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Cryo-electron microscopy (cryo-EM) represents a powerful technology for determining atomic models of biological macromolecules(Kühlbrandt, 2014). Despite this promise, human-guided cryo-EM data collection practices limit the impact of cryo-EM because of a path planning problem: cryo-EM datasets typically represent 2-5% of the total sample area. Here, we address this fundamental problem by formalizing cryo-EM data collection as a path planning optimization from low signal data. Within this framework, we incorporate reinforcement learning (RL) and deep regression to design an algorithm that uses distributed surveying of cryo-EM samples at low magnification to learn optimal cryo-EM data collection policies. Our algorithm - cryoRL - solves the problem of path planning on cryo-EM grids, allowing the algorithm to maximize data quality in a limited time without human intervention. A head-to-head comparison of cryoRL versus human subjects shows that cryoRL performs in the top 10% of test subjects, surpassing the majority of users in collecting high-quality images from the same sample. CryoRL establishes a general framework that will enable human-free cryo-EM data collection to increase the impact of cryo-EM across life sciences research.

We previously reported CD63-BCAR4 fusion as a novel oncogene that significantly enhanced cell migration and metastasis in lung cancer. To identify effective inhibitors of metastatic activity induced by BCAR4 fusion, we screened a drug library of 381 FDA-approved compounds. The effect of drugs on cell migration was evaluated by monitoring wound healing. Drugs that decreased the cellular mobility of fusion-overexpressing cells compared with that of control cells were selected as candidates. Library screening revealed that erlotinib, canertinib, and lapatinib demonstrated inhibitory effects on cell migration. Activation of the EGFR signaling pathway was detected after ectopic expression of CD63-BCAR4 in normal bronchial epithelial cells, as observed by the increased phosphorylation of tyrosine residues in the EGFR protein. We also confirmed increased levels of the phosphorylated EGFR protein in resected tumors from mice injected with CD63-BCAR4 overexpressing cells. Tyrosine kinase inhibitors (TKIs) of the EGFR family significantly inhibit the migration of BCAR4 fusion-overexpressing cells and induce apoptosis at high concentrations. Among the EGFR family TKIs, canertinib, a dual EGFR/HER2 inhibitor, showed the best inhibitory effect on the migration and viability of BCAR4 fusion-overexpressing cells. We examined the effect of canertinib

Transitional cell carcinoma (TCC) is the most common malignant tumor of the canine urinary tract and tends to have a poor prognosis due to its invasive potential. Recent studies have reported that up to 80% of canine urothelial carcinoma has the BRAF V595E mutation, which is homologous to the human V600E mutation. Activating the BRAF mutation is an actionable target for developing effective therapeutic agents inhibiting the BRAF/mitogen-activated protein kinase (MAPK) pathway in canine cancer as well as human cancer. We established novel canine TCC cell lines from two tumor tissues and one metastatic lymph node of canine TCC patients harboring the BRAF V595E mutation. Tumor tissues highly expressed the BRAF mutant and phosphorylated extracellular signal-related kinases (ERK)1/2 proteins. The derived cell lines demonstrated activated MAPK pathways. We also evaluated the cell lines for sensitivity to BRAF inhibitors. Sorafenib, a multiple kinase inhibitor targeting RAF/vascular endothelial growth factor receptor (VEGFR), successfully inhibited the BRAF/MAPK pathway and induced apoptosis. The established canine TCC cell lines responded with greater sensitivity to sorafenib than to vemurafenib, which is known as a specific BRAF inhibitor in human cancer. Our results demonstrated that canine TCC cells showed different responses compared to human cancer with the BRAF V600E mutation. These cell lines would be valuable research materials to develop therapeutic strategies for canine TCC patients.

Due to the rapid expansion of the leisure industry, there were about 32,000 golf caddies in South Korea in 2020, an increase of 18.5% compared to 2016. Consequently, they face an increasing industrial accident rate, which is presumed to be the result of exposure to various harmful factors. Through a survey and oral interview of 221 caddies across more than 20 golf courses, health protective measures, protective measures for caddies, preparation for golf cart operation, physical burden, compliance with golf cart safety during games, and golf course responses to emotional labor were investigated in this study to identify safety and health problems of caddies and suggest prevention measures. Preliminary interviews were conducted to confirm golf courses’ safety and health status and participants’ characteristics. Golf caddies’ health and safety were confirmed using frequency analysis, independent sample t-test, one-way analysis of variance (ANOVA), Pearson correlation analysis, and multiple regression analysis. The results showed that caddies’ workplaces were relatively vulnerable to safety and health issues and caddies were exposed to various harmful risk factors. In addition, it was confirmed that golf caddy protective measures, golf cart safety compliance, physical burden, and health protection affect golf courses’ response level to caddies’ emotional labor.

15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is the key enzyme that catalyses the conversion of prostaglandin E2 to a keto metabolite. The expression of 15-PGDH is ubiquitously repressed in vari...

There is an increasing need to explore the mechanism of the progression of non-alcoholic fatty liver disease. Steroid metabolism is closely linked to hepatic steatosis and steroids are excreted as bile acids (BAs). Here, we demonstrated that feeding WKAH/HkmSlc inbred rats a diet supplemented with cholic acid (CA) at 0.5 g/kg for 13 weeks induced simple steatosis without obesity. Liver triglyceride and cholesterol levels were increased accompanied by mild elevation of aminotransferase activities. There were no signs of inflammation, insulin resistance, oxidative stress, or fibrosis. CA supplementation increased levels of CA and taurocholic acid (TCA) in enterohepatic circulation and deoxycholic acid (DCA) levels in cecum with an increased ratio of 12 alpha-hydroxylated BAs to non-12 alpha-hydroxylated BAs. Analyses of hepatic gene expression revealed no apparent feedback control of BA and cholesterol biosynthesis. CA feeding induced dysbiosis in cecal microbiota with enrichment of DCA producers, which underlines the increased cecal DCA levels. The mechanism of steatosis was increased expression of Srebp1 (positive regulator of liver lipogenesis) through activation of the liver X receptor by increased oxysterols in the CA-fed rats, especially 4 beta-hydroxycholesterol (4 beta OH) formed by upregulated expression of hepatic Cyp3a2, responsible for 4 beta OH formation. Multiple regression analyses identified portal TCA and cecal DCA as positive predictors for liver 4 beta OH levels. The possible mechanisms linking these predictors and upregulated expression of Cyp3a2 are discussed. Overall, our observations highlight the role of 12 alpha-hydroxylated BAs in triggering liver lipogenesis and allow us to explore the mechanisms of hepatic steatosis onset, focusing on cholesterol and BA metabolism.

Background/aim The rapid increase in the number of people who are overweight or obese, which increases the risk of diseases and health problems, is becoming an important issue. Herein, we investigated whether olive leaf extract (OLE) has potent anti-obesity effects in high-fat induced mouse models. Materials and methods C57BL/6 mice were randomized into normal control, high-fat diet (HFD), HFD with OLE, and HFD with garcinia groups and administered experimental diets for 12 weeks. Body weight and food intake were measured once per week and obesity-related biomarkers were evaluated in the serum and adipose tissue. Results OLE significantly suppressed weight gain, food efficiency ratio, visceral fat accumulation, and serum lipid composition in HFD-induced mice. Furthermore, the expression of adipogenesis- and thermogenesis-related molecules was decreased in the OLE-treated group. Conclusion OLE prevents obesity development by regulating the expression of molecules involved in adipogenesis and thermogenesis.

This study assessed whether quantile regression can identify design specifications that lead to particularly long glances, which might go unnoticed with traditional analyses focusing on conditional means of off-road glances. Although substantial research indicates that long glances contribute disproportionately to crash risk, few studies have directly assessed the tails of the distribution. Failing to examine the distribution tails might underestimate the disproportionate risk on long glances imposed by secondary tasks. We applied quantile regression to assess the effects of secondary task type (reading or entry), system delay (delay or no delay), and text length (long or short) on off-road glance duration at 15th, 50th, and 85th quantiles. The results show that entry task, long text, and some combinations of variables led to longer glances than that would be expected given the central tendency of glance distributions. Quantile regression identifies secondary task features that produce long glances, which might be neglected by traditional analyses with conditional means.

Objective The aim of this multi-institutional study was to determine the prognostic impact of tumour parameters, such as tumour size (TS), tumour volume (TV), and marker expression, on survival during radiation therapy (RT) for cervical cancer patients. Methods A total of 231 patients with histologically confirmed cervical cancer, classified as Federation of Gynecology and Obstetrics (FIGO) Ib2-IVa, were enrolled in this study. Pre- and mid-RT pelvic magnetic resonance imaging (MRI) and squamous cell carcinoma antigen (SCC-ag) analysis were performed twice, during RT and just before brachytherapy. Results The median follow-up time was 27.8months (range, 2–116months). Multivariate analysis revealed that stage (odds ratio [OR], 2.936 and 95% confidence interval [CI], 1.119–7.707; P =0.029), tumour volume reduction rate (TVRR) (OR, 3.435 and 95% CI, 1.062–11.106; P =0.039), and SCC-ag reduction rate (SCCRR) (OR, 5.104 and 95% CI, 1.769–14.727; P =0.003) were independently associated with overall survival (OS), while pre-RT TS (OR, 2.148 and 95% CI, 1.221–3.810; P =0.009), mid-RT TV (OR, 3.106 and 95% CI, 1.685–5.724; P P =0.016) were associated with progression-free survival (PFS). Based on the prognostic factor analysis, patients with the highest prognostic risk score of 3 showed poorer overall survival and progression free survival than patients with lower prognostic risk scores. Conclusion We identified that tumour parameters such as TVRR, SCCRR, pre-RT TS, and mid-RT TV areindependent and strong prognostic parameters for patients with cervical cancer receiving RT. This scoring system-based prognostic factor analysis could be used to help develop optimized treatment plans for cervical cancer patients during RT.

Understanding the dynamics of secondary bile acid (SBA) formation in the gut by SBA-producing bacteria is important for host health, as SBAs have been shown to affect host pathophysiology and gut microbiota composition. However, our knowledge of SBA producers is limited in light of the diversity of gut microbes. Here, we isolated six novel SBA-producing bacteria from rat cecal contents, all of which were members of known species of gut microbes. Anaerostipes caccae D10, Bacteroides nordii C5, Clostridioides difficile D7, and Clostridium cadaveris G11 were capable of oxidizing cholic acid and chenodeoxycholic acid into 7-oxo-derivatives with varying yields. B. nordii C5 and its type strain JCM 12987T had the highest molar yield, ∼90%. Clostridium disporicum F4 and Clostridium subterminale C4 epimerized cholic acid into ursocholic acid with yields of ∼85%; the corresponding type strains lacked epimerization activity. Furthermore, although not novel as an SBA producer, Clostridium scindens G10 that produced deoxycholic acid from cholic acid was isolated for the first time from rodents. These findings will contribute to elucidation of SBA formation in the gut.

The visual-manual distraction guidelines by National Highway Traffic Safety Administration (NHTSA) provide a method to assess potential distraction of secondary tasks. According to the method, one instance of “testable task” is performed once by 24 participants, and three glance measures (i.e., mean duration of off-road glances, total eyes off road time, and proportion of long glances) are used to decide whether the task imposes acceptable demand on the driver. The current study investigates variability from both participants and task instances (e.g., different telephone numbers used for dialing telephone number task) reflected in these glance measures, with repeated sampling of participants and repeated sampling of task instances. While NHTSA test method is vulnerable to both sources of variability, multi-level statistical modeling and sampling task instances offers a promising approach to overcome this limitation.

The radiocephalic arteriovenous fistula (AVF) provides optimal vascular access for hemodialysis; it has a higher long-term patency rate and fewer complications than other vascular access methods. However, the AVF has a high primary failure rate. The presence of small-diameter vessels at anastomosis sites is an important risk factor for AVF failure. However, in a recent study, despite selecting an adequate artery and vein for creating an AVF by routine preoperative vascular mapping, AVF maturation and primary failure occurred. Thus, pre-existing arteriosclerosis at AVF anastomosis sites likely contributes to AVF failure. In this review, we discuss the relationship between pathologic changes and AVF patency in hemodialysis patients. Because arteriosclerosis of the major arteries such as the coronary and carotid arteries is associated with cardiovascular mortality, we also review the impact of arteriosclerosis of upper arm arteries at AVF anastomosis sites on cardiovascular mortality in hemodialysis patients.

BACKGROUND Elevated whole blood viscosity (WBV) is associated with increasing blood flow resistance in the microcirculation and is used to predict the occurrence and outcome of cardiovascular diseases. OBJECTIVE We evaluated the analytical performance of the ZL 6000i (Zonci Technology, Beijing, China), new fully automated cone-plate rotational type viscometer. METHODS We collected blood samples from 287 adults to establish a reference range. We evaluated total precision for 20 days using quality control (QC) samples and within-run precision was evaluated by performing 50 consecutive measurements of blood samples. Aliquots of blood samples were stored at room temperature and 5°C to assess the effect of storage time and temperature on viscosity measurement. RESULTS The reference ranges and median values of WBV were significantly higher in males than in females due to difference in hematocrit level. The coefficients of variation (CVs) for precision using QC and human blood samples were

Prostaglandin E

As in-vehicle infotainment systems gain new functionality, their potential to distract drivers increases. Searching for an item on interface is a critical concern because a poorly designed interface that draws drivers’ attention to less important items can extend drivers’ search for items of interest and pull attention away from roadway events. This potential can be assessed in simulator-based experiments, but computational models of driver behavior might enable designers to assess this potential and revise their designs more quickly than if they have to wait weeks to compile human subjects data. One such model, reported in this paper, predicts the sequence of eye fixations of drivers based on a Boolean Map-based Saliency model augmented with top-down feature bias. Comparing the model predictions to empirical data shows that the model can predict search time, especially in cluttered scenes and when a target item is highlighted. We also describe the integration of this model into a web application ( http://distraction.engr.wisc.edu/ ) that can help assess the distraction potential of interface designs.

15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is the key enzyme that catalyses the conversion of prostaglandin E

Background This study aimed to examine the relationship between alcohol consumption and intraocular pressure (IOP) according to facial flushing in Korean men with obesity. Methods The study included 479 Korean men with a body mass index of ≥25 kg/m2 (75 non-drinkers, 174 with drinking-related facial flushing, and 230 without facial flushing) who underwent health check-ups between October 1, 2016 and March 31, 2017. Multivariate logistic regression was used to assess the relationship between alcohol consumption and high IOP (≥21 mm Hg). Results Flushers consuming ≤16 drinks per week had a significantly higher risk of high IOP than non-drinkers, depending on alcohol consumption (≤8 standard drinks: odds ratio [OR], 4.49; 95% confidence interval [CI], 1.05- 19.25; >8 but ≤16 standard drinks: OR, 8.14; 95% CI, 1.37-48.45). However, when the consumption was >16 drinks per week, the high IOP risk did not significantly increase (OR, 0.71; 95% CI, 0.05-10.69). In addition, there was no significant relationship between alcohol consumption and high IOP among non-flushers consuming ≤8 drinks per week (OR, 2.07; 95% CI, 0.52-8.19). However, a significantly increased risk of high IOP was observed among nonflushers consuming >8 drinks per week, depending on alcohol consumption (>8 but ≤16 standard drinks: OR, 4.84; 95% CI, 1.14-20.61; >16 standard drinks: OR, 4.08; 95% CI, 1.02-16.26). Conclusion This study suggests that obese men with alcohol flush reactions may have an increased risk of high IOP with the consumption of smaller amounts of alcohol than non-flushers.