Deficiency of factor-inhibiting HIF creates a tumor-promoting immune microenvironment.

Hypoxia signaling influences tumor development through both cell-intrinsic and -extrinsic pathways. Inhibiting hypoxia-inducible factor (HIF) function has recently been approved as a cancer treatment strategy. Hence, it is important to understand how regulators of HIF may affect tumor growth under physiological conditions. Here we report that in aging mice factor-inhibiting HIF (FIH), one of the most studied negative regulators of HIF, is a haploinsufficient suppressor of spontaneous B cell lymphomas, particular pulmonary B cell lymphomas. FIH deficiency alters immune composition in aged mice and creates a tumor-supportive immune environment demonstrated in syngeneic mouse tumor models. Mechanistically, FIH-defective myeloid cells acquire tumor-supportive properties in response to signals secreted by cancer cells or produced in the tumor microenvironment with enhanced arginase expression and cytokine-directed migration. Together, these data demonstrate that under physiological conditions, FIH plays a key role in maintaining immune homeostasis and can suppress tumorigenesis through a cell-extrinsic pathway.

Vimentin inhibits α-tubulin acetylation via enhancing α-TAT1 degradation to suppress the replication of human parainfluenza virus type 3.

We previously found that, among human parainfluenza virus type 3 (HPIV3) proteins, the interaction of nucleoprotein (N) and phosphoprotein (P) provides the minimal requirement for the formation of cytoplasmic inclusion bodies (IBs), which are sites of RNA synthesis, and that acetylated α-tubulin enhances IB fusion and viral replication. In this study, using immunoprecipitation and mass spectrometry assays, we determined that vimentin (VIM) specifically interacted with the N-P complex of HPIV3, and that the head domain of VIM was responsible for this interaction, contributing to the inhibition of IB fusion and viral replication. Furthermore, we found that VIM promoted the degradation of α-tubulin acetyltransferase 1 (α-TAT1), through its head region, thereby inhibiting the acetylation of α-tubulin, IB fusion, and viral replication. In addition, we identified a 20-amino-acid peptide derived from the head region of VIM that participated in the interaction with the N-P complex and inhibited viral replication. Our findings suggest that VIM inhibits the formation of HPIV3 IBs by downregulating α-tubulin acetylation via enhancing the degradation of α-TAT1. Our work sheds light on a new mechanism by which VIM suppresses HPIV3 replication.

Clinical characteristics and heterogeneity of generalized pustular psoriasis: A comparative study in a large retrospective cohort.

Generalized pustular psoriasis (GPP) is a rare and potentially life-threatening skin disease and the clinical heterogeneity of which is largely unknown. Retrospective cohort analysis was conducted on hospitalized GPP patients between January 2010 and November 2022. A total of 416 patients with GPP and psoriasis vulgaris (PV) respectively were included, matched 1:1 by sex and age. The heterogeneity of GPP was stratified by PV history and age. Compared with PV, GPP was significantly associated with prolonged hospitalization (11.7 vs. 10.3 day, p < 0.001), elevated neutrophil lymphocyte ratio (NLR) (5.93 vs. 2.44, p < 0.001) and anemia (13.9% vs. 1.2%, p < 0.001). Moreover, GPP alone (without PV history) was a relatively severer subtype with higher temperature (37.6°C vs. 38.0°C, p = 0.002) and skin infections (5.2% vs. 11.4%, p = 0.019) than GPP with PV. For patients across different age, compared with juvenile patients, clinical features support a severer phenotype in middle-aged, including higher incidence of anaemia (7.5% vs. 16.0%, p = 0.023) and NLR score (3.83 vs. 6.88, p < 0.001). Interleukin-6 (r = 0.59), high density lipoprotein cholesterol (r = -0.56), albumin (r = -0.53) and C-reactive protein-to-albumin ratio (r = 0.49) were the most relevant markers of severity in GPP alone, GPP with PV, juvenile and middle-aged GPP, respectively. This retrospective cohort suggests that GPP is highly heterogeneous and GPP alone and middle-aged GPP exhibit severe disease phenotypes. More attention on the heterogeneity of this severe disease is warranted to meet the unmet needs and promote the individualized management of GPP.

Formylpeptide receptor 1 contributes to epidermal barrier dysfunction-induced skin inflammation through NOD-like receptor C4-dependent keratinocyte activation.

BACKGROUND: Skin barrier dysfunction may both initiate and aggravate skin inflammation. However, the mechanisms involved in the inflammation process remain largely unknown. OBJECTIVES: We sought to determine how skin barrier dysfunction enhances skin inflammation and molecular mechanisms. METHODS: Skin barrier defect mice were established by tape stripping or topical use of acetone on wildtype mice, or filaggrin deficiency. RNA-Seq was employed to analyse the differentially expressed genes in mice with skin barrier defects. Primary human keratinocytes were transfected with formylpeptide receptor (FPR)1 or protein kinase R-like endoplasmic reticulum (ER) kinase (PERK) small interfering RNA to examine the effects of these gene targets. The expressions of inflammasome NOD-like receptor (NLR)C4, epidermal barrier genes and inflammatory mediators were evaluated. RESULTS: Mechanical (tape stripping), chemical (acetone) or genetic (filaggrin deficiency) barrier disruption in mice amplified the expression of proinflammatory genes, with transcriptomic profiling revealing overexpression of formylpeptide receptor (Fpr1) in the epidermis. Treatment with the FPR1 agonist fMLP in keratinocytes upregulated the expression of the NLRC4 inflammasome and increased interleukin-1ß secretion through modulation of ER stress via the PERK-eIF2α-C/EBP homologous protein pathway. The activation of the FPR1-NLRC4 axis was also observed in skin specimens from old healthy individuals with skin barrier defect or elderly mice. Conversely, topical administration with a FPR1 antagonist, or Nlrc4 silencing, led to the normalization of barrier dysfunction and alleviation of inflammatory skin responses in vivo. CONCLUSIONS: In summary, our findings show that the FPR1-NLRC4 inflammasome axis is activated upon skin barrier disruption and may explain exaggerated inflammatory responses that are observed in disease states characterized by epidermal dysfunction. Pharmacological inhibition of FPR1 or NLRC4 represents a potential therapeutic target.

NIR-IIb fluorescence antiangiogenesis copper nano-reaper for enhanced synergistic cancer therapy.

The formation of blood vessel system under a relatively higher Cu2+ ion level is an indispensable precondition for tumor proliferation and migration, which was assisted in forming the tumor immune microenvironment. Herein, a copper ions nano-reaper (LMDFP) is rationally designed not only for chelating copper ions in tumors, but also for combination with photothermal therapy (PTT) to improve antitumor efficiency. Under 808 nm laser irradiation, the fabricated nano-reaper converts light energy into thermal energy to kill tumor cells and promotes the release of D-penicillamine (DPA) in LMDFP. Photothermal properties of LMDFP can cause tumor ablation in situ, which further induces immunogenic cell death (ICD) to promote systematic antitumor immunity. The released DPA exerts an anti-angiogenesis effect on the tumor through chelating copper ions, and inhibits the expression of programmed death ligand 1 (PD-L1), which synergizes with PTT to enhance antitumor immunity and inhibit tumor metastasis. Meanwhile, the nanoplatform can emit near-infrared-IIb (NIR-IIb) fluorescence under 980 nm excitation, which can be used to track the nano-reaper and determine the optimal time point for PTT. Thus, the fabricated nano-reaper shows powerful potential in inhibiting tumor growth and metastasis, and holds great promise for the application of copper nanochelator in precise tumor treatment.

Novel Compound MMV1804559 from the Global Health Priority Box Exhibits In Vitro and In Vivo Activity against Madurella mycetomatis.

OBJECTIVES: Eumycetoma is a neglected tropical disease (NTD) characterized by subcutaneous lesions and the formation of grains. Attempts to treat eumycetoma involve a combination of antifungal treatment and surgery, although the outcome is frequently disappointing. Therefore, there is a need to identify novel antifungal drugs to treat eumycetoma. In this respect, Medicines for Malaria Venture (MMV) has assembled libraries of compounds for researchers to use in drug discovery research against NTD. Therefore, we screened two MMVOpen compound libraries to identify novel leads for eumycetoma. METHODS: A total of 400 compounds from the COVID Box and the Global Health Priority Box were screened in vitro at 100 µM and 25 µM against the most common causative agents of eumycetoma, namely Madurella mycetomatis and Falciformispora senegalensis, and the resulting IC50 and MIC50 values were obtained. Compounds with an IC50 < 8 µM were identified for possible in vivo efficacy studies using an M. mycetomatis grain model in Galleria mellonella larvae. RESULTS: Out of the 400 compounds, 22 were able to inhibit both M. mycetomatis and F. senegalensis growth at 100 µM and 25 µM, with compounds MMV1593278, MMV020335, and MMV1804559 being selected for in vivo testing. Of these three, only the pyrazolopyrimidine derivative MMV1804559 was able to prolong the survival of M. mycetomatis-infected G. mellonella larvae. Furthermore, the grains in MMV1804559-treated larvae were significantly smaller compared to the PBS-treated group. CONCLUSION: MMV1804559 shows promising in vitro and in vivo activity against M. mycetomatis.

A Falciformispora senegalensis grain model in Galleria mellonella larvae.

Eumycetoma is a subcutaneous implantation mycosis often found in the foot. One of the hallmarks of eumycetoma is the formation of grains. These grains are either black or white, and the consistency and morphology differs per causative agent. The two most common causative agents of black-grain eumycetoma are Madurella mycetomatis and Falciformispora senegalensis. Since grains cannot be formed in vitro, in vivo models are needed to study grain formation. Here, we used the invertebrate Galleria mellonella to establish an in vivo grain model for F. senegalensis. Three different F. senegalensis strains were selected, and four different inocula were used to infect G. mellonella larvae, ranging from 0.04 mg/larvae to 10 mg/larvae. Larval survival was monitored for 10 days. Grain formation was studied macroscopically and histologically. The efficacy of antifungal therapy was determined for itraconazole, amphotericin B, and terbinafine. A concentration of 10 mg F. senegalensis per larva was lethal for the majority of the larvae within 10 days. At this inoculum, grains were formed within 24 h after infection. The grains produced in the larvae resembled those formed in human patients. Amphotericin B given at 1 mg/kg 4 h, 28 h, and 52 h after infection prolonged larval survival. No enhanced survival was noted for itraconazole or terbinafine. In conclusion, we developed a F. senegalensis grain model in G. mellonella larvae in which grains were formed that were similar to those formed in patients. This model can be used to monitor grain formation over time and study antifungal efficacy.

Within eumycetoma lesions, the causative agents are embedded in grains. However, the grains differ per causative agent. In this study, we developed a grain model of Falciformispora senegalensis in the larvae of Galleria mellonella. This model can be used in the future to study the efficacy of novel antifungal agents.

Brønsted acid-promoted ring-opening and annulation of thioamides and 2H-azirines to synthesize 2,4,5-trisubstituted thiazoles.

In this study, a metal-free synthesis of 2,4,5-trisubstituted thiazoles using 2H-azirines and thioamides is disclosed. Under the catalysis of HClO4, the protocol was realized through a novel chemical bond breaking of 2H-azirine, which is usually achieved using a metal catalyst. It provides an efficient and green route for the synthesis of substituted thiazoles with a broad substrate scope. Preliminary mechanistic studies show that such a reaction may involve a ring-opening reaction, annulation, and a hydrogen atom rearrangement process.

Large-scale and stacked transfer of bilayers MoS2devices on a flexible polyimide substrate.

Two-dimensional transition metal dichalcogenides (TMDs), as flexible and stretchable materials, have attracted considerable attention in the field of novel flexible electronics due to their excellent mechanical, optical, and electronic properties. Among the various TMD materials, atomically thin MoS2has become the most widely used material due to its advantageous properties, such as its adjustable bandgap, excellent performance, and ease of preparation. In this work, we demonstrated the practicality of a stacked wafer-scale two-layer MoS2film obtained by transferring multiple single-layer films grown using chemical vapor deposition. The MoS2field-effect transistor cell had a top-gated device structure with a (PI) film as the substrate, which exhibited a high on/off ratio (108), large average mobility (∼8.56 cm2V-1s-1), and exceptional uniformity. Furthermore, a range of flexible integrated logic devices, including inverters, NOR gates, and NAND gates, were successfully implemented via traditional lithography. These results highlight the immense potential of TMD materials, particularly MoS2, in enabling advanced flexible electronic and optoelectronic devices, which pave the way for transformative applications in future-generation electronics.

Antifungal Activity of Natural Naphthoquinones and Anthraquinones against Madurella mycetomatis.

Eumycetoma, the fungal form of the neglected tropical disease mycetoma, is a crippling infectious disease with low response rates to currently available antifungal drugs. In this study, a series of natural naphthoquinones and anthraquinones was evaluated for their activity against Madurella mycetomatis, which is the most common causative agent of eumycetoma. The metabolic activity of Madurella mycetomatis as well as the viability of Galleria mellonella larvae upon treatment with quinones was investigated. Several hydroxy-substituted naphthoquinones exhibited activity against Madurella mycetomatis. In particular, naphthazarin (5,8-dihydroxy-1,4-naphthoquinone) was identified as a considerably active antifungal compound against Madurella mycetomatis (IC50 =1.4 µM), while it showed reduced toxicity to Galleria mellonella larvae, which is a well-established in vivo invertebrate model for mycetoma drug studies.

Effects of temperature on cathepsin B, cathepsin D and acid phosphatase during embryo development of the hard tick Haemaphysalis longicornis.

The effects of temperature on the expression patterns and enzyme activity of cathepsin B (HlCatB), cathepsin D (HlCatD) and acid phosphatase (HlACP) during the embryo development of Haemaphysalis longicornis (bisexual population) were investigated in this study. Eggs were exposed to 20 °C (low temperature), 26 °C (normal temperature), and 30 °C (high temperature) immediately after laying, and collected on odd days of embryo development to measure HlCatB, HlCatD and HlACP gene expression using quantitative real-time PCR, as well as three enzyme activities using spectrophotometry. Then the associations between mRNA expression levels of three enzymes and their enzyme activities were assessed. Compared with normal temperature, the mRNA expression peaks of HlCatB were higher and appeared later at low and high temperatures and the activity of HlCatB increased on most days of embryonic development at high temperature. As for HlCatD, the expression peak appeared later at low temperature, but earlier at high temperature. The activity peaks of HlCatD were lower and appeared earlier at low and high temperatures. As for HlACP, the expression peak was higher and appeared later at low temperature, whereas it formed no prominent peak at high temperature. The activity peak of HlACP was higher at low temperature, but lower at high temperature. The linear regression analysis showed that activities of three enzymes were associated with their mRNA expression levels (P < 0.05). Three enzymes are involved in the embryo adaptation to temperature stress. Moreover, the mRNA expression level may be another factor affecting its enzyme activity.

Wafer-Scale Demonstration of MBC-FET and C-FET Arrays Based on Two-Dimensional Semiconductors.

Two-dimentional semiconductors have shown potential applications in multi-bridge channel field-effect transistors (MBC-FETs) and complementary field-effect transistors (C-FETs) due to their atomic thickness, stackability, and excellent electrical properties. However, the exploration of MBC-FET and C-FET based on large-scale 2D semiconductors is still lacking. Here, based on a reliable vertical stacking of wafer-scale 2D semiconductors, large-scale MBC-FETs and C-FETs using n-type MoS2 and p-type MoTe2 are successfully fabricated. The drive current of an MBC-FET with two layers of MoS2 channel (20 µm/10 µm) is up to 60 µA under 1 V bias. Compared with the single-gate MoS2 FET, the carrier mobility of MBC-FET is 2.3 times higher and the sub-threshold swing is 70% smaller. Furthermore, NAND and NOR logic circuits are also constructed based on two vertically stacked MoS2 channels. Then, C-FET arrays are fabricated by 3D integrating n-type MoS2 FET and p-type MoTe2 FET, which exhibit a voltage gain of 7 V/V when VDD  = 4 V. In addition, this C-FET device can directly convert light signals to an electrical digital signal within a single device. The demonstration of MBC-FET and C-FET based on large-scale 2D semiconductors will promote the application of 2D semiconductors in next-generation circuits.

Discovery of a highly potent CECR2 bromodomain inhibitor with 7H-pyrrolo[2,3-d] pyrimidine scaffold.

Cat eye syndrome chromosome region candidate 2 (CECR2) bromodomain is a module of CECR2-containing remodeling factor (CERF), which is a chromatin remodeling complex correlating with transcriptional control and adjustment of chromatin architecture. Potent chemical probes would be beneficial to gain insights into the biochemical and pharmacological functions of CECR2 BRD. Herein, we report the discovery of a series of CECR2 BRD inhibitors with 7H-pyrrolo[2,3-d] pyrimidine scaffold based on molecular docking model of TP-248 and CECR2 BRD. The most potent inhibitor of this series, DC-CBi-22 with IC50 of 8.0 ± 1.4 nM against CECR2 BRD and selectivity over BPTF BRD up to 24.9-fold. The SARs were detailed according to molecular docking. DC-CBi-22 would serve as a useful chemical probe for the study of CECR2.

iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition.

The most frequently mutated protein in human cancer is p53, a transcription factor (TF) that regulates myriad genes instrumental in diverse cellular outcomes including growth arrest and cell death. Cell context-dependent p53 modulation is critical for this life-or-death balance, yet remains incompletely understood. Here we identify sequence signatures enriched in genomic p53-binding sites modulated by the transcription cofactor iASPP. Moreover, our p53-iASPP crystal structure reveals that iASPP displaces the p53 L1 loop-which mediates sequence-specific interactions with the signature-corresponding base-without perturbing other DNA-recognizing modules of the p53 DNA-binding domain. A TF commonly uses multiple structural modules to recognize its cognate DNA, and thus this mechanism of a cofactor fine-tuning TF-DNA interactions through targeting a particular module is likely widespread. Previously, all tumor suppressors and oncoproteins that associate with the p53 DNA-binding domain-except the oncogenic E6 from human papillomaviruses (HPVs)-structurally cluster at the DNA-binding site of p53, complicating drug design. By contrast, iASPP inhibits p53 through a distinct surface overlapping the E6 footprint, opening prospects for p53-targeting precision medicine to improve cancer therapy.

Analysis of the chloride ion removal mechanism from simulated wastewater by discarded vitamin tablets.

Vitamin (VM) tablets are often discarded or incinerated as medical waste, and untreated highly chlorinated wastewater is discharged, polluting the environment. In this study, Cu2+ was reduced by vitamin C (VC, a component of VM), and the precipitate formed by the reaction of its product with Cl- in water was used to remove Cl- from simulated wastewater. This allows for the resourceful use of waste VM, while also achieving the goal of dechlorinating wastewater. Meanwhile, the effect of various parameters on dechlorination was studied, and the dechlorination mechanism was analyzed. According to the results, the removal rate of Cl- increased first and then decreased with pH, removal time and reaction temperature. Using VC in VM to dechlorinate simulated wastewater, the removal rate of Cl- was 94.31% under optimum conditions: pH 2.5, temperature 30 °C and reaction time 10 minutes. According to the dechlorination process, it can be inferred that Cu2+ is reduced to Cu+ by VC, and Cu+ and Cl- coprecipitate to remove Cl-. Therefore, it is feasible to use discarded VM to treat high concentration chlorine-containing wastewater.

Exploration of the effect of mixed probiotics on microbiota of allergic asthma mice.

Co-relation between allergic asthma and microbiota varying with diet has been extensively investigated, implicating that oral supplement of alternative pharmaceuticals are potential for asthma control. Probiotics are of great concern due to its beneficial effects on the host, whereas the potential mechanisms and the optimal dose need to be further explored. In the present study, three different doses of mixed strains were given orally to mouse model of allergic asthma induced by ovalbumin (OVA). Continuous administration of mixed probiotics could alleviate OVA-induced allergic inflammation through reducing costimulatory molecules on the surface of dendritic cells (DCs) and increasing mucosal gut-primed Tregs induced by mesenteric CD103+DCs. Mixed probiotics-induced protective effect relates to gut microbiota instead of lung microbes. Microbial diversity and Bacteroidetes/Firmicutes (B/F) ratio are augmented upon probiotic strains. Interestingly, treatment with mixed strain lead to an increased levels of genus Lactobacillus. Lactobacillus genus-Operational Taxonomic Unit (OUT) analysis indicated that OTU9 may be the dominant strain from mixed probiotics providing protective effect. The low dose seems to be the best in the whole study. Our results provide new evidence for probiotic application in allergic diseases and support the idea that targeted gut microbiota will be an effective approach for allergic airway diseases.

Premonitory symptoms in migraine from China: A multi-clinic study of 4821 patients.

OBJECTIVE: To observe the prevalence and characteristics of premonitory symptoms in Chinese migraineurs and explore their associations with migraine-related factors. METHOD: Migraineurs who visited a tertiary headache clinic and one of nine neurology clinics between May 2014 and November 2019 were studied. RESULT: Among the 4821 patients meeting the migraine criteria (International Classification of Headache Disorders, 3rd edition), 1038 (21.5%) patients experienced at least one premonitory symptom. The most common premonitory symptoms were neck stiffness, dizziness, yawning and drowsiness. The logistic regression analysis demonstrated that aura, photophobia, aggravation by routine physical activity, triggers, family history, depression, coffee consumption and physical exercise were associated with an increased probability of experiencing premonitory symptoms (p ≤ 0.001). The premonitory symptoms of migraine with and without aura differ in prevalence and most common symptoms. The cluster analysis revealed pairwise clustering of the following premonitory symptoms: Photophobia/phonophobia, concentration change/dysesthesia, loquacity/overactivity, yawning/drowsiness, fatigue/dizziness, and mood change/irritability. The correlation analysis of triggers and premonitory symptoms revealed that temperature change, environment change, sleep disorder, activity and stress were related to multiple premonitory symptoms, and that food, light, menstruation, alcohol and odor were related to special premonitory symptoms (p ≤ 0.001). CONCLUSION: The prevalence of premonitory symptoms among migraineurs in China is 21.5%. Some factors influence the probability of experiencing premonitory symptoms. Paired premonitory symptoms in the clustering analysis may share similar origins. Certain triggers associated with multiple premonitory symptoms may induce brain dysfunction; however, other triggers that overlap with corresponding special premonitory symptoms may be premonitory symptoms or a form of premonitory symptom.

Functional identification and characterization of GST genes in the Asian gypsy moth in response to poplar secondary metabolites.

The Asian gypsy moth, Lymantria dispar, as one of the most important forest pests in the world, can feed on more than 500 species of host plants, causing serious damage to the forests. Poplar is one of the favorite host plants of L. dispar. The present study aimed to explore the effects of poplar secondary metabolites on the growth and detoxification function of L. dispar larvae. We also aimed to study the expression of glutathione S-transferase (GST) genes in different developmental stages and in response to treatment with secondary metabolites. Six kinds of main secondary metabolites and three groups of characteristic mixed secondary metabolites were selected as follows: Caffeic acid, salicin, rutin, quercetin, catechol, flavone, mixture 1 (salicin and flavone), mixture 2 (salicin, caffeic acid and catechol), and mixture 3 (flavone, caffeic acid and catechol) according to the content changes of secondary metabolites in poplar. The thirteen GST genes were selected as candidate genes to study the expression of GST genes in different developmental stages and after treatment with secondary metabolites using quantitative real-time reverse transcription PCR. The LdGSTe4 and LdGSTo1 genes could be induced by secondary metabolites and were screened to explore their detoxification function against secondary metabolites using RNA interference technology. The results showed that salicin and rutin significantly induced the expression of LdGSTe4 and LdGSTo1. Under the stress of secondary metabolites, LdGSTe4 silencing affected the adaptability of L. dispar larvae to salicin and rutin. LdGSTe4 silencing resulted in a significant decrease in the body weight of L. dispar, but had little effect on the relative growth rate, relative consumption rate, efficiency of conversion of ingested food, efficiency of conversion of digested food, and approximate digestibility, as well as the survival rate and development time. These results provide a deeper understanding of the adaptive mechanism of L. dispar to host plants, form the foundation for the further research into the host resistance mechanism, and identify target genes for breeding resistant transgenic poplar.

Neutrophil exosomes enhance the skin autoinflammation in generalized pustular psoriasis via activating keratinocytes.

Generalized pustular psoriasis (GPP) is a rare and severe inflammatory skin disease that can be life-threatening. Gene mutations are found in some cases, but its immune pathogenesis is largely unknown. Here, we observed that the neutrophil:lymphocyte ratio in patients with GPP was higher than that in healthy controls and decreased after effective treatment. Neutrophils isolated from patients with GPP induced higher expressions of inflammatory genes including IL-1ß, IL-36G, IL-18, TNF-α, and C-X-C motif chemokine ligands in keratinocytes than normal neutrophils did. Moreover, neutrophils from patients with GPP secreted more exosomes than controls, which were then rapidly internalized by keratinocytes, increasing the expression of these inflammatory molecules via activating NF-κB and MAPK signaling pathways. The proteomic profiles in neutrophil exosomes further characterized functional proteins and identified olfactomedin 4 as the critical differentially expressed protein that mediates the autoimmune inflammatory responses of GPP. These results demonstrate that neutrophil exosomes have an immune-regulatory effect on keratinocytes, which modulates immune cell migration and autoinflammation in GPP.-Shao, S., Fang, H., Zhang, J., Jiang, M., Xue, K., Ma, J., Zhang, J., Lei, J., Zhang, Y., Li, B., Yuan, X., Dang, E., Wang, G. Neutrophil exosomes enhance the skin autoinflammation in generalized pustular psoriasis via activating keratinocytes.

The Control of Developmental Phase Transitions by microRNAs and Their Targets in Seed Plants.

Seed plants usually undergo various developmental phase transitions throughout their lifespan, mainly including juvenile-to-adult and vegetative-to-reproductive transitions, as well as developmental transitions within organ/tissue formation. MicroRNAs (miRNAs), as a class of small endogenous non-coding RNAs, are involved in the developmental phase transitions in plants by negatively regulating the expression of their target genes at the post-transcriptional level. In recent years, cumulative evidence has revealed that five miRNAs, miR156, miR159, miR166, miR172, and miR396, are key regulators of developmental phase transitions in plants. In this review, the advanced progress of the five miRNAs and their targets in regulating plant developmental transitions, especially in storage organ formation, are summarized and discussed, combining our own findings with the literature. In general, the functions of the five miRNAs and their targets are relatively conserved, but their functional divergences also emerge to some extent. In addition, potential research directions of miRNAs in regulating plant developmental phase transitions are prospected.