Miracle-dz/UniFAR-FTUs huggingface dataset:
A unique mechanism of β-blocker action: Carvedilol stimulates β-arrestin signaling

For many years, β-adrenergic receptor antagonists (β-blockers or βAR antagonists) have provided significant morbidity and mortality benefits in patients who have sustained acute myocardial infarction. More recently, β-adrenergic receptor antagonists have been found to provide survival benefits in patients suffering from heart failure, although the efficacy of different β-blockers varies widely in this condition. One drug, carvedilol, a nonsubtype-selective βAR antagonist, has proven particularly effective in the treatment of heart failure, although the mechanism(s) responsible for this are controversial. Here, we report that among 16 clinically relevant βAR antagonists, carvedilol displays a unique profile of in vitro signaling characteristics. We observed that in β2 adrenergic receptor (β2AR)-expressing HEK-293 cells, carvedilol has inverse efficacy for stimulating Gs-dependent adenylyl cyclase but, nonetheless, stimulates (i) phosphorylation of the receptor's cytoplasmic tail on previously documented G protein-coupled receptor kinase sites; (ii) recruitment of β-arrestin to the β2AR; (iii) receptor internalization; and (iv) activation of extracellular regulated kinase 1/2 (ERK 1/2), which is maintained in the G protein-uncoupled mutant β2ART68F,Y132G,Y219A (β2ARTYY) and abolished by β-arrestin2 siRNA. Taken together, these data indicate that carvedilol is able to stabilize a receptor conformation which, although uncoupled from Gs, is nonetheless able to stimulate β-arrestin-mediated signaling. We hypothesize that such signaling may contribute to the special efficacy of carvedilol in the treatment of heart failure and may serve as a prototype for a new generation of therapeutic β2AR ligands.
UNI ScholarWorks UNI ScholarWorks

Emotion regulation is a concept that has existed within the literature for decades, but the presence of emotion regulation programs in schools is a relatively new concept in research (Durlak et al., 2011). Research suggests that emotional regulation skills are related to improved peer relationships and academic success (Denham & Brown, 2010; Durlak et al., 2011). Students who exhibited well-adjusted, or adaptive, emotion regulation had better peer relationships and were more productive and accurate when completing academic tasks (Denham & Brown, 2010; Dvir et al., 2014; Kim & Cicchetti, 2010; Kim‐Spoon et al., 2013; Lereya et al., 2015). For this reason, many schools have implemented programs designed to teach students adaptive emotion regulation strategies (Dingle et al., 2016; Hammond et al., 2009; Houck
Relationship between microRNA expression levels and histopathological features of dysplasia in oral leukoplakia.

BACKGROUND Increased expression of microRNAs (miRNAs), miR-21, miR-345, and miR-181b has been demonstrated in oral leukoplakia (OL) that progresses to oral squamous cell carcinoma (OSCC), suggesting a miRNA signature with potential prognostic value. On the basis of these findings, this pilot study aimed to investigate the cytological and histopathological features that are used to grade oral dysplasia and determine associations with the expression of these 3 potentially cancer-related miRNAs. We also compared the expression levels of these miRNAs in OL with normal oral mucosa and OSCC. METHODS We evaluated miRNA expression by qPCR in 22 samples of OL demonstrating different grades of dysplasia, as well as 17 cases of OSCC, and 6 samples of normal oral mucosa. We associated the miRNAs expression profiles with cytological and histopathological features of OL. RESULTS OSCC cases showed increased expression of all 3 miRNAs when compared with OL and normal oral mucosa. Increased expression of miR-21 was also observed in OL when compared with normal oral mucosa. We found a higher expression of miR-21 and miR-181b in OL that presented with an increased number of mitotic figures, increased nuclear/cytoplasmic ratio, or hyperchromasia. Increased expression of miR-21 was also detected in OL with abnormally superficial mitosis. Higher expression of miR-345 was observed in OL with an increased number and size of nucleoli or increased nuclear/cytoplasmic ratio. CONCLUSIONS In conclusion, the present study shows that some cytological and histopathological parameters used to grade dysplasia are associated with altered miRNA expression.
Harmony and Discord in Endothelial Calcium Entry

Harmony and Discord in Endothelial Calcium Entry To The Editor: This letter addresses the recent report by Abdullaev et al.1 In 2006, the seminal work of Feske and colleagues2 identified membrane proteins that were named Orais, after the Greek keepers of Heaven’s gate: Harmony (Orai1), Justice (Orai2), and Peace (Orai3). The proteins emerged through a study of severe combined immune deficiency (SCID), which is caused by a defect in Ca entry of T lymphocytes. A mutation in the Orai1 gene underlies the defect. There has been particular interest in Orais because of their relationship with the widely occurring store-operated Ca -entry (SOCE) phenomena, which reflect Ca -permeable plasma membrane mechanisms that respond to the depletion status of endoplasmic reticular Ca stores. In lymphocytes, the storeoperated mechanism is commonly observed as a Ca -selective and inwardly rectifying current, ICRAC. The mechanism is defective in SCID and rescued by expression of wild-type Orai1.2 In predicted structure Orais belong to the tetraspanin protein family3 rather than resembling known ion channels but mutations in Orais modify ion-selectivity, suggesting Orais generate ion permeation.4
The Regulation of Sleep

Insomnia is rightly regarded as one of the marks of an over­ wrought or worried nervous system, and conversely we may take it that sound sleep lasting for a reasonable period, say from six to nine hours in the case of adults, is a fair test of nervous com­ petence. Various accidental causes may temporarily interfere with sleep in the healthy; but still the rule holds good, and a normal brain reveals its condition by obedience to this daily rhythmic variation. Custom can do much to contract one’s nat­ ural term of sleep, a fact of which we are constantly reminded in these days of high pressure; but the process is too artificial to be freely employed. Laborious days with scanty intervals of rest go far to secure all the needful conditions of insomnia. In allot­ ting hours of sleep it is impossible to adopt any maxim or uniform custom. The due allowance varies with the individual. Age, constitution, sex, fatigue, exercise, each has its share of influence. Young persons and hard workers naturally need and should have more sleep than those who neither grow nor labor. Women have by common consent been assigned a longer period of rest than men, and this argument, in the event of their doing hard work, is in strict accord with their generally lighter phys­ ical construction and recurrent infirmities. Absolute rule there is none, and it is of little moment to fix an exact average allow­ ance, provided the recurrence of sleep be regular, and its amount sufficient for the needs of a given person, so that fatigue does not result in such nerve prostration and irritability as to render healthy rest altogether impossible. —London Lancet.
Pseudocnoside A, a new cytotoxic and antiproliferative triterpene glycoside from the sea cucumber Pseudocnus dubiosus leoninus

A new triterpene glycoside, pseudocnoside A (1), was isolated from the sea cucumber Pseudocnus dubiosus leoninus. The structure of the new compound was established on the basis of extensive NMR spectroscopic analysis (1H and 13C NMR, 1H,1H-COSY, HMBC, HSQC, TOCSY and NOESY), HR-ESI-MS data and chemical transformations. In addition, the cytotoxicity and antiproliferative activities of 1 and structurally related triterpene glycosides isolated from the sea cucumbers Psolus patagonicus and Hemioedema spectabilis were evaluated against cancer cell lines A-549 and HeLa.
Mechanics of post-fusion exocytotic vesicle

Exocytosis is an important cellular process controlled by metabolic signaling. It involves vesicle fusion to the plasma membrane, followed by the opening of a fusion pore, and the subsequent release of the vesicular lumen content into the extracellular space. While most modeling efforts focus on the events leading to membrane fusion, how the vesicular membrane remodels after fusing to plasma membrane remains unclear. This latter event dictates the nature and the efficiency of exocytotic vesicular secretions, and is thus critical for exocytotic function. We provide a generic membrane mechanical model to systematically study the fate of post-fusion vesicles. We show that while membrane stiffness favors full-collapse vesicle fusion into the plasma membrane, the intravesicular pressure swells the vesicle and causes the fusion pore to shrink. Dimensions of the vesicle and its associated fusion pore further modulate this mechanical antagonism. We systematically define the mechanical conditions that account for the full spectrum of the observed vesicular secretion modes. Our model therefore can serve as a unified theoretical framework that sheds light on the elaborate control mechanism of exocytosis.
Plant Wax n‐Alkane and n‐Alkanoic Acid Signatures Overprinted by Microbial Contributions and Old Carbon in Meromictic Lake Sediments

Specific n‐alkanes and n‐alkanoic acids are commonly used as biomarkers in paleoenvironmental reconstruction, yet any individual homologue may originate from multiple biological sources. Here we improve source and age controls for these compounds in meromictic systems by measuring the radiocarbon (14C) ages of specific homologues preserved in twentieth century Lake Pavin (France) sediments. In contrast to many studies, 14C ages generally decreased with increasing carbon chain length, from 7.3 to 2.6 ka for the C14‐C30 n‐alkanoic acids and from 9.2 to 0.3 ka for the C21‐C33 n‐alkanes. Given a known hard water effect, these values suggest that aquatic microbial sources predominate and contributed to most of the homologues measured. Only the longest chain n‐alkanes exclusively represent inputs of higher plant waxes, which were previously sequestered in soils over centennial to millennial timescales prior to transport and deposition. These findings suggest that biomarker source and age should be carefully established for lacustrine settings.
Measurement of Agriculture-Related Air Pollutant Emissions using Point and Remote Sensors

70 Introduction . 71 Materials and Methods . 74 Results and Discussion . 84 Conclusions . 98 Acknowledgments . 99 References . 100 IV. PARTICULATE MATTER EMISSIONS ESTIMATES FROM AGRICULTURAL SPRING TILLAGE OPERATIONS USING LIDAR AND INVERSE MODELING . 103 Abstract . 103 Introduction . 104 Methodology . 107 Results and Discussion . 129 Conclusions . 149 Acknowledgments . 150 References . 151 V. AMMONIA MEASUREMENTS AND EMISSIONS FROM A CALIFORNIA DAIRY USING POINT AND REMOTE SENSORS . 157 Abstract . 157 Introduction . 158 Materials and Methods . 160 Results and Discussion . 185 Conclusions . 209 Acknowledgments . 210 References . 211 VI. USING A DEPOSITION-ENABLED BACKWARD LAGRANGIAN STOCHASTIC MODEL TO ESTIMATE PARTICULATE MATTER AREA SOURCE EMISSIONS THROUGH INVERSE MODELING . 217 Abstract . 217 ix Page Introduction . 218 Model Formulation . 222 Model Testing . 230 Results and Discussion . 241 Conclusions . 257 Acknowledgments . 259 References . 259 VII. CONCLUSIONS . 264 VIII. ENGINEERING SIGNIFICANCE . 269 APPENDICES . 271 Appendix A: Data . 272 Appendix B: Journal Copyright Releases . 273 Appendix C: Permission-to-Use Letters . 280 Appendix D: List of Acronyms and Symbols . 296 Appendix E: Vitae . 303
Conversion of a single-facility pediatric antimicrobial stewardship program to multi-facility application with computerized provider order entry and clinical decision support

Summary Objective: Antimicrobial stewardship programs (ASPs) help meet quality and safety goals with regard to antimicrobial use. Prior to CPOE implementation, the ASP at our pediatric tertiary hospital developed a paper-based order set containing recommendations for optimization of dosing. In adapting our ASP for CPOE, we aimed to preserve consistency in our ASP recommendations and expand ASP expertise to other hospitals in our health system. Methods: Nine hospitals in our health system adopted pediatric CPOE and share a common domain (Cerner Millenium™). ASP clinicians developed sixty individual electronic order sets (vendor reference PowerPlans™) to be used independently or as part of larger electronic order sets. Analysis of incidents reported during CPOE implementation and medication variances reports was used to determine the effectiveness of the ASP adaptation. Results: 769 unique PowerPlans™ were used 15,889 times in the first 30 days after CPOE implementation. Of these, 43 were PowerPlans™ included in the ASP design and were used a total of 1149 times (7.2% of all orders). During CPOE implementation, 437 incidents were documented, 1.1% of which were associated with ASP content or workflow. Additionally, analysis of medication variance following CPOE implementation showed that ASP errors accounted for 2.9% of total medication variances. Discussion: ASP content and workflow accounted for proportionally fewer incidents than expected as compared to equally complex and frequently used CPOE content. Conclusions: Well-defined ASP recommendations and modular design strengthened successful CPOE implementation, as well as the adoption of specialized pediatric ASP expertise with other facilities. Citation: Webber EC, Warhurst HM, Smith SS, Cox EG, Crumby AS, Nichols KR. Conversion of a single-facility pediatric antimicrobial stewardship program to multifacility application with computerized provider order entry and clinical decision support. Appl Clin Inf 2013; 4: 556–568 http://dx.doi. org/10.4338/ACI-2013-07-RA-0054
Gene Expression Profiling in BRAF-Mutated Melanoma Reveals Patient Subgroups with Poor Outcomes to Vemurafenib That May Be Overcome by Cobimetinib Plus Vemurafenib

Purpose: The association of tumor gene expression profiles with progression-free survival (PFS) outcomes in patients with BRAFV600-mutated melanoma treated with vemurafenib or cobimetinib combined with vemurafenib was evaluated. Experimental Design: Gene expression of archival tumor samples from patients in four trials (BRIM-2, BRIM-3, BRIM-7, and coBRIM) was evaluated. Genes significantly associated with PFS (P < 0.05) were identified by univariate Cox proportional hazards modeling, then subjected to unsupervised hierarchical clustering, principal component analysis, and recursive partitioning to develop optimized gene signatures. Results: Forty-six genes were identified as significantly associated with PFS in both BRIM-2 (n = 63) and the vemurafenib arm of BRIM-3 (n = 160). Two distinct signatures were identified: cell cycle and immune. Among vemurafenib-treated patients, the cell-cycle signature was associated with shortened PFS compared with the immune signature in the BRIM-2/BRIM-3 training set [hazard ratio (HR) 1.8; 95% confidence interval (CI), 1.3–2.6, P = 0.0001] and in the coBRIM validation set (n = 101; HR, 1.6; 95% CI, 1.0–2.5; P = 0.08). The adverse impact of the cell-cycle signature on PFS was not observed in patients treated with cobimetinib combined with vemurafenib (n = 99; HR, 1.1; 95% CI, 0.7–1.8; P = 0.66). Conclusions: In vemurafenib-treated patients, the cell-cycle gene signature was associated with shorter PFS. However, in cobimetinib combined with vemurafenib-treated patients, both cell cycle and immune signature subgroups had comparable PFS. Cobimetinib combined with vemurafenib may abrogate the adverse impact of the cell-cycle signature. Clin Cancer Res; 23(17); 5238–45. ©2017 AACR.
Physiology of the small intestine after resection and transplant

Purpose of reviewRecent studies have evaluated intestinal physiology following bowel resection; understanding changes in small bowel physiology after intestinal transplantation has received less attention. In this review, we will examine recent studies focused on changes in intestinal physiology following resection and intestinal transplantation. Recent findingsAbsorption, immunity, and motility are fundamental components of small bowel physiology. Absorption after resection or transplantation is mediated by adaptation and enterocyte function. After resection, adaptation results in increased villus height and crypt depth. Hepatocyte growth factor and epidermal growth factors cause enterocyte hypertrophy and hyperplasia, allowing greater peptide uptake. Little is known about intestinal adaptation after transplant, but enteral autonomy is attainable. Immunity in small bowel after transplantation relies on a balance of innate and adaptive immune responses in the presence of the luminal microbiota. Intraepithelial lymphocytes are decreased following small bowel resection. After small bowel transplant, the number and the ratio of intraepithelial lymphocytes to enterocytes, as well as changes in the microbiota, can be used to identify rejection. After intestinal transplant, immune-mediated dysmotility is common. Perioperative infliximab in addition to tacrolimus may decrease the inflammation that contributes to dysmotility. SummaryAs intestinal transplantation becomes more successful, understanding how absorption, immunity, and motility changes will allow for optimization of bowel function.
The effect of the 1992 California motorcycle helmet use law on motorcycle crash fatalities and injuries.

OBJECTIVE To determine the effects of the California motorcycle helmet use law on statewide fatalities and a large sample of nonfatal injuries before and after law implementation. DESIGN Police reports and death certificates were collected for motorcycle crash fatalities in California for 1991 (prelaw) and 1992 (postlaw). Official counts of registered motorcycles provided a statewide basis for exposure to a motorcycle crash. Autopsy results were collected for fatalities in 11 counties. Hospital records were reviewed for nonfatal injuries in 28 hospitals in 10 of the 11 counties. Police reports were linked to injury data for the riders. SUBJECTS AND PATIENTS A total of 850 fatalities and injury data for 547 fatally injured riders and 3252 nonfatally injured patients. MAIN OUTCOME MEASURES Changes in number and rates among statewide fatalities were estimated. The number and pattern of head injuries in fatally and nonfatally injured motorcycle riders were evaluated. RESULTS After implementation of the helmet use law, statewide motorcycle crash fatalities decreased by 37.5%, from 523 fatalities in 1991 to 327 in 1992, more than 37%, and an estimated 92 to 122 fatalities were prevented. Motorcycle fatality rates were reduced by 26.5%, from 70.1 per 100,000 registered motorcycles in 1991 to 51.5 per 100,000 in 1992. Head injuries decreased significantly among both fatally and nonfatally injured motorcyclists. CONCLUSION Enactment of an unrestricted helmet law significantly reduces the incidence of motorcycle crash fatalities and the number and severity of head injuries.
Five-year trajectories of social networks and social support in older adults with major depression

ABSTRACT Background: Research with nondepressed adults suggests that social networks and social support are stable over the life course until very late age. This may not hold true for older adults with depression. We examined baseline status and trajectories of social networks and social support at the group and individual levels over five years. Methods: The sample consisted of 339 initially depressed adults aged 59 or older (M = 69 years) enrolled in a naturalistic study of depression. Measures of social ties, including social network size, frequency of interaction, instrumental support, and subjective support, were administered at baseline and yearly for five years. Results: Latent growth curve models were estimated for each aspect of social ties. On average, social network size and frequency of interaction were low at baseline and remained stable over time, whereas subjective and instrumental support were high at baseline yet increased over time. There was significant variation in the direction and rate of change over time, which was not predicted by demographic or clinical factors. Conclusions: Because increasing social networks may be ineffective and may not be possible for a portion of people who already receive maximal support, interventions to increase social support may only work for a portion of older depressed adults.
AB0/Rhesus Blood Group Does Not Influence Clinicopathological Tumor Characteristics or Oncological Outcome in Patients Undergoing Radical Prostatectomy

Objectives AB0 blood group is an inherited characteristic that has been associated with the incidence as well as the prognosis of several malignancies. The aim of the current study was to clarify the role of the blood group in cancer epidemiology and clinical outcome of patients with prostate cancer (PCa). Methods Data from 3,574 patients undergoing radical prostatectomy between 2009 and 2010 at a single European institution were retrospectively analyzed. The correlation of AB0 and Rhesus blood group with PCa-related characteristics and oncological outcome were evaluated using univariable and multivariable Cox proportional hazard models. Results Median follow-up was 36.9 months. The overall distributions of AB0, as well as Rhesus blood groups among patients with PCa, did not differ from the distribution observed in the normal population. There was no significant association between AB0/Rhesus blood groups and Gleason score, prostate volume, surgical margin, pT-stage, pN-status, or preoperative prostate-specific antigen level. In multivariable Cox regression analysis, no statistically significant correlation between AB0/Rhesus group and biochemical recurrence was observed (all p > 0.05). Conclusion Our data suggest no relevant association of AB0/Rhesus blood group with adverse clinicopathological tumor characteristics or oncological outcome after surgery in contrast to several other malignancies.
PET-CT guided curative conformal radiation therapy in limited stage small cell lung cancer.

BACKGROUND The prognosis of small cell lung cancer (SCLC) has been improving with the advances in diagnostic and therapeutic modalities. Positron emission tomography/computed tomography (FDG-PET/CT) which has been studied in non-small cell lung cancer (NSCLC) for a long time, and it has only recently been applied to SCLC. Therefore we sought to observe firstly the prognostic importance of the FDG uptake in limited disease small cell lung cancer (LD-SCLC) patients and secondly the clinical outcomes and toxicity profiles of LD-SCLC patients treated with conformal radiation therapy (RT) using FDG-PET/CT simulation. METHODS Between 2009 and 2011, 33 LD-SCLC patients with LD-SCLC underwent disease staging using FDG-PET/CT conformal RT. Thoracic radiation was administered at a daily fraction of 2 Gy. Total dose was prescribed according to the treatment protocol such as, concurrent or sequential chemotherapy and in some patients according to the response of CT. All patients underwent chemotherapy. Survival was estimated using the Kaplan-Meier method. RESULTS The median age of the patients was 58 years (range, 38-77 years). The median follow-up time was 20 months (range, 6.6-47.6 months). The 3-year overall survival (OS) and locoregional control rates were 23% and 48%, respectively. CONCLUSIONS There are few studies examining the impact of PET-CT and the prognostic significance of FDG-uptake on outcomes in patients with LD-SCLC. Higher RT doses in response to higher FDG uptake may be safely applied for the purpose of locoregional control.