FBXO11 constitutes a major negative regulator of MHC class II through ubiquitin-dependent proteasomal degradation of CIITA.

Major histocompatibility complex (MHC) class I and II molecules play critical roles in the activation and regulation of adaptive immunity through antigen presentation to CD8+ and CD4+ T cells, respectively. Strict regulation of MHC expression is critical for proper immune responses. CIITA (MHC class II transactivator), an NLR (nucleotide-binding domain, leucine-rich-repeat containing) protein, is a master regulator of MHC class II (MHC-II) gene transcription. Although it has been known that CIITA activity is regulated at the transcriptional and protein levels, the mechanism to determine CIITA protein level has not been elucidated. Here, we show that FBXO11 is a bona fide E3 ligase of CIITA and regulates CIITA protein level through ubiquitination-mediated degradation. A nonbiased proteomic approach for CIITA-binding protein identified FBXO11, a member of the Skp1-Cullin-1-F-box E3 ligase complex, as a binding partner of CIITA but not MHC class I transactivator, NLRC5. The cycloheximide chase assay showed that the half-life of CIITA is mainly regulated by FBXO11 via the ubiquitin-proteasome system. The expression of FBXO11 led to the reduced MHC-II at the promoter activity level, transcriptional level, and surface expression level through downregulation of CIITA. Moreover, human and mouse FBXO11-deficient cells display increased levels of MHC-II and related genes. In normal and cancer tissues, FBXO11 expression level is negatively correlated with MHC-II. Interestingly, the expression of FBXO11, along with CIITA, is associated with prognosis of cancer patients. Therefore, FBXO11 is a critical regulator to determine the level of MHC-II, and its expression may serve as a biomarker for cancer.

Endoscopic treatment of Bouveret syndrome with a combination of electrohydraulic lithotripsy and balloon expansion: A case report.

Bouveret syndrome is a rare type of ileus caused by the impaction of gallstones passing through a cholecystoenteric fistula in the duodenum. Endoscopic treatment with minimally invasive procedures is preferable for patients with this syndrome, typically for elderly individuals with a high surgical risk. Conventional endoscopic techniques often fail to remove impacted stones that are generally large and occasionally solid. We report the case of an 88-year-old bedridden woman with severe dementia who presented with difficulty in breathing. The patient was diagnosed with aspiration pneumonia. In addition, computed tomography showed a cholecystoduodenal fistula and a gallstone 37 mm in diameter that impacted the duodenal bulb. Bouveret syndrome was diagnosed on the basis of the computed tomography findings. The impacted stone was too large and hard to split with standard endoscopic lithotripsy using grasping forceps, mechanical lithotripter, polypectomy snare, basket catheter, and electrohydraulic lithotripsy (EHL). However, EHL with a dual-channel therapeutic endoscope was achieved to drill a narrow hole approximately 20 mm deep into the stone, in four sessions. The stone was subsequently split by inflating the balloon, which was inserted into the hole, to 10 mm in diameter at 3 atm. All the split stones were spontaneously excreted during defecation after a few days. If the gallstone is too hard to fragment by endoscopic EHL alone, a combination of EHL and balloon expansion might be a useful alternative.

Breaking the hard-sphere model with fluorite and antifluorite solid solutions.

Using the hard-sphere model with the existing tabulated values of ionic radii to calculate the lattice parameters of minerals does not always match experimental data. An adaptation of this crystallographic model is proposed by considering the cations and anions as hard and soft close-packed spheres, respectively. We demonstrate the relevance of this "hybrid model" by combining Pauling's first rule with experimental unit-cell parameters of fluorite and antifluorite-structured systems to revise the ionic radii of their constitutive species.

Antigen-presenting T cells provide critical B7 co-stimulation for thymic iNKT cell development via CD28-dependent trogocytosis.

Invariant natural killer T (iNKT) cell development in the thymus depends on T cell receptor recognition of CD1d ligand on CD4/CD8 double-positive thymocytes. We previously reported that B7-CD28 co-stimulation is required for thymic iNKT cell development, but the cellular and molecular mechanisms underlying this co-stimulatory requirement are not understood. Here we report that CD28 expression on CD1d-expressing antigen-presenting T cells is required for thymic iNKT cell development. Mechanistically, antigen-presenting T cells provide co-stimulation through an unconventional mechanism, acquiring B7 molecules via CD28-dependent trogocytosis from B7-expressing thymic epithelial cells, dendritic cells, and B cells and providing critical B7 co-stimulation to developing iNKT cells. Thus, the present study demonstrates a mechanism of B7 co-stimulation in thymic T cell development by antigen-presenting T cells.

Does earlier acquisition of motor competence promote pubertal physical activity in Japanese elementary school children: A 4-year follow-up study.

This 4-year follow-up study investigated which profile of motor competence (MC) in early childhood more strongly correlated with moderate-to-vigorous physical activity (MVPA) in early pubescence. A total of 247 first-grade children (152 boys) aged 6 to 7 years old participated in the baseline measurement. MVPA was measured using an accelerometer annually until the fifth grade. Body fat percentage was assessed using dual-energy X-ray absorptiometry at baseline. MC included fundamental movement skills (FMS) and motor performance, which were assessed in terms of locomotor and object control. FMS was assessed by the Test of Gross Motor Development-2, while motor performance (locomotor: run, hop, jump, and side-step, object control: throw, kick, and hand dribble) was assessed by Japanese Physical Fitness and Motor Abilities Test at baseline. Multiple regression analysis showed that locomotor and object control performance were significant predictors of MVPA in later grades in boys but not in girls. These associations between locomotor performance and MVPA mainly remained significant after controlling for body fat and MVPA at baseline. FMS in both genders was not a significant predictor of MVPA in early pubescence. This study suggests that appropriate strategies for increasing MVPA from prepubescence to early pubescence may differ between boys and girls.

Neighborhood-level socioeconomic factors moderate the association between physical activity and relative age effect: a cross-sectional survey study with Japanese adolescents.

BACKGROUND: Relative age effect is defined as a phenomenon where children born early generally perform better than children born later in the same cohort. Physical activity is an important factor that might be influenced by the relative age effect. Socioeconomic factors (e.g., parent's income, education level) are also associated with the adolescent's physical activity. However, no existing study has examined whether socioeconomic factors moderate the relative age effect on the adolescent's physical activity. This study aims to clarify whether and how birth month and socioeconomic factors relate to organized sports and physical activity among adolescents in Japan. METHODS: We conducted a questionnaire survey targeting 21,491 adolescents who live in a widespread neighborhood. We included 8102 adolescents (4087 males and 4015 females: mean age 13.1 ± 1.4) in the analysis. Based on the participants' birth months, we divided them into four groups (April to June, July to September, October to December, January to March). We asked participants to report their organized sports participation. Using the International Physical Activity Questionnaire for Japanese Early Adolescents, we identified their moderate to vigorous physical activity (MVPA). Neighborhood-level socioeconomic factors (areal deprivation, average annual income, education level) were analyzed based on national surveys, such as the population census. We performed multilevel logistic and linear regression analysis for organized sports participation and MVPA, respectively. Moreover, a simple slope analysis was implemented if the interaction between birth month and socioeconomic factor was significant in the multilevel linear regression analysis. RESULTS: Among males, relatively younger adolescents (adolescents who were born later in the same grade) were less likely to participate in organized sports activites (OR=0.90, 95% CI 0.82-0.97, p<0.05), while both males and females engaged in less MVPA (b=-0.54, b=-0.25, p< 0.01, respectively). We observed an interaction between birth month and socioeconomic factors. Among males in low-income neighborhoods, and females in more deprived neighborhoods, relatively younger adolescents engaged in less MVPA. CONCLUSIONS: Socioeconomic factors moderate the relative age effect on adolescents' physical activity. The relative age effect on adolescents' physical activity might be more likely to appear among adolescents from socioeconomically disadvantaged neighborhoods.

Cumulative risk of developing a new symptom in patients with primary biliary cholangitis and its impact on prognosis.

Background and Aim: Symptoms of primary biliary cholangitis (PBC) frequently impair one's quality of life (QOL). Nonetheless, with improved treatment, the prognosis of PBC also improves. QOL plays an important role in patients with PBC. In this study, we aimed to reevaluate the transition of new symptom development in PBC and its predictive factors. Methods: This retrospective multicenter study enrolled 382 patients with PBC for symptom analysis. The impact of a newly developed symptom on PBC prognosis was investigated by Kaplan-Meier analysis with propensity score matching and logistic progression analysis. Results: The cumulative risk of developing a new symptom after 10 and 20 years of follow-up was 7.6 and 28.2%, and specifically that of pruritus, which was the most common symptom, was 6.7 and 23.3%, respectively. In Cox hazard risk analysis, serum Alb level (hazard ratio [HR], 1.097; 95% confidence interval [CI], 1.033-1.165; P = 0.002), the serum D-Bil level (HR, 6.262; 95% CI, 2.522-15.553, P < 0.001), and Paris II criteria (HR, 0.435; 95% CI, 0.183-1.036; P = 0.037) were significant independent predictors of a new symptom. Kaplan-Meier analysis showed that the overall survival and liver-related death were not significant between patients with and without a new symptom. Conclusion: The cumulative risk of new symptom development is roughly 30% 20 years after diagnosis and could be predicted by factors including serum albumin levels, serum D-Bil level, and Paris II criteria.

TRIM22 negatively regulates MHC-II expression.

The development of cancer treatment has recently achieved a remarkable breakthrough, and checkpoint blockade immunotherapy has received much attention. To enhance the therapeutic efficacy of checkpoint blockade immunotherapy, recent studies have revealed the importance of activation of CD4+ T cells via an increase in major histocompatibility complex (MHC) class II molecules in cancer cells. Here, we demonstrate that tripartite motif-containing (TRIM) 22, negatively regulates MHC-II expression. Gene knockout of TRIM22 using Cas9-sgRNAs led to an increase of MHC-II proteins, while TRIM22 overexpression remarkably decreased MHC-II proteins. mRNA levels of MHC-II and class II transactivator (CIITA), which plays an essential role in the regulation of MHC-II transcription, were not affected by TRIM22. Furthermore, TRIM22 knockout did not suppress the degradation of MHC-II protein but rather promoted it. These results suggest that TRIM22 decreases MHC-II protein levels through a combination of multiple mechanisms other than transcription or degradation. We showed that inhibition of TRIM22 can increase the amount of MHC-II expression in cancer cells, suggesting a possibility of providing the biological basis for a possible therapeutic target to potentiate checkpoint blockade immunotherapy.

Mirizzi Syndrome Type IV Successfully Treated with Peroral Single-operator Cholangioscopy-guided Electrohydraulic Lithotripsy: A Case Report with Literature Review.

A 76-year-old man presented with liver dysfunction and intrahepatic bile duct dilatation. Imaging studies showed two large stones that had become impacted in the common hepatic duct, which was fused with the gallbladder. The patient was diagnosed with Mirizzi syndrome type IV. Hepaticojejunostomy and stone removal failed due to dense gallbladder adhesions involving the right hepatic artery. The bile flow was temporarily restored; however, the patient experienced cholangitis 16 months later. The stones were extracted via peroral single-operator cholangioscopy (SOC)-guided electrohydraulic lithotripsy. This is the first case in which stones were completely removed by SOC-guided treatment in a patient with Mirizzi syndrome type IV.

Coil Formation of a Silicone String Using UV-Ozone Treatment.

Microcoils are used in various mechanical devices. However, existing methods for producing microcoils from polymers often require expensive equipment. In this study, microcoils were prepared using a cost-effective and simple method. The material used was silicone, which is a biocompatible polymeric material. Silicone was solidified inside glass capillaries to form thin, straight strings with a diameter of 140 µm. The string was then transformed to a coil shape by oxidation using UV-ozone treatment while it was prestretched and pretwisted. The resilience force from the prestretching and pretwisting forces caused the string to bend and twist, respectively. As a result of the combination of these deformation modes, a coil was formed. As an application of the coils, an actuator was prepared, which repeatedly transforms between straight and coiled shapes. The actuation was caused by the swelling/deswelling of silicone with hexane. A large strain of 54% was obtained.

Longitudinal increase in albumin-bilirubin score is associated with non-malignancy-related mortality and quality of life in patients with liver cirrhosis.

Due to the developments in the treatment for hepatitis, it is possible to prevent the progression of liver fibrosis and improve patients' prognosis even if it has already led to liver cirrhosis (LC). Consequently, a two-step study was conducted. To begin with, a retrospective study was conducted to identify the potential predictors of non-malignancy-related mortality from LC. Then, we prospectively analyzed the validity of these parameters as well as their association with patients' quality of life. In the retrospective study, 89 cases were included, and the multivariate Cox regression analysis indicated that age (P = 0.012), model for end-stage liver disease (MELD) score (P = 0.012), and annual rate of change of the albumin-bilirubin (ALBI) score (P < 0.001) were significantly associated with LC prognosis. In the prospective study, 70 patients were included, and the patients were divided into cirrhosis progression and non-progression groups. The univariate logistic regression analysis indicated the serum procollagen type III N-terminal peptide level (P = 0.040) and MELD score (P = 0.010) were significantly associated with the annual rate of change of the ALBI score. Furthermore, the mean Chronic Liver Disease Questionnaire score worsened from 5.3 to 4.9 in the cirrhosis progression group (P = 0.034). In conclusion, a longitudinal increase in the ALBI score is closely associated with non-malignancy-related mortality and quality of life.

Association Between Age of Achieving Gross Motor Development Milestones During Infancy and Body Fat Percentage at 6 to 7 Years of Age.

OBJECTIVES: The later achievement of gross motor milestones during infancy is associated with adiposity in early childhood. However, the associations between gross motor development and adiposity after entering primary school are unclear. This study examined the associations between the ages at which six gross motor milestones were achieved and adiposity during early school years. METHODS: This retrospective study was conducted in 2012 and 2013. Data were collected from 225 first-grade primary school children (mean age, 6.9 years; 39% girls). Adiposity was assessed using dual-energy X-ray absorptiometry and expressed as body fat percentage. Data describing the ages of achieving six gross motor milestones (holding head up, sitting, crawling, standing supported, walking supported, and independent walking) were obtained from the Maternal and Child Health Handbooks. RESULTS: Mean body fat percentage was 21.7%. Multiple linear regression analyses revealed that later ages of achieving crawling (p < .001 [95% confidence interval: 0.33-1.16]), standing supported (p < .001 [95% confidence interval: 0.64-1.65]), and walking supported [p = .013 (95% confidence interval: 0.13-1.07)] were associated with increased fat. However, the ages of achieving holding head up (p = .053), sitting (p = .175), and independent walking (p = .736) were not statistically significant. CONCLUSIONS: Achieving crawling, standing supported, and walking supported later predict increased body fat when aged 6-7 years. The practice of observing gross motor milestone achievements may allow early targeted interventions to optimize body composition before beginning school and thereby, potentially prevent childhood obesity.

Association of Neighborhood Food Environment and Physical Activity Environment With Obesity: A Large-Scale Cross-Sectional Study of Fifth- to Ninth-Grade Children in Japan.

Objective: This study examined the relationship between neighborhood food and physical activity environment, and obesity among elementary and junior high school students in Japan. Methods: The participants were fifth- to ninth-grade children (n=7277), who were attending municipal schools in Japan. Percent overweight (POW) was calculated using their age, gender, height, and weight, which were collected through a questionnaire. A POW of < 20% was considered non-obese, while ≥ 20% was considered obese. Furthermore, using a geographic information system, we investigated the density of convenience stores, fast-food stores, casual restaurants, supermarkets and department stores, parks, sports facilities, stations, and intersections in the school district. Additionally, from the census, we obtained information regarding the population density of the municipality where the participants' schools were located. Multiple logistic regression analysis was used to examine the relationship between obesity and food environment (the food environment model), between obesity and physical activity environment (the physical activity environment model), and among obesity, food, and physical activity environment (the food and physical activity environment model). Results: In the food environment model and the food and physical activity environment model, the density of convenience stores showed a significant positive association. In the physical activity environment model, the density of stations showed a significant negative association. Conclusion: This study's findings can contribute to the development of appropriate community interventions for improving children's health in Japan and similar areas.

Loss of FAM83H promotes cell migration and invasion in cutaneous squamous cell carcinoma via impaired keratin distribution.

BACKGROUNDS: FAM83H is essential for amelogenesis, but recent reports implicate that FAM83H is involved in the tumorigenesis. We previously clarified that TRIM29 binds to FAM83H to regulate keratin distribution and squamous cell migration. However, little is known about FAM83H in normal/malignant skin keratinocytes. OBJECTIVE: To investigate the expression of FAM83H in cutaneous squamous cell carcinoma (SCC) and its physiological function. METHODS: Immunohistochemical analysis and RT-PCR of human SCC tissues were performed. Next, we examined the effect of FAM83H knockdown/overexpression in SCC cell lines using cell proliferation, migration, and invasion assay. To investigate the molecular mechanism, immunoprecipitation of FAM83H was examined. Further, Immunofluorescence staining was performed. Finally, we examined the correlation between the expressions of FAM83H and the keratin distribution. RESULTS: FAM83H expression was lower in SCC lesions than in normal epidermis and correlated with differentiation grade. The mRNA expression levels of FAM83H in SCC tumors were also lower than in normal epidermis. The knockdown of FAM83H enhanced SCC cell migration and invasion, whereas the overexpression of FAM83H led to decreases in both. Furthermore, the knockdown of FAM83H enhanced the cancer cell metastasis in vivo. FAM83H formed a complex with TRIM29 and keratins. The knockdown of FAM83H altered keratin distribution and solubility. Clinically, the loss of FAM83H correlates with an altered keratin distribution. CONCLUSION: Our findings reveal a critical function for FAM83H in regulating keratin distribution, as well as in the migration/invasion of cutaneous SCC, suggesting that FAM83H could be a crucial molecule in the tumorigenesis of cutaneous SCC.

Primary Nondural Central Nervous System Marginal ZoneB-Cell Lymphoma of the Mucosa-Associated Lymphoid Tissue Type Mimicking CNS Inflammatory Diseases.

Marginal zone B-cell lymphomas (MZBCLs) are non-Hodgkin lymphomas arising from postgerminal center marginal zone B cells. MZBCLs are subclassified into extranodal, nodal, and splenic MZBCLs. Primary nondural central nervous system (CNS) MZBCLs of the mucosa-associated lymphoid tissue (MALT) type are among the extranodal examples. Their clinicopathological features are not well characterized. Therefore, the clinicopathological features of 8 primary nondural CNS MZBCLs of the MALT type were assessed to establish their pathological diagnostic criteria. Histologically, all cases of primary nondural CNS MZBCLs of the MALT type showed perivascular expansive monotonous proliferation of small atypical B lymphoid cells with plasma cell differentiation, low Ki-67 labeling index, and minimal invasion from the perivascular space. In addition, no vascular changes such as glomeruloid changes, obliterative fibrointimal proliferation, and intramural lymphocytic infiltration were seen. These key histological characteristics should be considered when diagnosing cases that are suspected to be primary nondural CNS MZBCLs of the MALT type. Additionally, regarding PCR for the detection of immunoglobulin heavy variable gene and T-cell receptor γ gene rearrangements, the former is detected, but the latter is not detected in all cases. Therefore, PCR detection including sequence analysis should be added when diagnosing difficult cases based on the key histological characteristics.