Salinomycin, a potent inhibitor of XOD and URAT1, ameliorates hyperuricemic nephropathy by activating NRF2, modulating the gut microbiota, and promoting SCFA production.

Long-term hyperuricemia can induce kidney damage, clinically referred to as hyperuricemic nephropathy (HN), which is characterized by renal fibrosis, inflammation, and oxidative stress. However, currently used uric acid-lowering drugs are not capable of protecting the kidneys from damage. Therefore, uric acid-lowering drugs that can also protect the kidneys are urgently needed. In this study, we first discovered that salinomycin, an antibiotic, can regulate uric acid homeostasis and ameliorate kidney damage in mice with HN. Mechanistically, salinomycin inhibited serum and hepatic xanthine oxidase (XOD) activities and downregulated renal urate transporter 1 (URAT1) expression and transport activity, thus exerting uric acid-lowering effects in mice with HN. Furthermore, we found that salinomycin promoted p-NRF2 Ser40 expression, resulting in increased nuclear translocation of NRF2 and activation of NRF2. More importantly, salinomycin affected the gut microbiota and promoted the generation of short-chain fatty acids (SCFAs) in mice with HN. In conclusion, our results revealed that salinomycin maintains uric acid homeostasis and alleviates kidney injury in mice with HN by multiple mechanisms, suggesting that salinomycin might be a desirable candidate for HN treatment in the clinic.

Developed metabolomics approach reveals the non-volatile color-contributing metabolites during Keemun congou black tea processing.

While key aroma and taste compounds of Keemun Congou black teas (KCBT) form during aeration and thermal stages, it is still unknown whether these processing stages also produce non-volatile color-contributing metabolites. Through integrating metabolomics with correlation and ridge regression analyses, 190 metabolites were identified as marker compounds that reclassified 15 KCBT samples collected from five processing stages into four groups. Meanwhile, the results of quantification and heatmap analysis showed that the concentrations of theaflavins and theasinensins significantly increased, as catechin decreased, after rolling, while flavonoid aglycones and polyunsaturated fatty acids increased throughout drying. Regression analysis between marker compound levels and total color difference values (∆E) revealed that the major color contributors were 3,5-dicaffeoylquinic acid, glucosyl-dehydrodigallic acid, theacitrin A, kaempferol-O-robinobioside, and (-)-epigallocatechin, with regression coefficients (absolute value) exceeding 4 × 10-2. Overall, the present study confirmed that rolling and drying were the two vital stages responsible for the color formation of KCBT.

Increased peripheral leukocyte aggravates brain injury and leads to poor outcome in stroke patients receiving intravenous thrombolysis: A study based on clinical evidence.

Whether the dynamic development of peripheral inflammation aggravates brain injury and leads to poor outcome in stroke patients receiving intravenous thrombolysis (IVT), remains unclear and warrants further study. In this study, total of 1034 patients with acute ischemic stroke who underwent IVT were enrolled. Serum leukocyte variation (whether increase from baseline to 24 h after IVT), National Institutes of Health Stroke Scale (NIHSS), infarct volume, early neurologic deterioration (END), the unfavorable outcome at 3-month (modified Rankin Scale [mRS] score ≥3) and mortality were recorded. Serum brain injury biomarkers, including Glial fibrillary acidic protein (GFAP), ubiquitin c-terminal hydrolase L1 (UCH-L1), S100ß, neuron-specific enolase (NSE), were measured to reflect the extent of brain injury. We found that patients with increased serum leukocytes had elevated brain injury biomarkers (GFAP, UCH-L1, and S100ß), larger infarct volume, higher 24 h NIHSS, higher proportion of END, unfavorable outcome and mortality. Furthermore, an increase in serum leukocytes was independently associated with infarct volume, 24 h NIHSS, END, and unfavorable outcome at 3 months, and serum UCH-L1, S100ß, and NSE levels. These results suggest that an increase in serum leukocytes indicates severe brain injury and may be used to predict the outcome of patients with ischemic stroke who undergo IVT.

Super-resolution landmark detection networks for medical images.

Craniomaxillofacial (CMF) and nasal landmark detection are fundamental components in computer-assisted surgery. Medical landmark detection method includes regression-based and heatmap-based methods, and heatmap-based methods are among the main methodology branches. The method relies on high-resolution (HR) features containing more location information to reduce the network error caused by sub-pixel location. Previous studies extracted HR patches around each landmark from downsampling images via object detection and subsequently input them into the network to obtain HR features. Complex multistage tasks affect accuracy. The network error caused by downsampling and upsampling operations during training, which interpolates low-resolution features to generate HR features or predicted heatmap, is still significant. We propose standard super-resolution landmark detection networks (SRLD-Net) and super-resolution UNet (SR-UNet) to reduce network error effectively. SRLD-Net used Pyramid pooling block, Pyramid fusion block and super-resolution fusion block to combine global prior knowledge and multi-scale local features, similarly, SR-UNet adopts Pyramid pooling block and super-resolution block. They can obviously improve representation learning ability of our proposed methods. Then the super-resolution upsampling layer is utilized to generate detail predicted heatmap. Our proposed networks were compared to state-of-the-art methods using the craniomaxillofacial, nasal, and mandibular molar datasets, demonstrating better performance. The mean errors of 18 CMF, 6 nasal and 14 mandibular landmarks are 1.39 ± 1.04, 1.31 ± 1.09, 2.01 ± 4.33 mm. These results indicate that the super-resolution methods have great potential in medical landmark detection tasks. This paper provides two effective heatmap-based landmark detection networks and the code is released in https://github.com/Runshi-Zhang/SRLD-Net.

Cancer-associated fibroblasts promote the progression and chemoresistance of HCC by inducing IGF-1.

Crosstalk between cancer-associated fibroblasts (CAFs) and tumour cells plays a critical role in multiple cancers, including hepatocellular carcinoma (HCC). CAFs contribute to tumorigenesis by secreting growth factors, modifying the extracellular matrix, supporting angiogenesis, and suppressing antitumor immune responses. However, effect and mechanism of CAF-mediated promotion of hepatocellular carcinoma cells are still unclear. In study, we demonstrated CAFs promoted the proliferation and inhibited the apoptosis of HCC cells by secreting interleukin-6 (IL-6), which induced autocrine insulin-like growth factor-1 (IGF-1) in HCC. IGF-1 promoted the progression and chemoresistance of HCC. IGF-1 receptor (IGF-1R) inhibitor NT157 abrogated the effect of CAF-derived IL-6 and autocrine IGF-1 on HCC. Mechanistic studies revealed that NT157 decreased IL-6-induced IGF-1 expression by inhibiting STAT3 phosphorylation and led to IRS-1 degradation, which mediated the proliferation of tumour by activating AKT signalling in ERK-dependent manner. Inhibition of IGF-1R also enhanced the therapeutic effect of sorafenib on HCC, especially chemoresistant tumours. STATEMENT OF SIGNIFICANCE: Our study showed IL-6-IGF-1 axis played crucial roles in the crosstalk between HCC and CAFs, providing NT157 inhibited of STAT3 and IGF-1R as a new targeted therapy in combination with sorafenib.

Gut bacterial type III secretion systems aggravate colitis in mice and serve as biomarkers of Crohn's disease.

BACKGROUND: Mesenteric adipose tissue (mAT) hyperplasia, known as creeping fat, is a pathologic characteristic of Crohn's disease (CD). In our previously reported cohort, we observed that Achromobacter pulmonis was the most abundant and prevalent bacteria cultivated from creeping fat. METHODS: A whole genomic sequencing and identification of T3SS orthologs of mAT-derived A. pulmonis were used. A functional type III secretion system (T3SS) mediated the pathogenic potential of A. pulmonis in vitro and in mouse colitis model. Furthermore, a T3SS Finder pipeline was introduced to evaluate gut bacterial T3SS orthologs in the feces of CD patients, ulcerative colitis and colorectal cancer patients. FINDINGS: Here, we reveal that mAT-derived A. pulmonis possesses a functional T3SS, aggravates colitis in mice via T3SS, and exhibits T3SS-dependent cytotoxicity via a caspase-independent mechanism in macrophages and epithelial cells, which demonstrated the pathogenic potential of the T3SS-harboring A. pulmonis. Metagenomic analyses demonstrate an increased abundance of Achromobacter in the fecal of Crohn's disease patients compared to healthy controls. A comprehensive comparison of total microbial vT3SS abundance in various intestine diseases demonstrated that the specific enrichment of vT3SS genes was shown in fecal samples of CD, neither ulcerative colitis nor colorectal cancer patients, and ten T3SS gene-based biomarkers for CD were discovered and validated in a newly recruited CD cohort. Furthermore, treatment with exclusive enteral nutrition (EEN), an intervention that improves CD patient symptomatology, was found associated with a significant reduction in the prevalence of T3SS genes in fecal samples. INTERPRETATION: These findings highlight the pathogenic significance of T3SSs in the context of CD and identify specific T3SS genes that could potentially function as biomarkers for diagnosing and monitoring the clinical status of CD patients. FUNDING: This work is supported by the National Key Research and Development Program of China (2020YFA0907800), the China Postdoctoral Science Foundation (2023M744089), the National Natural Science Foundation of China (32000096), the Shenzhen Science and Technology Programs (KQTD20200820145822023, RCIC20231211085944057, and ZDSYS20220606100803007), National Key Clinical Discipline, Guangdong Provincial Clinical Research Center for Digestive Diseases (2020B1111170004), Qingfeng Scientific Research Fund of the China Crohn's & Colitis Foundation (CCCF) (CCCF-QF-2022B71-1), and the Sixth Affiliated Hospital, Sun Yat-sen University Clinical Research 1010 Program 1010CG(2023)-08. These funding provided well support for this research work, which involved data collection, analysis, interpretation, patient recruitment and so on.

Multimodal Distillation Pre-training Model for Ultrasound Dynamic Images Annotation.

With the development of medical technology, ultrasonography has become an important diagnostic method in doctors' clinical work. However, compared with the static medical image processing work such as CT, MRI, etc., which has more research bases, ultrasonography is a dynamic medical image similar to video, which is captured and generated by a real-time moving probe, so how to deal with the video data in the medical field and cross modal extraction of the textual semantics in the medical video is a difficult problem that needs to be researched. For this reason, this paper proposes a pre-training model of multimodal distillation and fusion coding for processing the semantic relationship between ultrasound dynamic Images and text. Firstly, by designing the fusion encoder, the visual geometric features of tissues and organs in ultrasound dynamic images, the overall visual appearance descriptive features and the named entity linguistic features are fused to form a unified visual-linguistic feature, so that the model obtains richer visual, linguistic cues aggregation and alignment ability. Then, the pre-training model is augmented by multimodal knowledge distillation to improve the learning ability of the model. The final experimental results on multiple datasets show that the multimodal distillation pre-training model generally improves the fusion ability of various types of features in ultrasound dynamic images, and realizes the automated and accurate annotation of ultrasound dynamic images.

Deep representation learning from electronic medical records identifies distinct symptom based subtypes and progression patterns for COVID-19 prognosis.

OBJECTIVE: Symptoms are significant kind of phenotypes for managing and controlling of the burst of acute infectious diseases, such as COVID-19. Although patterns of symptom clusters and time series have been considered the high potential prediction factors for the prognosis of patients, the elaborated subtypes and their progression patterns based on symptom phenotypes related to the prognosis of COVID-19 patients still need be detected. This study aims to investigate patient subtypes and their progression patterns with distinct features of outcome and prognosis. METHODS: This study included a total of 14,139 longitudinal electronic medical records (EMRs) obtained from four hospitals in Hubei Province, China, involving 2,683 individuals in the early stage of COVID-19 pandemic. A deep representation learning model was developed to help acquire the symptom profiles of patients. K-means clustering algorithm is used to divide them into distinct subtypes. Subsequently, symptom progression patterns were identified by considering the subtypes associated with patients upon admission and discharge. Furthermore, we used Fisher's test to identify significant clinical entities for each subtype. RESULTS: Three distinct patient subtypes exhibiting specific symptoms and prognosis have been identified. Particularly, Subtype 0 includes 44.2% of the whole and is characterized by poor appetite, fatigue and sleep disorders; Subtype 1 includes 25.6% cases and is characterized by confusion, cough with bloody sputum, encopresis and urinary incontinence; Subtype 2 includes 30.2% cases and is characterized by dry cough and rhinorrhea. These three subtypes demonstrate significant disparities in prognosis, with the mortality rates of 4.72%, 8.59%, and 0.25% respectively. Furthermore, symptom cluster progression patterns showed that patients with Subtype 0 who manifest dark yellow urine, chest pain, etc. in the admission stage exhibit an elevated risk of transforming into the more severe subtypes with poor outcome, whereas those presenting with nausea and vomiting tend to incline towards entering the milder subtype. CONCLUSION: This study has proposed a clinical meaningful approach by utilizing the deep representation learning and real-world EMR data containing symptom phenotypes to identify the COVID-19 subtypes and their progression patterns. The results would be potentially useful to help improve the precise stratification and management of acute infectious diseases.

The impact of Astragaloside IV on the inflammatory response and gut microbiota in cases of acute lung injury is examined through the utilization of the PI3K/AKT/mTOR pathway.

OBJECTIVES: Astragaloside IV (AS-IV) is a natural triterpenoid saponin compound with a variety of pharmacological effects, and several studies have clarified its anti-inflammatory effects, which may make it an effective alternative treatment against inflammation. In the study, we aimed to investigate whether AS-IV could attenuate the inflammatory response to acute lung injury and its mechanisms. METHODS: Different doses of AS-IV (20mg·kg-1, 40mg·kg-1, and 80mg·kg-1) were administered to the ALI rat model, followed by collection of serum and broncho alveolar lavage fluid (BALF) for examination of the inflammatory response, and HE staining of the lung and colon tissues, and interpretation of the potential molecular mechanisms by quantitative real-time PCR (qRT-PCR), Western blotting (WB). In addition, fecal samples from ALI rats were collected and analyzed by 16S rRNA sequencing. RESULTS: AS-IV decreased the levels of TNF-α, IL-6, and IL-1ß in serum and BALF of mice with Acute lung injury (ALI). Lung and colon histopathology confirmed that AS-IV alleviated inflammatory infiltration, tissue edema, and structural changes. qRT-PCR and WB showed that AS-IV mainly improved inflammation by inhibiting the expression of PI3K, AKT and mTOR mRNA, and improved the disorder of intestinal microflora by increasing the number of beneficial bacteria and reducing the number of harmful bacteria. CONCLUSION: AS-IV reduces the expression of inflammatory factors by inhibiting the PI3K/AKT/mTOR pathway and optimizes the composition of the gut microflora in AIL rats.

[Identification of the binding proteins of organic acid metabolites by matrix thermal shift assay].

Organic acid metabolites exhibit acidic properties. These metabolites serve as intermediates in major carbon metabolic pathways and are involved in several biochemical pathways, including the tricarboxylic acid (TCA) cycle and glycolysis. They also regulate cellular activity and play crucial roles in epigenetics, tumorigenesis, and cellular signal transduction. Knowledge of the binding proteins of organic acid metabolites is crucial for understanding their biological functions. However, identifying the binding proteins of these metabolites has long been a challenging task owing to the transient and weak nature of their interactions. Moreover, traditional methods are unsuitable for the structural modification of the ligands of organic acid metabolites because these metabolites have simple and similar structures. Even minor structural modifications can significantly affect protein interactions. Thermal proteome profiling (TPP) provides a promising avenue for identifying binding proteins without the need for structural modifications. This approach has been successfully applied to the identification of the binding proteins of several metabolites. In this study, we investigated the binding proteins of two TCA cycle intermediates, i.e., succinate and fumarate, and lactate, an end-product of glycolysis, using the matrix thermal shift assay (mTSA) technique. This technique involves combining single-temperature (52 ℃) TPP and dose-response curve analysis to identify ligand-binding proteins with high levels of confidence and determine the binding affinity between ligands and proteins. To this end, HeLa cells were lysed, followed by protein desalting to remove endogenous metabolites from the cell lysates. The desalted cell lysates were treated with fumarate or succinate at final concentrations of 0.004, 0.04, 0.4, and 2 mmol/L in the experimental groups or 2 mmol/L sodium chloride in the control group. Considering that the cellular concentration of lactate can be as high as 2-30 mmol/L, we then applied lactate at final concentrations of 0.2, 1, 5, 10, and 25 mmol/L in the experimental groups or 25 mmol/L sodium chloride in the control group. Using high-sensitivity mass spectrometry coupled with data-independent acquisition (DIA) quantification, we quantified 5870, 5744, and 5816 proteins in succinate, fumarate, and lactate mTSA experiments, respectively. By setting stringent cut-off values (i.e., significance of changes in protein thermal stability (p-value)<0.001 and quality of the dose-response curve fitting (square of Pearson's correlation coefficient, R2)>0.95), multiple binding proteins for these organic acid metabolites from background proteins were confidently determined. Several known binding proteins were identified, notably fumarate hydratase (FH) as a binding protein for fumarate, and α-ketoglutarate-dependent dioxygenase (FTO) as a binding protein for both fumarate and succinate. Additionally, the affinity data for the interactions between these metabolites and their binding proteins were obtained, which closely matched those reported in the literature. Interestingly, ornithine aminotransferase (OAT), which is involved in amino acid biosynthesis, and 3-mercaptopyruvate sulfurtransferase (MPST), which acts as an antioxidant in cells, were identified as lactate-binding proteins. Subsequently, an orthogonal assay technique developed in our laboratory, the solvent-induced precipitation (SIP) technique, was used to validate the mTSA results. SIP identified OAT as the top target candidate, validating the mTSA-based finding that OAT is a novel lactate-binding protein. Although MPST was not identified as a lactate-binding protein by SIP, statistical analysis of MPST in the mTSA experiments with 10 or 25 mmol/L lactate revealed that MPST is a lactate-binding protein with a high level of confidence. Peptide-level empirical Bayes t-tests combined with Fisher's exact test also supported the conclusion that MPST is a lactate-binding protein. Lactate is structurally similar to pyruvate, the known binding protein of MPST. Therefore, assuming that lactate could potentially occupy the binding site of pyruvate on MPST. Overall, the novel binding proteins identified for lactate suggest their potential involvement in amino acid synthesis and redox balance regulation.

LC-MS and GC-MS based metabolomics analysis revealed the impact of tea trichomes on the chemical and flavor characteristics of white tea.

To explore the influence of tea trichomes on the quality of white tea, liquid chromatography quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS), and headspace solid phase microextraction gas chromatography-mass spectrometry (HS-SPME-GC-MS) were used to identify non-volatile and volatile compounds white tea without trichomes (WTwt) and pure trichomes (PT). It was found that the bitter and astringent compounds, caffeine (CAF), epigallocatechin gallate (EGCG), epicatechin gallate (ECG) and flavonol glycosides, were mainly enriched in the WTwt, with 16.3-fold, 47.1-fold and 28.7-fold decrease in CAF and EGCG and ECG, respectively, and the content of these compounds in PT were lower than the taste thresholds. In PT, kaempferol-3-O-(p-coumaroyl)-glucoside and kaempferol-3-O-(di-p-coumaroyl)-glucoside were non-volatile marker compounds, and decanal was significant aroma contributor with rOAV = 250.86. Moreover, the compounds in trichomes mainly contributed to the fruity and floral aroma of white tea, among which benzyl alcohol, (E)-geranylacetone, decanal, dodecanal and 6-methyl-5-hepten-2-one were the crucial aroma components, which were 2.1, 1.7, 1.8, 1.4 and 2.2 times as much as the WTwt in the PT, respectively. In conclusion, trichomes can improve the quality of white tea by reducing the bitterness and astringency, increasing the umami, as well as enhancing the fruity and floral aromas.

Determining the Minimal Clinically Important Difference (MCID) and Responsiveness of the Chinese Version of Zurich Chronic Middle Ear Inventory (ZCMEI-21-Chn): A Prospective Multicenter Study.

OBJECTIVES: This study aimed to establish the minimal clinically important difference (MCID) and assess the responsiveness of the Chinese version of Zurich Chronic Middle Ear Inventory (ZCMEI-21-Chn). STUDY DESIGN: Prospective multicenter study. SETTING: Four Chinese tertiary referral centers admitting patients nationwide. PATIENTS: 230 adult patients with chronic otitis media (COM) undergoing tympanoplasty. INTERVENTION: Patients were required to complete the ZCMEI-21-Chn to measure health-related quality of life both preoperatively and postoperatively. An anchor-based method was used to determine the MCID of the derivative cohort by including the Global Rating of Change Questionnaire as an anchor. The generalizability and consistency with functional outcomes of the MCID estimates were externally examined in a validation cohort using a receiver operating characteristic curve analysis. RESULTS: A total of 161 and 69 patients were included in the derivative and validation cohort. The mean preoperative and postoperative ZCMEI-21-Chn total scores were 28.4 (standard deviation [SD] 14.5) and 17.5 (SD 12.6). The mean change in ZCMEI-21-Chn score was 10.9 (SD 14.3, p < 0.001). The MCIDs of the ZCMEI-21-Chn for improvement and deterioration were estimated at 13 (SD 13.0) and -7 (SD 12.9), accordingly. For patients who have reported an improved health-related quality of life, a cutoff value of 15.6 dB HL for elevation of the air-conducted hearing threshold was noticed. However, change of clinical importance judged according to MCID and Japan Otological Society criteria disagreed with each other, notably with a Cohen's kappa ( κ ) of 0.14 ( p = 0.21) in the validation cohort. CONCLUSION: This study is the first to establish the MCID of a COM-specific questionnaire in Chinese. For the COM population undergoing surgical intervention, MCID values of 13 for improvement and -7 for deterioration are recommended. The results were externally validated to be generalizable to nationwide usage, yet distinguishable from the audiological criteria. The availability of the MCID greatly adds to the clinical utility of the ZCMEI-21-Chn by enabling a clinically meaningful interpretation of its score changes.

Unraveling anti-aging mystery of green tea in C. elegans: Chemical truth and multiple mechanisms.

Tea drinking impacts aging and aging-related diseases. However, knowledge of anti-aging molecules other than the major catechins in complex tea extracts remains limited. Here we used Caenorhabditis elegans to analyze the longevity effects of tea extracts and constituents comprehensively. We found that the hot water extract of green tea prolonged lifespan and heathspan. Further, the MeOH fraction prolonged lifespan significantly longer than other fractions. Correlation analysis between mass spectroscopic data and anti-aging activity suggests that ester-type catechins (ETCs) are the major anti-aging components, including 4 common ETCs, 6 phenylpropanoid-substituted ester-type catechins (PSECs), 5 cinnamoylated catechins (CCs), 7 ester-type flavoalkaloids (ETFs), and 4 cinnamoylated flavoalkaloids (CFs). CFs (200 µM) are the strongest anti-aging ETCs (with the longest 73% lifespan extension). Green tea hot water extracts and ETCs improved healthspan by enhancing stress resistance and reducing ROS accumulation. The mechanistic study suggests that they work by multiple pathways. Moreover, ETCs modulated gut microbial homeostasis, increased the content of short-chain fatty acids, and reduced fat content. Altogether, our study provides new evidence for the anti-aging benefits of green tea and insights into a deep understanding of the chemical truth and multi-target mechanism.

Treatment of primary nasal tuberculosis with anti-tumor necrosis factor immunotherapy: A case report.

BACKGROUND: Primary nasal tuberculosis (TB) is a rare form of extrapulmonary TB, particularly in patients receiving anti-tumor necrosis factor (TNF) immunotherapy. As a result, its diagnosis remains challenging. CASE SUMMARY: A 58-year-old male patient presented to the ear, nose, and throat department with right-sided nasal obstruction and bloody discharge for 1 month. He was diagnosed with psoriatic arthritis and received anti-TNF immunotherapy for 3 years prior to presentation. Biopsy findings revealed chronic granulomatous inflammation and a few acid-fast bacilli, suggestive of primary nasal TB. He was referred to our TB management department for treatment with oral anti-TB agents. After 9 months, the nasal lesions had disappeared. No recurrence was noted during follow-up. CONCLUSION: The diagnosis of primary nasal TB should be considered in patients receiving TNF antagonists who exhibit thickening and crusting of the nasal septum mucosa or inferior turbinate, particularly when pathological findings suggest granulomatous inflammation.

The role of autophagy regulated by the PI3K/AKT/mTOR pathway and innate lymphoid cells in eosinophilic chronic sinusitis with nasal polyps.

BACKGROUND: The PI3K/Akt/mTOR pathway and autophagy are important physiological processes. But their roles in eCRSwNP remains controversial. METHODS: In this study, we used the eCRSwNP mouse model, PI3K/Akt/mTOR pathway inhibitors, and autophagy inhibitors and activators to investigate the regulatory effects of the PI3K/Akt/mTOR pathway on autophagy, and their effects on eosinophilic inflammation, and tissue remodeling. The role of ILC2s in eCRSwNP was also studied, and the relationship between ILC2s and autophagy was preliminarily determined. RESULTS: Our results show that eosinophilic inflammation in eCRSwNP mice could be inhibited by promoting the autophagy; otherwise, eosinophilic inflammation could be promoted. Meanwhile, inhibition of the PI3K/Akt/mTOR pathway can further promote autophagy and inhibit eosinophilic inflammation. Meanwhile, inhibiting the PI3K/Akt/mTOR pathway and promoting autophagy can reduce the number of ILC2s and the severity of tissue remodeling in the nasal polyps of eCRSwNP mice. CONCLUSIONS: We conclude that the PI3K/Akt/mTOR pathway plays roles in eosinophilic inflammation and tissue remodeling of eCRSwNP, in part by regulating the level of autophagy. The downregulation of autophagy is a pathogenesis of eCRSwNP; therefore, the recovery of normal autophagy levels might be a new target for eCRSwNP therapy. Furthermore, autophagy might inhibit eosinophilic inflammation and tissue remodeling, in part by reducing the number of ILC2s.

Molecular Evolution of Protein Sequences and Codon Usage in Monkeypox Viruses.

The monkeypox virus (mpox virus, MPXV) epidemic in 2022 has posed a significant public health risk. Yet, the evolutionary principles of MPXV remain largely unknown. Here, we examined the evolutionary patterns of protein sequences and codon usage in MPXV. We first demonstrated the signal of positive selection in OPG027, specifically in the Clade I lineage of MPXV. Subsequently, we discovered accelerated protein sequence evolution over time in the variants responsible for the 2022 outbreak. Furthermore, we showed strong epistasis between amino acid substitutions located in different genes. The codon adaptation index (CAI) analysis revealed that MPXV genes tended to use more non-preferred codons compared to human genes, and the CAI decreased over time and diverged between clades, with Clade I > IIa and IIb-A > IIb-B. While the decrease in fatality rate among the three groups aligned with the CAI pattern, it remains unclear whether this correlation was coincidental or if the deoptimization of codon usage in MPXV led to a reduction in fatality rates. This study sheds new light on the mechanisms that govern the evolution of MPXV in human populations.

An insight into trichomes-deficiency and trichomes-rich black teas by comparative metabolomics: The impact of oxidized trichomes on metabolic profiles and infusion color.

Tea trichomes were regarded as an essential evaluation index for reflecting tea flavor quality in terms of aroma and influence on infusion color. This study reveals the impact of golden oxidized trichomes on the color, volatile and non-volatile metabolites of black teas through comparative metabolomics combined quantitative analysis on hongbiluo (trichomes-deficiency black teas), hongjinluo (trichomes-rich black teas), and trichomes (from hongjinluo). Forty-six volatile components were detected using headspace solid-phase microextraction gas chromatography-mass spectrometry, while the results suggested that the contribution of trichomes to black teas is limited. A total of 60 marker non-volatile compounds were identified, including catechins, catechin oxidation products, flavonoid glycosides, organic acids, hydrolysable tannins and amino acids. Notably, p-coumaroyl-kaempferol glucosides, and catechin dimers demonstrated high levels in independent trichomes and showed a positive correlation with the brightness and yellow hue of black tea infusions, specifically kaempferol 3-O-di-(p-coumaroyl)-hexoside. Furthermore, results from fractional extraction analysis of separated trichomes provided that N-ethyl-2-pyrrolidinone-substituted epicatechin gallates, acylated kaempferol glycosides, and chromogenic catechins dimers, such as theaflavins, were primary color contributors in oxidized trichomes. Especially, we found that epicatechin gallate (ECG) and its derivates, 3'-O-methyl-ECG and N-ethyl-2-pyrrolidinone-substituted ECG, highly accumulated in trichomes, which may be associated with the varieties of hongbiluo and hongjinluo black teas. Eventually, addition tests were applied to verify the color contribution of trichome mixtures. Our findings employed comprehensive information revealing that golden oxidized trichomes contributed significantly to the brightness and yellow hue of black tea infusion, but their contribution to the aroma and metabolic profile is limited. These findings may contribute to the effective modulation of the infusion color during black tea production by regulating the proportion of tea trichomes or screening trichomes-rich or deficiency varieties.

Turbulent flow field in maglev centrifugal blood pumps of CH-VAD and HeartMate III: secondary flow and its effects on pump performance.

Secondary flow path is one of the crucial aspects during the design of centrifugal blood pumps. Small clearance size increases stress level and blood damage, while large clearance size can improve blood washout and reduce stress level. Nonetheless, large clearance also leads to strong secondary flows, causing further blood damage. Maglev blood pumps rely on magnetic force to achieve rotor suspension and allow more design freedom of clearance size. This study aims to characterize turbulent flow field and secondary flow as well as its effects on the primary flow and pump performance, in two representative commercial maglev blood pumps of CH-VAD and HeartMate III, which feature distinct designs of secondary flow path. The narrow and long secondary flow path of CH-VAD resulted in low secondary flow rates and low disturbance to the primary flow. The flow loss and blood damage potential of the CH-VAD mainly occurred at the secondary flow path, as well as the blade clearances. By contrast, the wide clearances in HeartMate III induced significant disturbance to the primary flow, resulting in large incidence angle, strong secondary flows and high flow loss. At higher flow rates, the incidence angle was even larger, causing larger separation, leading to a significant decrease of efficiency and steeper performance curve compared with CH-VAD. This study shows that maglev bearings do not guarantee good blood compatibility, and more attention should be paid to the influence of secondary flows on pump performance when designing centrifugal blood pumps.

Hearing loss prevalence and burden of disease in China: Findings from provincial-level analysis.

BACKGROUND: Without timely and effective rehabilitation, hearing loss may profoundly affect human life quality. China has a large population of hearing-impaired individuals, which imposes a heavy health burden on society. Moreover, this population is projected to increase rapidly owing to China's aging society. METHODS: We used data from a population-representative epidemiological investigation of hearing loss and ear diseases in four Chinese provinces. We estimated the national prevalence using multiple linear regression of the age-group proportions and prevalence in 31 provinces with clustering analysis. We used years lived with disability (YLDs) to analyze the disease burden and forecasted the prevalence of hearing loss by 2060 in China. RESULTS: An estimated 115 million people had moderate-to-complete hearing loss in 2015 across the 31 provinces of China (8.4% of 1.37 billion people). Of these, 85.7% were older than age 50 years (99 million people) and 2.4% were younger than 20 years old (2.8 million people). Of all YLDs attributable to hearing loss, 68.9% were attributable to moderate-to-complete cases. By 2060, a projected 242 million people in China will have moderate-to-complete hearing loss, a 110.0% increase from 2015. CONCLUSIONS: The hearing loss prevalence in China is high. Population aging and socioeconomic factors substantially affect the prevalence and severity of hearing loss and the disease burden. The prevalence and severity of hearing loss are unevenly distributed across different provinces. Future public health policies should take these trends and regional variations into account.

Cerebral autoregulation: A reliable predictor of prognosis in patients receiving intravenous thrombolysis.

AIMS: To investigate the characteristics of dynamic cerebral autoregulation (dCA) after intravenous thrombolysis (IVT) and assess the relationship between dCA and prognosis. METHODS: Patients with unilateral acute ischemic stroke receiving IVT were prospectively enrolled; those who did not were selected as controls. All patients underwent dCA measurements, by quantifying the phase difference (PD) and gain, at 1-3 and 7-10 days after stroke onset. Simultaneously, two dCA-based nomogram models were established to verify the predictive value of dCA for patients with mild-to-moderate stroke. RESULTS: Finally, 202 patients who received IVT and 238 who did not were included. IVT was positively correlated with higher PD on days 1-3 and 7-10 after stroke onset. PD values in both sides at 1-3 days after stroke onset and in the affected side at 7-10 days after onset were independent predictors of unfavorable outcomes in patients who received IVT. Additionally, in patients with mild-to-moderate stroke who received IVT, the dCA-based nomogram models significantly improved the risk predictive ability for 3-month unfavorable outcomes. CONCLUSION: IVT has a positive effect on dCA in patients with acute stroke; furthermore, dCA may be useful to predict the prognosis of patients with IVT.