Small RNA SmsR1 modulates acidogenicity and cariogenic virulence by affecting protein acetylation in Streptococcus mutans.

Post-transcriptional regulation by small RNAs and post-translational modifications (PTM) such as lysine acetylation play fundamental roles in physiological circuits, offering rapid responses to environmental signals with low energy consumption. Yet, the interplay between these regulatory systems remains underexplored. Here, we unveil the cross-talk between sRNAs and lysine acetylation in Streptococcus mutans, a primary cariogenic pathogen known for its potent acidogenic virulence. Through systematic overexpression of sRNAs in S. mutans, we identified sRNA SmsR1 as a critical player in modulating acidogenicity, a key cariogenic virulence feature in S. mutans. Furthermore, combined with the analysis of predicted target mRNA and transcriptome results, potential target genes were identified and experimentally verified. A direct interaction between SmsR1 and 5'-UTR region of pdhC gene was determined by in vitro binding assays. Importantly, we found that overexpression of SmsR1 reduced the expression of pdhC mRNA and increased the intracellular concentration of acetyl-CoA, resulting in global changes in protein acetylation levels. This was verified by acetyl-proteomics in S. mutans, along with an increase in acetylation level and decreased activity of LDH. Our study unravels a novel regulatory paradigm where sRNA bridges post-transcriptional regulation with post-translational modification, underscoring bacterial adeptness in fine-tuning responses to environmental stress.

Cetuximab plus FOLFOXIRI versus cetuximab plus FOLFOX as conversion regimen in RAS/BRAF wild-type patients with initially unresectable colorectal liver metastases (TRICE trial): A randomized controlled trial.

BACKGROUND: It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM. METHODS AND FINDINGS: This open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI [0.37, 1.83], Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range [IQR], [50.0, 69.7] versus 55.0%, IQR [42.8, 63.8], Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR [12.8, 40.5]), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio [HR] 0.74, 95% CI [0.50, 1.11], Log-rank p = 0.14). Grade ≥ 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia (44.1% versus 27.0%, p = 0.03) and diarrhea (5.9% versus 0%, p = 0.03). The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility, as well as the lack of a centralized assessment for ORR and resection. CONCLUSIONS: The combination of cetuximab with FOLFOXIRI did not significantly improve ORR compared to cetuximab plus FOLFOX. Despite achieving an enhanced DpR, this improvement did not translate into improved R0 resection rates or PFS. Moreover, the triplet arm was associated with an increase in treatment-related toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03493048.

Investigating the therapeutic effects and mechanisms of Roxadustat on peritoneal fibrosis Based on the TGF-ß/Smad pathway.

Peritoneal fibrosis (PF) is particularly common in individuals undergoing peritoneal dialysis (PD). Fibrosis of the parenchymal tissue typically progresses slowly. Therefore, preventing and reducing the advancement of fibrosis is crucial for effective patient treatment. Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), primarily used to treat and improve renal anemia. Recent studies have found that HIF-1α possesses antioxidant activity and exerts a certain protective effect in ischemic heart disease and spinal cord injury, while it can also delay the progression of pulmonary and renal fibrosis. This study establishes the mice model through intraperitoneal injection of 4.25 % peritoneal dialysate fluid (PDF) and explores the therapeutic effects of Roxadustat by inducing TGF-ß1-mediated epithelial-mesenchymal transition (EMT) in Met-5A cells. The aim is to investigate the protective role and mechanisms of Roxadustat against PD-related PF. We observed thicker peritoneal tissue and reduced permeability in animals with PD-related PF samples. This was accompanied by heightened inflammation, which Roxadustat alleviated by lowering the levels of inflammatory cytokines (IL-6, TNF-α). Furthermore, Roxadustat inhibited EMT in PF mice and TGF-ß1-induced Met-5A cells, as evidenced by decreased expression of fibrotic markers, such as fibronectin, collagen I, and α-SMA, alongside an elevation in the expression of the epithelial marker, E-cadherin. Roxadustat also significantly decreased the expression of TGF-ß1 and the phosphorylation of p-Smad2 and p-Smad3. In conclusion, Roxadustat ameliorates peritoneal fibrosis through the TGF-ß/Smad pathway.

Sub2Full: split spectrum to boost optical coherence tomography despeckling without clean data.

Optical coherence tomography (OCT) suffers from speckle noise, causing the deterioration of image quality, especially in high-resolution modalities such as visible light OCT (vis-OCT). Here, we proposed an innovative self-supervised strategy called Sub2Full (S2F) for OCT despeckling without clean data. This approach works by acquiring two repeated B-scans, splitting the spectrum of the first repeat as a low-resolution input, and utilizing the full spectrum of the second repeat as the high-resolution target. The proposed method was validated on vis-OCT retinal images visualizing sublaminar structures in the outer retina and demonstrated superior performance over state-of-the-art Noise2Noise (N2N) and Noise2Void (N2V) schemes.

Computed Diffusion-Weighted Images of Rectal Cancer: Image Quality, Restaging, and Treatment Response after Neoadjuvant Therapy.

BACKGROUND: Computed diffusion-weighted images (cDWI) of random b value could be derived from acquired DWI (aDWI) with at least two different b values. However, its comparison between aDWI and cDWI images in locally advanced rectal cancer (LARC) patients after neoadjuvant therapy (NT) is needed. PURPOSE: To compare the cDWI and aDWI in image quality, restaging, and treatment response of LARC after NT. STUDY TYPE: Retrospective. POPULATION: Eighty-seven consecutive patients. FIELD STRENGTH/SEQUENCE: 3.0 T/DWI. ASSESSMENT: All patients underwent two DWI sequences, including conventional acquisition with b = 0 and 1000 s/mm2 (aDWIb1000 ) and another with b = 0 and 700 s/mm2 on a 3.0-T MR scanner. The images of the latter were used to compute the diffusion images with b = 1000 s/mm2 (cDWIb1000 ). Four radiologists with 3, 4, 14, and 25 years of experience evaluated the images to compare the image quality, TN restaging performance, and treatment response between aDWIb1000 and cDWIb1000 . STATISTICAL TESTS: Interclass correlation coefficients, weighted κ coefficient, paired Wilcoxon, and McNemar or Fisher test were used. A significance level of 0.05 was used. RESULTS: The cDWIb1000 images were superior to the aDWIb1000 ones in both subjective and objective image quality. In T restaging, the overall diagnostic accuracy of cDWIb1000 images was higher than that of aDWIb1000 images (57.47% vs. 49.43%, P = 0.289 for the inexperienced radiologist; 77.01% vs. 63.22%, significant for the experienced radiologist), with better sensitivity in determining ypT0-Tis tumors. Additionally, it increased the sensitivity in detecting ypT2 tumors for the inexperienced radiologist and ypT3 tumors for the experienced radiologist. N restaging and treatment response were found to be similar between two sequences for both radiologists. DATA CONCLUSION: Compared to aDWIb1000 images, the computed ones might serve as a wise approach, providing comparable or better image quality, restaging performance, and treatment response assessment for LARC after NT. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 2.

Fully automated artificial intelligence-based coronary CT angiography image processing: efficiency, diagnostic capability, and risk stratification.

OBJECTIVES: To prospectively investigate whether fully automated artificial intelligence (FAAI)-based coronary CT angiography (CCTA) image processing is non-inferior to semi-automated mode in efficiency, diagnostic ability, and risk stratification of coronary artery disease (CAD). MATERIALS AND METHODS: Adults with indications for CCTA were prospectively and consecutively enrolled at two hospitals and randomly assigned to either FAAI-based or semi-automated image processing using equipment workstations. Outcome measures were workflow efficiency, diagnostic accuracy for obstructive CAD (≥ 50% stenosis), and cardiovascular events at 2-year follow-up. The endpoints included major adverse cardiovascular events, hospitalization for unstable angina, and recurrence of cardiac symptoms. The non-inferiority margin was 3 percentage difference in diagnostic accuracy and C-index. RESULTS: In total, 1801 subjects (62.7 ± 11.1 years) were included, of whom 893 and 908 were assigned to the FAAI-based and semi-automated modes, respectively. Image processing times were 121.0 ± 18.6 and 433.5 ± 68.4 s, respectively (p <0.001). Scan-to-report release times were 6.4 ± 2.7 and 10.5 ± 3.8 h, respectively (p < 0.001). Of all subjects, 152 and 159 in the FAAI-based and semi-automated modes, respectively, subsequently underwent invasive coronary angiography. The diagnostic accuracies for obstructive CAD were 94.7% (89.9-97.7%) and 94.3% (89.5-97.4%), respectively (difference 0.4%). Of all subjects, 779 and 784 in the FAAI-based and semi-automated modes were followed for 589 ± 182 days, respectively, and the C-statistic for cardiovascular events were 0.75 (0.67 to 0.83) and 0.74 (0.66 to 0.82) (difference 1%). CONCLUSIONS: FAAI-based CCTA image processing significantly improves workflow efficiency than semi-automated mode, and is non-inferior in diagnosing obstructive CAD and risk stratification for cardiovascular events. CLINICAL RELEVANCE STATEMENT: Conventional coronary CT angiography image processing is semi-automated. This observation shows that fully automated artificial intelligence-based image processing greatly improves efficiency, and maintains high diagnostic accuracy and the effectiveness in stratifying patients for cardiovascular events. KEY POINTS: • Coronary CT angiography (CCTA) relies heavily on high-quality and fast image processing. • Full-automation CCTA image processing is clinically non-inferior to the semi-automated mode. • Full automation can facilitate the application of CCTA in early detection of coronary artery disease.

Detection of uridine diphosphate glucuronosyltransferase 1A1 for pancreatic cancer imaging and treatment via a "turn-on" fluorescent probe.

Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) is expressed ubiquitously in cancer cells and can metabolize exogenous substances. Studies show higher UGT1A1 levels in pancreatic cancer cells than normal cells. Therefore, we need a method to monitor the activity level of UGT1A1 in pancreatic cancer cells and in vivo. Here, we report a fluorescent probe, BCy-panc, for UGT1A1 imaging in cells and in vivo. Compared with other molecular probes, this probe is readily prepared, with high selectivity and sensitivity for the detection of UGT1A1. Our results show that BCy-panc rapidly detects UGT1A1 in pancreatic cancer. In addition, there is an urgent need for evidence to clarify the relationship between UGT1A1 and pancreatic cancer development. The present investigation found that the increase of UGT1A1 by chrysin was effective in inducing apoptosis in pancreatic cancer cells. These results indicate that the synergistic effect of chrysin and cisplatin at the cellular level is superior to that of cisplatin alone. The UGT1A1 level may be a biomarker for early diagnosis of cancer. Meanwhile, UGT1A1 plays a crucial role in pancreatic cancer, and the combination of chrysin and cisplatin may provide effective ideas for pancreatic cancer treatment.

Short-chain fatty acids: bridges between diet, gut microbiota, and health.

In recent years, gut microbiota has become a hot topic in the fields of medicine and life sciences. Short-chain fatty acids (SCFAs), the main metabolites of gut microbiota produced by microbial fermentation of dietary fiber, play a vital role in healthy and ill hosts. SCFAs regulate the process of metabolism, immune, and inflammation and have therapeutic effects on gastrointestinal and neurological disorders, as well as antitumor properties. This review summarized the production, distribution, and molecular mechanism of SCFAs, as well as their mechanisms of action in healthy and ill hosts. In addition, we also emphasized the negative effects of SCFAs, aiming to provide the public with a more comprehensive understanding of SCFAs.

Bibenzyl and naphthalene derivatives from Dendrobium chrysanthum and their anti-hepatic-steatosis activities.

In this study, 16 new compounds, six bibenzyls (1-6) and 10 naphthalenes (7-13), including three pairs of naphthalene enantiomers and three known compounds (14-16), were isolated from Dendrobium chrysanthum. Structurally, compounds 1-5 are previously undescribed dimeric bibenzyls, uniquely linked by unusual carbon bonds. The structures of the compounds were determined using spectroscopy and X-ray crystallography. The screening results indicated that 1, 2, and 5 showed remarkable lipid-lowering activities in FFA-induced HepG2 cells, with EC50 values ranging from 3.13 to 6.57 µM. Moreover, 1, 2, and 5 significantly decreased both the mRNA and protein levels of the target SREBP-1c, and 5 also reduced PPARα mRNA and protein levels. Therefore, 1, 2, and 5 are potential drugs against hepatic steatosis by targeting PPARα or SREBP-1c.

Deep learning image reconstruction generates thinner slice iodine maps with improved image quality to increase diagnostic acceptance and lesion conspicuity: a prospective study on abdominal dual-energy CT.

BACKGROUND: To assess the improvement of image quality and diagnostic acceptance of thinner slice iodine maps enabled by deep learning image reconstruction (DLIR) in abdominal dual-energy CT (DECT). METHODS: This study prospectively included 104 participants with 136 lesions. Four series of iodine maps were generated based on portal-venous scans of contrast-enhanced abdominal DECT: 5-mm and 1.25-mm using adaptive statistical iterative reconstruction-V (Asir-V) with 50% blending (AV-50), and 1.25-mm using DLIR with medium (DLIR-M), and high strength (DLIR-H). The iodine concentrations (IC) and their standard deviations of nine anatomical sites were measured, and the corresponding coefficient of variations (CV) were calculated. Noise-power-spectrum (NPS) and edge-rise-slope (ERS) were measured. Five radiologists rated image quality in terms of image noise, contrast, sharpness, texture, and small structure visibility, and evaluated overall diagnostic acceptability of images and lesion conspicuity. RESULTS: The four reconstructions maintained the IC values unchanged in nine anatomical sites (all p > 0.999). Compared to 1.25-mm AV-50, 1.25-mm DLIR-M and DLIR-H significantly reduced CV values (all p < 0.001) and presented lower noise and noise peak (both p < 0.001). Compared to 5-mm AV-50, 1.25-mm images had higher ERS (all p < 0.001). The difference of the peak and average spatial frequency among the four reconstructions was relatively small but statistically significant (both p < 0.001). The 1.25-mm DLIR-M images were rated higher than the 5-mm and 1.25-mm AV-50 images for diagnostic acceptability and lesion conspicuity (all P < 0.001). CONCLUSIONS: DLIR may facilitate the thinner slice thickness iodine maps in abdominal DECT for improvement of image quality, diagnostic acceptability, and lesion conspicuity.

The toxin-antitoxin RNA guards of CRISPR-Cas evolved high specificity through repeat degeneration.

Recent discovery of ectopic repeats (outside CRISPR arrays) provided unprecedented insights into the nondefense roles of CRISPR-Cas. A striking example is the addiction module CreTA (CRISPR-regulated toxin-antitoxins), where one or two (in most cases) ectopic repeats produce CRISPR-resembling antitoxic (CreA) RNAs that direct the CRISPR effector Cascade to transcriptionally repress a toxic RNA (CreT). Here, we demonstrated that CreTA repeats are extensively degenerated in sequence, with the first repeat (ψR1) being more diverged than the second one (ψR2). As a result, such addiction modules become highly specific to their physically-linked CRISPR-Cas loci, and in most cases, CreA could not harness a heterologous CRISPR-Cas to suppress its cognate toxin. We further disclosed that this specificity primarily derives from the degeneration of ψR1, and could generally be altered by modifying this repeat element. We also showed that the degenerated repeats of CreTA were insusceptible to recombination and thus more stable compared to a typical CRISPR array, which could be exploited to develop highly stable CRISPR-based tools. These data illustrated that repeat degeneration (a common feature of ectopic repeats) improves the stability and specificity of CreTA in protecting CRISPR-Cas, which could have contributed to the widespread occurrence and deep diversification of CRISPR systems.

Social participation in older people with hearing impairment in Chinese community: A latent profile analysis.

OBJECTIVES: Hearing impairment may lead to increased communication difficulties for older people, making their social participation less optimistic. However, there is little research on the social participation of older people with hearing impairment, especially based on the characteristics of their social participation. This study aimed to identify different social participation profiles in older people with hearing impairment and to explore sociodemographic characteristics, disease-related characteristics and psychosocial factors with different social participation profiles. METHODS: A cross-sectional study of 300 older people with hearing impairment using the sociodemographic questionnaire, the Impact on Participation and Autonomy Questionnaire, the Lubben Social Network Scale-6, Medical Outcomes Study Social Support Survey and Geriatric Depression Scale-15 from May to August 2023 in a community of Beijing, China. Latent profile analysis was used to analyse the latent profiles of social participation in elderly with hearing impairment. Multiple logistic regression was used to explore the predictors of different profiles. RESULTS: The social participation of older people with hearing impairment in the community can be classified into three potential profiles: Profile 1 - high social participation group (76.05 %), Profile 2 - moderate social participation group (17.34 %), Profile 3 - low social participation group (6.61 %). Age, types of chronic diseases, self-reported health, severity of hearing impairment, social network, social support and depression were predictors of different profiles. CONCLUSIONS: Nurses should pay attention to the characteristics, depression, social network and support of older people with different hearing impairment to improve social participation in different profiles. IMPLICATIONS AND RECOMMENDATIONS: This was the first study exploring latent profiles of social participation in older people with hearing impairment. Insights from this study are useful for gerontological nursing to distinguish different profiles and further identify the characteristics of different profiles in older people with hearing impairment by characterizing the level of social participation in the community and better implement interventions according to profiles.

Social network and related factors in older people with sensory impairment in the community: Using principal component analysis.

AIM: Older people with sensory impairment are more likely to have smaller and weaker social network due to their reduced ability, which lowers their quality of life. However, there is little research on the social network in older people with sensory impairment, especially the related factors. The aim of the study was to explore the related factors of social network and to provide evidence for the improvement of social network to promote successful aging in older people with sensory impairment. METHODS: A cross-sectional study was conducted among 374 participants for hearing and vision assessment and questionnaire survey in a community, Beijing. Data were collected and analyzed by principal component analysis (PCA) and multiple logistic regression using IBM SPSS 25.0 software. RESULTS: PCA showed that there were six risk factors whose eigenvalues >1 were extracted, with a total variance of 56.555%. Multiple logistic regression analysis of principal component indicated that five factors including physical health factor, social interaction factor, psychological status factor, lifestyle factor, and family condition factor, were statistically significant (p < 0.05). CONCLUSIONS: The social network of older people with sensory impairment is relatively poor. Physical health factor, social interaction factor, psychological status factor, lifestyle factor, and family condition factor may be related factors. Medical staff should pay attention to physical, psychological and social characteristics of older people, especially with sensory impairment, to carry out necessary measures to improve social network and avoid social isolation.

BNIP3 as a potential biomarker for the identification of prognosis and diagnosis in solid tumours.

BACKGROUND: Traditional radiotherapy and chemotherapy have been intensively studied for their role in the treatment of tumours. However, these therapies often cause side effects for patients, which calls for the development of novel treatment options for tumours. B-cell lymphoma-2 (Bcl-2)/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) reportedly apoptosis-inducing effects in tumour cells and is associated with the progression and treatment of multiple tumours. Nevertheless, little is known about its potential role in tumour diagnosis and targeted therapy. FINDINGS: The results of the study demonstrated that the interaction of BNIP3 with HDAC1 may affect the progression of breast invasive cancer (BRCA), sarcoma (SARC), kidney renal clear cell carcinoma (KIRC), and low-grade glioma (LGG). BNIP3 seemed to exert its effects in BRCA and SARC primarily through gene silencing and integrator complex, and in KIRC and LGG, mainly by affecting olfactory function, suggesting that targeted therapy can be developed based on the above signalling pathway and downstream molecules. INTERPRETATION: BNIP3 has emerged as a promising therapeutic and diagnostic target for BRCA, SARC, KIRC, and LGG, providing new insights into tumour molecular therapies in the clinic.

A Novel Strategy to Directly Quantify Polyethylene Microplastics in PM2.5 Based on Pyrolysis-Gas Chromatography-Tandem Mass Spectrometry.

The broad application of plastic products has resulted in a considerable release of microplastics (MPs) into the ecosystem. While MPs in other environmental matrices (e.g., soil and water) have been studied for a long time, the atmospheric fine particulate matter (PM2.5)-bound MPs are rarely investigated due to the lack of an appropriate analytical approach. The prevalently used visual and spectroscopic means (e.g., optical microscopy, Fourier-transform infrared spectroscopy, and Raman spectroscopy) suffer from obvious drawbacks that cannot precisely detect MPs of tiny sizes and provide quantitative information. In the present study, a novel strategy that does not require sample pretreatment was developed to first effectuate accurate quantification of polyethylene MP (PE-MP) in PM2.5 based on pyrolysis-gas chromatography-tandem mass spectrometry (Pyr-GC-MS/MS). It featured acceptable recoveries (97%-110%), high sensitivity (LOD = 1 pg), and qualified precisions (RSD of 3%-13%). Employing this approach, for the first time, exact atmospheric concentrations of PE-MPs in PM2.5 from megacities in North (Zhengzhou and Taiyuan) and South (Guangzhou) China were obtained, and relatively serious pollution was found in Taiyuan. The 100% sample detection rates also suggested the widespread occurrence and possible human exposure risks of PM2.5-bound PE-MPs. In brief, the new strategy could conduct direct, sensitive, and accurate quantification of PE-MP in PM2.5, favoring further studies of environmental fates, distributions, and toxicities of atmospheric MPs.

Identification of a novel KLHL3-interacting motif in the C-terminal region of WNK4.

Mutations in with-no-lysine [K] kinase 4 (WNK4) and kelch-like 3 (KLHL3) are linked to pseudohypoaldosteronism type 2 (PHAII, also known as familial hyperkalemic hypertension or Gordon's syndrome). WNK4 is degraded by a ubiquitin E3 ligase with KLHL3 as the substrate adaptor for WNK4. Several PHAII-causing mutations, e.g. those in the acidic motif (AM) of WNK4 and in the Kelch domain of KLHL3, impair the binding between WNK4 and KLHL3. This results in a reduction in WNK4 degradation and an increase in WNK4 activity, leading to PHAII. Although the AM is important in interacting with KLHL3, it is unclear whether this is the only motif in WNK4 responsible for KLHL3-interacting. In this study, a novel motif of WNK4 that is capable of mediating the degradation of the protein by KLHL3 was identified. This C-terminal motif (termed as CM) is located in amino acids 1051-1075 of WNK4 and is rich in negatively charged residues. Both AM and CM responded to the PHAII mutations in the Kelch domain of KLHL3 in a similar manner, but AM is dominant among the two motifs. The presence of this motif likely allows WNK4 protein to respond to the KLHL3-mediated degradation when the AM is dysfunctional due to a PHAII mutation. This may be one of the reasons why PHAII is less severe when WNK4 is mutated compared to KLHL3 is mutated.

A Stretchable Solid Ionic Electrode-Based Triboelectric Nanogenerator for Biomechanical Energy Harvesting and Self-Powered Sensors.

Stretchable power devices and self-powered sensors have become increasingly desired for wearable electronics and artificial intelligence. In this study, an all-solid-state triboelectric nanogenerator (TENG) is reported, whose one solid-state structure prevents delamination during stretch and release cycles and increasing the patch adhesive force (3.5 N) and strain (586% elongation at break). Through the synergetic virtues of stretchability, ionic conductivity, and excellent adhesion to the tribo-layer, reproducible open-circuit voltage (VOC ) of 84 V, charge (QSC ) of 27.5 nC, and short-circuit current (ISC ) of 3.1 µA after drying at 60°C or 20,000 contact-separation cycles are obtained. Apart from contact-separation, this device shows unprecedented electricity generation through stretch-release of solid materials leading to a linear relationship between VOC and strain. For the first time, this work provides a clear explanation of the working mechanism of contact-free stretching-releasing and investigates the relationships of exerted force, strain, thickness of the device, and electric output. Benefitting from the one solid-state structure, this contact-free device remains stable even after repeated stretch-release cycling, maintaining 100% of its VOC after 2500 stretch-release cycles. These findings provide a strategy toward highly conductive and stretchable electrodes for harvesting mechanical energy and health monitoring.

Increased SLAMF7+CD8+ T cells are associated with the pathogenesis of experimental autoimmune pancreatitis in mice.

BACKGROUND: IgG4-related autoimmune pancreatitis (AIP) is considered to be a T cell-mediated autoimmune disease. However, CD8+ T cells have only received brief mention, and have yet to be completely studied. The study aimed to investigate the expression of signaling lymphocytic activation molecule family 7 (SLAMF7) on CD8+ T cells and the features of SLAMF7+CD8+ T cells in MRL/Mp mice with AIP. METHODS: A murine model of AIP was established by intraperitoneal injection with polyinosinic:polycytidylic acid (poly I:C) for 8 weeks. Dexamethasone treatment was daily administrated for the last 2 weeks during a 6-week course of poly I:C. SLAMF7 expression on CD8+ T cells in the spleen and pancreas was detected by flow cytometry. Granzyme B (GZMB) and cytokines including IFN-γ, TNF-α, and IL-2, were monitored in an in vitro T cell activation assay. Dexamethasone suppression assays were performed to downregulate SLAMF7 expression on T cells upon T cell receptor stimulation. RESULTS: AIP in MRL/Mp mice was induced by repeated intraperitoneal administration of poly I:C and CD8+ T cells were increased in the inflamed pancreas. SLAMF7+CD8+ T cells were elevated in the spleen and pancreas of AIP mice. SLAMF7+CD8+ T subsets produced more GZMB, IFN-γ, TNF-α and IL-2 than SLAMF7-CD8+ T subsets. Dexamethasone treatment ameliorated pancreatic inflammatory and fibrosis of AIP. Dexamethasone could downregulate SLAMF7+CD8+ T cells and reduce GZMB, IFN-γ and TNF-α levels both in vitro and in vivo. CONCLUSIONS: Increased SLAMF7+CD8+ T cells exhibit enhanced cytotoxicity and cytokines secretion capacity, which may be involved in the pathogenesis of AIP.

Motion artifact removal in coronary CT angiography based on generative adversarial networks.

OBJECTIVES: Coronary motion artifacts affect the diagnostic accuracy of coronary CT angiography (CCTA), especially in the mid right coronary artery (mRCA). The purpose is to correct CCTA motion artifacts of the mRCA using a GAN (generative adversarial network). METHODS: We included 313 patients with CCTA scans, who had paired motion-affected and motion-free reference images at different R-R interval phases in the same cardiac cycle and included another 53 CCTA cases with invasive coronary angiography (ICA) comparison. Pix2pix, an image-to-image conversion GAN, was trained by the motion-affected and motion-free reference pairs to generate motion-free images from the motion-affected images. Peak signal-to-noise ratio (PSNR), structural similarity (SSIM), Dice similarity coefficient (DSC), and Hausdorff distance (HD) were calculated to evaluate the image quality of GAN-generated images. RESULTS: At the image level, the median of PSNR, SSIM, DSC, and HD of GAN-generated images were 26.1 (interquartile: 24.4-27.5), 0.860 (0.830-0.882), 0.783 (0.714-0.825), and 4.47 (3.00-4.47), respectively, significantly better than the motion-affected images (p < 0.001). At the patient level, the image quality results were similar. GAN-generated images improved the motion artifact alleviation score (4 vs. 1, p < 0.001) and overall image quality score (4 vs. 1, p < 0.001) than those of the motion-affected images. In patients with ICA comparison, GAN-generated images achieved accuracy of 81%, 85%, and 70% in identifying no, < 50%, and ≥ 50% stenosis, respectively, higher than 66%, 72%, and 68% for the motion-affected images. CONCLUSION: Generative adversarial network-generated CCTA images greatly improved the image quality and diagnostic accuracy compared to motion-affected images. KEY POINTS: • A generative adversarial network greatly reduced motion artifacts in coronary CT angiography and improved image quality. • GAN-generated images improved diagnosis accuracy of identifying no, < 50%, and ≥ 50% stenosis.

Improving lesion conspicuity in abdominal dual-energy CT with deep learning image reconstruction: a prospective study with five readers.

OBJECTIVES: To evaluate image quality, diagnostic acceptability, and lesion conspicuity in abdominal dual-energy CT (DECT) using deep learning image reconstruction (DLIR) compared to those using adaptive statistical iterative reconstruction-V (Asir-V) at 50% blending (AV-50), and to identify potential factors impacting lesion conspicuity. METHODS: The portal-venous phase scans in abdominal DECT of 47 participants with 84 lesions were prospectively included. The raw data were reconstructed to virtual monoenergetic image (VMI) at 50 keV using filtered back-projection (FBP), AV-50, and DLIR at low (DLIR-L), medium (DLIR-M), and high strength (DLIR-H). A noise power spectrum (NPS) was generated. CT number and standard deviation values of eight anatomical sites were measured. Signal-to-noise (SNR), and contrast-to-noise ratio (CNR) values were calculated. Five radiologists assessed image quality in terms of image contrast, image noise, image sharpness, artificial sensation, and diagnostic acceptability, and evaluated the lesion conspicuity. RESULTS: DLIR further reduced image noise (p < 0.001) compared to AV-50 while better preserved the average NPS frequency (p < 0.001). DLIR maintained CT number values (p > 0.99) and improved SNR and CNR values compared to AV-50 (p < 0.001). DLIR-H and DLIR-M showed higher ratings in all image quality analyses than AV-50 (p < 0.001). DLIR-H provided significantly better lesion conspicuity than AV-50 and DLIR-M regardless of lesion size, relative CT attenuation to surrounding tissue, or clinical purpose (p < 0.05). CONCLUSIONS: DLIR-H could be safely recommended for routine low-keV VMI reconstruction in daily contrast-enhanced abdominal DECT to improve image quality, diagnostic acceptability, and lesion conspicuity. KEY POINTS: • DLIR is superior to AV-50 in noise reduction, with less shifts of the average spatial frequency of NPS towards low frequency, and larger improvements of NPS noise, noise peak, SNR, and CNR values. • DLIR-M and DLIR-H generate better image quality in terms of image contrast, noise, sharpness, artificial sensation, and diagnostic acceptability than AV-50, while DLIR-H provides better lesion conspicuity than AV-50 and DLIR-M. • DLIR-H could be safely recommended as a new standard for routine low-keV VMI reconstruction in contrast-enhanced abdominal DECT to provide better lesion conspicuity and better image quality than the standard AV-50.