phenotypes. Increased levels of ciR-loop, R-loop, and DNA damage along with decreased cell numbers are observed in testis and hippocampus of Xpo4 heterozygotes. This study sheds light on the understandings of mechanism of circRNA export and reveals the significance of efficient nuclear export of circRNAs in cellular physiology.

Comprehensive analysis of transcriptome characteristics and identification of TLK2 as a potential biomarker in dermatofibrosarcoma protuberans.

Background: Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous sarcoma characterized by local invasion and recurrence. RNA sequencing (RNA-seq) allows the qualification of cellular RNA populations and provides information on the transcriptional state. However, few studies have comprehensively analyzed DFSP transcriptional data. Methods: Fourteen DFSP samples with paired non-neoplastic soft tissue from Chinese patients undergoing Mohs micrographic surgery were used for RNA-seq analysis. Differential expression analysis and enrichment analysis for RNA-seq data were performed to identify fusion genes, biomarkers, and microenvironment characteristics of DFSP. Results: This study systemically describes the transcriptomic characteristics of DFSP. First, we performed gene fusion analysis and identified a novel FBN1-CSAD fusion event in a DFSP patient with fibrosarcomatous transformation. Then, we identified TLK2 as a biomarker for DFSP based on functional enrichment analysis, and validated its accuracy for diagnosing DFSP by immunohistochemical staining and joint analysis with public data. Finally, microenvironment analysis described the infiltration characteristics of immune and stromal cells in DFSP. Conclusion: This study demonstrates that RNA-seq can serve as a promising strategy for exploring molecular mechanisms in DFSP. Our results provide new insights into accurate diagnosis and therapeutic targets of DFSP.

Fe3N nanoparticles embedded in N-doped porous magnetic graphene for peroxymonosulfate activation: Radical and nonradical mechanism.

The persistence of pharmaceutical and personal care products (PPCPs) such as norfloxacin (NFX) poses a serious threat to the water environment, and the development of efficient and cost-effective advanced oxidation catalysts is an important step toward resolving this issue. Herein, Fe and N co-doped graphene (FeNGO) was synthesized from graphene oxide (GO), urea, and iron salt via simple impregnation pyrolysis, and applied for activating peroxymonosulfate (PMS) to degrade NFX. FeNGO possessed a two-dimensional porous sheet structure and was rich in defects, nitrogen species, and active sites. Compared with the control catalyst doped with N or Fe alone, FeNGO/PMS system showed the best degradation performance with 97.7% removal of NFX after 30 min, the rate constant was 7.1 and 1.7 times than that for NGO and FeGO, respectively. Fe3N was the main active site of FeNGO, and it is confirmed that singlet oxygen (1O2) and superoxide radical (O2•-) were the primary oxidation active species (ROS) during NFX degradation. The formation of 1O2 came from the transformation of O2•- and PMS decomposition. FeNGO showed strong pH adaptability, and also exhibited stale degradation performance in saliferous water matrices. It is believed that this work will offer theoretical and practical guidance for PMS activation by non-radical pathways.

Efficient degradation of norfloxacin by carbonized polydopamine-decorated g-C3N4 activated peroxymonosulfate: Performance and mechanism.

The use of metal-free graphite carbon nitride (CN) to activate peroxymonosulfate (PMS) has attracted extensive attention for organic pollutants degradation. In this work, we prepared carbonized polydopamine-decorated g-C3N4 (CP-700) for activation of PMS to degrade norfloxacin (NOR). The CP-700 composite was obtained by using CN as a base material on which dopamine underwent an autopolymerization reaction to form a CN-PDA complex, followed by pyrolysis. The apparent porous structure and graphitization provided a large number of active sites for catalytic degradation, enabling CP-700 to exhibit excellent catalytic performance during PMS activation. The degradation of NOR was not hindered by sulfate radical (SO4•-) and hydroxyl radical (•OH). Singlet oxygen (1O2) and mediated electron transfer were ultimately identified as the primary mechanisms. According to the linear positive correlation (R2 = 0.9922) between the semi-quantitative carbonyl group (CO) and the reaction rate constant, it was determined that the carbonyl group served as the important active site. The excellent electron transfer ability of CP-700 was evidenced by electrochemical techniques and the electron transfer pathway in the system was that PMS was adsorbed on the CP-700 surface to form metastable complex, and then the electron transfer between NOR and metastable complex was achieved. Based on the non-radical pathway, CP-700/PMS system showed a high tolerance to solution pH (3.0-11.0) and inorganic anions. The cyclic degradation experiments indicated that the system maintained a high degradation capability without the addition of additional CP-700, elucidating its potential application in the degradation of organic pollutants in the water.

Multidisciplinary approach to assess the toxicities of arsenic and barium in drinking water.

Well water could be a stable source of drinking water. Recently, the use of well water as drinking water has been encouraged in developing countries. However, many kinds of disorders caused by toxic elements in well drinking water have been reported. It is our urgent task to resolve the global issue of element-originating diseases. In this review article, our multidisciplinary approaches focusing on oncogenic toxicities and disturbances of sensory organs (skin and ear) induced by arsenic and barium are introduced. First, our environmental monitoring in developing countries in Asia showed elevated concentrations of arsenic and barium in well drinking water. Then our experimental studies in mice and our epidemiological studies in humans showed arsenic-mediated increased risks of hyperpigmented skin and hearing loss with partial elucidation of their mechanisms. Our experimental studies using cultured cells with focus on the expression and activity levels of intracellular signal transduction molecules such as c-SRC, c-RET, and oncogenic RET showed risks for malignant transformation and/or progression arose from arsenic and barium. Finally, our original hydrotalcite-like compound was proposed as a novel remediation system to effectively remove arsenic and barium from well drinking water. Hopefully, comprehensive studies consisting of (1) environmental monitoring, (2) health risk assessments, and (3) remediation will be expanded in the field of environmental health to prevent various disorders caused by environmental factors including toxic elements in drinking water.

Identification of mecciRNAs and their roles in the mitochondrial entry of proteins.

Mammalian mitochondria have small genomes encoding very limited numbers of proteins. Over one thousand proteins and noncoding RNAs encoded by the nuclear genome must be imported from the cytosol into the mitochondria. Here, we report the identification of hundreds of circular RNAs (mecciRNAs) encoded by the mitochondrial genome. We provide both in vitro and in vivo evidence to show that mecciRNAs facilitate the mitochondrial entry of nuclear-encoded proteins by serving as molecular chaperones in the folding of imported proteins. Known components involved in mitochondrial protein and RNA importation, such as TOM40 and PNPASE, interact with mecciRNAs and regulate protein entry. The expression of mecciRNAs is regulated, and these transcripts are critical for the adaption of mitochondria to physiological conditions and diseases such as stresses and cancers by modulating mitochondrial protein importation. mecciRNAs and their associated physiological roles add categories and functions to the known eukaryotic circular RNAs and shed novel light on the communication between mitochondria and the nucleus.

Electrooxidation enables highly regioselective dearomative annulation of indole and benzofuran derivatives.

The dearomatization of arenes represents a powerful synthetic methodology to provide three-dimensional chemicals of high added value. Here we report a general and practical protocol for regioselective dearomative annulation of indole and benzofuran derivatives in an electrochemical way. Under undivided electrolytic conditions, a series of highly functionalized five to eight-membered heterocycle-2,3-fused indolines and dihydrobenzofurans, which are typically unattainable under thermal conditions, can be successfully accessed in high yield with excellent regio- and stereo-selectivity. This transformation can also tolerate a wide range of functional groups and achieve good efficiency in large-scale synthesis under oxidant-free conditions. In addition, cyclic voltammetry, electron paramagnetic resonance (EPR) and kinetic studies indicate that the dehydrogenative dearomatization annulations arise from the anodic oxidation of indole into indole radical cation, and this process is the rate-determining step.

Topographic specificity of alpha power during auditory spatial attention.

Visual and somatosensory spatial attention both induce parietal alpha (8-14 â€‹Hz) oscillations whose topographical distribution depends on the direction of spatial attentional focus. In the auditory domain, contrasts of parietal alpha power for leftward and rightward attention reveal qualitatively similar lateralization; however, it is not clear whether alpha lateralization changes monotonically with the direction of auditory attention as it does for visual spatial attention. In addition, most previous studies of alpha oscillation did not consider individual differences in alpha frequency, but simply analyzed power in a fixed spectral band. Here, we recorded electroencephalography in human subjects when they directed attention to one of five azimuthal locations. After a cue indicating the direction of an upcoming target sequence of spoken syllables (yet before the target began), alpha power changed in a task-specific manner. Individual peak alpha frequencies differed consistently between central electrodes and parieto-occipital electrodes, suggesting multiple neural generators of task-related alpha. Parieto-occipital alpha increased over the hemisphere ipsilateral to attentional focus compared to the contralateral hemisphere, and changed systematically as the direction of attention shifted from far left to far right. These results showing that parietal alpha lateralization changes smoothly with the direction of auditory attention as in visual spatial attention provide further support to the growing evidence that the frontoparietal attention network is supramodal.

Causal links between parietal alpha activity and spatial auditory attention.

Both visual and auditory spatial selective attention result in lateralized alpha (8-14 Hz) oscillatory power in parietal cortex: alpha increases in the hemisphere ipsilateral to attentional focus. Brain stimulation studies suggest a causal relationship between parietal alpha and suppression of the representation of contralateral visual space. However, there is no evidence that parietal alpha controls auditory spatial attention. Here, we performed high definition transcranial alternating current stimulation (HD-tACS) on human subjects performing an auditory task in which they directed attention based on either spatial or nonspatial features. Alpha (10 Hz) but not theta (6 Hz) HD-tACS of right parietal cortex interfered with attending left but not right auditory space. Parietal stimulation had no effect for nonspatial auditory attention. Moreover, performance in post-stimulation trials returned rapidly to baseline. These results demonstrate a causal, frequency-, hemispheric-, and task-specific effect of parietal alpha brain stimulation on top-down control of auditory spatial attention.

Impoverished auditory cues limit engagement of brain networks controlling spatial selective attention.

Spatial selective attention enables listeners to process a signal of interest in natural settings. However, most past studies on auditory spatial attention used impoverished spatial cues: presenting competing sounds to different ears, using only interaural differences in time (ITDs) and/or intensity (IIDs), or using non-individualized head-related transfer functions (HRTFs). Here we tested the hypothesis that impoverished spatial cues impair spatial auditory attention by only weakly engaging relevant cortical networks. Eighteen normal-hearing listeners reported the content of one of two competing syllable streams simulated at roughly +30° and -30° azimuth. The competing streams consisted of syllables from two different-sex talkers. Spatialization was based on natural spatial cues (individualized HRTFs), individualized IIDs, or generic ITDs. We measured behavioral performance as well as electroencephalographic markers of selective attention. Behaviorally, subjects recalled target streams most accurately with natural cues. Neurally, spatial attention significantly modulated early evoked sensory response magnitudes only for natural cues, not in conditions using only ITDs or IIDs. Consistent with this, parietal oscillatory power in the alpha band (8-14 â€‹Hz; associated with filtering out distracting events from unattended directions) showed significantly less attentional modulation with isolated spatial cues than with natural cues. Our findings support the hypothesis that spatial selective attention networks are only partially engaged by impoverished spatial auditory cues. These results not only suggest that studies using unnatural spatial cues underestimate the neural effects of spatial auditory attention, they also illustrate the importance of preserving natural spatial cues in assistive listening devices to support robust attentional control.

A unique system that can sensitively assess the risk of chemical leukoderma by using murine tail skin.

Chemical leukoderma is a patchy hypopigmentation in the skin. Phenol derivatives such as raspberry ketone have been reported to cause the development of occupationally induced leukoderma. Recently, 2% (w/w) rhododenol, a reduced form of raspberry ketone used in a skin-lightning agent, also caused the development of leukoderma in >16,000 users, about 2% of all users, in Asian countries including Japan. However, a method for assessing the risk of leukoderma caused by 2% rhododenol has not been established despite the fact that the development of leukoderma caused by 30% rhododenol was previously shown in animal experiments. Establishment of a novel technique for risk assessment of leukoderma in humans caused by external treatment with chemicals is needed to prevent a possible future chemical disaster. This study demonstrated that external treatment with 2% rhododenol and the same concentration of raspberry ketone caused the development of leukoderma in murine tail skin without exception with significant decreases in the amount of melanin and number of melanocytes in the epidermis. Thus, a novel in vivo technique that can assess the risk of leukoderma caused by 2% rhododenol was developed. The unique technique using tail skin has the potential to prevent chemical leukoderma in the future.

Adsorption of molybdenum by melanin.

BACKGROUND: Melanin is detectable in various sense organs including the skin in animals. It has been reported that melanin adsorbs toxic elements such as mercury, cadmium, and lead. In this study, we investigated the adsorption of molybdenum, which is widely recognized as a toxic element, by melanin. METHODS: Molybdenum level of the mouse skin was measured by inductively coupled plasma mass spectrometry. The pigmentation level of murine skin was digitalized as the L* value by using a reflectance spectrophotometer. An in vitro adsorption assay was performed to confirm the interaction between molybdenum and melanin. RESULTS: Our analysis of hairless mice with different levels of skin pigmentation showed that the level of molybdenum increased with an increase in the level of skin pigmentation (L* value). Moreover, our analysis by Spearman's correlation coefficient test showed a strong correlation (r = - 0.9441, p < 0.0001) between L* value and molybdenum level. Our cell-free experiment using the Langmuir isotherm provided evidence for the adsorption of molybdenum by melanin. The maximum adsorption capacity of 1 mg of synthetic melanin for molybdenum was 131 µg in theory. CONCLUSION: Our in vivo and in vitro results showed a new aspect of melanin as an adsorbent of molybdenum.

The beta oscillation conditions in a simplified basal ganglia network.

Parkinson's disease is a type of motor dysfunction disease that is induced mainly by abnormal interactions between the subthalamic nucleus (STN) and globus pallidus (GP) neurons. Periodic oscillatory activities with frequencies of 13-30 Hz are the main physiological characteristics of Parkinson's disease. In this paper, we built a class of STN-GP networks to explore beta oscillation conditions. A theoretical formula was obtained for generating oscillations without internal GP connections. Based on this formula, we studied the effects of cortex inputs, striatum inputs, coupling weights and delays on oscillation conditions, and the theoretical results are in good agreement with the numerical results. The onset mechanism can be explained by the model, and the internal GP connection has little effect on oscillations. Finally, we compared oscillation conditions with those in previous studies and found that the delays and coupling weights required for generating oscillations may decrease as the number of nuclei increases. We hope that the results obtained will inspire future theoretical and experimental studies.

Survival-based bioinformatics analysis to identify hub genes and key pathways in non-small cell lung cancer.

BACKGROUND: Lung cancer is one of the leading causes of cancer mortality worldwide. Here, we performed an integrative bioinformatics analysis to screen hub genes and critical pathways in non-small cell lung cancer (NSCLC) based on the overall survival rate of differentially expressed genes (DEGs). METHODS: Four datasets from the gene expression omnibus (GEO) were used to identify the DEGs. To obtain robust DEGs in NSCLC, only the DEGs that co-existed in the four datasets were selected for subsequent analysis. To identify the genes correlated with overall survival, the overall survival of these genes was then analyzed using the Kaplan-Meier plotter database. The genes significantly correlated with survival were used to perform gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) analysis; next, these genes were used to construct a protein-protein interaction network. MCODE and CytoHubba were used to identify the clusters and hub genes. Finally, the hub genes were validated in the Cancer Genome Atlas (TCGA) and the Human Protein Atlas (HPA). RESULTS: We found 522 up-regulated DEGs, and 989 down-regulated DEGs between the NSCLC and normal lung tissue, and 895 of them were correlated with a higher overall survival. GO analysis showed that the DEGs that were associated with a higher overall survival were enriched in cell division, cell cycle, DNA replication, angiogenesis, and cell migration. KEGG analysis was consistent with GO analysis and showed that p53 signaling pathway, pyrimidine metabolism, cGMP-PKG signaling pathway and renin secretion pathway were associated with overall survival in NSCLC. In the protein-protein analysis, we identified seven clusters and six hub genes which were BUB1B, CCNB1, CENPE, KIF18A, NDC10, and MAD2L1. Of these genes, CENPE and KIF18A had not been reported until now. Finally, the dysregulated expression of the six hub genes was validated by the data from the TCGA and HPA. CONCLUSIONS: We identified the hub genes and potential mechanisms of NSCLC based on multiple-microarray analysis and overall survival; then, validated the hub genes in the TCGA and HPA database. These hub genes may serve as potential therapeutic targets.