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Abstract During endosomal recycling, Sorting Nexin 17 (SNX17) facilitates the transport of numerous membrane cargo proteins by tethering them to the Retriever complex. Despite its importance, the mechanisms underlying this interaction have remained elusive. Here, we provide biochemical, structural, cellular, and proteomic analyses of the SNX17-Retriever interaction. Our data reveal that SNX17 adopts an autoinhibited conformation in the basal state, with its FERM domain sequestering its C-terminal tail. The binding of cargo proteins to the FERM domain displaces the C-terminal tail through direct competition. The released tail engages with Retriever by binding to a highly conserved interface between its VPS35L and VPS26C subunits, as revealed by cryogenic electron microscopy (cryo-EM). Disrupting this interface impairs the Retriever-SNX17 interaction, subsequently affecting the recycling of SNX17-dependent cargoes and altering the composition of the plasma membrane proteome. Intriguingly, the SNX17-binding pocket on Retriever can be utilized by other ligands containing a consensus acidic C-terminal tail motif. Together, our findings uncover a mechanism underlying endosomal trafficking of critical cargo proteins and reveal how Retriever can potentially engage with other regulatory factors or be exploited by pathogens.

Background/Aims The Gout Impact Scale (GIS), a part of the Gout Assessment Questionnaire 2.0, is used to measure gout-specific health-related quality of life (HRQOL). Although several studies have been conducted on the factors affecting the HRQOL of patients with gout, few have focused on lifestyle factors. This study aimed to investigate the correlation between lifestyle habits and HRQOL using the GIS in patients with gout. Methods We used data from the Urate-Lowering TheRApy in Gout (ULTRA) registry, a prospective cohort of Korean patients with gout treated at multiple centers nationwide. The patients were aged ≥18 years and met the 2015 American College of Rheumatology/European League Against Rheumatism gout classification criteria. They were asked to complete a GIS and questions regarding their lifestyle habits at enrollment. Results The study included 232 patients. ‘Gout concern overall’ scores in the GIS were significantly lower in patients who exercised more frequently and consumed soft drinks and meat less, and ‘well-being during attack’ scores were significantly lower in patients who consumed vegetables and exercised more frequently. The frequency of vegetable consumption had a negative linear relationship with the ‘well-being during attack’ and ‘gout concern during attack’ scores (p = 0.01, p = 0.001, respectively). The frequency of exercise had a negative linear relationship with the ‘gout concern overall’ and ‘gout concern during attack’ scores (p = 0.04 and p = 0.002, respectively). Conclusions Patients with gout who frequently consumed vegetables and exercised regularly experienced less impact of gout, exhibiting a better GIS that represented HRQOL.

ABSTRACT Purpose The prognosis of microinvasive breast cancer (MIBC) is controversial, with a high reported rate of local recurrence (LR). This study aimed to evaluate the characteristics, treatments, and prognosis of patients with MIBC compared to those with carcinoma in situ (CIS) or early invasive cancer. Methods Patients who diagnosed with CIS or stage I breast cancer were retrospectively enrolled. Using the Kaplan–Meier method, local recurrence‐free survival (LRFS), systemic recurrence‐free survival (SRFS), and cancer‐specific survival (CSS) were compared according to T stage. The prognostic factors associated with LRFS were identified using the Cox proportional hazards model. Results According to T stage, 517 (21.6%), 200 (8.4%), 207 (8.7%), 363 (15.2%), and 1101 (46.1%) patients had Tis, T1mi, T1a, T1b, and T1c tumors, respectively. The proportion of human epidermal growth factor receptor 2‐positive tumors was significantly higher in patients with MIBC (p

Preoperative evaluations of the tumor size in breast cancer are essential for obtaining negative margins and performing oncoplastic surgery. Here, the tumor sizes measured using ultrasonography (USG), magnetic resonance imaging (MRI), and pathology were compared. Patients with a single mass observed using USG who underwent surgery between March 2016 and February 2019 were reviewed. Patients with multiple lesions, positive surgical margins, or had undergone neoadjuvant chemotherapy were excluded. The largest tumor diameter was measured during each examination. The intraclass correlation coefficient (ICC) was used for statistical analysis to compare concordance in tumor size. Nine hundred and ninety-six patients were analyzed and divided into subgroups according to their menopausal status, MRI features, pathological subtypes, and intrinsic subtypes. In all patients, MRI has higher concordance with the pathological findings than USG. In subgroup analysis, there was a significant difference between the ICC of USG and MRI for the premenopausal, non-mass enhancement (NME), and lobular types. According to the intrinsic subtype analysis, in luminal A and human epidermal growth factor receptor 2 (HER-2) breast cancer, MRI revealed higher ICC values than USG. In triple-negative breast cancer (TNBC), USG showed a higher ICC, but the difference between USG and MRI was small. MRI may be more helpful in predicting the tumor size for patients who are premenopausal, have NME, and have lobular cancer. On the other hand, USG is considered more helpful in luminal A and HER-2. Concordance differs depending on the clinicopathological characteristics and should be considered in the surgical plan.

BackgroundLymphovascular invasion (LVI) is a significant risk factor for lymph node metastasis in gastric cancer (GC) and is closely related to the prognosis and recurrence of GC. This study aimed to establish clinical models, radiomics models and combination models for the diagnosis of GC vascular invasion.MethodsThis study enrolled 146 patients with GC proved by pathology and who underwent radical resection of GC. The patients were assigned to the training and validation cohorts. A total of 1,702 radiomic features were extracted from contrast-enhanced computed tomography images of GC. Logistic regression analyses were performed to establish a clinical model, a radiomics model and a combined model. The performance of the predictive models was measured by the receiver operating characteristic (ROC) curve.ResultsIn the training cohort, the age of LVI negative (−) patients and LVI positive (+) patients were 62.41 ± 8.41 and 63.76 ± 10.08 years, respectively, and there were more male (n = 63) than female (n = 19) patients in the LVI (+) group. Diameter and differentiation were the independent risk factors for determining LVI (−) and (+). A combined model was found to be relatively highly discriminative based on the area under the ROC curve for both the training (0.853, 95% CI: 0.784–0.920, sensitivity: 0.650 and specificity: 0.907) and the validation cohorts (0.742, 95% CI: 0.559–0.925, sensitivity: 0.736 and specificity: 0.700).ConclusionsThe combined model had the highest diagnostic effectiveness, and the nomogram established by this model had good performance. It can provide a reliable prediction method for individual treatment of LVI in GC before surgery.

This study facilitates university student profiling by constructing a prediction model to forecast the classification of future students participating in a survey, thereby enhancing the utility and effectiveness of the questionnaire approach. In the context of the ongoing digital transformation of campuses, higher education institutions are increasingly prioritizing student educational development. This shift aligns with the maturation of big data technology, prompting scholars to focus on profiling university student education. While earlier research in this area, particularly foreign studies, focus on extracting data from specific learning contexts and often relied on single data sources, our study addresses these limitations. We employ a comprehensive approach, incorporating questionnaire surveys to capture a diverse array of student data. Considering various university student attributes, we create a holistic profile of the student population. Furthermore, we use clustering techniques to develop a categorical prediction model. In our clustering analysis, we employ the K-means algorithm to group student survey data. The results reveal four distinct student profiles: Diligent Learners, Earnest Individuals, Discerning Achievers, and Moral Advocates. These profiles are subsequently used to label student groups. For the classification task, we leverage these labels to establish a prediction model based on the Back Propagation neural network, with the goal of assigning students to their respective groups. Through meticulous model optimization, an impressive classification accuracy of 90.22% is achieved. Our research offers a novel perspective and serves as a valuable methodological reference for university student profiling.

Abstract Achieving target serum uric acid (SUA) levels is important in gout management. Guidelines recommend lowering SUA levels to

Objective: Implantation of an endovascular device disrupts the homeostatic CD31:CD31 interactions among quiescent endothelial cells (ECs), platelets, and circulating leukocytes. The aim of this study was to design an endothelial-mimetic coating of nitinol and cobalt-chromium (CoCr) surfaces and stents using synthetic CD31 peptides, to promote device endothelialization and pacific integration within the arterial wall. Methods: Peptides mimicking the domains 1 (D1) and 2 (D2) of CD31 were synthetized and immobilized onto experimental nitinol and CoCr surfaces using a three-step, dip-coating, mussel-inspired protocol using copper-free click chemistry. Human aortic EC phenotype and endothelialization assessment using parallel scratch tests were carried out using five synthetic CD31 peptides coated on 4.8-mm nitinol and CoCr flat disks and were compared with control disks. The CD31 peptide exhibiting the best results in vitro was then immobilized on clinical-grade 3 × 40-mm self-expanding nitinol and 2.5 × 20.0-mm balloon-expandable CoCr stents. Such devices were implanted in native arteries of White New Zealand rabbits, and compared with control uncoated bare metal stents (BMS) and drug-eluting stents 7 and 30 days after implantation using resin cross-sections and scanning electron microscopy (n = 2-3 per group at each time point). Results: Membrane-distal CD31 D1 and D2 peptides exhibited a distinct capability to foster a healthy endothelial phenotype and to promote endothelialization in vitro. By day 7 after implantation, CD31 nitinol and CoCr stents were evenly covered by wholesome ECs, devoid of thromboinflammatory signs, in contrast with both BMS and drug-eluting stents. Such results were consistent until day 30. Conclusions: Membrane-distal CD31 biomimetic peptides seem to camouflage the device surface effectively, preventing local reactions and promoting rapid and seamless endovascular integration. : Clinical Relevance: Despite significant technical advancements, the challenge of vascular stent healing persists. In this preclinical study, we developed a novel endothelial-mimetic coating inspired by the trans-homophilic portion of CD31, a glycoprotein predominantly expressed by endothelial cells and pivotal in circulatory homeostasis. After successive peptide design and surface functionalization, both in vitro and in vivo experiments demonstrated the potential of the CD31-coated surface to promote the acquisition of a physiological endothelial cell phenotype, facilitating rapid healing and peaceful integration of stents. Further studies with larger sample sizes, extended follow-up periods, and assessment of the impact on in-stent restenosis are essential before translating this strategy to clinical applications.

Abstract A key feature in intestinal immunity is the dynamic intestinal barrier, which separates the host from resident and pathogenic microbiota through a mucus gel impregnated with antimicrobial peptides. Using a forward genetic screen, we have found a mutation in Tvp23b, which conferred susceptibility to chemically induced and infectious colitis. Trans-Golgi apparatus membrane protein TVP23 homolog B (TVP23B) is a transmembrane protein conserved from yeast to humans. We found that TVP23B controls the homeostasis of Paneth cells and function of goblet cells, leading to a decrease in antimicrobial peptides and more penetrable mucus layer. TVP23B binds with another Golgi protein, YIPF6, which is similarly critical for intestinal homeostasis. The Golgi proteomes of YIPF6 and TVP23B-deficient colonocytes have a common deficiency of several critical glycosylation enzymes. TVP23B is necessary for the formation of the sterile mucin layer of the intestine and its absence disturbs the balance of host and microbe in vivo.

Let $ N $ be a sufficiently large integer. In this paper, it is proved that, with at most $ O\big(N^{4/9+\varepsilon}\big) $ exceptions, all even positive integers up to $ N $ can be represented in the form $ p_1^2+p_2^3+p_3^3+p_4^3+p_5^3+p_6^3 $, where $ p_1, p_2, p_3, p_4, p_5, p_6 $ are prime numbers.

Human papillomavirus type 18 (HPV18) has high carcinogenic power in invasive cervical cancer (ICC) development. However, the underlying mechanism remains elusive. The carcinogenic properties of HPV18 require the PDZ‐binding motif of its E6 oncoprotein (HPV18 E6) to degrade its target PSD95/Dlg/ZO‐1 (PDZ) proteins. In this study, we demonstrated that the PDZ protein membrane‐associated guanylate kinase, WW and PDZ domain containing 3 (MAGI3) inhibited the Wnt/β‐catenin pathway, and subsequently cervical cancer (CC) cell migration and invasion, via decreasing β‐catenin levels. By reducing MAGI3 protein levels, HPV18 E6 promoted CC cell migration and invasion through activation of Wnt/β‐catenin signaling. Furthermore, HPV18 rather than HPV16 was preferentially associated with the downregulation of MAGI3 and activation of the Wnt/β‐catenin pathway in CC. These findings shed light on the mechanism that gives HPV18 its high carcinogenic potential in CC progression.

Purpose Sentinel lymph node biopsy (SLNB) using both a radioactive isotope (RI) and blue dye is considered highly effective; however, there were limitations with the use of both agents in some hospitals, and blue dye has been shown to have some adverse effects. Additionally, preoperative prediction of sentinel lymph node (SLN) status using the maximum standardized uptake value (SUVmax) on positron emission tomography-computed tomography (PET-CT) can help avoid unnecessary axillary dissection or SLNB. Thus, we evaluated the efficacy and oncologic safety of SLNB using an RI alone in terms of long-term outcomes and determined the association between SLN metastasis and SUVmax of the primary tumor. Methods This retrospective study was conducted at Konyang University Hospital between March 2011 and May 2018. Overall, 142 patients with breast cancer who underwent SLNB using an RI alone were enrolled. Data on identification and false-negative rates were collected. The SUVmax of primary tumors on PET-CT were analyzed for their association with SLN metastasis. Results The identification and false-negative rates were 98.6% and 0%, respectively. There was no axillary local recurrence in patients with negative SLN findings. The correlation between the SUVmax of the primary tumor and SLN status was significant (r=0.249, P=0.005); the cutoff value for negative SLN metastasis was

Abstract Background Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease characterized by the development of anti-nuclear antibodies. Susceptibility to SLE is multifactorial, with a combination of genetic and environmental risk factors contributing to disease development. Like other polygenic diseases, a significant proportion of estimated SLE heritability is not accounted for by common disease alleles analyzed by SNP array-based GWASs. Death-associated protein 1 (DAP1) was implicated as a candidate gene in a previous familial linkage study of SLE and rheumatoid arthritis, but the association has not been explored further. Results We perform deep sequencing across the DAP1 genomic segment in 2032 SLE patients, and healthy controls, and discover a low-frequency functional haplotype strongly associated with SLE risk in multiple ethnicities. We find multiple cis-eQTLs embedded in a risk haplotype that progressively downregulates DAP1 transcription in immune cells. Decreased DAP1 transcription results in reduced DAP1 protein in peripheral blood mononuclear cells, monocytes, and lymphoblastoid cell lines, leading to enhanced autophagic flux in immune cells expressing the DAP1 risk haplotype. Patients with DAP1 risk allele exhibit significantly higher autoantibody titers and altered expression of the immune system, autophagy, and apoptosis pathway transcripts, indicating that the DAP1 risk allele mediates enhanced autophagy, leading to the survival of autoreactive lymphocytes and increased autoantibody. Conclusions We demonstrate how targeted sequencing captures low-frequency functional risk alleles that are missed by SNP array-based studies. SLE patients with the DAP1 genotype have distinct autoantibody and transcription profiles, supporting the dissection of SLE heterogeneity by genetic analysis.

An integrated interferometric fiber optic velocimetry sensor has been proposed and demonstrated at the central wavelength of 638 nm. The sensor is based on the principle of two laser-beams’ interference. The light signal scattered from the particles or vapor is demodulated to measure the water surface velocity and water vapor velocity. Three velocity measurement experiments are carried out to measure the velocity, and the experimental data shows that the velocity increases linearly in the range of 4 mm·s−1 to 100 mm·s−1, with a slope of linear fitting curve of 0.99777 and the R-Square of 1.00000. The velocity calculated from frequency shift fits well with the reference velocity. The maximum average relative error in the three velocity measurements is less than 2.5%. In addition, the maximum speed of 4.398 m·s−1 is confirmed in the rotating disk calibration experiment, which expands the sensor’s velocity measurement range. To solve the problem that it is difficult to directly measure the velocity of small-scale water surface flow velocity, especially from the aspect of the low velocity of air-water surface, the interferometric fiber optic sensor can be applied to the measurement of water surface velocity and wind velocity on the water surface.

Summary: Myeloid lineage cells use TLRs to recognize and respond to diverse microbial ligands. Although unique transcription factors dictate the outcome of specific TLR signaling, whether lineage-specific differences exist to further modulate the quality of TLR-induced inflammation remains unclear. Comprehensive analysis of global gene transcription in human monocytes, monocyte-derived macrophages, and monocyte-derived dendritic cells stimulated with various TLR ligands identifies multiple lineage-specific, TLR-responsive gene programs. Monocytes are hyperresponsive to TLR7/8 stimulation that correlates with the higher expression of the receptors. While macrophages and monocytes express similar levels of TLR4, macrophages, but not monocytes, upregulate interferon-stimulated genes (ISGs) in response to TLR4 stimulation. We find that TLR4 signaling in macrophages uniquely engages transcription factor IRF1, which facilitates the opening of ISG loci for transcription. This study provides a critical mechanistic basis for lineage-specific TLR responses and uncovers IRF1 as a master regulator for the ISG transcriptional program in human macrophages.

Introduction and objectiveAnkylosing spondylitis (AS) has characteristics of spinal bone bridge and fusion. Although BMD reduction in AS may be presumed to be due to spinal inflammation, this study was designed to confirm whether immobilization of the spine due to syndesmophytes is related to BMD reduction, as immobilization itself is a risk factor for BMD reduction.MethodsAmong male patients diagnosed with AS according to the modified New York criteria, those who underwent bone density tests with quantitative computed tomography (QCT) were retrospectively analyzed through a chart review. The correlation between the presence or absence of bone bridges for each vertebral body level of the L spine confirmed with radiography and BMD confirmed with QCT was analyzed.ResultsA total of 47 male patients with AS were enrolled. The mean patient age was 46.8 ± 8.2 years, and the mean disease duration was 7.9 ± 6.4 years. The trabecular BMD of the lumbar spine (L1-L4) ranged from 23.1 to 158.45 mg/cm3 (mean 102.2 ± 37 mg/cm3), as measured with QCT. The lumbar BMD measurements showed that 30 patients (63.8%) had osteopenia or osteoporosis. Bone bridge formation showed a negative correlation with BMD. Low BMD was significantly correlated with bone bridge in the vertebral body (p < 0.05). Positive correlations were observed between bone bridge score and BASMI flexion score, whereas significant negative correlations were found between BMD and BASMI flexion score (p < 0.05).ConclusionDecreased mobility of the vertebrae due to bone bridge formation affects the decrease in BMD in patients with AS.

CD4 T cell polarizations and functions are regulated by cytokines from innate cells. Here the authors show that IL-1 deficiency does not impair the differentiation of Th1, Th2 and Th17, but IL-1 signaling is required for maintaining the expressions of their respective key cytokines to ‘license’ the functions of these T cell subsets.

Respiratory syncytial virus (RSV) is a major respiratory pathogen of infants and young children. Multiple strains of both subgroup A and B viruses circulate during each seasonal epidemic. Genetic heterogeneity among RSV genomes, in large part due to the error prone RNA-dependent, RNA polymerase, could mediate variations in pathogenicity. We evaluated clinical strains of RSV for their ability to induce the innate immune response. Subgroup B viruses were used to infect human pulmonary epithelial cells (A549) and primary monocyte-derived human macrophages (MDM) from a variety of donors. Secretions of IL-6 and CCL5 (RANTES) from infected cells were measured following infection. Host and viral transcriptome expression were assessed using RNA-SEQ technology and the genomic sequences of several clinical isolates were determined. There were dramatic differences in the induction of IL-6 and CCL5 in both A549 cells and MDM infected with a variety of clinical isolates of RSV. Transcriptome analyses revealed that the pattern of innate immune activation in MDM was virus-specific and host-specific. Specifically, viruses that induced high levels of secreted IL-6 and CCL5 tended to induce cellular innate immune pathways whereas viruses that induced relatively low level of IL-6 or CCL5 did not induce or suppressed innate immune gene expression. Activation of the host innate immune response mapped to variations in the RSV G gene and the M2-1 gene. Viral transcriptome data indicated that there was a gradient of transcription across the RSV genome though in some strains, RSV G was the expressed in the highest amounts at late times post-infection. Clinical strains of RSV differ in cytokine/chemokine induction and in induction and suppression of host genes expression suggesting that these viruses may have inherent differences in virulence potential. Identification of the genetic elements responsible for these differences may lead to novel approaches to antiviral agents and vaccines.

Targeted sequencing of sixteen SLE risk loci among 1349 Caucasian cases and controls produced a comprehensive dataset of the variations causing susceptibility to systemic lupus erythematosus (SLE). Two independent disease association signals in the HLA-D region identified two regulatory regions containing 3562 polymorphisms that modified thirty-seven transcription factor binding sites. These extensive functional variations are a new and potent facet of HLA polymorphism. Variations modifying the consensus binding motifs of IRF4 and CTCF in the XL9 regulatory complex modified the transcription of HLA-DRB1, HLA-DQA1 and HLA-DQB1 in a chromosome-specific manner, resulting in a 2.5-fold increase in the surface expression of HLA-DR and DQ molecules on dendritic cells with SLE risk genotypes, which increases to over 4-fold after stimulation. Similar analyses of fifteen other SLE risk loci identified 1206 functional variants tightly linked with disease-associated SNPs and demonstrated that common disease alleles contain multiple causal variants modulating multiple immune system genes.

BACKGROUND: Phosphatase of regenerating liver-3 (PRL-3) is a member of the novel phosphatases of regenerating liver family, characterized by one protein tyrosine phosphatase active domain and a C-terminal prenylation (CCVM) motif. Though widely proposed to facilitate metastasis in many cancer types, PRL-3's cellular localization and the function of its CCVM motif in metastatic process remain unknown. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, a series of Myc tagged PRL-3 wild type or mutant plasmids were expressed in B16F1 melanoma cells to investigate the relationship between PRL-3's cellular localization and metastasis. With immuno-fluorescence microcopy and cell adhesion/migration assay in vitro, and an experimental passive metastasis model in vivo, we found that CCVM motif is critical for the localization of PRL-3 on cell plasma membrane and the lung metastasis of melanoma. In particular, Cystine170 is the key site for prenylation in this process. CONCLUSIONS/SIGNIFICANCE: These results suggest that cellular localization of PRL-3 is highly correlated with its function in tumor metastasis, and inhibition of PRL-3 prenylation might be a new approach to cancer therapy.