Mechanosynthesis of Pyrrole-2-carboxylic Acids via Copper-Catalyzed Spiroannulation/Ring-Opening Aromatization of 4-Arylidene Isoxazol-5-ones with Enamino Esters.

An efficient and practical tandem reaction of 4-arylidene isoxazol-5-ones with enamino esters catalyzed by an inexpensive copper salt has been established in a ball mill. This innovative approach yields a diverse array of structurally novel pyrrole-2-carboxylic acids, showing excellent tolerance toward different functional groups. By integrating spiroannulation and ring-opening aromatization processes, this protocol introduces a facile and cost-effective strategy for synthesizing highly functionalized pyrrole derivatives.

Chemodivergent mechanosynthesis of cyclopentenyl and pyrrolinyl spirobarbiturates from unsaturated barbiturates and enamino esters.

A novel and interesting controllable spirocyclization of unsaturated barbiturates with enamino esters for the assembly of cyclopentenyl and pyrrolinyl spirobarbiturates has been developed under ball-milling conditions. The present protocol features high chemoselectivity and efficiency, excellent functional group tolerance and mild reaction conditions.

Exploring the novel antioxidant peptides in low-salt dry-cured ham: Preparation, purification, identification and molecular docking.

Dry-cured ham is important source of bioactive peptides. In this study, the antioxidant activities of peptides and components from low and fully salted dry-cured hams were compared by peptidomics. And novel antioxidant peptides were identified and characterized. The results showed that the peptides (<3 KDa) extracted from low-salt dry-cured ham had higher antioxidant activity. Therefore, the antioxidant peptides in low-salt dry-cured ham were further characterized and the mechanism of their antioxidant activity was investigated. From the five candidate peptides selected, we found DWPDARGIWHND (DD12) to be highly stable, non-sensitizing, and non-toxic with the highest free radical scavenging activity. Molecular docking predicted that DD12 interacted with Keap1 through hydrogen-bond formation and hydrophobic interactions, suggesting that DD12 had good cellular antioxidant activity. DD12 peptide can bind to DPPH• and ABTS•+, resulting in strong free radical scavenging activity. Our findings support the development and application of natural antioxidant peptides in dry-cured ham.

Epidermal keratinocyte-specific STAT3 deficiency aggravated atopic dermatitis-like skin inflammation in mice through TSLP upregulation.

Atopic dermatitis (AD) is one of the most common inflammatory skin diseases with complex pathogenesis involving epidermal barrier dysfunction, skin microbiome abnormalities and type-2-skewed immune dysregulation. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that plays critical roles in various biological processes. However, the role of STAT3 in epidermal keratinocytes in AD remains unclear. In this study, we generated an epidermal keratinocyte-specific Stat3-deficient mouse strain (termed Stat3 cKO mice). After topical 2,4-dinitrochlorobenzene (DNCB) treatment, Stat3 cKO mice developed worsened AD-like skin inflammation with increased Ki67+ cells, decreased filaggrin and loricrin expression, and downregulated S100A9 and LL37. The dominant microbial population in Stat3 cKO mice changed from Ralstonia to Staphylococcus. DNCB-treated Stat3 cKO mice displayed more infiltrating type-2 inflammatory cells, including mast cells, eosinophils, and CD4+T cells, accompanied by increased skin IL-4 and serum IgE levels. Moreover, thymic stromal lymphopoietin (TSLP), mainly produced by keratinocytes, was highly expressed in the ear skin of Stat3 cKO mice and chemoattracted more TSLPR+ cells. TSLP blockade significantly alleviated DNCB-induced AD-like skin inflammation in Stat3 cKO mice. Thus, epidermal keratinocyte-specific STAT3 deficiency can aggravate AD-like skin inflammation in mice, possibly through TSLP dysregulation.

pH-Dependent phosphate separation using a tripodal hexaurea receptor.

We demonstrate that a tripodal hexaurea receptor can selectively bind PO43- anions via 12 hydrogen bonds with up to 3.8 × 106 M-1 binding affinity in DMSO, which is 38-fold stronger than SO42-. This receptor facilitates the extraction of PO43- from strongly basic aqueous solutions into chloroform using liquid-liquid extraction, followed by its release as the H2PO4- anion into an acidic solution. This pH-dependent phosphate extraction successfully enables selective separation of phosphate and sulfate anions.

Gut Microbiome Composition of the Fire Ant Solenopsis invicta: an Integrated Analysis of Host Genotype and Geographical Distribution.

Gut symbiotic bacteria are known to be closely related to insect development, nutrient metabolism, and disease resistance traits, but the most important factors leading to changes in these communities have not been well clarified. To address this, we examined the associations between the gut symbiotic bacteria and the host genotype and geographical distribution of Solenopsis invicta in China, where it is invasive and has spread primarily by human-mediated dispersal. Thirty-two phyla were detected in the gut symbiotic bacteria of S. invicta. Proteobacteria were the most dominant group among the gut symbiotic bacteria. Furthermore, the Bray-Curtis dissimilarity matrices of the gut symbiotic bacteria were significantly positively correlated with the geographical distance between the host ant colonies, but this relationship was affected by the social form. The distance between monogyne colonies had a significant effect on the Bray-Curtis dissimilarity matrices of gut symbiotic bacteria, but the distance between polygyne colonies did not. Moreover, the Bray-Curtis dissimilarity matrices were positively correlated with Nei's genetic distance of the host but were not correlated with the COI-based genetic distance. This study provides a scientific basis for further understanding the ecological adaptability of red imported fire ants during invasion and dispersal. IMPORTANCE We demonstrated that gut microbiota composition and diversity varied among populations. These among-population differences were associated with host genotype and geographical distribution. Our results suggested that population-level differences in S. invicta gut microbiota may depend more on environmental factors than on host genotype.

UBE2L3 Reduces TRIM21 Expression and IL-1ß Secretion in Epidermal Keratinocytes and Improves Psoriasis-Like Skin.

Proinflammatory cytokines, such as IL-1ß, are important mediators of psoriasis. UBE2L3, an E2 enzyme, is thought to be an indirect target of IL-1ß secretion by binding to ubiquitin ligases such as TRIM21. However, its role in psoriasis remains unknown. In this study, we found that UBE2L3 expression was decreased in psoriatic epidermis, whereas caspase 1 and IL-1ß signaling were strongly activated. When normal human epidermal keratinocytes were stimulated with nigericin, adenosine triphosphate, and poly(dA:dT), downregulation of UBE2L3 and increased secretion of IL-1ß were observed. Treatment with a caspase 1 inhibitor reversed the decrease in the level of UBE2L3. In addition, UBE2L3 overexpression reduced TRIM21, decreased signal transducer and activator of transcription 3 pathway activity, and reduced the level of the IL-1ß precursor (pro‒IL-1ß). Consistently, silencing UBE2L3 enhanced TRIM21 expression, signal transducer and activator of transcription 3 activation, and pro‒IL-1ß production. Finally, in an imiquimod-induced mouse model, UBE2L3 reduction and caspase 1 activation were localized in the epidermis, whereas overexpression of UBE2L3 ameliorated psoriasis-like lesions and reduced pro‒IL-1ß and mature IL-1ß levels in the epidermis. Thus, UBE2L3 may be a protective biomarker that regulates IL-1ß and inhibits TRIM21 in the epidermis of psoriasis.

The epidermal immune microenvironment plays a dominant role in psoriasis development, as revealed by mass cytometry.

Psoriasis is a common chronic inflammatory skin disease. The diversity and heterogeneity of immune cells in human skin have been studied in recent years, but the spatial distribution of immune cells at the single-cell level in the human psoriatic epidermis and dermis remains unclear. In this study, we mapped psoriatic skin immune cells from paired lesional, perilesional, and nonlesional skin samples using mass cytometry. Phenotypic dendritic cells (DCs) were found in the psoriatic epidermis and dermis. Psoriatic dermal CD1c+CD11b+ cDC2s migrated to the epidermis in the perilesional skin during the preinitiation stage. CD1c+CD11b+ cDC2s rapidly replaced EpCAM+CD11clow LC cells and initiated inflammation. Simultaneously, CD207+CD11chi LC and CD5+ T cells accumulated in the psoriatic epidermis and orchestrated epidermal inflammation in psoriasis. The immune cell pool in the psoriatic dermis primarily included APCs and T cells. However, unlike that in the dermis, the epidermal immune environment was more significant and coincided with the inflammation occurring during psoriasis.The epidermal immune microenvironment plays a dominant role in psoriasis. Langerhans cells, epidermis-resident memory T cells and macrophages together contribute to healthy epidermal immune homeostasis. However, psoriatic CD1c+CD11b+ epidermal cDC2s are positioned in the perilesional area, replacing EpCAM+CD11clow LCs rapidly and initiating inflammation. Epidermal CD141+ cDC1s, CD1c+ cDC2s, CD14+ moDCs, and BDCA2+ pDCs orchestrate psoriatic inflammation. Meanwhile, CD11chi LCs and CD5+ T cells accumulate in the psoriatic epidermis.

Biologics for psoriasis patients under 18 years of age: Real-world evidence from the Chinese psoriasis real world evidence research group.

Background: Treatment for pediatric psoriasis is challenging because of the lack of real-world evidence, especially for biological therapies. Objectives: This study evaluated the efficacy and safety of biologics in children with psoriasis based on real-world evidence. Methods: Pediatric psoriasis patients aged <18 years who were treated with biologics in our hospital (2020-2022) were prospectively analyzed. Patients treated with adalimumab, secukinumab, or ixekizumab were followed up for at least 16 weeks, and 22 of 38 patients completed the 52-week observation period. Dermatologist raters were blinded to ensure the reliability of the PASI, BSA, and PGA score assessments. PASI 75 or PGA 0/1 at week 12 represented an efficient indicator. Results: Thirty-eight patients (20 males and 18 females; median age, 12.6 ± 4.1 years) were enrolled, and none were lost to follow-up. All participants were diagnosed with psoriasis, including plaque psoriasis (n = 36), nail psoriasis (n = 1), and pustular psoriasis (n = 1). Within 12 weeks, all patients achieved scores above PASI 75 and PGA 0/1. The average time to reach PASI 75 was 4.3 ± 2.0, 3.2 ± 1.8, and 2.4 ± 0.4 weeks in patients using adalimumab, secukinumab, and ixekizumab, respectively, and, 27.2% (3/11), 86.4% (19/22), and 75.0% (3/4) of these patients achieved PASI 100 at week 12, respectively. Moreover, 18 of 20 patients with plaque psoriasis maintained ≥PASI 75 after 52 weeks. The most commonly reported adverse effect was upper respiratory tract infection, and no severe adverse effects were reported. Conclusions: Our real-world data demonstrated the safety and effectiveness of adalimumab, secukinumab, and ixekizumab in children with psoriasis.

Separation of Sulfate Anion From Aqueous Solution Governed by Recognition Chemistry: A Minireview.

The sulfate anion (SO4 2-) is known as an end metabolite of cysteine and methionine, and its proper concentration is associated with the expression of key functions in the physiological system. Thus, maintaining sulfate concentration at a precise level is of great significance for biology, environments, and industrial productions. Fundamental research for sulfate anion chemistry can help understand sulfate-associated physiological processes and related applications, for example, remediation. In this minireview, we summarized recent research progresses in sulfate recognition and separation using crystallization and liquid-liquid extraction. We focused on the studies wherein molecular recognition is the key element and is considered the driving force for selective sulfate separations from aqueous solution.

Posterior cruciate ligament reconstruction with independent internal brace reinforcement: surgical technique and clinical outcomes with a minimum two year follow-up.

PURPOSE: We developed an augmentation technique for PCL reconstruction with independent internal brace reinforcement and evaluated the functional outcome after PCL reconstruction employing autologous hamstrings augmented with an internal brace system for patients with isolated or combined grade 3 posterior instability who were treated with this technique. METHODS: From January 2016 to January 2018, patients with isolated or combined grade 3 PCL tears who underwent single-bundle PCL reconstruction using autologous hamstrings augmented with independent internal braces were studied. The function of the operated knee was evaluated according to the International Knee Documentation Committee (IKDC) score, Lysholm score, and Tegner activity score. The patients were asked the level of returned to their previous sport. Posterior knee laxity was examined with a KT-1000 arthrometer, and data on range of motion (ROM), re-operation, and other complications were collected. RESULTS: A total of 33 consecutive patients who received single-bundle PCL reconstruction using autologous hamstrings augmented with independent internal braces with a minimum two years follow-up were included in this study. Two patients had undergone this procedure during the study period and were not included in this study (one had combined bone fractures, and one patient had previous meniscus surgery). Thirty-one patients were available for final analysis. The mean follow-up was 45.35 ± 10.88 months (range 29-66 months). The average IKDC subjective knee evaluation scores from 51.65 ± 12.35 to 84.52 ± 6.42, the Lysholm score from 53.90 ± 11.86 to 85.68 ± 4.99, and the Tegner score from 2.81 ± 0.79 to 6.71 ± 1.83 (P < 0.05 for all). The mean total posterior side-to-side difference in knee laxity, assessed using a KT-1000 arthrometer, decreased from 12.13 ± 2.66 mm pre-operatively to 1.87 ± 0.56 mm post-operatively at 70° (P < 0.05). Most patients (29/31) had normal or near normal knee ROM post-operatively; two patients revealed a 6-15° loss of knee flexion compared with the contralateral knee. Twenty-nine patients (93.55%) returned to a normal daily exercise level. Twenty-three patients (74.19%) returned to competitive sports with high-level sports (Tegner score of 6 or above; eleven patients (35.48%) reported to be on the same level as well as the Tegner level); six patients (19.35%) returned to recreational sports (Tegner score of 4 or 5). Two patients had Tegner scores of 2 and 3, indicating poor function level. No patient needed PCL revision surgery during the follow-up period. CONCLUSION: Single-bundle PCL reconstruction with internal brace augmentation for PCL injury exhibited satisfactory posterior stability and clinical outcomes in patients with isolated or combined grade 3 PCL injuries at a minimum two year follow-up.

Combined metabolomic and transcriptomic analysis evidences the interaction between sugars and phosphate in rice.

Phosphorus is one of the macro-elements required by plants, but phosphate (Pi), the only form that can be absorbed by plants, is always limited for plant growth and development. To adapt to Pi deficiency, plants have evolved a complex regulatory system to improve Pi acquisition and utilization efficiency. In this study, metabolomic and transcriptomic analyses were performed to exam the global metabolites and gene expressions profiles responding to Pi deficiency in rice. A total of 23 metabolites were co-changed in leaves and roots after Pi deficiency, with sucrose, trehalose and melibiose significant accumulated. A total of 779 genes were co-changed in these leaves and roots. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that differentially expressed genes and differentially accumulated metabolites were co-enriched in galactose metabolism. Further exogenous sugars supply with rice roots could induce Pi starvation responsiveness and the expression of OsPHR2, which codes the central regulator for Pi starvation responsiveness in rice. This work revealed the interaction between sugars and phosphate in rice, and the importance of OsPHR2 in this interaction.

Cutaneous nerve fibers participate in the progression of psoriasis by linking epidermal keratinocytes and immunocytes.

Recent studies have illustrated that psoriatic lesions are innervated by dense sensory nerve fibers. Psoriatic plaques appeared to improve after central or peripheral nerve injury. Therefore, the nervous system may play a vital role in psoriasis. We aimed to clarify the expression of nerve fibers in psoriasis and their relationship with immune cells and keratinocytes, and to explore the effect of skin nerve impairment. Our results illustrated that nerve fibers in psoriatic lesions increased and were closely innervated around immune cells and keratinocytes. RNA-seq analysis showed that peripheral sensory nerve-related genes were disrupted in psoriasis. In spinal cord hemi-section mice, sensory impairment improved psoriasiform dermatitis and inhibited the abnormal proliferation of keratinocytes. Botulinum toxin A alleviated psoriasiform dermatitis by inhibiting the secretion of calcitonin gene-related peptide. Collectively, cutaneous nerve fibers participate in the progression of psoriasis by linking epidermal keratinocytes and immunocytes. Neurological intervention may be a new treatment strategy for psoriasis.

Cranial irradiation impairs intrinsic excitability and synaptic plasticity of hippocampal CA1 pyramidal neurons with implications for cognitive function.

Radiation therapy is a standard treatment for head and neck tumors. However, patients often exhibit cognitive impairments following radiation therapy. Previous studies have revealed that hippocampal dysfunction, specifically abnormal hippocampal neurogenesis or neuroinflammation, plays a key role in radiation-induced cognitive impairment. However, the long-term effects of radiation with respect to the electrophysiological adaptation of hippocampal neurons remain poorly characterized. We found that mice exhibited cognitive impairment 3 months after undergoing 10 minutes of cranial irradiation at a dose rate of 3 Gy/min. Furthermore, we observed a remarkable reduction in spike firing and excitatory synaptic input, as well as greatly enhanced inhibitory inputs, in hippocampal CA1 pyramidal neurons. Corresponding to the electrophysiological adaptation, we found reduced expression of synaptic plasticity marker VGLUT1 and increased expression of VGAT. Furthermore, in irradiated mice, long-term potentiation in the hippocampus was weakened and GluR1 expression was inhibited. These findings suggest that radiation can impair intrinsic excitability and synaptic plasticity in hippocampal CA1 pyramidal neurons.

Comparison of Long-Term Effectiveness and Safety of Microwave and Surgery in the Treatment of Axillary Osmidrosis: A Single-Center Retrospective Study.

BACKGROUND: A microwave-based device is a newly developed method for treating axillary osmidrosis. Few studies have compared the difference between microwave therapy and subcutaneous curettage for axillary osmidrosis. OBJECTIVE: To compare the long-term effectiveness, complications, and recurrence of osmidrosis after microwave therapy and subcutaneous curettage. METHODS AND MATERIALS: Medical records of 155 patients with osmidrosis treated with microwave therapy or subcutaneous curettage were reviewed retrospectively. Demographic data, visual analog scale for odor, hyperhidrosis disease scale, complications, and recurrence were analyzed. RESULTS: Osmidrosis improved significantly in both treatment groups at 6 months. Effective improvement was observed in 90% and 23% of the patients in the surgery and microwave groups, respectively, after 3 years postoperatively. The recurrence rates were 39% and 21% in the microwave and surgery groups, respectively. The transient complication rate was higher in the microwave group, and long-term complications only occurred in the surgery group. CONCLUSION: Subcutaneous curettage is a more effective approach for axillary osmidrosis. However, microwave therapy is recommended for patients with cosmetic concerns.

N(6)-methyladenosine-binding protein YTHDF1 suppresses EBV replication and promotes EBV RNA decay.

N6 -methyladenosine (m6 A) modification of mRNA mediates diverse cellular and viral functions. Infection with Epstein-Barr virus (EBV) is causally associated with nasopharyngeal carcinoma (NPC), 10% of gastric carcinoma, and various B-cell lymphomas, in which the viral latent and lytic phases both play vital roles. Here, we show that EBV transcripts exhibit differential m6 A modification in human NPC biopsies, patient-derived xenograft tissues, and cells at different EBV infection stages. m6 A-modified EBV transcripts are recognized and destabilized by the YTHDF1 protein, which leads to the m6 A-dependent suppression of EBV infection and replication. Mechanistically, YTHDF1 hastens viral RNA decapping and mediates RNA decay by recruiting RNA degradation complexes, including ZAP, DDX17, and DCP2, thereby post-transcriptionally downregulating the expression of EBV genes. Taken together, our results reveal the critical roles of m6 A modifications and their reader YTHDF1 in EBV replication. These findings contribute novel targets for the treatment of EBV-associated cancers.

Controllable Tandem [3+2] Cyclization of Aromatic Aldehydes with Maleimides: Rhodium(III)-Catalyzed Divergent Synthesis of Indane-Fused Pyrrolidine-2,5-dione.

Controllable rhodium(III)-catalyzed tandem [3+2] cyclization of aromatic aldehydes with maleimides is developed for the divergent synthesis of stereoselective indane-fused pyrrolidine-2,5-dione. Switchable access to different products could be achieved by employing different additives and varying the reaction time. This atom-economic transformation proceeds efficiently via the C-H bond activation directed by weakly coordinating aldehydes and is characterized by exclusive stereoselectivity, air atmosphere, and being free of nitrogen-based transient directing groups.

The Ras/ERK signaling pathway couples antimicrobial peptides to mediate resistance to dengue virus in Aedes mosquitoes.

Aedes mosquitoes can transmit dengue and several other severe vector-borne viral diseases, thereby influencing millions of people worldwide. Insects primarily control and clear the viral infections via their innate immune systems. Mitogen-Activated Protein Kinases (MAPKs) and antimicrobial peptides (AMPs) are both evolutionarily conserved components of the innate immune systems. In this study, we investigated the role of MAPKs in Aedes mosquitoes following DENV infection by using genetic and pharmacological approaches. We demonstrated that knockdown of ERK, but not of JNK or p38, significantly enhances the viral replication in Aedes mosquito cells. The Ras/ERK signaling is activated in both the cells and midguts of Aedes mosquitoes following DENV infection, and thus plays a role in restricting the viral infection, as both genetic and pharmacological activation of the Ras/ERK pathway significantly decreases the viral titers. In contrast, inhibition of the Ras/ERK pathway enhances DENV infection. In addition, we identified a signaling crosstalk between the Ras/ERK pathway and DENV-induced AMPs in which defensin C participates in restricting DENV infection in Aedes mosquitoes. Our results reveal that the Ras/ERK signaling pathway couples AMPs to mediate the resistance of Aedes mosquitoes to DENV infection, which provides a new insight into understanding the crosstalk between MAPKs and AMPs in the innate immunity of mosquito vectors during the viral infection.

EZH2-inhibitor DZNep enhances apoptosis of renal tubular epithelial cells in presence and absence of cisplatin.

BACKGROUND: The enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and induces the trimethylation of histone H3 lysine 27 (H3K27me3) in the promoter of many key genes; EZH2 acts as a transcriptional repressor and is an epigenetic regulator for several cancers. However, the role of EZH2 in nonneoplastic diseases, such as kidney diseases, is unknown and has been investigated. MATERIALS AND METHOD: NRK-52E cells were treated with DZNep, a potent inhibitor of EZH2, with different concentrations and for different times to evaluate the apoptosis level of NRK-52E cells by Western blot and Flow cytometry analysis. The binding of EZH2 to the Deptor promoter was determined by ChIP assay. RESULTS: The inhibition of EZH2 with 3-deazaneplanocin A (DZNep), a specific inhibitor of EZH2, led to the apoptosis of NRK-52E cells and the inhibition of mTORC1 and mTORC2 activity. A ChIP assay demonstrated that EZH2 bound the promoter region of Deptor, an endogenous inhibitor of mTORC1 and mTORC2, and regulated the transcription of Deptor by modulating H3K27me3 in its promoter region. Further experiments were performed to examine the effects of EZH2 inhibition on cisplatin-induced injured cells. Cisplatin induced the activation of mTORC1 and mTORC2 and apoptosis in NRK-52E cells, and DZNep inhibited mTORC1 and mTORC2 activity and aggravated cell apoptosis. CONCLUSIONS: These data suggested that EZH2 inhibition increased the transcription of Deptor by modifying H3K27me3 in its promoter region, subsequently inhibited mTORC1 and mTORC2 activities, downregulated the expression of apoptosis suppressor genes, and finally led to apoptosis in renal tubular cells. The inhibition of EZH2 aggravated the cisplatin-induced injury in renal tubular cells by inactivating the mTOR complexes. The present study provides new insight into renal protection and suggests that EZH2 might be a target.