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Abstract Tuberculosis drug resistance contributes to the spread of tuberculosis. Immunotherapy is an effective strategy for treating tuberculosis, with the regulation of macrophage-mediated anti-tuberculosis immunity being crucial. Norcantharidin (NCTD), a drug used in tumor immunotherapy, has significant immunomodulatory effects. Thus, NCTD may have an anti-tuberculosis role by regulating immunity. Understanding how NCTD affects the proteome of Mtb-infected macrophages can provide valuable insights into potential treatments. This study aimed to investigate the impact of NCTD (10 μg/mL) on the proteome of macrophages infected with Mtb H37Ra using liquid chromatography-tandem mass spectrometry (LC–MS/MS) analysis. A total of 69 differentially regulated proteins (DRPs) were identified, with 28 up-regulated and 41 down-regulated in the NCTD-treated group. Validation of six DRPs (CLTCL1, VAV1, SP1, TRIM24, MYO1G, and WDR70) by Western blot analysis confirmed the accuracy of the LC–MS/MS method used in this study. NCTD modulates various protein expressions involved in chromatin-modifying enzymes, RHO GTPases activating PAKs, Fc gamma R-mediated phagocytosis, T cell receptor signaling pathway, and antigen processing and presentation. Overall, the research provides new insights into the effects of NCTD on the proteome of Mtb-infected macrophages. The identified changes highlight potential targets for future therapeutic interventions aimed at enhancing host immunity against Mtb infection or developing new anti-TB drugs based on these findings.

Objective: Osteoclast (OC) over-activation is an important cause of bone loss that is strongly correlated with inflammation. Although the CD163/TWEAK/Fn14 axis has been implicated in several inflammatory pathologies, its contributions to inflammatory bone loss remain poorly understood. This study aimed to evaluate the interaction of the CD163/TWEAK/Fn14 axis with OC in inflammatory bone loss. Methods: To assess the role of CD163 in bone homeostasis, we characterized the bone phenotypes of CD163-deficient mice and their wild-type littermates. CD163 and TWEAK levels were evaluated in the bone marrow of mice with LPS-induced bone loss and individuals with rheumatoid arthritis (RA). Bone mass changes were assessed using uCT and histology following supplementation with recombinant mouse CD163 protein (rCD163) or blockade of TWEAK/Fn14 signaling in CD163-deficient mice and mice with LPS-induced bone loss. The impact of CD163/TWEAK on OC differentiation and bone resorption capacity was analyzed in vitro. Results: CD163 deficiency caused decreased bone mass and increased OC abundance. Lower CD163 expression and higher TWEAK expression were observed in the bone marrow of mice with LPS-induced bone loss and individuals with RA. TWEAK, mainly derived from CD68+ macrophages, was responsible for bone loss, and supplementing rCD163 or blocking TWEAK/Fn14 signaling contributed to rescue bone loss. TWEAK/Fn14 synergistically promoted RANKL-dependent OC differentiation and bone resorption capability through downstream mitogen-activated protein kinases (MAPK) signaling, while the pro-osteoclastic effect of TWEAK was suppressed by CD163. Conclusion: Our findings suggest that the CD163/TWEAK/Fn14 axis is a potential therapeutic target for inflammatory bone loss by regulating osteoclastogenesis.

Halomonas bluephagenesis TD serves as an exceptional chassis for next generation industrial biotechnology to produce various products. However, the simultaneous editing of multiple loci in H. bluephagenesis TD remains a significant challenge. Herein, we report the development of a multiple loci genome editing system, named CRISPR-deaminase-assisted base editor (CRISPR-BE) in H. bluephagenesis TD. This system comprises two components: a cytidine (CRISPR-cBE) and an adenosine (CRISPR-aBE) deaminase-based base editor. CRISPR-cBE can introduce a cytidine to thymidine mutation with an efficiency of up to 100 % within a 7-nt editing window in H. bluephagenesis TD. Similarly, CRISPR-aBE demonstrates an efficiency of up to 100 % in converting adenosine to guanosine mutation within a 7-nt editing window. CRISPR-cBE has been further validated and successfully employed for simultaneous multiplexed editing in H. bluephagenesis TD. Our findings reveal that CRISPR-cBE efficiently inactivated all six copies of the IS1086 gene simultaneously by introducing stop codon. This system achieved an editing efficiency of 100 % and 41.67 % in inactivating two genes and three genes, respectively. By substituting the Pcas promoter with the inducible promoter PMmp1, we optimized CRISPR-cBE system and ultimately achieved 100 % editing efficiency in inactivating three genes. In conclusion, our research offers a robust and efficient method for concurrently modifying multiple loci in H. bluephagenesis TD, opening up vast possibilities for industrial applications in the future.

The effect of addition of different levels of lotus leaf powder on the flavor of dried minced pork slices (DMPS) was studied by examining its sensory flavor attributes, flavor substances, lipid and protein oxidation levels, Maillard reaction degree, and microstructure. The results showed that addition of lotus leaf powder significantly affected the flavor of DMPS. Addition of lotus leaf powder at 0.2% and 0.4% improved the flavor of DMPS by inhibiting the oxidation of lipids and proteins and consequently reducing the contents of the fat rancidity flavor compounds hexanal and nonanal, and the fishy odor compound trimethylamine. The generation of phenethyl alcohol, (E)-2-hexenal, and methyl acetate provided DMPS with a delicate fragrance of lotus. However, adding 0.6% or 0.8% lotus leaf powder significantly decreased the contents of sweet amino acids and the umami taste intensity of DMPS, and exacerbated lipid and protein oxidation by disrupting the microstructure of DMPS. Furthermore, lotus leaf powder suppressed the production of volatile heterocyclic compounds in DMPS by inhibiting the Maillard reaction. Therefore, addition of an appropriate amount of lotus leaf powder could effectively improve the flavor of DMPS.

Abstract Background The average daily gain (ADG) of preweaning calves significantly influences their adult productivity and reproductive performance. Gastrointestinal microbes are known to exert an impact on host phenotypes, including ADG. The aim of this study was to investigate the mechanisms by which gastrointestinal microbiome regulate ADG in preweaning calves and to further validate them by isolating ADG-associated rumen microbes in vitro. Results Sixteen Holstein heifer calves were selected from a cohort with 106 calves and divided into higher ADG (HADG; n = 8) and lower ADG (LADG; n = 8) groups. On the day of weaning, samples of rumen contents, hindgut contents, and plasma were collected for rumen metagenomics, rumen metabolomics, hindgut metagenomics, hindgut metabolomics, and plasma metabolomics analyses. Subsequently, rumen contents of preweaning Holstein heifer calves from the same dairy farm were collected to isolate ADG-associated rumen microbes. The results showed that the rumen microbes, including Pyramidobacter sp. C12-8, Pyramidobacter sp. CG50-2, Pyramidobacter porci, unclassified_g_Pyramidobacter, Pyramidobacter piscolens, and Acidaminococcus fermentans, were enriched in the rumen of HADG calves (LDA > 2, P 0.50, P

AbstractObjective Atrial fibrillation (AF), the most common cardiac arrhythmia, presents significant health challenges, and the intricate connection between insomnia and AF has garnered substantial attention. This cohort study aims to investigate the relationship between insomnia and AF recurrences following radiofrequency ablation.Materials and Methods Data were retrieved from an electronic database of patients who underwent radiofrequency ablation for AF. The primary endpoint was AF recurrence. We utilized a multivariable Cox model, coupled with three propensity score methods, for analysis.Results Between January 1, 2017, and June 1, 2022, 541 patients who underwent radiofrequency ablation for AF were recorded in the database. After excluding 185 patients, the final cohort comprised 356 patients. Among them, 68 were afflicted by insomnia, while 288 were not. Over a median follow-up of 755 days, one patient died, and 130 (36.5%) experienced AF recurrence. Multivariate Cox regression analysis revealed that the insomnia group had a higher risk of AF recurrence compared to the non-insomnia group (HR: 1.83, 95% CI: 1.16–2.89). Further landmark analysis showed no significant difference in AF recurrence rates during the initial 1-year follow-up. However, beyond 1 year, the insomnia group demonstrated a significantly higher AF recurrence rate. As the number of insomnia symptoms increased, the risk of AF recurrence also rose significantly, indicating a dose-response relationship.Conclusion This study establishes a significant link between insomnia and long-term AF recurrence following radiofrequency ablation. It underscores the importance of identifying and addressing insomnia in patients with AF undergoing radiofrequency ablation.

Tissue kallikrein (TK) has emerged as a potential neuroprotective agent in ischemic stroke (IS), yet the optimal timing and mechanisms of TK therapy remain unclear. Here, we established a causal link between lower baseline TK levels and an increased risk of stroke through a retrospective, multicenter cohort study involving 2115 initially non-stroke subjects monitored for 5 years. Sequentially, we observed a notable increase in bradykinin receptor 2 (B2R) levels during the ischemic phase of the IS model, while levels of TK and bradykinin receptor 1 (B1R) remained stable. Intriguingly, both B1R and B2R exhibited a significant elevation 24 h after reperfusion. Further investigations in preclinical models demonstrated that TK supplementation activates the PI3K/AKT signaling pathway via enhanced B2R expression during the ischemic phase, leading to nuclear translocation of Hif-1α. This activation enhances the expression of VEGF and eNOS, thereby fortifying the neurovascular unit. Moreover, it suppresses the activation of the kallikrein-kinin system induced by reperfusion injury, effectively reducing inflammation, ROS production, apoptosis, and endothelial barrier dysfunction. Thus, our findings highlight the significance of TK supplementation during the ischemic phase in attenuating reperfusion-induced injury in IS, providing a mechanistic rationale for determining the optimal timing for TK supplementation therapy.

Abstract Purpose To use artificial intelligence to establish an automatic diagnosis system for corneal endothelium diseases (CEDs). Methods We develop an automatic system for detecting multiple common CEDs involving an enhanced compact convolutional transformer (ECCT). Specifically, we introduce a cross-head relative position encoding scheme into a standard self-attention module to capture contextual information among different regions and employ a token-attention feed-forward network to place greater focus on valuable abnormal regions. Results A total of 2723 images from CED patients are used to train our system. It achieves an accuracy of 89.53%, and the area under the receiver operating characteristic curve (AUC) is 0.958 (95% CI 0.943–0.971) on images from multiple centres. Conclusions Our system is the first artificial intelligence-based system for diagnosing CEDs worldwide. Images can be uploaded to a specified website, and automatic diagnoses can be obtained; this system can be particularly helpful under pandemic conditions, such as those seen during the recent COVID-19 pandemic.

Objective To evaluate the effects of remimazolam versus propofol on the quality of postoperative recovery in patients undergoing vocal cord polypectomy with supportive laryngoscopy by the 15-item quality of recovery scale (QoR-15). Methods A total of 90 patients who underwent vocal cord polypectomy with supported laryngoscopy from the Fourth Clinical College of Xinxiang Medical University from December 2022 to October 2023 were divided into remimazolam combined with mivacurium group (group R) and propofol combined with mivacurium group (group P) by random block design method, with 45 cases in each group. By intravenous administration, patients in group R and group P were given remiazolam 0.2 to 0.3 mg/kg and propofol 1.5 to 2.0 mg/kg, respectively. After the disappearance of eyelash reflex, sufentanil 0.3 g/kg and mivacurium 0.25 mg/kg were given to all patients. The quality of postoperative recovery was evaluated by the QoR-15 scale 1 day before, 1 day and 2 days after surgery. Mean arterial pressure, heart rate, pulse oxygen saturation, and Modified Observers Assessment of Alertness/Sedation Scale (MOAA/S) scores of the two groups were recorded at different time points. The time required including surgery, recovery of spontaneous breathing, endotracheal tube removal, and post anesthesia care unit (PACU) stay after surgery,and the occurrence of intra- and post-operative adverse reactions were recorded. Results The QoR-15 scale score of group R was lower than that of group P (P＜0.05) on the first day after surgery, but it was not clinically significant because the minimum clinically significant change value of QoR-15 scale score was 6 points. The recovery time of spontaneous breathing and extubation time in group R were longer than those in group P (P＜0.05), but there was no significant difference in PACU stay time between the two groups (P＞0.05). The incidences of hypotension and injection site pain in group R were lower than those in group P (24.4% vs 64.4%, χ2=14.580, P＜0.01; 6.7% vs 84.4%, χ2=54.878, P＜0.01), and no significant difference was found in the incidence of other adverse reactions (P＞0.05). ConclusionIn the anesthesia of vocal cord polypectomy under supported laryngoscopy, the quality of patients recovery using remimazolam is comparable to that of propofol. While meeting perioperative needs, it can maintain more stable hemodynamics, without significant injection site pain, and can improve perioperative patients comfort."

The purpose of this study was to comprehensively analyze the genetic diversity of the Pekin duck conserved population with five generations and to evaluate the effectiveness of the current conservation strategy. In total, 277 Pekin duck conserved individuals and 40 Mallards as ancestral controls were collected. Each duck was sequenced at about 10X whole-genome coverage, while over 7.4 million single nucleotide polymorphisms (SNPs) in total were detected for genetic diversity analysis. Both the expected heterozygosity and observed heterozygosity values exceeded 0.3. The genetic differentiation (FST) values ranged from 0.007 to 0.039, and the Polymorphism information content (PIC) values ranged from 0.29 to 0.34. These results indicate no significant differentiation between generations, and the genetic diversity remains high. In particular, the inbreeding coefficient has been strictly controlled and has not increased rapidly during the conservation. Overall, the inbreeding coefficient of the conserved Pekin duck population was higher than that of its wild ancestors, indicating that domestication has resulted in reduced genetic diversity. This is the first report using whole genome resequencing data to systematically evaluate the genomic dynamics across several generations in ducks. The results show that the strategy of free mating and random seed retention within sire families is effective for maintaining the genetic diversity of the conserved Pekin duck population.

Photoplethysmography (PPG) is a ubiquitous physiological measurement that detects beat-to-beat pulsatile blood volume changes and hence has a potential for monitoring cardiovascular conditions, particularly in ambulatory settings. A PPG dataset that is created for a particular use case is often imbalanced, due to a low prevalence of the pathological condition it targets to predict and the paroxysmal nature of the condition as well. To tackle this problem, we propose log-spectral matching GAN (LSM-GAN), a generative model that can be used as a data augmentation technique to alleviate the class imbalance in a PPG dataset to train a classifier. LSM-GAN utilizes a novel generator that generates a synthetic signal without a up-sampling process of input white noises, as well as adds the mismatch between real and synthetic signals in frequency domain to the conventional adversarial loss. In this study, experiments are designed focusing on examining how the influence of LSM-GAN as a data augmentation technique on one specific classification task - atrial fibrillation (AF) detection using PPG. We show that by taking spectral information into consideration, LSM-GAN as a data augmentation solution can generate more realistic PPG signals.

Myxobacteria are well known for multicellular social behaviors and valued for biosynthesis of natural products. Myxobacteria social behaviors such as clumping growth severely hamper strain cultivation and genetic manipulation. Using Myxococcus xanthus DK1622, we engineered Hu04, which is deficient in multicellular behavior and pigmentation. Hu04, while maintaining nutritional growth and a similar metabolic background, exhibits improved dispersed growth, streamlining operational procedures. It achieves high cell densities in culture and is promising for synthetic biology applications.

ABSTRACT Renal angiomyolipoma has two histological variants: classical and epithelioid. Epithelioid angiomyolipoma is considered as a potential malignant tumor, often leading to recurrence and metastasis, with rapid progression in most of the cases. The lung is one of the most commonly reported sites of metastasis, and pulmonary metastasis of renal angiomyolipoma is usually diagnostic by computed tomography (CT) scans. Here, we report for the first time renal angiomyolipoma with lung metastasis by combining CT and magnetic resonance imaging (MRI).

Adverse events of atrial fibrillation (AF) have been commonly reported in lymphoma patients in treating Bruton's tyrosine kinase inhibitors (BTKi). The incidence rate of AF can vary depending on the specific types of BTKi and the patient population. Totally 45 published studies have revealed that the overall incidence rate of AF is 5% (95% CI 4%–7%). By performing a subtype single-rate analysis, the second-generation BTKi shows a lower AF incidence rate and lower cardiovascular toxicity. In the subtype single-rate analysis, we conclude the different AF incidence rates of Ibrutinib (10%, 95% CI 7%–13%), Acalabrutinib (4%, 95% CI 1%–6%), Orelabrutinib (0%, 95% CI 0%–1%), and Zanubrutinib (0%, 95% CI 0%–1%). The comprehensive analysis of AF inspires us to better predict and manage AF and other cardiovascular events in treating lymphoma. Meticulous evaluation, collaboration between cardiologists and hematologists, and discovery of new biomarkers are essential for its management.