Salivary factor LTRIN from Aedes aegypti facilitates the transmission of Zika virus by interfering with the lymphotoxin-ß receptor.

Pathogens have co-evolved with mosquitoes to optimize transmission to hosts. Mosquito salivary-gland extract is known to modulate host immune responses and facilitate pathogen transmission, but the underlying molecular mechanisms of this have remained unknown. In this study, we identified and characterized a prominent 15-kilodalton protein, LTRIN, obtained from the salivary glands of the mosquito Aedes aegypti. LTRIN expression was upregulated in blood-fed mosquitoes, and LTRIN facilitated the transmission of Zika virus (ZIKV) and exacerbated its pathogenicity by interfering with signaling through the lymphotoxin-ß receptor (LTßR). Mechanically, LTRIN bound to LTßR and 'preferentially' inhibited signaling via the transcription factor NF-κB and the production of inflammatory cytokines by interfering with the dimerization of LTßR during infection with ZIKV. Furthermore, treatment with antibody to LTRIN inhibited mosquito-mediated infection with ZIKV, and abolishing LTßR potentiated the infectivity of ZIKV both in vitro and in vivo. This study provides deeper insight into the transmission of mosquito-borne diseases in nature and supports the therapeutic potential of inhibiting the action of LTRIN to disrupt ZIKV transmission.

Epigenetic switch reshapes epithelial progenitor cell signatures and drives inflammatory pathogenesis in hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a complex inflammatory skin disease with undefined mechanistic underpinnings. Here, we investigated HS epithelial cells and demonstrated that HS basal progenitors modulate their lineage restriction and give rise to pathogenic keratinocyte clones, resulting in epidermal hyperproliferation and dysregulated inflammation in HS. When comparing to healthy epithelial stem/progenitor cells, in HS, we identified changes in gene signatures that revolve around the mitotic cell cycle, DNA damage response and repair, as well as cell-cell adhesion and chromatin remodeling. By reconstructing cell differentiation trajectory and CellChat modeling, we identified a keratinocyte population specific to HS. This population is marked by S100A7/8/9 and KRT6 family members, triggering IL1, IL10, and complement inflammatory cascades. These signals, along with HS-specific proinflammatory cytokines and chemokines, contribute to the recruitment of certain immune cells during the disease progression. Furthermore, we revealed a previously uncharacterized role of S100A8 in regulating the local chromatin environment of target loci in HS keratinocytes. Through the integration of genomic and epigenomic datasets, we identified genome-wide chromatin rewiring alongside the switch of transcription factors (TFs), which mediated HS transcriptional profiles. Importantly, we identified numerous clinically relevant inflammatory enhancers and their coordinated TFs in HS basal CD49fhigh cells. The disruption of the S100A enhancer using the CRISPR/Cas9-mediated approach or the pharmacological inhibition of the interferon regulatory transcription factor 3 (IRF3) efficiently reduced the production of HS-associated inflammatory regulators. Our study not only uncovers the plasticity of epidermal progenitor cells in HS but also elucidates the epigenetic mechanisms underlying HS pathogenesis.

Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival.

Muscle wasting and cachexia have long been postulated to be key determinants of cancer-related death, but there has been no direct experimental evidence to substantiate this hypothesis. Here, we show that in several cancer cachexia models, pharmacological blockade of ActRIIB pathway not only prevents further muscle wasting but also completely reverses prior loss of skeletal muscle and cancer-induced cardiac atrophy. This treatment dramatically prolongs survival, even of animals in which tumor growth is not inhibited and fat loss and production of proinflammatory cytokines are not reduced. ActRIIB pathway blockade abolished the activation of the ubiquitin-proteasome system and the induction of atrophy-specific ubiquitin ligases in muscles and also markedly stimulated muscle stem cell growth. These findings establish a crucial link between activation of the ActRIIB pathway and the development of cancer cachexia. Thus ActRIIB antagonism is a promising new approach for treating cancer cachexia, whose inhibition per se prolongs survival.

Interference with LTßR signaling by tick saliva facilitates transmission of Lyme disease spirochetes.

Lyme spirochetes have coevolved with ticks to optimize transmission to hosts using tick salivary molecules (TSMs) to counteract host defenses. TSMs modulate various molecular events at the tick-host interface. Lymphotoxin-beta receptor (LTßR) is a vital immune receptor and plays protective roles in host immunity against microbial infections. We found that Ltbr knockout mice were more susceptible to Lyme disease spirochetes, suggesting the involvement of LTßR signaling in tick-borne Borrelia infection. Further investigation showed that a 15-kDa TSM protein from Ixodes persulcatus (I. persulcatus salivary protein; IpSAP) functioned as an immunosuppressant to facilitate the transmission and infection of Lyme disease spirochetes. IpSAP directly interacts with LTßR to block its activation, thus inhibiting the downstream signaling and consequently suppressing immunity. IpSAP immunization provided mice with significant protection against I. persulcatus-mediated Borrelia garinii infection. Notably, the immunization showed considerable cross-protection against other Borrelia infections mediated by other ixodid ticks. One of the IpSAP homologs from other ixodid ticks showed similar effects on Lyme spirochete transmission. Together, our findings suggest that LTßR signaling plays an important role in blocking the transmission and pathogenesis of tick-borne Lyme disease spirochetes, and that IpSAP and its homologs are promising candidates for broad-spectrum vaccine development.

Advances in molecular pathogenesis of hidradenitis suppurativa: Dysregulated keratins and ECM signaling.

Hidradenitis suppurativa (HS) is characterized by deep-seated, highly inflamed, and painful lumps/abscesses, fistulae, and sinus tracts that grow extensively deep in the dermis and are highly immunogenic in nature. In about one-third of the HS patients there is strong evidence for the role of γ-secretase mutations along with dysregulated Notch signaling. However, the contribution of dysregulated Notch signaling in HS pathogenesis in relation to hair follicle alterations and hyper-activation of the immune system remains undefined. A genome-wide association study (GWAS), proteomic data and functional investigations of identified sequence variants in HS pathology are not fully revealing. The disease initiation or progression may involve bacterial infection besides intrinsic functional defects in keratinocytes, which may be key to further exacerbate immune cell infiltration and cytokine production in and around the lesional tissue. The absence of a suitable animal model that could fully recapitulate the pathogenesis of HS is a major impediment for proper understanding the underlying mechanisms and development of effective treatments. The presence of extracellular matrix (ECM) degradation products along with dysregulation in keratinocytes and, dermal fibroblasts ultimately affect immune regulation and are various components of HS pathogenesis. Bacterial infection further exacerbates the complexity of the disease progression. While anti-TNFα therapy shows partial efficacy, treatment to cure HS is absent. Multiple clinical trials targeting various cytokines, complement C5a and ECM products are in progress. This review provides state-of-the-art information on these aspects with a focus on dysregulated keratinocyte and immune cells; and role of ECM, and Keratin functions in this regard.

The emerging role of mtDNA release in sepsis: Current evidence and potential therapeutic targets.

Sepsis is a systemic inflammatory reaction caused by infection, and severe sepsis can develop into septic shock, eventually leading to multiorgan dysfunction and even death. In recent years, studies have shown that mitochondrial damage is closely related to the occurrence and development of sepsis. Recent years have seen a surge in concern over mitochondrial DNA (mtDNA), as anomalies in this material can lead to cellular dysfunction, disruption of aerobic respiration, and even death of the cell. In this review, we discuss the latest findings on the mechanisms of mitochondrial damage and the molecular mechanisms controlling mitochondrial mtDNA release. We also explored the connection between mtDNA misplacement and inflammatory activation. Additionally, we propose potential therapeutic targets of mtDNA for sepsis treatment.

Prevalence and Characteristics of Covert/Minimal Hepatic Encephalopathy in Patients With Liver Cirrhosis: A Systematic Review and Meta-Analysis.

INTRODUCTION: Covert/minimal hepatic encephalopathy (C/MHE) is the mildest form of hepatic encephalopathy (HE), but it is closely related to the quality of life and prognosis of patients with cirrhosis. Currently, the epidemiological data of C/MHE have not been well described. METHODS: We searched the PubMed, Embase, and Cochrane Library databases for relevant articles. We performed a random-effects meta-analysis of proportions to estimate the pooled prevalence of C/MHE in patients with cirrhosis. We also examined potential risk factors for C/MHE by comparing characteristics of patients with and without C/MHE. RESULTS: Finally, a total of 101 studies were included. The prevalence of C/MHE was 40.9% (95% confidence interval, 38.3%-43.5%) among patients with cirrhosis worldwide. The pooled C/MHE prevalence was 39.9% (95% confidence interval 36.7%-43.1%) based on studies using the psychometric HE score as a diagnostic tool. Meta-regression models showed that geographic region, sample size, mean age, sex ratio, and Child-Pugh classification were influencing factors for the heterogeneity of C/MHE prevalence. The presence of C/MHE was found to be associated with various factors including age, level of education, alcoholic etiology, Child-Pugh classification, MELD score, history of overt HE, presence of other complications, and laboratory tests related to impaired liver function. DISCUSSION: This study reports detailed data on the prevalence of C/MHE as well as clinical features associated with C/MHE, suggesting that C/MHE is one of the most common complications of liver cirrhosis.

A critical role for the nuclear protein Akirin in larval development in Henosepilachna vigintioctopunctata.

Akirin is a nuclear protein that controls development in vertebrates and invertebrates. The function of Akirin has not been assessed in any Coleopteran insects. We found that high levels of akirin transcripts in Henosepilachna vigintioctopunctata, a serious Coleopteran potato defoliator (hereafter Hvakirin), were present at prepupal, pupal and adult stages, especially in larval foregut and fat body. RNA interference (RNAi) targeting Hvakirin impaired larval development. The Hvakirin RNAi larvae arrested development at the final larval instar stage. They remained as stunted larvae, gradually blackened and finally died. Moreover, the remodelling of gut and fat body was inhibited in the Hvakirin depleted larvae. Two layers of cuticles, old and newly formed, were noted in the dsegfp-injected animals. In contrast, only a layer of cuticle was found in the dsakirin-injected beetles, indicating the arrest of larval development. Furthermore, the expression of three transforming growth factor-ß cascade genes (Hvsmox, Hvmyo and Hvbabo), a 20-hydroxyecdysone (20E) receptor gene (HvEcR) and six 20E response genes (HvHR3, HvHR4, HvE75, HvBrC, HvE93 and Hvftz-f1) was significantly repressed, consistent with decreased 20E signalling. Conversely, the transcription of a juvenile hormone (JH) biosynthesis gene (Hvjhamt), a JH receptor gene (HvMet) and two JH response genes (HvKr-h1 and HvHairy) was greatly enhanced. Our findings suggest a critical role of Akirin in larval development in H. vigintioctopunctata.

Enhancing Iron(III) Oxide Photoelectrochemical Water Splitting Performance Using Defect Engineering and Heterostructure Construction.

Fe2O3 is a promising semiconductor for photoelectrochemical (PEC) water decomposition. However, severe charge recombination problems limit its applications. In this study, a F-Fe2O3-x/MoS2 nanorod array photoanode was designed and prepared to facilitate charge separation. Detailed characterization and experimental results showed that F doping in Fe2O3 regulated the electronic structure to improve the conductivity of Fe2O3 and induced abundant oxygen vacancies to increase the carrier concentration and promote charge separation in bulk. In addition, the internal electric field between F-Fe2O3-x and MoS2 facilitated the qualitative transfer of the photogenerated charge, thus inhibiting their recombination. The synergistic effect between the oxygen vacancy and F-Fe2O3-x/MoS2 heterojunction significantly enhanced the PEC performance of Fe2O3. This study provides a universal strategy for designing other photoanode materials with high-efficiency charge separation.

Silver/Antimony-Base Multifunctional Double Perovskite with H/F Substitution Enhance Properties.

Two-dimensional double perovskites have experienced rapid development due to their outstanding optoelectronic properties and diverse structural characteristics. However, the synthesis of high-performance multifunctional compounds and the regulation of their properties still lack relevant examples. Herein, we synthesized two multifunctional compounds, (C6H14N)4AgSbBr8 (1) and (F2-C6H12N)4AgSbBr8 (2), which exhibit high solid-state phase transition temperature, bistable dielectric constant switching, second harmonic generation (SHG), and bright emission. Through H/F substitution, the transition temperature increases and achieves a smaller band gap attributed to reduced interlayer spacing. Furthermore, we investigated the broad emission mechanism of the compounds through first-principles calculation and variable-temperature fluorescence, confirming the presence of the STE1 emission. Our work provides insight into the further development of multifunctional compounds and chemical modification that enhances compound properties.

Cold Snare Polypectomy With or Without Submucosal Injection for Endoscopic Resection of Colorectal Polyps: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND AND AIMS: The impact of submucosal injection during cold snare polypectomy (CSP) remains uncertain. We conducted an evidence-based comparison of conventional CSP (C-CSP) and CSP with submucosal injection (SI-CSP) for colorectal polyp resection. METHODS: PubMed, Embase, and the Cochrane Library databases were searched for randomized controlled trials (RCTs) comparing C-CSP with SI-CSP. Major outcomes included the rates of complete resection, en bloc resection, polyp retrieval, and adverse events, as well as the duration of polypectomy. Data were analyzed by using a random-effects model. RESULTS: A total of seven RCTs were included. Complete resection rates for all polyps (RR 0.98; 95% CI 0.93-1.03), polyps ≤ 10 mm (RR 0.99; 95% CI 0.96-1.02) and polyps > 10 mm (RR 0.92; 95% CI 0.69-1.12) were not substantially different between C-CSP and SI-CSP groups. En bloc resection rate (RR 0.93; 95% CI 0.79-1.09) and polyp retrieval rate (RR 1.00; 95% CI 0.99-1.01) were also not significantly different between the two groups. The SI-CSP group required a prolonged polypectomy time than the C-CSP group (SMD - 0.89; 95% CI -1.29 to -0.49). Adverse events were rare in both groups. CONCLUSIONS: SI-CSP is not an optimal substitute for CSP in the resection of colorectal polyps, particularly diminutive and small polyps.

Portal vein velocity predicts portal vein system thrombosis after splenectomy with esophagogastric devascularization.

BACKGROUND: Portal vein system thrombosis (PVST) is a potentially fatal complication after splenectomy with esophagogastric devascularization (SED) in cirrhotic patients with portal hypertension. However, the impact of portal vein velocity (PVV) on PVST after SED remains unclear. Therefore, this study aims to explore this issue. METHODS: Consecutive cirrhotic patients with portal hypertension who underwent SED at Tongji Hospital between January 2010 and June 2022 were enrolled. The patients were divided into two groups based on the presence or absence of PVST, which was assessed using ultrasound or computed tomography after the operation. PVV was measured by duplex Doppler ultrasound within one week before surgery. The independent risk factors for PVST were analyzed using univariate and multivariate logistic regression analysis. A nomogram based on these variables was developed and internally validated using 1000 bootstrap resamples. RESULTS: A total of 562 cirrhotic patients with portal hypertension who underwent SED were included, and PVST occurred in 185 patients (32.9%). Multivariate logistic regression analysis showed that PVV was the strongest independent risk factor for PVST. The incidence of PVST was significantly higher in patients with PVV ≤ 16.5 cm/s than in those with PVV > 16.5 cm/s (76.2% vs. 8.5%, p < 0.0001). The PVV-based nomogram was internally validated and showed good performance (optimism-corrected c-statistic = 0.907). Decision curve and clinical impact curve analyses indicated that the nomogram provided a high clinical benefit. CONCLUSION: A nomogram based on PVV provided an excellent preoperative prediction of PVST after splenectomy with esophagogastric devascularization.

Twist is required for muscle development of the adult legs in Henosepilachna vigintioctopunctata.

Although muscle development has been widely studied in Drosophila melanogaster, it was a great challenge to apply to developmental processes of other insect muscles. This study was focused on the functional characterization of a basic helix-loop-helix transcription factor gene twist in an herbivorous ladybird Henosepilachna vigintioctopunctata. Its transcript (Hvtwist) levels were detected in all developmental stages. RNA interference (RNAi)-aided knockdown of Hvtwist at the penultimate larval instar stage impaired pupation, and caused a deformed adult in the legs. The tarsi were malformed and did not support the bodies in an upright position. The climbing ability was impaired. Moreover, around 50% of the impaired adults had a malformed elytrum. In addition, they consumed less foliage and did not lay eggs. A hematoxylin-eosin staining of the leg demonstrated that the tibial extensor (TE) and the tibial flexor (TF) muscles were originated from the femurs while levator and depressor muscles of the tarsus (TL and TD) were located in the tibia in the control adults, in which tarsal segments were devoid of muscles. RNAi treatment specific to Hvtwist expression markedly impaired TE and TF muscles in the femurs, and prevented the development of TL and TD muscles in the tibia. Therefore, our findings demonstrate Twist plays a vital role in the myogenesis in H. vigintioctopunctata adult legs.

Molecular characterization of the cytochrome P450 enzyme CYP18A1 in Henosepilachna vigintioctopunctata.

In insects, the expression of 20E response genes that initiate metamorphosis is triggered by a pulse of 20-hydroxyecdysone (20E). The 20E pulse is generated through two processes: synthesis, which increases its level, and inactivation, which decreases its titer. CYP18A1 functions as an ecdysteroid 26-hydroxylase and plays a role in 20E removal in several representative insects. However, applying 20E degradation activity of CYP18A1 to other insects remains a significant challenge. In this study, we discovered high levels of Hvcyp18a1 during the larval and late pupal stages, particularly in the larval epidermis and fat body of Henosepilachna vigintioctopunctata, a damaging Coleopteran pest of potatoes. RNA interference (RNAi) targeting Hvcyp18a1 disrupted the pupation. Approximately 75% of the Hvcyp18a1 RNAi larvae experienced developmental arrest and remained as stunted prepupae. Subsequently, they gradually turned black and eventually died. Among the Hvcyp18a1-depleted animals that successfully pupated, around half became malformed pupae with swollen elytra and hindwings. The emerged adults from these deformed pupae appeared misshapen, with shriveled elytra and hindwings, and were wrapped in the pupal exuviae. Furthermore, RNAi of Hvcyp18a1 increased the expression of a 20E receptor gene (HvEcR) and four 20E response transcripts (HvE75, HvHR3, HvBrC, and HvαFTZ-F1), while decreased the transcription of HvßFTZ-F1. Our findings confirm the vital role of CYP18A1 in the pupation, potentially involved in the degradation of 20E in H. vigintioctopunctata.

Corneal densitometry in Chinese adults with healthy corneas: associations with sex, age, ocular metrics, and optical characteristics.

BACKGROUND: Standardized corneal densitometry (CD) values in large samples of healthy Chinese individuals are scarce. Therefore, we aimed to determine the standard CD values using a Scheimpflug camera in healthy corneas, investigate the correlations of sex, age, and ocular parameters with corneal density, and explore the impact of corneal density on the forward scattering and optical quality of the eye. METHODS: This retrospective observational study involved 990 healthy Chinese individuals, including 494 males and 496 females (mean age: 23.88 ± 6.90 years). The CD values at various depths and radial areas of 0-12 mm were measured using a Scheimpflug camera. Densitometric measurements were expressed in standardized grayscale units (GSU). The optical scatter index (OSI), modulation transfer function cutoff values (MTFcutoff), and Strehl's ratio (SR) were also determined using an optical quality analysis system. RESULTS: The average CD within a 12 mm diameter area was 16.26 ± 1.35 GSU. The highest and lowest optical densities at different depths were observed in the anterior (21.41 ± 2.16 GSU) and posterior (12.00 ± 1.01 GSU) layers, respectively (P < 0.001). Similarly, the maximum and minimum optical densities at different radial areas were observed in the 10-12 mm (14.09 ± 0.93 GSU) and 2-6 mm (25.93 ± 4.77 GSU) circles, respectively (P < 0.001). There was no significant difference in the average CD within a 12 mm diameter area between males and females (P > 0.05). However, upon adjusting for age, central corneal thickness (CCT), corneal curvature, white-to-white (WTW) corneal diameter, and axial length, females exhibited a greater average CD within the 12 mm diameter and in the 6-10 mm and 10-12 mm circles than males. Age-related changes in CD were evident, except in the 2-6 mm circle. CCT, corneal curvature, WTW corneal diameter, and partial depth correlated with CD in the radial area, and CD in different areas correlated with the OSI, MTFcutoff, and SR (P < 0.05). CONCLUSIONS: This study provides the normative CD measurement data of Chinese adults with healthy corneas, emphasizing the significance of sex, age, CCT, corneal curvature, and WTW corneal diameter in CD evaluation. Notably, elevated CD can lead to increased forward scattering within the eye, thereby affecting the optical quality.

Establishment and pathophysiological evaluation of a novel model of acute compartment syndrome in rats.

BACKGROUND: Researches have used intra-compartmental infusion and ballon tourniquest to create high intra-compartmental pressure in animal models of Acute Compartment Syndrome (ACS). However, due to the large differences in the modeling methods and the evaluation criteria of ACS, further researches of its pathophysiology and pathogenesis are hindered. Currently, there is no ideal animal model for ACS and this study aimed to establish a reproducible, clinically relevant animal model. METHODS: Blunt trauma and fracture were caused by the free falling of weights (0.5 kg, 1 kg, 2 kg) from a height of 40 cm onto the lower legs of rats, and the application of pressures of 100 mmHg, 200 mmHg, 300 mmHg and 400 mmHg to the lower limbs of rats using a modified pressurizing device for 6 h. The intra-compartmental pressure (ICP) and the pressure change (ΔP) of rats with single and combined injury were continuously recorded, and the pathophysiology of the rats was assessed based on serum biochemistry, histological and hemodynamic changes. RESULTS: The ΔP caused by single injury method of different weights falling onto the lower leg did not meet the diagnosis criteria for ACS (< 30 mmHg). On the other hand, a combined injury method of a falling weight of 1.0 kg and the use of a pressurizing device with pressure of 300 mmHg or 400 mmHg for 6 h resulted in the desired ACS diagnosis criteria with a ΔP value of less than 30 mmHg. The serum analytes, histological damage score, and fibrosis level of the combined injury group were significantly increased compared with control group, while the blood flow was significantly decreased compared with control group. CONCLUSION: We successfully established a new preclinical ACS-like rat model, by the compression of the lower leg of rats with 300 mmHg pressure for 6 h and blunt trauma by 1.0 kg weight falling.

The Cd resistant mechanism of Proteus mirabilis Ch8 through immobilizing and detoxifying.

Cadmium (Cd) pollution is a serious global environmental problem, which requires a global concern and practical solutions. Microbial remediation has received widespread attention owing to advantages, such as environmental friendliness and soil amelioration. However, Cd toxicity also severely deteriorates the remediation performance of functional microorganisms. Analyzing the mechanism of bacterial resistance to Cd stress will be beneficial for the application of Cd remediation. In this study, the bacteria strain, up to 1400 mg/L Cd resistance, was employed and identified as Proteus mirabilis Ch8 (Ch8) through whole genome sequence analyses. The results indicated that the multiple pathways of immobilizing and detoxifying Cd maintained the growth of Ch8 under Cd stress, which also possessed high Cd extracellular adsorption. Firstly, the changes in surface morphology and functional groups of Ch8 cells were observed under different Cd conditions through SEM-EDS and FTIR analyses. Under 100 mg/L Cd, Ch8 cells exhibited aggregation and less flagella; the Cd biosorption of Ch8 was predominately by secreting exopolysaccharides (EPS) and no significant change of functional groups. Under 500 mg/L Cd, Ch8 were present irregular polymers on the cell surface, some cells with wrapping around; the Cd biosorption capacity exhibited outstanding effects (38.80 mg/g), which was mainly immobilizing Cd by secreting and interacting with EPS. Then, Ch8 also significantly enhanced the antioxidant enzyme activity and the antioxidant substance content under different Cd conditions. The activities of SOD and CAT, GSH content of Ch8 under 500 mg/L Cd were significantly increased by 245.47%, 179.52%, and 241.81%, compared to normal condition. Additionally, Ch8 significantly induced the expression of Acr A and Tol C (the resistance-nodulation-division (RND) efflux pump), and some antioxidant genes (SodB, SodC, and Tpx) to reduce Cd damage. In particular, the markedly higher expression levels of SodB under Cd stress. The mechanism of Ch8 lays a foundation for its application in solving soil remediation.

Synthesis, Structural Characterization, and Biological Activities of 1,3,4- Thiadiazole Derivatives Containing Sulfonylpiperazine Structures.

To develop novel bacterial biofilm inhibiting agents, a series of 1,3,4-thiadiazole derivatives containing sulfonylpiperazine structures were designed, synthesized, and characterized using 1H nuclear magnetic resonance (1H NMR), 13C nuclear magnetic resonance (13C NMR), and high-resolution mass spectrometry. Meanwhile, their biological activities were evaluated, and the ensuing structure-activity relationships were discussed. The bioassay results showed the substantial antimicrobial efficacy exhibited by most of the compounds. Among them, compound A24 demonstrated a strong efficacy with an EC50 value of 7.8 µg/mL in vitro against the Xanthomonas oryzae pv. oryzicola (Xoc) pathogen, surpassing commercial agents thiodiazole copper (31.8 µg/mL) and bismerthiazol (43.3 µg/mL). Mechanistic investigations into its anti-Xoc properties revealed that compound A24 operates by increasing the permeability of bacterial cell membranes, inhibiting biofilm formation and cell motility, and inducing morphological changes in bacterial cells. Importantly, in vivo tests showed its excellent protective and curative effects on rice bacterial leaf streak. Besides, molecular docking showed that the hydrophobic effect and hydrogen-bond interactions are key factors between the binding of A24 and AvrRxo1-ORF1. Therefore, these results suggest the utilization of 1,3,4-thiadiazole derivatives containing sulfonylpiperazine structures as a bacterial biofilm inhibiting agent, warranting further exploration in the realm of agrochemical development.

IRF4 induces M1 macrophage polarization and aggravates ulcerative colitis progression by the Bcl6-dependent STAT3 pathway.

Ulcerative colitis (UC) is an idiopathic chronic intestinal inflammation. An increasing body of evidence shows that macrophages play an important role in the pathogenesis of UC. Interferon regulatory factor 4 (IRF4) is crucial for the development of autoimmune diseases via regulating immune cells. This research was designed to explore the function of IRF4 in UC and its association with macrophage polarization. The in vitro model of UC was established by stimulating colonic epithelial cells with tumor necrosis factor α (TNF-α). A mouse model of UC was constructed by injecting C57BL/6 mice with dextran sulfate sodium salt. Flow cytometry was used to assess percentage of CD11b+ CD86+ and CD11b+ CD206+ cells in bone marrow macrophages. Occult blood tests were used to detect hematochezia. Hematoxylin and eosin staining assay was used to assess colon pathological changes. Enzyme-linked immunosorbent assay (ELISA) was used to detect concentrations of inflammatory cytokines. The interaction of IRF4 and B-cell lymphoma 6 (Bcl6) was confirmed using GST pull-down and coimmunoprecipitation assays. Our findings revealed that IRF4 promoted cell apoptosis and stimulated M1 macrophage polarization in vitro. Furthermore, IRF4 aggravated symptoms of the mouse model of UC and aggravated M1 macrophage polarization in vivo. IRF4 negatively regulated Bcl6 expression. Downregulation of Bcl6 promoted apoptosis and M1 macrophage polarization in the presence of IRF4 in vitro and in vivo. Moreover, Bcl6 positively mediated the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. In conclusion, IRF4 aggravated UC progression through promoting M1 macrophage polarization via Bcl6/JAK2/STAT3 pathway. These findings suggested that IRF4 might be a good target to competitively inhibit or to treat with UC.

Low-Divergence hBN Single-Photon Source with a 3D-Printed Low-Fluorescence Elliptical Polymer Microlens.

Efficiently collecting light from single-photon emitters is crucial for photonic quantum technologies. Here, we develop and use an ultralow fluorescence photopolymer to three-dimensionally print micrometer-sized elliptical lenses on individual precharacterized single-photon emitters in hexagonal boron nitride (hBN) nanocrystals, operating in the visible regime. The elliptical lens design beams the light highly efficiently into the far field, rendering bulky objective lenses obsolete. Using back focal plane imaging, we confirm that the emission is collimated to a narrow low-divergence beam with a half width at half-maximum of 2.2°. Using photon correlation measurements, we demonstrate that the single-photon character remains undisturbed by the polymer lens. The strongly directed emission and increased collection efficiency is highly beneficial for quantum optical experiments. Furthermore, our approach paves the way for a highly parallel fiber-based detection of single photons from hBN nanocrystals.