bluuebunny/crossref_metadata_2025 huggingface dataset:
HPV73 a nonvaccine type causes cervical cancer
Authors: Amaro‐Filho Sergio M. , Gradissimo Ana , Usyk Mykhaylo , Moreira Fabio C.B. , de Almeida Liz M. , Moreira Miguel A.M. , Burk Robert D.
Published: April 2019

HPV73 is classified as possibly oncogenic. It is neither routinely evaluated in HPV screening, nor covered by any of the prophylactic vaccines. We sought to investigate the carcinogenic characteristics of HPV73. Molecular studies were performed on eight cervix cancer biopsy specimens containing HPV73 from a cross‐sectional cancer cohort of 590 women referred to the National Cancer Institute in Rio de Janeiro, Brazil. Transcriptional activity of HPV73 was evaluated by detection of spliced transcripts of E6/E6* and E1^E4 in cDNA created from RNA isolated from fresh tissue. Disruption of viral E1 and E2 genes in the tumor DNA was assessed by overlapping PCR amplification. Evaluation of viral integration was performed using a customized capture panel and next‐generation sequencing, and an in‐house bioinformatic pipeline. HPV73 E6/E6* transcripts were found in 7/7 specimens with available RNA, and three also had HPV73 E1^E4 transcripts. Disruption of E1 and E2 genes was observed in 4/8 specimens. Integration of HPV73 sequences into the cancer cell genomes was identified in all cervix cancer tissues. These results provide evidence that HPV73 is an oncogenic virus that can cause invasive cervix cancer. With current molecular screening and HPV vaccination, not all cervix cancers will be prevented.
PARP inhibition by olaparib alleviates chronic asthma‐associated remodeling features via modulating inflammasome signaling in mice
Authors: Sethi Gurupreet S. , Sharma Sukriti , Naura Amarjit S.
Published: April 2019

Despite the reported role of poly(ADP‐ribose) polymerase (PARP) in asthma inflammation, its contribution during remodeling is not clearly known. The main aim of the current investigation was to examine the potential of olaparib, a pharmacological inhibitor of PARP against airway remodeling using an ovalbumin (OVA)‐based murine model of chronic asthma. The results demonstrated that post‐challenge olaparib treatment (5 mg/kg i.p., 30 min after OVA exposure) for six weeks (3 days/week) attenuates inflammation, mucus production, and collagen deposition in lungs. Additionally, olaparib blunted the protein expression of STAT‐6 and GATA‐3 considerably along with a modest reduction in p65‐NF‐κB phosphorylation. Furthermore, olaparib normalized the OVA‐induced redox imbalance as reflected by data on reactive oxygen species, malondialdehyde, protein carbonyls, and reduced glutathione/oxidized glutathione ratio. Interestingly, the protection offered by olaparib was further linked with the altered level of NLRP3 inflammasome‐mediated IL‐1β release and consequent expression of its downstream targets matrix metalloproteinase‐9 and transforming growth factor beta. Suppressed collagen deposition in the lungs correlates well with the reduced expression of vimentin upon olaparib treatment. Finally, olaparib restored the expression of histone deacetylase 2, a steroid‐responsive element in asthma. Overall, results suggest that olaparib prevents OVA‐induced airway inflammation as well as remodeling via modulating inflammasome signaling in mice. © 2019 IUBMB Life, 1–11, 2019
Family physician perceptions of the role and value of the clinical pharmacist in the management of patients with type 2 diabetes
Authors: Harmes Kathryn M. , Shih Elizabeth , Plegue Melissa , Shultz Cameron , Diez Heidi L.
Published: April 2019

Purpose

Clinical pharmacists can help primary care physicians (PCPs) manage medications for patients with poorly controlled type 2 diabetes. Studies have shown that clinical pharmacist involvement in care can improve outcomes such as glycosylated hemoglobin (A1C), blood pressure and lipid control, and decrease episodes of hypoglycemia. Despite these findings, some PCPs may be slow or disinclined to refer to clinical pharmacists when available. This study addressed PCP perceptions regarding referral to clinical pharmacists and endocrinologists for patients with poorly controlled type 2 diabetes.

Methods

Physicians from five family medicine sites were surveyed. Physicians were queried regarding their patterns for patient referral to endocrinologists and/or clinical pharmacists. Clinical contributions and importance of factors to consider when referring were compared between clinical pharmacists and endocrinologists using paired t tests.

Results

Fifty physicians responded to the survey, resulting in a response rate of 73.5%. The majority of PCPs indicated that they have referred to endocrinologists (89.5%) and clinical pharmacists (93.5%) for specialty care. PCPs tended to refer to clinical pharmacists sooner and at lower A1C values than to endocrinologists. PCPs also considered multiple medical comorbidities, history of noncompliance with medical recommendations, low reading ability or math skills, complex psychosocial situations, fear of needles, or difficulty affording medications or supplies to be more important when referring patients to clinical pharmacists than endocrinologists.

Conclusion

We hypothesized that referrals to a clinical pharmacist or endocrinologist are made with careful consideration of the patients' needs. PCPs reported increased utilization of clinical pharmacists for patients with nonmedical needs, indicating that extra time, education, and psychosocial support provided by the clinical pharmacist is highly valued.
A novel screening method for transition metal‐based anticancer compounds using zebrafish embryo‐larval assay and inductively coupled plasma‐mass spectrometry analysis
Authors: Karas Brittany F. , Côrte‐Real Leonor , Doherty Cathleen L. , Valente Andreia , Cooper Keith R. , Buckley Brian T.
Published: April 2019

As novel metallodrugs continue to emerge, they are evaluated using models, including zebrafish, that offer unique sublethal endpoints. Testing metal‐based anticancer compounds with high‐throughput zebrafish toxicological assays requires analytical methods with the sensitivity to detect these sublethal tissue doses in very small sample masses (e.g., egg mass 100 μg). A robust bioanalytical model, zebrafish embryos coupled with inductively coupled plasma‐mass spectrometry (ICPMS) for measurement of delivered dose, creates a very effective means for screening metal‐based chemotherapeutic agents. In this study, we used ICPMS quantitation with the zebrafish embryo assays to detect metal equivalents at multiple response endpoints for two compounds, the chemotherapeutic agent cisplatin and ruthenium (Ru)‐based prospective metallodrug, PMC79. We hypothesized that cisplatin and PMC79 have different mechanisms for inducing apoptosis and result in similar lesions but different potencies following water‐borne exposure. An ICPMS method was developed to detect the metal in waterborne solution and tissue (detection limit: 5 parts per trillion for Ru or platinum [Pt]). The Ru‐based compound was more potent (LC50: 7.8 μm) than cisplatin (LC50: 158 μm) and induced disparate lesions. Lethality from cisplatin exposure exhibited a threshold (values >15 mg/L) while no threshold was observed for delayed hatching (lowest observed adverse effect level 3.75 mg/L cisplatin; 8.7 Pt (ng)/organism). The Ru organometallic did not have a threshold for lethality. Cisplatin‐induced delayed hatching was investigated further by larval‐Pt distribution and preferentially distributed to the chorion. We propose that zebrafish embryo‐larval assays coupled with ICPMS serve as a powerful platform to evaluate relative potency and toxic effects of metallodrug candidates.
Metabolic control by dehydroascorbic acid: Questions and controversies in cancer cells
Authors: Ferrada Luciano , Salazar Katterine , Nualart Francisco
Published: April 2019

For a long time, the effect of vitamin C on cancer cells has been a controversial concept. From Linus Pauling's studies in 1976, it was proposed that ascorbic acid (AA) could selectively kill tumor cells. However, further research suggested that vitamin C has no effect on tumor survival. In the last decade, new and emerging functions for vitamin C have been discovered using the reduced form, AA, and the oxidized form, dehydroascorbic acid (DHA), independently. In this review, we summarized the latest findings related to the effects of DHA on the survival and metabolism of tumor cells. At the same time, we put special emphasis on the bystander effect and the recycling capacity of vitamin C in various cellular models, and how these concepts can affect the experimentation with vitamin C and its therapeutic application in the treatment against cancer.
A Phase 1 Mass Balance Study of 14C‐Labeled Talazoparib in Patients With Advanced Solid Tumors
Authors: Yu Yanke , Chung Chin‐Hee , Plotka Anna , Quinn Kevin , Shi Haihong , Pápai Zsuzsanna , Nguyen Linh , Wang Diane
Published: April 2019

This paper describes the pharmacokinetics (PK), mass balance, metabolic profiling, and safety of talazoparib after a single oral dose of 14C‐talazoparib in 6 patients with advanced solid tumors. Patients were aged ≥18 years, with a histologically confirmed advanced solid tumor at screening. A single 1‐mg dose of talazoparib oral solution supplemented with 100 µCi of 14C‐labeled talazoparib was administered. Blood, urine, and feces samples were collected at various time points and analyzed for talazoparib and 14C radioactivity. Metabolic profiling and identification were also carried out. Mean recovery of 14C radioactivity was 68.7% in urine and 19.7% in feces. Talazoparib was minimally metabolized. Renal excretion of unchanged talazoparib was a major route of elimination, with mean recovery of 54.6% of the administered dose, whereas fecal excretion of talazoparib was limited, with mean recovery of 13.6% of the administered dose. No major metabolites of talazoparib were identified in plasma, and no metabolites that individually represented more than 10% of the administered dose were recovered in urine or feces. The concentration‐time profiles of unchanged talazoparib, total 14C radioactivity in plasma, and total 14C radioactivity in whole blood were similar, with a median time at peak concentrations of 30 minutes and mean half‐life of 89.8, 96.2, and 77.6 hours, respectively. Talazoparib was minimally metabolized, and renal excretion of unchanged talazoparib was the major route of elimination.
Inverse Association of Fibrates and Liver Cancer: A Population‐Based Case‐Control Study in Taiwan
Authors: Li I‐Hsun , Shih Jui‐Hu , Tsai Chien‐Sung , Chien Wu‐Chien , Kao Hui‐Han , Pan Ke‐Ting , Cheng Yih‐Dih , Kao Li‐Ting
Published: April 2019

This large‐scale case‐control study in Taiwan elucidated the potential connection between fibrate use and liver cancer by using the Longitudinal Health Insurance Database 2005 with a propensity‐score–matching design. In total, 4173 patients diagnosed as having liver cancer were included as cases, and 4173 propensity‐score–matched patients without liver cancer were identified as controls. The association between previous fibrate use and liver cancer occurrence was demonstrated using conditional logistic regression. Fibrate use was noted in 371 (8.89%) cases and 481 (11.53%) controls. After adjustments, the cases had significantly lower odds of previous fibrate use than did the controls (adjusted odds ratio 0.70, 95%CI 0.60‐0.82); moreover, regardless of the patients’ sex, age group, and comorbidities, the cases were less likely to have used fibrates than were the controls. Dose‐dependent analysis revealed that 1‐695 cumulative defined daily doses of fibrates may significantly induce a protective effect for liver cancer. Although other fibrate dose intervals did not reach statistical significance, the dose‐response curve presented the trend of a protective effect for liver cancer among the fibrate users. In summary, fibrate use had a significant protective effect against liver cancer in this Asian population.
Understanding the present and preparing for the future: Exploring the needs of diagnostic and elective genomic medicine patients
Authors: East Kelly M. , Cochran Meagan , Kelley Whitley V. , Greve Veronica , Emmerson Kristina , Raines Grace , Cochran Jesse Nicholas , Hott Adam M. , Bick David
Published: April 2019

Advances in genomic knowledge and technology have increased the use of comprehensive clinical sequencing tests. Genome sequencing has established utility for diagnosing patients with rare, undiagnosed diseases as well as interest in an elective context, without a clinical indication for testing. The Smith Family Clinic for Genomic Medicine, LLC in Huntsville, AL is a private practice genomic medicine clinic caring for both diagnostic (79%) and elective (21%) patients. Diagnostic and elective patients are seen on a clinical basis and receive standard care. Genome sequencing is provided on a self‐pay basis, with assistance available for diagnostic patients who have financial need. Here, we describe demographics and motivations of the distinct patient populations and our experiences engaging patients in online education. Diagnostic patients were motivated by the possibility of receiving an explanation for symptoms (96%) while elective patients were motivated by the chance to learn about future disease risk (57%). Elective patients were less likely to engage with online education, with only 28% reading all assigned topics compared to 54% of diagnostic patients. Understanding the needs, interests, and barriers unique to diagnostic and elective patients is critical to inform individualized and scalable best practices in patient education and engagement.
Thermodynamics‐based modelling of gas chromatography separations across column geometries and systems, including the prediction of peak widths
Authors: Stevenson Keisean A. J. M. , Harynuk James J.
Published: April 2019

Thermodynamics‐based models have been demonstrated to be useful for predicting retention time and peak widths in gas chromatography and two‐dimensional gas chromatography separations. However, the collection of data to train the models can be time consuming, which lessens the practical utility of the method. In this contribution, a method for obtaining thermodynamic‐based data to predict peak widths in temperature‐programmed gas chromatography is presented. Experimental work to collect data for peak width prediction is identical to that required to collect data for retention time prediction using approaches that we have presented previously. Using this combined approach, chromatograms including retention times and peak widths are predicted with very high accuracy. Typical errors in retention time are < 0.5%, while errors in peak width are typically < 5% as demonstrated using polycycic aromatic hydrocarbons and a mixture containing compounds with aldehyde, ketone, alkene, alkane, alcohol, and ester functionalities.
Spatial variation in the biochemical and isotopic composition of corals during bleaching and recovery
Authors: Wall Christopher B. , Ritson‐Williams Raphael , Popp Brian N. , Gates Ruth D.
Published: April 2019

Ocean warming and the increased prevalence of coral bleaching events threaten coral reefs. However, the biology of corals during and following bleaching events under field conditions is poorly understood. We examined bleaching and postbleaching recovery in Montipora capitata and Porites compressa corals that either bleached or did not bleach during a 2014 bleaching event at three reef locations in Kāne‘ohe Bay, O‘ahu, Hawai‘i. We measured changes in chlorophylls, tissue biomass, and nutritional plasticity using stable isotopes (δ13C, δ15N). Coral traits showed significant variation among periods, sites, bleaching conditions, and their interactions. Bleached colonies of both species had lower chlorophyll and total biomass, and while M. capitata chlorophyll and biomass recovered 3 months later, P. compressa chlorophyll recovery was location dependent and total biomass of previously bleached colonies remained low. Biomass energy reserves were not affected by bleaching, instead M. capitata proteins and P. compressa biomass energy and lipids declined over time and P. compressa lipids were site specific during bleaching recovery. Stable isotope analyses did not indicate increased heterotrophic nutrition in bleached colonies of either species, during or after thermal stress. Instead, mass balance calculations revealed that variations in δ13C values reflect biomass compositional change (i.e., protein : lipid : carbohydrate ratios). Observed δ15N values reflected spatiotemporal variability in nitrogen sources in both species and bleaching effects on symbiont nitrogen demand in P. compressa. These results highlight the dynamic responses of corals to natural bleaching and recovery and identify the need to consider the influence of biomass composition in the interpretation of isotopic values in corals.
Direct Fabrication of Nanodomes‐Combined Surface Relief Gratings on Azobenzene Polymer Films with Controlled Shapes and Sizes
Authors: Kim Kang‐Han , Lee Yong Min , Ryou Myung‐Hyun , Jeong Yong‐Cheol
Published: April 2019

In this study, we present nanodomes‐combined surface relief gratings (SRGs) of azopolymer films with controlled shapes and sizes. We investigate the effect of the polarization mode of light interference on leading nanodomes in the conventional SRG patterns. In addition, we also systematically study the relationship between Bragg distance of light interference and shapes of nanodomes. From this, we explain the anisotropic self‐assembled behavior nanodomes in photoaddressable azopolymer films regarding polarization modes as well as spatial confinement effect. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2019, 57, 731–737
Quantitative risk assessment of a natural gas pipeline in an underground utility tunnel
Authors: Fang Weipeng , Wu Jiansong , Bai Yiping , Zhang Laobing , Reniers Genserik
Published: April 2019

With rapid urbanization in China, many underground utility tunnels have been established these years. This huge underground construction facilitates city life, but may introduce societal risks due to the installation of high‐risk pipelines. Natural gas pipelines have the potential to cause catastrophic accident if a gas leakage and a subsequent explosion occurs. The potential hazards in the gas compartments of a utility tunnel are quite different from those in conventional directly buried gas pipelines. This study developed a dynamic quantitative risk analysis method for natural gas pipelines in a utility tunnel. First, potential accident scenarios of natural gas pipelines situated in a utility tunnel were identified and implemented in a Bow‐tie diagram based on case studies of typical gas pipeline accidents and expert experience. Then, a Bayesian network was established from the Bow‐tie diagram using a mapping algorithm. Based on a comprehensive analysis of the results of probability updating and sensitivity analysis, critical influencing factors were identified. The proposed framework provides a predictive analysis of the gas pipeline accident evolution process from causes to consequences and examines key challenges in gas pipeline risk management in utility tunnels. © 2019 American Institute of Chemical Engineers Process Saf Prog: e12051 2019
Performance of anti‐Müllerian hormone (AMH) levels measured by Beckman Coulter Access AMH assay to predict oocyte yield following controlled ovarian stimulation for in vitro fertilization
Authors: Asada Yoshimasa , Tsuiki Miyako , Sonohara Megumi , Fukunaga Noritaka , Hattori Yukio , Inoue Daichi , Ito Rie , Hashiba Yoshiki
Published: April 2019

Purpose

We evaluated the performance of anti‐Müllerian hormone (AMH) measured by the Beckman Coulter fully automated Access assay to predict oocyte yield following controlled ovarian stimulation (COS) for in vitro fertilization (IVF).

Methods

The correlation between the Access assay and the pre‐mixing method with Generation II ELISA assay (Gen II pre‐mix assay) was assessed using 230 blood samples. The relationship of AMH level measured by the Access assay and the actual number of oocytes retrieved following COS was assessed using 3296 IVF cycles. The performances of AMH, follicle stimulating hormone (FSH), and estradiol (E2) in predicting the responses to COS were also evaluated by constructing receiver operating characteristic (ROC) curves.

Results

The AMH levels measured just before oocyte retrieval by the Access assay and the number of oocytes retrieved following COS showed a good correlation with R = 0.655. The ROC analysis revealed that the sensitivity of AMH was comparable with or lower than that of E2 but higher than that of FSH.

Conclusions

With the improved Access AMH assays, AMH was as sensitive as E2 and could become an accurate marker of ovarian response to COS in more than 3000 Japanese IVF patients.
Bone Marrow Mesenchymal Stromal Cell Treatment in Patients with Osteoarthritis Results in Overall Improvement in Pain and Symptoms and Reduces Synovial Inflammation
Authors: Chahal Jaskarndip , Gómez-Aristizábal Alejandro , Shestopaloff Konstantin , Bhatt Shashank , Chaboureau Amélie , Fazio Antonietta , Chisholm Jolene , Weston Amanda , Chiovitti Julia , Keating Armand , Kapoor Mohit , Ogilvie-Harris Darrell J. , Syed Khalid A. , Gandhi Rajiv , Mahomed Nizar N. , Marshall Kenneth W. , Sussman Marshall S. , Naraghi Ali M. , Viswanathan Sowmya
Published: April 2019

Patients with late-stage Kellgren-Lawrence knee osteoarthritis received a single intra-articular injection of 1, 10, or 50 million bone marrow mesenchymal stromal cells (BM-MSCs) in a phase I/IIa trial to assess safety and efficacy using a broad toolset of analytical methods. Besides safety, outcomes included patient-reported outcome measures (PROMs): Knee Injury and Osteoarthritis Outcome Score (KOOS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC); contrast-enhanced magnetic resonance imaging (MRI) for cartilage morphology (Whole Organ MRI Scores [WORMS]), collagen content (T2 scores), and synovitis; and inflammation and cartilage turnover biomarkers, all over 12 months. BM-MSCs were characterized by a panel of anti-inflammatory markers to predict clinical efficacy. There were no serious adverse events, although four patients had minor, transient adverse events. There were significant overall improvements in KOOS pain, symptoms, quality of life, and WOMAC stiffness relative to baseline; the 50 million dose achieved clinically relevant improvements across most PROMs. WORMS and T2 scores did not change relative to baseline. However, cartilage catabolic biomarkers and MRI synovitis were significantly lower at higher doses. Pro-inflammatory monocytes/macrophages and interleukin 12 levels decreased in the synovial fluid after MSC injection. The panel of BM-MSC anti-inflammatory markers was strongly predictive of PROMs over 12 months. Autologous BM-MSCs are safe and result in significant improvements in PROMs at 12 months. Our analytical tools provide important insights into BM-MSC dosing and BM-MSC reduction of synovial inflammation and cartilage degradation and provide a highly predictive donor selection criterion that will be critical in translating MSC therapy for osteoarthritis. Stem Cells Translational Medicine  2019;8:746–757
Cryo‐EM‐On‐a‐Chip: Custom‐Designed Substrates for the 3D Analysis of Macromolecules
Authors: Alden Nick A. , Varano A. Cameron , Dearnaley William J. , Solares Maria J. , Luqiu William Y. , Liang Yanping , Sheng Zhi , McDonald Sarah M. , Damiano John , McConnell Jennifer , Dukes Madeline J. , Kelly Deborah F.
Published: April 2019

The fight against human disease requires a multidisciplinary scientific approach. Applying tools from seemingly unrelated areas, such as materials science and molecular biology, researchers can overcome long‐standing challenges to improve knowledge of molecular pathologies. Here, custom‐designed substrates composed of silicon nitride (SiN) are used to study the 3D attributes of tumor suppressor proteins that function in DNA repair events. New on‐chip preparation strategies enable the isolation of native protein complexes from human cancer cells. Combined techniques of cryo‐electron microscopy (EM) and molecular modeling reveal a new modified form of the p53 tumor suppressor present in aggressive glioblastoma multiforme cancer cells. Taken together, the findings provide a radical new design for cryo‐EM substrates to evaluate the structures of disease‐related macromolecules.
Chemical Confinement and Utility of Lithium Polysulfides in Lithium Sulfur Batteries
Authors: Tang Tianyu , Hou Yanglong
Published: April 2019

Lithium sulfur (Li–S) batteries featuring abundant resources and cost‐efficiency are regarded as a promising next‐generation energy storage system with high theoretical capacity and energy density. However, several drawbacks impede the development of Li–S batteries, especially the shuttle effects of soluble lithium polysulfides (LiPS) which lead to severe capacity decay and short cycling lifespan. Though the existence of LiPS can result in performance decline and battery failure, the management of the LiPS should be balanced. This review focuses on both sides of the LiPS. One is the confinement of LiPS by chemical interactions between novel cathode hosts with LiPS, another is the utility of the LiPS in Li–S batteries with stable performance. Ultimately, the future developments and prospects of Li–S batteries are discussed.
Frequency Dependent Fatigue Strength Investigations on Tempered Steel and Nodular Cast Iron
Authors: Thumann Philipp , Marburg Steffen , Meinhardt Josef , Saubiez Jean‐Marc , Hoogen Michael , Suck Bertram , Wagner Marcus
Published: April 2019

This paper presents experimental fatigue tests on specially shaped specimens made from quenched and tempered steel 42CrMoS4 and nodular cast iron EN‐GJS‐600‐3. The specimens are geometrically designed to resemble actual subcomponents of forming and cutting dies for sheet metal manufacturing. These subcomponents have failed in the past.Experiments are carried out using a fictive load‐time function, which is a modification of an actually measured load curve and has variable mean and amplitude values. This first test series serves as a general validation of a subsequent fatigue analysis. A second test series is carried out with constant mean and amplitude values with a load ratio . Here, the load frequencies in the individual test runs are varied between f = 5 Hz and f = 45 Hz in order to investigate the influence of the frequency. Both series are performed on a servo‐hydraulic testing machine.The experimental data is then statistically evaluated. The values for the scatter correlate with data from the literature. The data from the test series with the fictive load‐time function can thus be used for subsequent validation of a fatigue calculation, which will be addressed in a future publication. Most significant are the findings from the second series of experiments with varied load frequencies, as a significant frequency influence could be detected. Furthermore, the hardening and softening behavior under cyclic loading and the fracture behavior of the materials are analyzed and compared with data from the literature.
Development and validation of a scientific (formal) reasoning test for college students
Authors: Kalinowski Steven T. , Willoughby Shannon
Published: April 2019

We present a multiple‐choice test, the Montana State University Formal Reasoning Test (FORT), to assess college students' scientific reasoning ability. The test defines scientific reasoning to be equivalent to formal operational reasoning. It contains 20 questions divided evenly among five types of problems: control of variables, hypothesis testing, correlational reasoning, proportional reasoning, and probability. The test development process included the drafting and psychometric analysis of 23 instruments related to formal operational reasoning. These instruments were administered to almost 10,000 students enrolled in introductory science courses at American universities. Questions with high discrimination were identified and assembled into an instrument that was intended to measure the reasoning ability of students across the entire spectrum of abilities in college science courses. We present four types of validity evidence for the FORT. (a) The test has a one‐dimensional psychometric structure consistent with its design. (b) Test scores in an introductory biology course had an empirical reliability of 0.82. (c) Student interviews confirmed responses to the FORT were accurate indications of student thinking. (d) A regression analysis of student learning in an introductory biology course showed that scores on the FORT predicted how well students learned one of the most challenging concepts in biology, natural selection.
Evolutionary journey and characterisation of a novel pan‐gene associated with beer strains of Saccharomyces cerevisiae
Authors: Vakirlis Nikolaos , Monerawela Chandre , McManus Gavin , Ribeiro Orquidea , McLysaght Aoife , James Tharappel , Bond Ursula
Published: April 2019

The sequencing of over a thousand Saccharomyces cerevisiae genomes revealed a complex pangenome. Over one third of the discovered genes are not present in the S. cerevisiae core genome but instead are often restricted to a subset of yeast isolates and thus may be important for adaptation to specific environmental niches. We refer to these genes as “pan‐genes,” being part of the pangenome but not the core genome.

Here, we describe the evolutionary journey and characterisation of a novel pan‐gene, originally named hypothetical (HYPO) open‐reading frame. Phylogenetic analysis reveals that HYPO has been predominantly retained in S. cerevisiae strains associated with brewing but has been repeatedly lost in most other fungal species during evolution. There is also evidence that HYPO was horizontally transferred at least once, from S. cerevisiae to Saccharomyces paradoxus. The phylogenetic analysis of HYPO exemplifies the complexity and intricacy of evolutionary trajectories of genes within the S. cerevisiae pangenome.

To examine possible functions for Hypo, we overexpressed a HYPO‐GFP fusion protein in both S. cerevisiae and Saccharomyces pastorianus. The protein localised to the plasma membrane where it accumulated initially in distinct foci. Time‐lapse fluorescent imaging revealed that when cells are grown in wort, Hypo‐gfp fluorescence spreads throughout the membrane during cell growth. The overexpression of Hypo‐gfp in S. cerevisiae or S. pastorianus strains did not significantly alter cell growth in medium‐containing glucose, maltose, maltotriose, or wort at different concentrations.
Inactivation of the uptake hydrogenase in the purple non-sulfur photosynthetic bacterium Rubrivivax gelatinosus CBS enables a biological water–gas shift platform for H2 production
Authors: Eckert Carrie A , Freed Emily , Wawrousek Karen , Smolinski Sharon , Yu Jianping , Maness Pin-Ching
Published: April 2019

Biological H2 production has potential to address energy security and environmental concerns if produced from renewable or waste sources. The purple non-sulfur photosynthetic bacterium Rubrivivax gelatinosus CBS produces H2 while oxidizing CO, a component of synthesis gas (Syngas). CO-linked H2 production is facilitated by an energy-converting hydrogenase (Ech), while a subsequent H2 oxidation reaction is catalyzed by a membrane-bound hydrogenase (MBH). Both hydrogenases contain [NiFe] active sites requiring 6 maturation factors (HypA-F) for assembly, but it is unclear which of the two annotated sets of hyp genes are required for each in R. gelatinosus CBS. Herein, we report correlated expression of hyp1 genes with Ech genes and hyp2 expression with MBH genes. Moreover, we find that while Ech H2 evolving activity is only delayed when hyp1 is deleted, hyp2 deletion completely disrupts MBH H2 uptake, providing a platform for a biologically driven water–gas shift reaction to produce H2 from CO.
Reputation as a Disciplinarian of International Organizations
Authors: Daugirdas Kristina
Published: April 2019

As a disciplinarian of international organizations, reputation has serious shortcomings. Even though international organizations have strong incentives to maintain a good reputation, reputational concerns will sometimes fail to spur preventive or corrective action. Organizations have multiple audiences, so efforts to preserve a “good” reputation may pull organizations in many different directions, and steps taken to preserve a good reputation will not always be salutary. Recent incidents of sexual violence by UN peacekeepers in the Central African Republic illustrate these points.
HCJ 3003/18 Yesh Din – Volunteers for Human Rights v. Chief of General Staff, Israel Defense Forces (IDF)
Authors: Shereshevsky Yahli
Published: April 2019

In Yesh Din v. Chief of General Staff, IDF, the Israeli Supreme Court (Court) unanimously dismissed two petitions by six human rights NGOs who challenged the rules of engagement (RoE) governing Israel Defense Forces (IDF) activities in clashes near the fence separating the Gaza Strip and Israel between March and May 2018. The decision discusses several controversial international law issues relating to the use of force in response to cross-border mass demonstrations. In addition, it provides a closer look at the application of international law by a domestic court that is conscious of a potential International Criminal Court (ICC) investigation.
Approaching Sacred Space
Authors: Bokser Baruch M.
Published: April 2019

Jonathan Z. Smith, in discussing the transformation of the notion of sacred space in Judaism and the shift from a “locative” type of religious activity to one not limited to a fixed place, points to the necessity “to take history … seriously” and to examine closely how that transformation took place. We can take up this charge and illuminate the larger processes at work by focusing on the narrower problem of the proper protocol required when approaching sacred space. This will enable us to see how the postbiblical tradition revises, while at the same time it preserves, the biblical model of a sacred center.
From Af Abet to Shire: the defeat and demise of Ethiopia's ‘Red’ Army 1988–89
Authors: Tareke Gebru
Published: April 2019

Within a period of just a year during the late 1980s, the Ethiopian Revolutionary or ‘Red’ Army suffered serious defeat in both Eritrea and Tigray. Although numerically and technically superior to its opponents, dissension in the army's ranks, political meddling from Addis Ababa, loss of will, and the remarkable skill and determination of its opponents prevented it from achieving victory. Two years after its humiliating defeat in Tigray, the army collapsed, and the military regime it had sustained disappeared. Eritrea succeeded in declaring its independence and the Tigrayan rebels seized power in Ethiopia. This article demonstrates that the Eritrean and Tigrayan forces ultimately won because they had grass-roots support and because they were able to back each other militarily and politically. In the meantime, the dictatorship in Addis Ababa was losing popular support as its ‘citizens’ were no longer willing to make the sacrifices that were necessary to continue the struggle. Only by considering these points can we appreciate why Africa's second-largest army was annihilated or, conversely, why the insurgents triumphed, for their success was not inevitable.
Behaviour of the shrimp ectosymbionts, Peregrinamor ohshimai (Mollusca: Bivalvia) and Phyllodurus sp. (Crustacea: Isopoda) through host ecdyses
Authors: Itani Gyo , Kato Makoto , Shirayama Yoshihisa
Published: April 2019

The behaviour of two ectosymbiotic animals, Peregrinamor ohshimai (a bivalve attached to the ventral cephalothorax of the host), and Phyllodurus sp. (a bopyrid isopod attached to the second pleopod of the host), during ecdyses of the host thalassinidean Upogebia shrimps was studied by time-lapse video of infested shrimps. In the intermoult stages of the hosts, both ectosymbionts did not move. However they moved on to the newly emerged body of the host at the time when the host moulted. Peregrinamor ohshimai began to move just after the host started moulting, whereas Phyllodurus sp. moved prior to ecdysis of the host and waited near the fissure from which the newly moulted body emerges first. There are highly correlated morphological relationships between the symbionts and the hosts. It is suggested that both ectosymbionts grow with the same host individuals after infection, keeping morphological affinity with their hosts without being discarded during ecdyses of the hosts.
The surface characteristics of pedal mucus: a potential aid to the settlement of marine organisms?
Authors: Holmes Sebastian P. , Cherrill Andrew , Davies Mark S.
Published: April 2019

Surface characteristics including wettability, thickness and adhesive potential of the pedal mucus produced by Patella vulgata and Littorina littorea were measured, to determine their effects on the settlement of marine organisms. The pedal mucus produced by P. vulgata was less wettable than that produced by L. littorea. For organisms that prefer to settle on hydrophobic substrata the pedal mucus produced by P. vulgata would be their preferred settlement site. The pedal mucus produced by stationary P. vulgata was thicker (mean thickness±SE=0·37±0·004 mm) than the pedal mucus produced by mobile P. vulgata and/or that produced by L. littorea, neither of which differed in their thickness (mean thickness±SE =0·10±0·01 mm).  The pedal mucus produced by P. vulgata had a greater adhesive potential (mean force of adhesion for the size range of mimics examined=3715–5380 Nm2) than the pedal mucus produced by L. littorea (mean force of adhesion for the size range of mimics examined=2846–3361 Nm2). Comparison of the adhesive potential of the pedal mucuses with a pedal mucus analogue, silicon grease, suggests that the pedal mucuses function as a Stefan (1874) adhesive when adhering organisms.
Reverie and the Return to Nature: Rousseau's Experience of Convergence
Authors: Lane Joseph H.
Published: April 2019

In this essay, I explore some connections between Rousseau's works and modern environmental works in which the author experiences what Rousseau characterizes as “reverie,” the blissful loss of consciousness of the self in the awareness that the self is truly only part of the all-encompassing whole, “Nature.” While others have recognized that Rousseau's writings share much of the form and substance of later nature writing, no one has explored how Rousseau's work helps us understand the character of nature writing as a genre of political thought. Based on a careful reading of some key passages from the Reveries and comparisons to the writings of Thoreau, I argue that Rousseau's peculiar approach to his own self-consciousness provides a key for understanding the character of writings of this sort and the limits that are always present within them. Environmentalists must reflect on Rousseau's suggestion “that the price paid for experiencing anything is the experience of ourselves as alienated.”
Cost of lipid lowering in patients with coronary artery disease by Case Method Learning
Authors: Kiessling Anna , Zethraeus Niklas , Henriksson Peter
Published: April 2019

Objectives:This investigation was undertaken to study the costs of a Case Method Learning (CML) -supported lipid-lowering strategy in secondary prevention of coronary artery disease (CAD) in primary care.

Methods:This prospective randomized controlled trial in primary care with an additional external specialist control group in Södertälje, Stockholm County, Sweden, included 255 consecutive patients with CAD. Guidelines were mailed to all general practitioners (GPs; n=54) and presented at a common lecture. GPs who were randomized to the intervention group participated in recurrent CML dialogues at their primary health-care centers during a 2-year period. A locally well-known cardiologist served as a facilitator. Assessment of low-density lipoprotein (LDL) cholesterol was performed at baseline and after 2 years. Analysis according to intention-to-treat—intervention and control groups (n=88)—was based on group affiliation at baseline. The marginal cost of lipid lowering comprised increased cost of lipid-lowering drugs in the intervention group compared with the primary care control group, cost of attendance of the GP's in the intervention group, and cost of time for preparation, travel, and seminars of the facilitator. Costs are as of 2002 with an exchange rate 1 US$=9.5 SEK (Swedish Crowns).

Results:Patients in the primary care intervention group had their LDL cholesterol reduced by 0.5 (confidence interval [CI], 0.1–0.9) mmol/L compared with the primary care control group (p<.05). No change occurred in controls. LDL cholesterol in the external specialist control group decreased by 0.6 (CI, 0.4–0.8) mmol/L. The cost of the educational intervention represented only 2 percent of the drug cost. The cost of lipid lowering in the intervention group, including the cost of the educational intervention, was actually lower than that of patients treated at the specialist clinic—106 US$ per mmol decrease in LDL cholesterol in the intervention group and 153 US$ per mmol decrease in LDL cholesterol in the specialist group. EuroQol 5D Index, which gives an estimate of global health-related quality of life, was 0.80 (CI, 0.75–0.85) in the present cohort.

Conclusions:The additional cost of CML was only 2 percent of the drug cost. Assuming the same gain in life expectancy per millimole decrease in LDL cholesterol as in the 4S-study gives a cost per gained quality-adjusted life year of US$ 24,000. This finding indicates that the CML-supported lipid-lowering strategy is cost-effective. The low cost of CML in primary care should probably warrant its use in the improvement of the quality of care in other major chronic diseases.
Data validation in an economic evaluation of surgery for colon cancer
Authors: Janson Martin , Carlsson Per , Haglind Eva , Anderberg Bo
Published: April 2019

Objectives:This study aimed to validate the accuracy of data retrieved in a prospective multicenter trial, the purpose of which was an economic evaluation of two techniques of surgery for colon cancer.

Methods:Within the Swedish contribution of the COLOR trial (Colon Cancer Open or Laparoscopic Resection), an economic evaluation of open versus laparoscopic surgical techniques was conducted. Data were collected by case record forms (CRF), patient diaries, and telephone surveys every 2 weeks. The study period was 12 weeks, and the perspective was societal. Data from the first consecutive forty patients to complete the health economic study protocol were validated. Retrieved data were compared with data from medical records and data from local social security offices for agreement.

Results:Statistically significant differences were found for duration of anesthesia, length of surgery, number of outpatient consultations by doctors and district nurses, complication rate, and the use of central venous lines. No significant differences were observed concerning length of hospital stay, disposable instruments cost, and time off work, all of which heavily influence total costs.

Conclusions:The present method of data collection regarding resources used in this setting seems to produce accurate data for economic evaluation; however, relative to complication rates, the method did not retrieve accurate data.
CO2 Inflow and Elements Desorption Prior to a Seismic Sequence, Amatrice‐Norcia 2016, Italy
Authors: Boschetti T. , Barbieri M. , Barberio M. D. , Billi A. , Franchini S. , Petitta M.
Published: April 2019

The 2016 Mw ≥ 6.0 Amatrice‐Norcia earthquakes (central Apennines, Italy) and the related seismic sequence were associated with increases in arsenic and vanadium concentrations recorded in groundwater springs a few months before the earthquakes occurred. To evaluate these signals as reliable seismic precursors and effective predictive tools, we studied the geochemical processes that caused these anomalies. Using chemical and isotope models, we show that increased concentrations of arsenic and vanadium, a slight increase in boron concentrations, and a concomitant lowering of the boron isotope ratio may be due to mineral desorption (e.g., from iron oxides and/or clays). We argue that a displacing effect on the trace elements sorbed on minerals was triggered by an excess of deep CO2 in groundwater, which occurred prior to the main seismic event as a result of preseismic crustal dilation. Our observations confirm the pivotal role of CO2 in the release of trace elements by alteration of solid phases and provide a new understanding of earthquake‐related water chemical anomalies.
Unraveling the Origins of a Record-Setting Marine Heat Wave
Authors: Cook Terri
Published: April 2019

The extreme heat wave in the southwestern Atlantic in 2017 was likely caused by upper atmosphere circulation patterns triggered by the Madden-Julian Oscillation tropical weather cycle.
The fishery performance indicators for global tuna fisheries
Authors: McCluney Jessica K. , Anderson Christopher M. , Anderson James L.
Published: April 2019

We characterize the ecological, economic, and community performance of 21 major tuna fisheries, accounting for at least 77% of global tuna production, using the Fishery Performance Indicators. Our analysis reveals that the biggest variations in performance among tuna fisheries are driven by the final markets that they target: international sashimi market tuna fisheries considerably outperform a comparison set of 62 non-tuna fisheries in the Fishery Performance Indicator database, international canned tuna market fisheries perform similarly to the comparison set, and tuna fisheries supplying local markets in coastal states considerably underperform the comparison set. Differences among regional fishery management organizations primarily reflect regional species composition and market access, despite stark variation in governance, management, and other enabling conditions. With a legacy of open access, tuna’s harvest sector performance is similar across all fisheries, reflecting only a normal return on the capital and skill invested: industrial vessels slightly outperform semi-industrial and artisanal vessels. Differences emerge in the post-harvest sector however, as value chains able to preserve quality and transport fish to high value markets outperform others.
KIBRA controls exosome secretion via inhibiting the proteasomal degradation of Rab27a
Authors: Song Lin , Tang Shi , Han Xiaolei , Jiang Ziying , Dong Lingling , Liu Cuicui , Liang Xiaoyan , Dong Jixin , Qiu Chengxuan , Wang Yongxiang , Du Yifeng
Published: April 2019

Exosomes are nanosized membrane vesicles released from cells after fusion of multivesicular bodies (MVBs) with the plasma membrane (PM) and play important roles in intercellular communication and numerous biological processes. However, the molecular mechanisms regulating exosome secretion remain poorly understood. Here we identify KIBRA as an adaptor-like protein that stabilizes Rab27a, which in turn controls exosome secretion both in vitro and in vivo. Knockdown or overexpression of KIBRA in neuronal and podocyte cell lines leads to a decrease or increase of exosome secretion, respectively, and KIBRA depletion increases MVB size and number. Comparing protein profiles between KIBRA knockout and wild-type mouse brain showed significantly decreased Rab27a, a small GTPase that regulates MVB-PM docking. Rab27a is stabilized by interacting with KIBRA, which prevents ubiquitination and degradation via the ubiquitin-proteasome pathway. In conclusion, we show that KIBRA controls exosome secretion via inhibiting the proteasomal degradation of Rab27a.