Developmental trajectories of professional preparedness among senior nursing students during clinical placement: A longitudinal study.

BACKGROUND: Newly graduated nurses' lack of professional competence is associated with inadequate preparation during their clinical placement as nursing students. Clinical placement is a critical stage in the development of nursing students' professional preparedness. However, research on the trajectory of nursing students' professional preparedness during clinical placement has not yielded findings with the same specificity. OBJECTIVES: The aim of this study is to estimate differences in professional preparedness levels at different clinical placement stages, to identify distinct patterns of professional preparedness trajectories during clinical placement, and to evaluate predictors of these trajectory group memberships. DESIGN: A quantitative longitudinal study. SETTINGS: Participants were recruited on a voluntary basis using convenience sampling at a tertiary hospital in Nanning, China. PARTICIPANTS: 224 senior nursing students were initially invited to participate in the study. A total of 178 nursing students successfully completed the follow-up assessments at baseline, as well as at 1 month, 4 months, and 8 months into their clinical placement. METHODS: Participants completed four online surveys, during which their professional preparedness level was measured using the Perceived Professional Preparedness questionnaire for senior nursing students. Professional preparedness scores at different time points were compared using one-way repeated measures ANOVA and latent growth model. Group-based trajectory model was applied to identify professional preparedness trajectories. Multiple logistic regression was adopted to determine the predictors of trajectory group memberships. RESULTS: The entire sample of Senior nursing students experienced a significant increase in professional preparedness during clinical placement. The best-fitting group-based trajectory model delineated three distinct trajectories: low-slowly increase trajectory (27.53 % of sample), moderate-rapidly increase trajectory (47.19 % of sample) and a high-stably increase trajectory (25.28 % of sample). Male, good and excellent academic performance, and very high degree of professional interest are the predictors of the moderate-rapidly increase trajectory. While male, good and excellent academic performance, high and very high degree of professional interest and participating in medical-related part-time employment are the predictors of the high-stable increase trajectory. CONCLUSIONS: Senior nursing students exhibit different levels of professional preparedness throughout their clinical placement. Simultaneously, three different trajectories were identified among the sample of nursing students. Therefore, in future research, greater attention should be directed towards the professional preparedness levels of nursing students with different trajectories, and early identification and targeted interventions should be prioritized.

Barleriside A, an aryl hydrocarbon receptor antagonist, ameliorates podocyte injury through inhibiting oxidative stress and inflammation.

Introduction: Increasing evidence shows that hyperactive aryl hydrocarbon receptor (AHR) signalling is involved in renal disease. However, no currently available intervention strategy is effective in halting disease progression by targeting the AHR signalling. Our previous study showed that barleriside A (BSA), a major component of Plantaginis semen, exhibits renoprotective effects. Methods: In this study, we determined the effects of BSA on AHR expression in 5/6 nephrectomized (NX) rats. We further determined the effect of BSA on AHR, nuclear factor kappa B (NF-ƙB), and the nuclear factor erythroid 2-related factor 2 (Nrf2) signalling cascade in zymosan-activated serum (ZAS)-stimulated MPC5 cells. Results: BSA treatment improved renal function and inhibited intrarenal nuclear AHR protein expression in NX-treated rats. BSA mitigated podocyte lesions and suppressed AHR mRNA and protein expression in ZAS-stimulated MPC5 cells. BSA inhibited inflammation by improving the NF-ƙB and Nrf2 pathways in ZAS-stimulated MPC5 cells. However, BSA did not markedly upregulate the expression of podocyte-specific proteins in the ZAS-mediated MPC5 cells treated with CH223191 or AHR siRNA compared to untreated ZAS-induced MPC5 cells. Similarly, the inhibitory effects of BSA on nuclear NF-ƙB p65, Nrf2, and AHR, as well as cytoplasmic cyclooxygenase-2, heme oxygenase-1, and AHR, were partially abolished in ZAS-induced MPC5 cells treated with CH223191 or AHRsiRNA compared with untreated ZAS-induced MPC5 cells. These results indicated that BSA attenuated the inflammatory response, partly by inhibiting AHR signalling. Discussion: Both pharmacological and siNRA findings suggested that BSA mitigated podocyte lesions by improving the NF-ƙB and Nrf2 pathways via inhibiting AHR signalling. Therefore, BSA is a high-affinity AHR antagonist that abolishes oxidative stress and inflammation.

Aberrant Modular Segregation of Brain Networks in Patients with Diabetic Retinopathy.

Background: Diabetic retinopathy (DR) is a prevalent ocular manifestation of diabetic microvascular complications and a primary driver of irreversible blindness. Existing studies have illuminated the presence of aberrant brain activity in individuals affected by DR. However, the alterations in the modular segregation of brain networks among DR patients remain inadequately understood. The study aims to explore the modular segregation of brain networks in patients with DR. Methods: We examined the blood oxygen levels dependent (BOLD) signals using resting-state functional magnetic resonance imaging (R-fMRI) in a cohort of 46 DRpatients and 43 age-matched healthy controls (HC). Subsequently, Modular analysis utilizing graph theory method was applied to quantify the degree of brain network segregation by computing the participation coefficient (PC). Deviations from typical PC values were further elucidated through intra- and inter-module connectivity analyses. Results: The DR group demonstrated significantly lower mean PC in the frontoparietal network (FPN), sensorimotor network (SMN), and visual network (VN) compared to the HCgroup. Moreover, increased inter-module connections were observed between the default-mode network (DMN) and SMN, as well as between FPN and VN within the DR group. In terms of nodal analysis, higher PC values were detected in the left thalamus, right frontal lobe, and right precentral gyrus in the DR group compared to the HC group. Conclusion: Patients with DR show impairments in primary sensory networks and higher cognitive networks within their functional brain networks. These changes may provide essential insights into the neurobiological mechanisms of DR by identifying alterations in the brain networks of DR patients and pinpointing sensitive neurobiological markers that could serve as vital imaging references for future treatments of diabetic retinopathy.

Geniposidic Acid Attenuates Chronic Tubulointerstitial Nephropathy Through Regulation of the NF-ƙB/Nrf2 Pathway Via Aryl Hydrocarbon Receptor Signaling.

Renal fibrosis is an outcome of chronic kidney disease, independent of the underlying etiology. Renal fibrosis is caused primarily by oxidative stress and inflammation. We identified the components of Plantaginis semen and elucidated their anti-fibrotic and anti-inflammatory mechanisms. The renoprotective components and underlying molecular mechanisms of P. semen were investigated in rats with adenine-induced chronic tubulointerstitial nephropathy (TIN) and in idole-3-acetic acid (IAA)-stimulated NRK-52E cells. Acetate and n-butanol extracts were found to be the bioactive fractions of P. semen. A total of 65 compounds including geniposidic acid (GPA), apigenin (APG), and acteoside (ATS) were isolated and identified. Among the seven main extract components, treatment with GPA, APG, and ATS reduced the serum levels of creatinine and urea in TIN rats. Mechanistically, GPA ameliorated renal fibrosis through repressing aryl hydrocarbon receptor (AHR) signaling and regulating redox signaling including inhibiting proinflammatory nuclear factor kappa B (NF-ƙB) and its target gene products as well as activated antioxidative nuclear factor-erythroid-2-related factor 2 (Nrf2) and its downstream target gene products in both TIN rats and IAA-stimulated NRK-52E cells. The inhibitory effect of GPA on AHR, NF-Ƙb, and Nrf2 signaling were partially abolished in IAA-stimulated NRK-52E cells treated with CH223191 compared with untreated IAA-stimulated NRK-52E cells. These data demonstrated that GPA alleviates oxidative stress and inflammation partly by suppressing AHR signaling.

Retinal nerve fiber layer defects and chronic kidney disease: the Kailuan Eye Study.

AIM: To investigate whether retinal nerve fiber layer defects (RNFLDs) is a potential risk factor for chronic kidney disease (CKD) in Chinese adults. METHODS: The Kailuan Eye Study was a population-based study that included 14 440 participants. All participants underwent detailed assessments, RNFLDs were diagnosed using color fundus photographs. RESULTS: Overall, 12 507 participants [8533 males (68.23%)] had complete systemic examination data and at least one evaluable fundus photograph. RNFLDs were found in 621 participants [5.0%; 95% confidence interval (CI): 4.6%-5.34%], and 70 cases of multiple RNFLDs were found (11.27%). After adjusting multiple factors, RNFLDs was significantly associated with CKD severity, the ORs of CKD stage 3, stage 4 and stage 5 were 1.698, 4.167, and 9.512, respectively. Multiple RNFLDs were also associated with CKD severity after adjusting multiple factors, the ORs of CKD stage 3 and stage 5 were 4.465 and 11.833 respectively. Furthermore, 2294 participants had CKD (18.34%, 95%CI: 17.68%-18.99%). After adjusting for other factors, CKD presence was significantly correlated with the presence of RNFLDs. CONCLUSION: The strongest risk factors for RNFLDs are CKD and hypertension. Conversely, RNFLDs can be an ocular feature in patients with CKD. Fundoscopy can help detect systemic diseases, and assessment for RNFLDs should be considered in CKD patients.

Exploring nature's battlefield: organismic interactions in the discovery of bioactive natural products.

Covering: up to March 2024.Microbial natural products have historically been a cornerstone for the discovery of therapeutic agents. Advanced (meta)genome sequencing technologies have revealed that microbes harbor far greater biosynthetic capabilities than previously anticipated. However, despite the application of CRISPR/Cas-based gene editing and high-throughput technologies to activate silent biosynthetic gene clusters, the rapid identification of new natural products has not led to a proportional increase in the discovery rate of lead compounds or drugs. A crucial issue in this gap may be insufficient knowledge about the inherent biological and physiological functions of microbial natural products. Addressing this gap necessitates recognizing that the generation of functional natural products is deeply rooted in the interactions between the producing microbes and other (micro)organisms within their ecological contexts, an understanding that is essential for harnessing their potential therapeutic benefits. In this review, we highlight the discovery of functional microbial natural products from diverse niches, including those associated with humans, nematodes, insects, fungi, protozoa, plants, and marine animals. Many of these findings result from an organismic-interaction-guided strategy using multi-omic approaches. The current importance of this topic lies in its potential to advance drug discovery in an era marked by increasing antimicrobial resistance.

The lifestyle and nutritional factors for dry eye disease in depression population: a retrospective case-control study.

Background: We aim to evaluate lifestyle and nutritional factors that lead to dry eye disease (DED) in a depressed population using data from the Taiwan BioBank (TWB). Methods: A retrospective case-control study was conducted, and patients with depression based on a questionnaire were selected as the depression group. Each patient in the depression group was matched by age and sex to two individuals without depression, and a total of 3,754 and 7,508 patients constituted the depression and non-depression groups, respectively. Based on the questionnaire, the primary outcome was the presence of DED. Additionally, the chi-square test and interaction test were applied to survey the effect of lifestyle and nutritional factors on DED in the depression and non-depression groups. Results: There were 822 (21.90%) and 958 (12.76%) DED patients in the depression and non-depression groups, respectively, and the incidence of DED was significantly higher in the depression group (p < 0.001). In terms of lifestyle and nutritional factors in the depression population, a higher rate of chronic pain and a sedentary lifestyle were observed than in the patients with depression without DED (both p < 0.05). According to the interaction test, the chronic pain (p = 0.0227) and sedentary lifestyle (p = 0.0002) were significant risk factors for DED presence in the depression group than in the non-depression group, while the persistent coffee consumption (p = 0.0005) and tea consumption (p = 0.0003) were significant protective factors for the DED exclusively for the depression group and not for the non-depression group. Conclusion: The depression population could be significantly benefited from physical activity, coffee intake and tea intake regarding DED development compared to the general population.

Spinal PTP1B Regulated NMDA Receptor-mediated Nociceptive Transmission and Peripheral Inflammation-induced Pain Sensitization.

Protein tyrosine phosphatases (PTPs) catalyze the dephosphorylation of several pain-related substrates in spinal cord dorsal horn and are critically involved in the modification of pain transmission. The current study demonstrated that protein tyrosine phosphatase 1B (PTP1B), a unique endoplasmic reticulum-resident member of PTP family, displayed an activity-dependent increase in its protein expression and synaptic localization in spinal dorsal horn of adult male rats. PTP1B interacted with the Src Homology 3 (SH3) domain of Synapse-Associated Protein 102 (SAP102), one of the postsynaptic scaffolding proteins that anchored PTP1B at postsynaptic sites. The SAP102-tethered PTP1B augmented the synaptic transmission mediated specifically by GluN2B subunit-containing N-methyl-D-aspartate subtype glutamate receptors. Interference with PTP1B activity or disruption of its interaction with SAP102 attenuated GluN2B-mediated nociceptive transmission and ameliorated pain sensitization induced by intraplantar injection of Complete Freund's Adjuvant. These data suggested that the activity-dependent synaptic redistribution of PTP1B served as an important mechanism regulating GluN2B receptor activity and that manipulation of PTP1B synaptic targeting might represent an effective approach for the treatment of chronic inflammatory pain.

Identification of target genes co-regulated by four key histone modifications of five key regions in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a cancer with high morbidity and mortality. Studies have shown that histone modification plays an important regulatory role in the occurrence and development of HCC. However, the specific regulatory effects of histone modifications on gene expression in HCC are still unclear. This study focuses on HepG2 cell lines and hepatocyte cell lines. First, the distribution of histone modification signals in the two cell lines was calculated and analyzed. Then, using the random forest algorithm, we analyzed the effects of different histone modifications and their modified regions on gene expression in the two cell lines, four key histone modifications (H3K36me3, H3K4me3, H3K79me2, and H3K9ac) and five key regions that co-regulate gene expression were obtained. Subsequently, target genes regulated by key histone modifications in key regions were screened. Combined with clinical data, Cox regression analysis and Kaplan-Meier survival analysis were performed on the target genes, and four key target genes (CBX2, CEBPZOS, LDHA, and UMPS) related to prognosis were identified. Finally, through immune infiltration analysis and drug sensitivity analysis of key target genes, the potential role of key target genes in HCC was confirmed. Our results provide a theoretical basis for exploring the occurrence of HCC and propose potential biomarkers associated with histone modifications, which may be potential drug targets for the clinical treatment of HCC.

Comparing upward: How parental social comparisons shape children's self-concept and mastery motivation in China.

The prevalence of Chinese parents using upward social comparisons to influence their children's behavior is well-documented. However, the lack of reliable tools for measuring parental social comparisons, combined with a limited understanding of their association with preschoolers' mastery motivation, highlights a significant gap in research. To bridge this gap, we undertook a comprehensive investigation. Study 1 involved the development of the Parental Social Comparison Scale. Study 2 and Study 3 explored the association between parental social comparisons and children's mastery motivation, considering perspectives from parents (N = 194; Mage = 33.72 years, SD = 4.97) and children (N = 102; Mage = 5.14 years, SD = 3.78). We found that parental social comparisons were positively associated with children's mastery motivation according to parents' perceptions but were negatively associated with mastery motivation through children's self-concept from children's perspectives.

Causal association of juvenile idiopathic arthritis or JIA-associated uveitis and gut microbiota: a bidirectional two-sample Mendelian randomisation study.

Background: The gut microbiota significantly influences the onset and progression of juvenile idiopathic arthritis (JIA) and associated uveitis (JIAU); however, the causality remains unclear. This study aims to establish a causal link between gut microbiota and JIA or JIAU. Methods: Using publicly available genome-wide association studies (GAWS) summary data, we conducted a two-sample Mendelian randomisation (MR) analysis employing various methods, namely inverse variance weighted (IVW), simple mode, weighted mode, weighted median and MR-Egger regression methods, to assess the causal association between JIA or JIAU and gut microbiota. Sensitivity analyses, including Cochrane's Q test, MR-Egger intercept test, leave-one-out analysis and MR-PRESSO, were performed to evaluate the robustness of the MR results. Subsequently, reverse MR analysis was conducted to determine causality between gene-predicted gut microbiota abundance and JIA or JIAU. Results: The MR analysis revealed a causal association between gut microbiota abundance variations and JIA or JIAU risk. Specifically, the increased abundance of genus Ruminococcaceae UCG013 (OR: 0.055, 95%CI: 0.006-0.103, p = 0.026) and genus Ruminococcaceae UCG003 (ß: 0.06, 95%CI: 0.003-0.117, p = 0.041) correlated with an increased risk of JIA, while genus Lachnospiraceae UCG001 (OR: 0.833, 95%CI: 0.699~0.993, p = 0.042) was associated with a reduced risk of JIA, among others. Sensitivity analysis confirmed MR analysis robustness. Conclusions: This study provides substantial evidence supporting a causal association between genetically predicted gut microbiota and JIA or JIAU. It highlights the significant role of intestinal flora in JIA or JIAU development, suggesting their potential as novel biomarkers for diagnosis and prevention. These findings offer valuable insights to mitigate the impact of JIA or JIAU.

In vitro antibacterial activity of danofloxacin against Escherichia coli isolated from pigeons and its pharmacokinetic in pigeons.

This experiment aimed to investigate the in vitro antimicrobial activity of danofloxacin against Escherichia coli (E. coli) isolated from pigeons, as well as the pharmacokinetics of danofloxacin in pigeons following oral (PO), intramuscular (IM), and intravenous (IV) administration. The minimum inhibitory concentration (MIC) of danofloxacin was first determined for 38 clinical E. coli strains using the micro broth dilution method. Subsequently, 30 healthy pigeons were weighed and randomly divided into 3 groups: IM, IV, and PO, with 10 pigeons in each group. Danofloxacin was given at 5 mg/kg body weight (BW) through 3 different routes. Blood was collected, and plasma was separated at various time points from 0 to 48 h. Plasma samples were analyzed for danofloxacin concentrations using a validated HPLC method. Pharmacokinetic analysis was performed using Phoenix software and a noncompartmental analytical (NCA) method. The results indicated that danofloxacin had a strong antibacterial effect on E. coli, with a MIC50 of 0.5 µg/mL. The noncompartmental analysis showed that after PO and IM administration at 5 mg/kg in pigeons, peak plasma concentrations (Cmax) of 0.61 and 1.62 µg/mL were reached at 4.5 and 0.53 h, respectively. The oral and intramuscular bioavailability (F) were 68.08% ± 24.82% and 87.82% ± 25.36%, respectively. Following IV administration, danofloxacin was widely distributed in pigeons, with volume of distribution (VZ) and volume of distribution at steady state (VSS) values of 6.11 ± 2.01 and 4.65 ± 1.62 L/kg, respectively, and was eliminated slowly, with an elimination half-life (t1/2λz) of 6.41 ± 2.15 h. Based on the calculated ratio values of AUC/MIC, the current IV, IM, and PO doses of 5 mg/kg of danofloxacin would be expected to effectively treat pigeons infected with E. coli strains with MIC values equal to or less than 0.5 µg/mL.

Establishment and performance analysis of a new multiplex detection method for influenza an and B virus antigen.

BACKGROUND: Influenza A and B virus detection is pivotal in epidemiological surveillance and disease management. Rapid and accurate diagnostic techniques are crucial for timely clinical intervention and outbreak prevention. Quantum dot-encoded microspheres have been widely used in immunodetection. The integration of quantum dot-encoded microspheres with flow cytometry is a well-established technique that enables rapid analysis. Thus, establishing a multiplex detection method for influenza A and B virus antigens based on flow cytometry quantum dot microspheres will help in disease diagnosis. AIM: To establish a codetection method of influenza A and B virus antigens based on flow cytometry quantum dot-encoded microsphere technology, which forms the foundation for the assays of multiple respiratory virus biomarkers. METHODS: Different quantum dot-encoded microspheres were used to couple the monoclonal antibodies against influenza A and B. The known influenza A and B antigens were detected both separately and simultaneously on a flow cytometer, and the detection conditions were optimized to establish the influenza A and B antigen codetection method, which was utilized for their detection in clinical samples. The results were compared with the fluorescence quantitative polymerase chain reaction (PCR) method to validate the clinical performance of this method. RESULTS: The limits of detection of this method were 26.1 and 10.7 pg/mL for influenza A and B antigens, respectively, which both ranged from 15.6 to 250000 pg/mL. In the clinical sample evaluation, the proposed method well correlated with the fluorescent quantitative PCR method, with positive, negative, and overall compliance rates of 57.4%, 100%, and 71.6%, respectively. CONCLUSION: A multiplex assay for quantitative detection of influenza A and B virus antigens has been established, which is characterized by high sensitivity, good specificity, and a wide detection range and is promising for clinical applications.

Targeting Lactobacillus johnsonii to reverse chronic kidney disease.

Accumulated evidence suggested that gut microbial dysbiosis interplayed with progressive chronic kidney disease (CKD). However, no available therapy is effective in suppressing progressive CKD. Here, using microbiomics in 480 participants including healthy controls and patients with stage 1-5 CKD, we identified an elongation taxonomic chain Bacilli-Lactobacillales-Lactobacillaceae-Lactobacillus-Lactobacillus johnsonii correlated with patients with CKD progression, whose abundance strongly correlated with clinical kidney markers. L. johnsonii abundance reduced with progressive CKD in rats with adenine-induced CKD. L. johnsonii supplementation ameliorated kidney lesion. Serum indole-3-aldehyde (IAld), whose level strongly negatively correlated with creatinine level in CKD rats, decreased in serum of rats induced using unilateral ureteral obstruction (UUO) and 5/6 nephrectomy (NX) as well as late CKD patients. Treatment with IAld dampened kidney lesion through suppressing aryl hydrocarbon receptor (AHR) signal in rats with CKD or UUO, and in cultured 1-hydroxypyrene-induced HK-2 cells. Renoprotective effect of IAld was partially diminished in AHR deficiency mice and HK-2 cells. Our further data showed that treatment with L. johnsonii attenuated kidney lesion by suppressing AHR signal via increasing serum IAld level. Taken together, targeting L. johnsonii might reverse patients with CKD. This study provides a deeper understanding of how microbial-produced tryptophan metabolism affects host disease and discovers potential pathways for prophylactic and therapeutic treatments for CKD patients.

[Comparison of the effects of using iRoot BP plus and MTA apical barrier surgery in young permanent teeth with chronic apical periodontitis].

PURPOSE: To explore the effect of using iRoot BP plus and MTA apical barrier surgery in young permanent teeth with chronic apical periodontitis. METHODS: A total of 122 patients with chronic periapical periodontitis with open root tips of permanent teeth were randomly divided into experimental group (n=61, 61 teeth) and a control group (n=61, 61 teeth). Patients in the experimental group received iRoot BP plus plus apical barrier surgery, while those in the control group received MTA apical barrier surgery. The old periapical index (O-PAI), apical transmission area, efficacy, treatment times, and inflammatory factor levels of the two groups of patients were compared at 3, 6, 9, and 12 months after surgery. SPSS 19.0 software package was used for statistical analysis. RESULTS: At 12 months after surgery, the O-PAI ratings of the experimental group and the control group were (1.48±0.36) and (1.71±0.42), respectively, and the apical transmission area was (0.51±0.14) and (1.09±0.31). There was a significant difference in the O-PAI ratings and apical transmission area between the two groups(P＜0.05). At 3 months, 6 months, and 12 months after surgery, the O-PAI scores of patients in both groups gradually decreased (P＜0.05). After 12 months of treatment, the success rates of the experimental group and the control group were 98.36% and 88.52%, respectively, with significant difference between the two groups (P＜0.05). The treatment frequency of patients in the experimental group and the control group was (3.64±0.58) times and (4.72±0.61) times, respectively, with a significant difference between the two groups(P＜0.05). After 3 months of treatment, the serum hs-CRP levels in the experimental group and the control group were (6.89±1.13) mg/L and (7.25±1.40) mg/L, respectively, with a significant difference compared to pre-treatment(P＜0.05). After 3 months of treatment, the serum IL-6 levels in the experimental group and the control group were (82.04±19.62) mg/L and (87.52±20.85) mg/L, respectively, with significant differences compared to pre-treatment (P＜0.05). There was no significant difference in serum IL-6 and hs-CRP levels between the two groups before and after treatment(P＞0.05). CONCLUSIONS: iRoot BP plus apical barrier surgery for the treatment of chronic apical periodontitis with open permanent teeth can reduce the O-PAI index, decrease the number of postoperative visits, and have a higher postoperative success rate.

Exploring the Anti-Inflammatory Effect of Tryptanthrin by Regulating TLR4/MyD88/ROS/NF-κB, JAK/STAT3, and Keap1/Nrf2 Signaling Pathways.

Tryptanthrin (TRYP) is the main active ingredient in Indigo Naturalis. Studies have shown that TRYP had excellent anti-inflammatory activity, but its specific mechanism has been unclear. In this work, the differentially expressed proteins resulting from TRYP intervention in LPS-stimulated RAW264.7 cells were obtained based on tandem mass tag proteomics technology. The anti-inflammatory mechanism of TRYP was further validated by a combination of experiments using the LPS-induced RAW264.7 cell model in vitro and the DSS-induced UC mouse model (free drinking 2.5% DSS) in vivo. The results demonstrated that TRYP could inhibit levels of NO, IL-6, and TNF-α in LPS-induced RAW264.7 cells. Twelve differential proteins were screened out. And the results indicated that TRYP could inhibit upregulated levels of gp91phox, p22phox, FcεRIγ, IKKα/ß, and p-IκBα and reduce ROS levels in vitro. Besides, after TRYP treatment, the health conditions of colitis mice were all improved. Furthermore, TRYP inhibited the activation of JAK/STAT3, nuclear translocation of NF-κB p65, and promoted the nuclear expression of Nrf2 in vitro and in vivo. This work preliminarily indicated that TRYP might suppress the TLR4/MyD88/ROS/NF-κB and JAK/STAT3 signaling pathways to exert anti-inflammatory effects. Additionally, TRYP could achieve antioxidant effects by regulating the Keap1/Nrf2 signaling pathway.

Regioselective Synthesis of α-Quaternary Amino Acid Derivatives Enabled by Photoinduced Energy Transfer.

α-Quaternary amino acids have found application in many biologically relevant compounds and pharmaceuticals. Although there are many methods for the synthesis of α-quaternary amino acids, most of them are mainly realized with the aid of transition metals and complex ligands. We present herein a 2,7-Br-4CzIPN catalyzed regioselective alkylation of azlactones with redox-active esters via radical-radical couplings. Strikingly, this approach is devoid of any metal or additive and shows broad scope and superior sensitive functional group compatibility.

Exploring the Origins and Evolution of Oxygenic and Anoxygenic Photosynthesis in Deeply Branched Cyanobacteriota.

Cyanobacteriota, the sole prokaryotes capable of oxygenic photosynthesis (OxyP), occupy a unique and pivotal role in Earth's history. While the notion that OxyP may have originated from Cyanobacteriota is widely accepted, its early evolution remains elusive. Here, by using both metagenomics and metatranscriptomics, we explore 36 metagenome-assembled genomes from hot spring ecosystems, belonging to two deep-branching cyanobacterial orders: Thermostichales and Gloeomargaritales. Functional investigation reveals that Thermostichales encode the crucial thylakoid membrane biogenesis protein, vesicle-inducing protein in plastids 1 (Vipp1). Based on the phylogenetic results, we infer that the evolution of the thylakoid membrane predates the divergence of Thermostichales from other cyanobacterial groups and that Thermostichales may be the most ancient lineage known to date to have inherited this feature from their common ancestor. Apart from OxyP, both lineages are potentially capable of sulfide-driven AnoxyP by linking sulfide oxidation to the photosynthetic electron transport chain. Unexpectedly, this AnoxyP capacity appears to be an acquired feature, as the key gene sqr was horizontally transferred from later-evolved cyanobacterial lineages. The presence of two D1 protein variants in Thermostichales suggests the functional flexibility of photosystems, ensuring their survival in fluctuating redox environments. Furthermore, all MAGs feature streamlined phycobilisomes with a preference for capturing longer-wavelength light, implying a unique evolutionary trajectory. Collectively, these results reveal the photosynthetic flexibility in these early-diverging cyanobacterial lineages, shedding new light on the early evolution of Cyanobacteriota and their photosynthetic processes.

Employing unnatural promiscuity of sortase to construct peptide macrocycle libraries for ligand discovery.

With the increasing attention paid to macrocyclic scaffolds in peptide drug development, genetically encoded peptide macrocycle libraries have become invaluable sources for the discovery of high-affinity peptide ligands targeting disease-associated proteins. The traditional phage display technique of constructing disulfide-tethered macrocycles by cysteine oxidation has the inherent drawback of reduction instability of the disulfide bond. Chemical macrocyclization solves the problem of disulfide bond instability, but the involved highly electrophilic reagents are usually toxic to phages and may bring undesirable side reactions. Here, we report a unique Sortase-mediated Peptide Ligation and One-pot Cyclization strategy (SPLOC) to generate peptide macrocycle libraries, avoiding the undesired reactions of electrophiles with phages. The key to this platform is to mine the unnatural promiscuity of sortase on the X residue of the pentapeptide recognition sequence (LPXTG). Low reactive electrophiles are incorporated into the X-residue side chain, enabling intramolecular cyclization with the cysteine residue of the phage-displayed peptide library. Utilizing the genetically encoded peptide macrocycle library constructed by the SPLOC platform, we found a high-affinity bicyclic peptide binding TEAD4 with a nanomolar KD value (63.9 nM). Importantly, the binding affinity of the bicyclic peptide ligand is 102-fold lower than that of the acyclic analogue. To our knowledge, this is the first time to mine the unnatural promiscuity of ligases to generate peptide macrocycles, providing a new avenue for the construction of genetically encoded cyclic peptide libraries.

[The Efficacy and Influencing Factors of Cyclosporine Alone in the Treatment of Children with Acquired Aplastic Anemia].

OBJECTIVE: To analyze the efficacy and influencing factors of cyclosporine (CsA) alone in the treatment of children with acquired aplastic anemia (AA). METHODS: The clinical data of children diagnosed with AA and treated with CsA alone from January 1, 2016 to December 31, 2020 in the Children's Hospital of Chongqing Medical University were collected, and the efficacy and influencing factors of CsA treatment were evaluated. RESULTS: Among the 119 patients, there were 62 male and 57 female, with a median age of 7 years and 1 month. There were 45 cases of very severe AA (VSAA), 47 cases of severe AA (SAA), and 27 cases of non-severe AA (NSAA). At 6 months after treatment, the efficacy of VSAA was lower than that of SAA and NSAA, and there was a statistical difference (P < 0.01). 6 cases died early, 16 cases relapsed, 2 cases progressed to AML and ALL. The results of univariate analysis showed that the high proportion of lymphocyte in the bone marrow at 6 months was an adverse factor for the efficacy of CsA, while high PLT count was a protective factor (P =0.008, P =0.002). The ROC curve showed that the cut-off values of PLT count and the proportion of bone marrow lymphocyte at 6 months were 16.5×109 /L, 68.5%, respectively. Multivariate analysis showed that the high proportion of lymphocyte in bone marrow at 6 months was an independent adverse factor for IST (P =0.020, OR =0.062), and high PLT count was a protective factor (P =0.044, OR =1.038). At 3 months of treatment, CsA response and NSAA were the risk factor for recurrence (P =0.001, 0.031). CONCLUSION: The efficacy of NSAA was higher than that of SAA and VSAA after 6 months of treatment with CsA alone. A high PLT count at the initial diagnosis was a good factor for the effectiveness of CsA, and a high proportion of bone marrow lymphocyte was an unfavorable factor. CsA response at 3 months and NSAA were risk factors for recurrence.