Miracle-dz/UniFAR-FTUs huggingface dataset:
Defining the mechanism of action of S1QELs, specific suppressors of superoxide production in the quinone-reaction site in mitochondrial complex I

Site-specific suppressors of superoxide production (named S1QELs) in the quinone-reaction site in mitochondrial respiratory complex I during reverse electron transfer have been previously reported; however, their mechanism of action remains elusive. Using bovine heart submitochondrial particles, we herein investigated the effects of S1QELs on complex I functions. We found that the inhibitory effects of S1QELs on complex I are distinctly different from those of other known quinone-site inhibitors. For example, the inhibitory potencies of S1QELs significantly varied depending on the direction of electron transfer (forward or reverse). S1QELs marginally suppressed the specific chemical modification of Asp160 in the 49-kDa subunit, located deep in the quinone-binding pocket, by the tosyl chemistry reagent AL1. S1QELs also failed to suppress the binding of a photoreactive quinazoline-type inhibitor ([125I]AzQ) to the 49-kDa subunit. Moreover, a photoaffinity labeling experiment with photoreactive S1QEL derivatives indicated that they bind to a segment in the ND1 subunit that is not considered to make up the binding pocket for quinone or inhibitors. These results indicate that unlike known quinone-site inhibitors, S1QELs do not occupy the quinone- or inhibitor-binding pocket; rather, they may indirectly modulate the quinone-redox reactions by inducing structural changes of the pocket through binding to ND1. We conclude that this indirect effect may be a prerequisite for S1QELs' direction-dependent modulation of electron transfer. This, in turn, may be responsible for the suppression of superoxide production during reverse electron transfer without significantly interfering with forward electron transfer.
The role of CD36 in endothelial albumin transcytosis.

Transcytosis is a transcellular transport process during which macromolecules trafﬁc across cells. The process is initiated by endocytosis on one side of the cell (e.g., luminal or apical), followed by vesicular trafﬁc and subsequent exocytosis on the opposite side (e.g., abluminal or basolateral) in a uni- or bidirectional manner. Generally, the initial endocytic step may be receptor-mediated and thus substrate-speciﬁc clathrin- caveolae-driven on the cell be nonspeciﬁc in case of macropinocytosis
Impact of Postoperative Complications on Survival and Recurrence After Resection of Colorectal Liver Metastases: Systematic Review and Meta-analysis.

MINI: Systematic review and meta-analysis on the effect of postoperative complications on oncologic results after colorectal cancer liver metastasis resection. The results based on data from 41 studies (12,817 patients) evidence the increased risk of mortality and recurrence for patients experiencing postresection complications. OBJECTIVE To study the effect of postoperative complications (POC) on overall survival (OS) and disease-free survival (DFS) after surgical resection of colorectal liver metastases (CRLM). SUMMARY BACKGROUND DATA Morbidity rates after liver resection can reach 45%. The negative impact of POC on oncologic outcomes has been reported in various types of cancer, especially colorectal. However, data on the consequences of POC after CRLM resection on long-term survival are scarce. METHODS Eligible studies examining the association between POC after CRLM resection and OS/DFS were sought using the PubMed and Web of Science databases. A random-effects model was used to calculate pooled effect estimate for OS and DFS hazard ratios (HR), estimating between-study variance with restricted maximum likelihood estimator with Hartung-Knapp adjustment. Subgroup analysis was used to control the effect of POC on OS and DFS for: 1) Method used to define postoperative complications, 2) Exclusion of early postoperative death from survival analysis, 3) Method of data extraction used, and 4) Tumor and treatment characteristics. RESULTS Forty-one studies were deemed eligible, including 12,817 patients. POC patients had a significant risk of reduced OS compared with no POC group (HR 1.43 [95% CI: 1.3, 1.57], P < 0.0001). POC had also a negative impact on DFS. The HR for reduced DFS was 1.38 [95% CI 1.27, 1.49], P < 0.0001. The negative impact of POC on survival and recurrence was confirmed in subgroup analysis. CONCLUSIONS Our findings evidence the negative impact of POC on survival and recurrence after CRLM resection.
Assessing the Knowledge, Attitudes, and Behaviors of Hookah Smoking among Ethiopian and Eritrean Americans

Abstract:The aims of this study were to estimate the prevalence of hookah smoking and describe its associated knowledge, attitudes, and behaviors among Ethiopian and Eritrean Americans. Approximately 400 participants completed an online survey on hookah tobacco use, perceptions of harm and social acceptability. Nearly 80% had tried hookah in their lifetime (ever users), and about 43% had smoked hookah in the past 30 days (current users). Hookah ever use was highest among people 24–29 years of age, but there were no significant differences by gender, education or employment. Ever users were less supportive of bans on hookah smoking in a bar or restaurant compared with never users, X2 (3, N = 396) = 57.56, p<. 001. Additionally, ever users more often reported hookah smoking was less harmful than cigarette smoking compared with never users. Future research is needed to understand the predictors of hookah smoking in this subpopulation and inform interventions.
Health Indicators of a Cohort of Midwest Farmers: Health Outcomes of Participants in the Certified Safe Farm Program

ABSTRACT Occupational illness, injury, and fatality rates for those working in production agriculture are higher than in any other industry. A potential risk factor contributing to occupational injuries across all industries is acute or chronic co-morbidity (e.g., obesity, high blood pressure, high cholesterol), and related health issues that increase the risk for an occupational injury or illness. These chronic health conditions have been associated not only with increased risk for injuries, but also higher health-care costs, and greater absenteeism. Certified Safe Farm (CSF) is a comprehensive intervention program aimed to reduce occupational health and safety hazards and to promote general health among farmers. Prior publications have described CSF program efforts to reduce hazardous exposures, disabling injuries, organic dust toxic syndrome, occupational health-care costs, and to increase positive occupational health behaviors. This paper reports on the general health indicators of a cohort of 438 Iowa farm owner/operators enrolled in the CSF program. Overall, this study found that the farming population in Iowa has higher body mass index (BMI), but lower total cholesterol, low-density lipoprotein (LDL), and lower prevalence of hypertension compared to the general population. There was evidence that the combination of high blood pressure, cholesterol, and BMI were related to increased injury rates. Poor self-reported health status was also related to increased injuries but was not related to clinical health indicators. The CSF intervention led to improvements on health outcomes, particularly among those in the 35 to 49 age group. Little research has focused on the individual’s general health status as a predictor of risk of occupational injury. This study suggests the need for additional research and interventions integrating occupational safety and health prevention along with health promotion.
PAR2 inhibition enhanced the sensitivity of colorectal cancer cells to 5-FU and reduced EMT signaling.

To investigate the underlying mechanisms that transforming growth factor (TGF)-β-mediated epithelial-to-mesenchymal transition (EMT) in tumor cells contributes to 5-Fu resistance. A series of experiments involving cell-viability and caspase-activity analyses, siRNA transfection, RNA isolation and quantitative-PCR (qPCR) assay, cell migration analysis, western blotting analysis of total protein and membrane protein were performed in this study. Mouse xenograft model was used to determine the effect of the PAR2 inhibitor in vivo. In this study, we found that protease-activated receptor-2 (PAR2) induction in 5-Fu therapy is correlated with TGF-β-mediated EMT and apoptosis resistance. PAR2 and TGF-β were both activated in response to 5-Fu treatment in vivo and in vitro, and whereas TGF-β inhibition sensitized CRC cells to 5-Fu and suppressed cell migration, PAR2 activation eliminated the effect TGF-β inhibition. Conversely, siRNA-mediated PAR2 depletion or PAR2 inhibition with a specific inhibitor produced a similar phenotype as TGF-β signal inhibition: 5-Fu sensitization and cell-migration suppression. Moreover, the results of xenograft experiments indicated that the PAR2 inhibitor can enhance cell killing by 5-Fu in vivo and suppress EMT signaling. Our results reveal the TGF-β effects require the coordinating action of PAR2, suggesting that PAR2 inhibition could a new therapeutic strategy to combat 5-Fu resistance in CRC.
Plasma citrulline, arginine, nitric oxide, and blood ammonia levels in neonatal calves with acute diarrhea

Background Plasma citrulline (CIT) concentration is considered to be a reliable marker of functional enterocyte mass, primarily in humans. However, information about CIT levels along with related metabolites, arginine (ARG), nitric oxide (NO), and ammonia in neonatal calves are lacking. Objectives To compare plasma CIT, ARG, NO, and whole blood ammonia concentrations in neonatal calves with acute diarrhea with those in healthy calves and to assess their possible relationships with diarrhea‐related criteria. Animals Seventy neonatal calves (60 with acute diarrhea and 10 healthy). Methods Observational case‐control study. Diarrheic calves were classified into subgroups on the basis of etiology, severity of diarrhea, degree of dehydration, and systemic inflammatory response syndrome (SIRS) status. Plasma CIT and ARG concentrations were measured by liquid chromatography/tandem mass spectrometry. Results Plasma CIT (median [range]: 67.5 [61.9‐75.4] vs 30.1 [15.0‐56.1] μmol/L) and ARG (170.7 [148.5‐219.5] vs 106.1 [54.4‐190.7] μmol/L) were lower and plasma NO (4.42 [3.29‐5.58] vs 6.78 [5.29‐8.92] μM) and blood ammonia concentrations (28.7 [26.1‐36.9] vs 59.8 [34.6‐99.5] μmol/L) were higher in the neonatal calves with diarrhea (P < .001). Plasma CIT (β = −0.29, P = .02), ARG (β = −0.33, P = .01), NO (β = 0.55, P < .001), and blood ammonia (β = 0.63, P <.001) were affected by SIRS status. Except for ammonia (0.52), the effects sizes for severity of diarrhea and degree of dehydration were small (ηp2 ≤ 0.45) for CIT, ARG, and NO. Conclusions and Clinical Importance The changes in these variables might have diagnostic, prognostic, and therapeutic value in diarrheic neonatal calves.
The complete mitochondrial genome sequence of Red knobby newt Tylototriton shanjing (Amphibia: Caudata)

Abstract The complete mitogenome of Tylototriton shanjing is 16,661 bp in length with GenBank accession number KR154461, which contains 13 protein-coding genes (PCGs), 22 transfer RNA genes (tRNA), 2 ribosomal RNA genes (rRNA), and 1 control region (CR). The overall base composition of this mitogenome is biased toward AT content at 59.45%. Most of the PCGs and tRNA genes are located on the H-strand, except for ND6 subunit gene and eight tRNA genes, which were distributed on the L-strand. The PCGs used “ATG” and “GTG” as the start codons, while “TAA”, “TAG”, “AGA”, and “T–” are used as stop codons. Almost all tRNA genes were folded into typical cloverleaf secondary structures. The T. shanjing genome had two tandem repeat sequences in the cob-noncoding region. The mitogenomic phylogenetic analyses shows that the genera Echinotriton and Tylototriton were clustered into a strong supported monophyletic clade, which is a sister clade to the genus Pleurodeles, this confirms the previous phylogenetic results.
Null Effects of Game Violence, Game Difficulty, and 2D:4D Digit Ratio on Aggressive Behavior

Researchers have suggested that acute exposure to violent video games is a cause of aggressive behavior. We tested this hypothesis by using violent and nonviolent games that were closely matched, collecting a large sample, and using a single outcome. We randomly assigned 275 male undergraduates to play a first-person-shooter game modified to be either violent or less violent and hard or easy. After completing the game-play session, participants were provoked by a confederate and given an opportunity to behave aggressively. Neither game violence nor game difficulty predicted aggressive behavior. Incidentally, we found that 2D:4D digit ratio, thought to index prenatal testosterone exposure, did not predict aggressive behavior. Results do not support acute violent-game exposure and low 2D:4D ratio as causes of aggressive behavior.
A Phase I Study of Pegylated Arginine Deiminase (Pegargiminase), Cisplatin, and Pemetrexed in Argininosuccinate Synthetase 1-Deficient Recurrent High-grade Glioma

Purpose: Patients with recurrent high-grade gliomas (HGG) are usually managed with alkylating chemotherapy ± bevacizumab. However, prognosis remains very poor. Preclinically, we showed that HGGs are a target for arginine depletion with pegargiminase (ADI-PEG20) due to epimutations of argininosuccinate synthetase (ASS1) and/or argininosuccinate lyase (ASL). Moreover, ADI-PEG20 disrupts pyrimidine pools in ASS1-deficient HGGs, thereby impacting sensitivity to the antifolate, pemetrexed. Patients and Methods: We expanded a phase I trial of ADI-PEG20 with pemetrexed and cisplatin (ADIPEMCIS) to patients with ASS1-deficient recurrent HGGs (NCT02029690). Patients were enrolled (01/16–06/17) to receive weekly ADI-PEG20 36 mg/m2 intramuscularly plus pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 intravenously once every 3 weeks for up to 6 cycles. Patients with disease control were allowed ADI-PEG20 maintenance. The primary endpoints were safety, tolerability, and preliminary estimates of efficacy. Results: Ten ASS1-deficient heavily pretreated patients were treated with ADIPEMCIS therapy. Treatment was well tolerated with the majority of adverse events being Common Terminology Criteria for Adverse Events v4.03 grade 1-2. The best overall response was stable disease in 8 patients (80%). Plasma arginine was suppressed significantly below baseline with a reciprocal increase in citrulline during the sampling period. The anti–ADI-PEG20 antibody titer rose during the first 4 weeks of treatment before reaching a plateau. Median progression-free survival (PFS) was 5.2 months (95% confidence interval (CI), 2.5–20.8) and overall survival was 6.3 months (95% CI, 1.8–9.7). Conclusions: In this recurrent HGG study, ADIPEMCIS was well tolerated and compares favorably to historical controls. Additional trials of ADI-PEG20 in HGG are planned.
Reply to Francescato et al.: Interpreting the averaging methods to estimate oxygen uptake kinetics parameters.

to the editor: We thank Dr. Francescato and colleagues for their interest in our study ([1][1]) and for their letter ([3][2]). The authors requested clarification of why we concluded that 1-s interpolation of breath-by-breath pulmonary oxygen uptake (Vo2P) data resulted in the most accurate and
An Epithelial–Mesenchymal Transition Gene Signature Predicts Resistance to EGFR and PI3K Inhibitors and Identifies Axl as a Therapeutic Target for Overcoming EGFR Inhibitor Resistance

Purpose: Epithelial–mesenchymal transition (EMT) has been associated with metastatic spread and EGF receptor (EGFR) inhibitor resistance. We developed and validated a robust 76-gene EMT signature using gene expression profiles from four platforms using non–small cell lung carcinoma (NSCLC) cell lines and patients treated in the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) study. Experimental Design: We conducted an integrated gene expression, proteomic, and drug response analysis using cell lines and tumors from patients with NSCLC. A 76-gene EMT signature was developed and validated using gene expression profiles from four microarray platforms of NSCLC cell lines and patients treated in the BATTLE study, and potential therapeutic targets associated with EMT were identified. Results: Compared with epithelial cells, mesenchymal cells showed significantly greater resistance to EGFR and PI3K/Akt pathway inhibitors, independent of EGFR mutation status, but more sensitivity to certain chemotherapies. Mesenchymal cells also expressed increased levels of the receptor tyrosine kinase Axl and showed a trend toward greater sensitivity to the Axl inhibitor SGI-7079, whereas the combination of SGI-7079 with erlotinib reversed erlotinib resistance in mesenchymal lines expressing Axl and in a xenograft model of mesenchymal NSCLC. In patients with NSCLC, the EMT signature predicted 8-week disease control in patients receiving erlotinib but not other therapies. Conclusion: We have developed a robust EMT signature that predicts resistance to EGFR and PI3K/Akt inhibitors, highlights different patterns of drug responsiveness for epithelial and mesenchymal cells, and identifies Axl as a potential therapeutic target for overcoming EGFR inhibitor resistance associated with the mesenchymal phenotype. Clin Cancer Res; 19(1); 279–90. ©2012 AACR.
The P5A ATPase Spf1p is stimulated by phosphatidylinositol 4-phosphate and influences cellular sterol homeostasis

P5A ATPases are expressed in the endoplasmic reticulum (ER) of all eukaryotic cells, and their disruption results in severe ER stress. However, the function of these ubiquitous membrane proteins, which belong to the P-type ATPase superfamily, is unknown. We purified a functional tagged version of the Saccharomyces cerevisiae P5A ATPase Spf1p and observed that the ATP hydrolytic activity of the protein is stimulated by phosphatidylinositol 4-phosphate (PI4P). Furthermore, SPF1 exhibited negative genetic interactions with SAC1, encoding a PI4P phosphatase, and with OSH1 to OSH6, encoding Osh proteins, which, when energized by a PI4P gradient, drive export of sterols and lipids from the ER. Deletion of SPF1 resulted in increased sensitivity to inhibitors of sterol production, a marked change in the ergosterol/lanosterol ratio, accumulation of sterols in the plasma membrane, and cytosolic accumulation of lipid bodies. We propose that Spf1p maintains cellular sterol homeostasis by influencing the PI4P-induced and Osh-mediated export of sterols from the ER.
Feature-Based Statistical Regularities of Distractors Modulate Attentional Capture

Ignoring salient distracting information is paramount to efficiently guiding attention during visual search. Learning to reject or suppress these strong sources of distraction leads to more effective visual search for targets. Participants can learn to overcome salient distractors if given reliable search regularities. If salient distractors appear in 1 location more frequently than any other, the visual system can use this environmental regularity to reduce attentional capture at the more frequent location (Wang & Theeuwes, 2018). We asked if reduced attentional capture is limited to location-based regularities, or, if the visual attentional system is configured to use feature-based regularities in reducing attentional capture as well. In 4 experiments examining attentional capture by task-irrelevant color singletons, participants searched for a shape singleton target among homogenously colored distractors. Critically, on a proportion of trials, a salient, color singleton distractor was presented. Color singleton distractors that appeared at a frequent location captured attention less than color singleton distractors that appeared at infrequent locations, replicating previous findings. In subsequent experiments we manipulated the frequency of the colors of the color singleton distractors and observed robust increases in capture based on color feature regularities. Despite strong location information, we observed reliable attentional capture attenuation by frequently presented distractor colors. Our results suggest that attentional capture is attenuated by both location and feature information.
Influence of autoclavation on the efficacy of extracted tooth roots used for vertical alveolar ridge augmentation

OBJECTIVES To assess the influence of autoclavation on the efficacy of extracted tooth roots (TR) used for vertical alveolar ridge augmentation and two-stage osseointegration. MATERIAL AND METHODS Maxillary premolars were randomly assigned to either autoclavation (TR-A) or were left untreated (TR-C) and used as block grafts for vertical alveolar ridge augmentation in both lower quadrants (n = 4 beagle dogs). At 12 weeks, titanium implants were inserted and left to heal for 3 weeks. Histological analyses considered vertical bone gain (BD-BC), augmented area (AA) and bone-to-implant contact (BIC) at vestibular (v) and oral (o) aspects. RESULTS Both TR-C and TR-A (exposures n = 3) grafts were associated with a replacement resorption and marked vertical bone gain. Median BD-BC (TR-C: 1.45 [v] to 1.62 mm [o] versus TR-A: 0.97 [v] to 1.79 mm [o]) and AA (TR-C: 0.64 [v] to 2.36 mm2 [o] versus TR-A: 0.22 [v] to 2.36 mm2 [o]) values were comparable in both groups. V BIC (TR-C: 49.32 [v] to 52.97% [o] versus TR-A: 25.34 [v] to 46.11% [o]) values were significantly higher in the TR-C group. CONCLUSIONS Both TR-C and TR-A grafts equally supported vertical alveolar ridge augmentation; however, osseointegration was partially facilitated in the TR-C group.
Production , Manufacturing and Logistics An improved ant colony optimization for vehicle routing problem

The vehicle routing problem (VRP), a well-known combinatorial optimization problem, holds a central place in logistics management. This paper proposes an improved ant colony optimization (IACO), which possesses a new strategy to update the increased pheromone, called ant-weight strategy, and a mutation operation, to solve VRP. The computational results for fourteen benchmark problems are reported and compared to those of other metaheuristic approaches. 2008 Elsevier B.V. All rights reserved.