bluuebunny/crossref_metadata_2025 huggingface dataset:
A computational pipeline to predict cardiotoxicity: From the atom to the rhythm
Authors: Yang Pei-Chi , DeMarco Kevin R. , Aghasafari Parya , Jeng Mao-Tsuen , Noskov Sergei Y. , Yarov-Yarovoy Vladimir , Vorobyov Igor , Clancy Colleen E.
Published: May 2019

We simulate and predict cardiotoxicity over multiple temporal and spatial scales from the drug chemistry to the cardiac rhythm.

Drug-induced proarrhythmia is so tightly associated with prolongation of the QT interval that QT prolongation has become widely accepted as a surrogate marker for arrhythmia. The problem is that QT interval as an arrhythmia indicator is too sensitive and not selective, resulting in many potentially useful drugs eliminated early in the drug discovery process. We first set out to predict the fundamental mode of binding for the proarrhythmic drug dofetilide with the promiscuous cardiac drug target, the hERG potassium channel. In a novel linkage between the atomistic and functional scales, computed binding affinities and rates from atomistic simulation are utilized here to parameterize function scale kinetic models of dofetilide interactions with the hERG channel. The kinetic model components are then integrated into predictive models at the cell and tissue scales to expose fundamental arrhythmia vulnerability mechanisms and complex interactions underlying emergent behaviors. Human clinical data from published studies were used to validate model framework and showed excellent agreement, demonstrating feasibility of the approach. The model predictions show that a clinically relevant dose of dofetilide increased arrhythmia vulnerability in all emergent TRIaD-linked parameters including Triangulation, Reverse use-dependence, beat-to-beat Instability and temporal and spatial action potential duration Dispersion. Application of machine learning demonstrated redundancy in the TRIaD linked parameters and suggested that changes in beat-to-beat instability were highly predictive of arrhythmia vulnerability in this setting. Here, we demonstrate the development and validation of a prototype multiscale model framework to predict electro-toxicity in the heart for the proarrhythmic drug dofetilide from the atom to the rhythm.

SIGNIFICANCE STATEMENT

Cardiotoxicity in the form of deadly abnormal rhythms is one of the most common and dangerous risks for drugs in development and clinical use. There is an urgent need for new approaches to screen and predict the effects of chemically similar drugs on the cardiac rhythmandto move beyond the QT interval as a diagnostic indicator for arrhythmia. To this end, we present a computational pipeline to predict cardiotoxicity over multiple temporal and spatial scales from the drug chemistry to the cardiac rhythm. We utilize predicted quantitative estimates of ion channel-drug interactions from our companion paper to simulate cardiotoxicity over multiple temporal and spatial scales from the drug chemistry to the cardiac rhythm.
The mineralization characteristics of organic carbon and particle composition analysis in reconstructed soil with different proportions of soft rock and sand
Authors: Guo Zhen , Han Jichang , Xu Yan , Tian Chang , Shi Chendi , Ge Lei , Li Juan , Cao Tingting
Published: May 2019

The organic carbon mineralization process can reflect the release intensity of soil CO2. Therefore, the study of organic carbon mineralization and particle composition analysis of soft rock and sand compound soil can provide technical support and theoretical basis for the theory of soil organic reconstruction. Based on the previous research, this paper mainly selected four typical treatments of 0:1 (CK), 1:5 (C1), 1:2 (C2) and 1:1 (C3), respectively, and analyzed the soil organic carbon mineralization process and particle composition by lye absorption method, laser particle size meter and scanning electron microscope. The results showed that there was no significant difference in organic carbon content between C1, C2 and C3 treatments, but they were significantly higher than CK treatment (P < 0.05). The organic carbon mineralization rate of each treatment accords with a logarithmic function throughout the culture period (P < 0.01), which can be divided into a rapid decline phase of 1-11 days and a steady decline phase of 11-30 days. The cumulative mineralization amount on the 11th day reached 54.96%-74.44% of the total mineralization amount. At the end of the culture, the cumulative mineralization and potential mineralizable organic carbon content of C1 and C2 treatments were significantly higher than those of CK treatment, and the cumulative mineralization rate was also the lowest with C1 and C2 treatment. The turnover rate constant of soil organic carbon in each treatment was significantly lower than that of CK treatment, and the residence time increased. With the increase of volume fraction of soft rock, the content of silt and clay particles increases gradually, the texture of soil changes from sandy soil to sandy loam, loam and silty loam, and because of the increase of small particles, the structure of soil appears to collapse when the volume ratio of soft rock was 50%. In summary, the ratio of soft rock to sand volume was 1:5-1: 2, which can effectively increased the accumulation of soil organic carbon. At this time, the distribution of soil particles was more uniform, the soil structure was stable, and the mineralization level of unit organic carbon was lower. The research results have practical significance for the large area popularization of soft rock and sand compound technology.
Patient experience: determinants and manifestations
Authors: Zakkar Moutasem
Published: May 2019

Purpose

Patient experience is a complex multidimensional phenomenon that has been linked to constructs that are also complex to conceptualize, such as patient-centeredness, patient expectations and patient satisfaction. The purpose of this paper is to shed light on the different dimensions of patient experience, including those that receive inadequate attention from policymakers such as the patient’s lived experience of illness and the impact of healthcare politics. The paper proposes a simple classification for these dimensions, which differentiates between two types of dimensions: the determinants and the manifestations of patient experience.

Design/methodology/approach

This paper uses a narrative review of the literature to explore select constructs and initiatives developed for theorizing or operationalizing patient experience. Literature topics reviewed include healthcare quality, medical anthropology, health policy, healthcare system and public health.

Findings

The paper identifies five determinants for patient experience: the experience of illness, patient’s subjective influences, quality of healthcare services, health system responsiveness and the politics of healthcare. The paper identifies two manifestations of patient experience: patient satisfaction and patient engagement.

Originality/value

The paper proposes a classification scheme of the dimensions of patient experience and a concept map that links together heterogeneous constructs related to patient experience. The proposed classification and the concept map provide a holistic view of patient experience and help healthcare providers, quality managers and policymakers organize and focus their healthcare quality improvement endeavors on specific dimensions of patient experience while taking into consideration the other dimensions.
Privacy engineering for learning analytics in a global market
Authors: Hoel Tore , Chen Weiqin
Published: May 2019

Purpose

Privacy is a culturally universal process; however, in the era of Big Data privacy is handled very differently in different parts of the world. This is a challenge when designing tools and approaches for the use of Educational Big Data (EBD) and learning analytics (LA) in a global market. The purpose of this paper is to explore the concept of information privacy in a cross-cultural setting to define a common point of reference for privacy engineering.

Design/methodology/approach

The paper follows a conceptual exploration approach. Conceptual work on privacy in EBD and LA in China and the west is contrasted with the general discussion of privacy in a large corpus of literature and recent research. As much of the discourse on privacy has an American or European bias, intimate knowledge of Chinese education is used to test the concept of privacy and to drive the exploration of how information privacy is perceived in different cultural and educational settings.

Findings

The findings indicate that there are problems using privacy concepts found in European and North-American theories to inform privacy engineering for a cross-cultural market in the era of Big Data. Theories based on individualism and ideas of control of private information do not capture current global digital practice. The paper discusses how a contextual and culture-aware understanding of privacy could be developed to inform privacy engineering without letting go of universally shared values. The paper concludes with questions that need further research to fully understand information privacy in education.

Originality/value

As far as the authors know, this paper is the first attempt to discuss – from a comparative and cross-cultural perspective – information privacy in an educational context in the era of Big Data. The paper presents initial explorations of a problem that needs urgent attention if good intentions of privacy supportive educational technologies are to be turned into more than political slogans.
Rock elasticity as a function of the uniaxial stress: laboratory measurements and theoretical modelling of vertical transversely isotropic and orthorhombic shales
Authors: Sviridov V.A. , Mayr S.I. , Shapiro S.A.
Published: May 2019

We apply a rock‐physics model that describes the relationship between the effective stress and rock elasticity. We experimentally obtain and analyse a data set containing one vertical transversely isotropic and one orthorhombic shale sample. The vertical transversely isotropic symmetry of the first sample is caused by the layered structure of the rock. The seismic orthorhombicity of the second sample could be explained after microscopic analysis of thin section, which demonstrates an imperfect disorder of inhomogeneities. Both samples were loaded uniaxially in a quasi‐static regime. During the loading, we measured stress‐dependent seismic velocities and sample deformations. For the analysis of the stress‐dependent velocities and stiffnesses, we modelled the measured data set using a recent generalization of the porosity deformation approach. Comparison of the experimentally determined and numerically modelled data supports the applicability of the theory and helps in the interpretation of experimentally obtained data. In agreement with the theory, uniaxial stress increases the elliptic component of the seismic anisotropy and does not impact the anellipticity parameter. We demonstrate the distinct influence of the stiff and compliant porosities on the stress sensitivity of the elastic properties.
Integrated metabolic strategy: A framework for predicting the evolution of carbon‐water tradeoffs within plant clades
Authors: Goud Ellie M. , Sparks Jed P. , Fishbein Mark , Agrawal Anurag A.
Published: May 2019

The fundamental tradeoff between carbon gain and water loss has long been predicted as an evolutionary driver of plant strategies across environments. Nonetheless, challenges in measuring carbon gain and water loss in ways that integrate over leaf lifetime have limited our understanding of the variation in and mechanistic bases of this tradeoff. Furthermore, the microevolution of plant traits within species versus the macroevolution of strategies among closely related species may not be the same, and accordingly, the latter must be addressed using comparative phylogenetic analyses.

Here we introduce the concept of ‘integrated metabolic strategy’ (IMS) to describe the ratio between carbon isotope composition (δ13C) and oxygen isotope composition above source water (Δ18O) of leaf cellulose. IMS is a measure of leaf‐level conditions that integrate several mechanisms contributing to carbon gain (δ13C) and water loss (Δ18O) over leaf lifespan, with larger values reflecting higher metabolic efficiency and hence less of a tradeoff. We tested how IMS evolves among closely related yet ecologically diverse milkweed species, and subsequently addressed phenotypic plasticity in response to water availability in species with divergent IMS.

Integrated metabolic strategy varied strongly among 20 Asclepias species when grown under controlled conditions, and phylogenetic analyses demonstrate species‐specific tradeoffs between carbon gain and water loss. Larger IMS values were associated with species from dry habitats, with larger carboxylation capacity, smaller stomatal conductance and smaller leaves; smaller IMS was associated with wet habitats, smaller carboxylation capacity, larger stomatal conductance and larger leaves. The evolution of IMS was dominated by changes in species’ demand for carbon (δ13C) more so than water conservation (Δ18O). Although some individual physiological traits showed phylogenetic signal, IMS did not.

In response to experimental decreases in soil moisture, three species maintained similar IMS across levels of water availability because of proportional increases in δ13C and Δ18O (or little change in either), while one species increased IMS due to disproportional changes in δ13C relative to Δ18O.

Synthesis. IMS is a broadly applicable mechanistic tool; IMS variation among and within species may shed light on unresolved questions relating to the evolution and ecology of plant ecophysiological strategies.
How Busyness Influences SEC Compliance Activities: Evidence from the Filing Review Process and Comment Letters
Authors: Gunny Katherine A. , Hermis Judith M.
Published: May 2019

The SEC reviews firm filings and issues comment letters on those filings. These comment letters play an important role in the assessment of firm value. These activities are seasonally compressed because over 70 percent of registrants have a December fiscal year‐end. Research in other settings finds that busyness leads to negative outcomes. We examine how busyness impacts the frequency, scope, and timeliness of comment letters. We find that the SEC issues fewer comment letters when busy, focuses its limited resources on the most severe cases of disclosure noncompliance, and extends the amount of time between receiving a firm's filing and issuing a comment letter. Despite this, we find no evidence that the SEC misses more serious compliance issues when busy. Our results have implications for policymakers responsible for allocating resources to the SEC.
A comparative analysis of common methods to identify waterbird hotspots
Authors: Sussman Allison L. , Gardner Beth , Adams Evan M. , Salas Leo , Kenow Kevin P. , Luukkonen David R. , Monfils Michael J. , Mueller William P. , Williams Kathryn A. , Leduc‐Lapierre Michele , Zipkin Elise F.
Published: May 2019

Hotspot analysis is a commonly used method in ecology and conservation to identify areas of high biodiversity or conservation concern. However, delineating and mapping hotspots is subjective and various approaches can lead to different conclusions with regard to the classification of particular areas as hotspots, complicating long‐term conservation planning.

We present a comparative analysis of recent approaches for identifying waterbird hotspots, with the goal of developing insights about the appropriate use of these methods. We selected four commonly used measures to identify persistent areas of high use: kernel density estimation, Getis‐Ord Gi*, hotspot persistence and hotspots conditional on presence, which represent the range of quantitative hotspot estimation approaches used in waterbird analyses. We applied each of the methods to aerial survey waterbird count data collected in the Great Lakes from 2012–2014. For each approach, we identified areas of high use for seven species/species groups and then compared the results across all methods and to mean effort‐corrected counts.

Our results indicate that formal hotspot analysis frameworks do not always lead to the same conclusions. The kernel density and Getis‐Ord Gi* methods yielded the most similar results across all species analysed and were generally correlated with mean effort‐corrected count data. We found that these two models can differ substantially from the hotspot persistence and hotspots conditional on presence estimation approaches, which were not consistently similar to one another. The hotspot persistence approach differed most significantly from the other methods but is the only method to explicitly account for temporal variation.

We recommend considering the ecological question and scale of conservation or management activities prior to designing survey methodologies. Deciding the appropriate definition and scale for analysis is critical for interpretation of hotspot analysis results as is inclusion of important covariates. Combining hotspot analysis methods using an integrative approach, either within a single analysis or post hoc, could lead to greater consistency in the identification of waterbird hotspots.
The rationale of dose–response curves in selecting cancer drug dosing
Authors: Martin Jennifer H. , Dimmitt Simon
Published: May 2019

Drug development for cancer chemotherapy has an interesting history. A mix of serendipity, animal, cell line, and standard pharmacological principles of dose, dose‐response, dose‐concentration, dose intensity and combination therapies have been used to develop optimal dosing schedules. However in practice, significant gaps in the translation of preclinical to clinical dosing schedules persist, and clinical development has instead moved to new drug development. A older chemotherapies are still the backbone of most solid tumour schedules, therapeutic drug monitoring has emerged as a method for optimising the dose for individual patients.
Body of evidence and approaches applied in the clinical development programme of fixed‐dose combinations in the European Union from 2010 to 2016
Authors: Nøhr‐Nielsen Asbjørn , De Bruin Marie Louise , Thomsen Mikael , Pipper Christian Bressen , Lange Theis , Bjerrum Ole Jannik , Lund Trine Meldgaard
Published: May 2019

Aims

To provide insights into the clinical development pathway for fixed‐dose combinations (FDCs), to consider strategies, and to elucidate the path to approval by assessing the body of evidence, as summarized in the European Public Assessment Reports.

Methods

The main resource was the European Public Assessment Reports for 36 FDCs, which included 239 clinical trials with 157 514 patients. The analyses focused on how prior knowledge of the active substances or combination, use of pharmacokinetic–pharmacodynamic modelling, and clinical trial design choice impact the size and strategy of the clinical development programme.

Results

FDC products primarily comprised 2 previously approved components (21/36, 71%) and had only 1 approved combination (21/36, 71%). Utilizing previously approved active substances resulted in fewer clinical trials, arms and patients, but FDC doses studied in the clinical development programme. Furthermore, dose‐finding trials were performed for less than half of FDCs consisting of 2 previously approved active substances. The standard approach to demonstrate contribution of active substances was through a factorial or single combination study. Finally, the use of pharmacokinetic modelling showed a significant decrease in the number of FDC doses studied.

Conclusions

The field of FDCs seems to be on the rise, utilizing new molecular entities, prior knowledge and re‐profiling drugs. However, a way to move FDC development forward might be through new regulatory and scientific paradigms, in which it is encouraged to utilize model‐based approaches to develop FDCs with multiple dose levels and dose ratios for exposure‐based treatment that will enable personalization.
Ursodeoxycholic acid accelerates bile acid enterohepatic circulation
Authors: Zhang Yunjing , Jiang Runqiu , Zheng Xiaojiao , Lei Sha , Huang Fengjie , Xie Guoxiang , Kwee Sandi , Yu Herbert , Farrar Christine , Sun Beicheng , Zhao Aihua , Jia Wei
Published: May 2019

Background and Purpose

Ursodeoxycholic acid (UDCA) is the first‐line treatment for primary biliary cholangitis, but its effects on the enterohepatic circulation of bile acid (BA) have been under‐investigated. Therefore, we studied the influence of UDCA on BA enterohepatic circulation in vivo and the mechanisms by which UDCA affects the BA kinetics.

Experimental Approach

Mice were treated with UDCA and other BAs to observe changes in BA pool and BA transporters involved in enterohepatic circulation. Isotope dilution techniques and biochemical analyses were applied to study BA kinetics after oral administration of UDCA, and the mechanism involved.

Key Results

Oral administration of UDCA in mice reduced the overall BA pool and produced a unique BA profile with high‐abundance conjugated UDCA species, including tauroursodeoxycholic acid (TUDCA) and GUDCA. We found increased expression of several main BA transporters in the ileum and liver. BA kinetic experiment showed that feeding UDCA shortened cycling time of BA and accelerated BA enterohepatic circulation. Additionally, we found evidence that the effect of UDCA administration on accelerating BA enterohepatic circulation was due to the inhibition of farnesoid X receptor (FXR) signalling in the ileum and FGF15/19 in the liver.

Conclusion and Implications

Oral administration of UDCA produced a unique BA profile with high‐abundance TUDCA and GUDCA and significantly accelerated BA enterohepatic circulation through the inhibition of intestinal FXR signalling and reduced level of FGF15/19, which in turn, induced the expression of BA transporters in the liver. These findings highlight a critical role for UDCA in maintaining the homeostasis of BA enterohepatic circulation in vivo.
Evolution of drainage, sediment‐flux and fluvio‐deltaic sedimentary systems response in hanging wall depocentres in evolving non‐marine rift basins: Paleogene of Raoyang Sag, Bohai Bay Basin, China
Authors: Chen Hehe , Zhu Xiaomin , Wood Lesli J. , Shi Ruisheng
Published: May 2019

The dynamics of sediment feeding into rift basins and the geomorphologic nature of source areas are critical elements in understanding the evolution of rifted basins. This study integrates seismic, well and geochronologic data on the western dipslope of the Raoyang Sag, a rift associated sub‐basin to the larger Bohai Bay Basin of China to define the history of drainage development for the basin and to assess the sedimentologic response to drainage evolution events. In the Paleogene‐age Lixian Slope, as indicated by paleo‐drainage configuration, progradational seismic geometries, compositional maturity and zircon‐tourmaline‐rutile maturity index trends, three drainages; the paleo‐Daqing River, paleo‐Tang River and paleo‐Dasha River drainages were feeding three closely spaced hanging wall deltaic depositional systems; Delta A fed from the northwest, Delta B fed from the west and Delta C fed from the southwest, respectively. From the late Eocene to early Oligocene, a decrease in sediment‐flux into the hanging wall is documented and petrographic analysis is used to link these changes to stream‐capture in the upstream catchment of the Daqing River. This change is coupled with morphologic changes in the geometries of Deltas A and C, both of which show decreasing deltaic areas, changes in lobe geometry and changes in distributary channel sizes. In addition, the progradational direction of Delta C changes from perpendicular‐to‐the‐rift axis to prograding oblique‐to‐the‐rift axis. It is apparent that the progradation and retrogradational changes in rift margin deltas do not happen in isolation, but such changes can affect growth and progradation direction in adjacent deltas. This work shows that the decrease in sediment‐flux, caused by a drainage capture, will result in a decrease in distributary channel size and delta size and may result in upstream deltas taking advantage of such decreasing confinement to prograde more obliquely to the rift axis.
Management of infections due to nontuberculous mycobacteria in solid organ transplant recipients—Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice
Authors: Longworth Sarah A. , Daly Jennifer S. ,   the AST Infectious Diseases Community of Practice
Published: May 2019

These updated guidelines from the American Society of Transplantation Infectious Diseases Community of Practice review the epidemiology, diagnosis, prevention, and management of nontuberculous mycobacterial infections in the pre‐ and post‐transplant period. NTM commonly cause one of five different clinical syndromes: pleuropulmonary disease, skin and soft tissue infection, osteoarticular infection, disseminated disease, including that caused by catheter‐associated infection, and lymphadenitis. Diagnosis of these infections can be challenging, particularly when they are isolated from nonsterile spaces, owing to their ubiquity in nature. Consequently, diagnosis of pulmonary infections with these pathogens requires fulfillment of microbiologic, radiographic, and clinical criteria to address this concern. A combination of culture and molecular diagnostic techniques is often required to make a species‐level identification. Treatment varies depending on the species isolated and is complex, owing to drug toxicities, need for long‐term multidrug regimens, and consideration of complex drug‐drug interactions between antimicrobials and immunosuppressive agents. Given these treatment challenges, efforts should be made in both the hospital and community settings to limit exposure to these pathogens to the extent feasible.
Migratory shorebird adheres to Bergmann's Rule by responding to environmental conditions through the annual lifecycle
Authors: Gibson Daniel , Hornsby Angela D. , Brown Mary B. , Cohen Jonathan B. , Dinan Lauren R. , Fraser James D. , Friedrich Meryl J. , Gratto‐Trevor Cheri L. , Hunt Kelsi L. , Jeffery Matthew , Jorgensen Joel G. , Paton Peter W. C. , Robinson Samantha G. , Rock Jen , Stantial Michelle L. , Weithman Chelsea E. , Catlin Daniel H.
Published: May 2019

The inverse relationship between body size and environmental temperature is a widespread ecogeographic pattern. However, the underlying forces that produce this pattern are unclear in many taxa. Expectations are particularly unclear for migratory species, as individuals may escape environmental extremes and reorient themselves along the environmental gradient. In addition, some aspects of body size are largely fixed while others are environmentally flexible and may vary seasonally. Here, we used a long‐term dataset that tracked multiple populations of the migratory piping ploverCharadrius melodusacross their breeding and non‐breeding ranges to investigate ecogeographic patterns of phenotypically flexible (body mass) and fixed (wing length) size traits in relation to latitude (Bergmann's Rule), environmental temperature (heat conservation hypothesis), and migratory distance. We found that body mass was correlated with both latitude and temperature across the breeding and non‐breeding ranges, which is consistent with predictions of Bergmann's Rule and heat conservation. However, wing length was correlated with latitude and temperature only on the breeding range. This discrepancy resulted from low migratory connectivity across seasons and the tendency for individuals with longer wings to migrate farther than those with shorter wings. Ultimately, these results suggest that wing length may be driven more by conditions experienced during the breeding season or tradeoffs related to migration, whereas body mass is modified by environmental conditions experienced throughout the annual lifecycle.
Export rivalry and exchange rate pass‐through
Authors: Sun Puyang , Tan Yong , Hou Xinyu
Published: May 2019

In this paper, we investigate the influence of market rivalry on firm‐level exchange rate pass‐through. Similar to Bloomet al. Econometrica,80, 1347–1393 (2013), we define market rivalry as product market proximity, and expect the cross market spillovers, that is, through leaked information or reputation, to affect firm‐level export price. Using a comprehensive dataset from Chinese exporters for the 2000–2007 period, we find that in response to a higher degree of market rivalry firms are less responsive to exchange fluctuations. This unresponsiveness suggests a higher degree of exchange rate pass‐through. The influence of market rivalry is stronger among firms that export consumption and heterogeneous products, and to developed countries. Our results are robust to different measures of market rivalry and specifications.
Gating in plant plasma membrane aquaporins: the involvement of leucine in the formation of a pore constriction in the closed state
Authors: Canessa Fortuna Agustina , Zerbetto De Palma Gerardo , Aliperti Car Lucio , Armentia Luciano , Vitali Victoria , Zeida Ari , Estrin Darío A. , Alleva Karina
Published: May 2019

The control of water permeability in plant PIP2 aquaporins has become a paradigmatic case study of the capping mechanism for pore closure in water channels. From structural data, it has been postulated that the gating process in PIP2 involves a conformational rearrangement in cytosolic loopD that generates an obstruction to the transport of water molecules inside the aquaporin pore. BvPIP2;2 is a PIP2 aquaporin from Beta vulgaris whose pH response has been thoroughly characterized. In this work, we study the participation of Leu206 in BvPIP2;2 gating triggered by cytosolic acidification and show that this residue acts as a plug that blocks water transport. Based on data obtained from in silico and in vitro studies, we demonstrate that Leu206, one of the residues lining the pore, is responsible for ~ 60% of water blockage. Cell osmotic swelling experiments and atomistic molecular dynamics simulations indicate that the replacement of Leu206 by an Ala residue maintains high water permeability under conditions where the pore is expected to be closed. The present work demonstrates that Leu206, located at the cytoplasmic entry of the channel, constitutes a crucial pH‐sensitive steric gate regulating water transport in PIP aquaporins.
Modeling optimal responses and fitness consequences in a changing Arctic
Authors: Reimer Jody R. , Mangel Marc , Derocher Andrew E. , Lewis Mark A.
Published: May 2019

Animals must balance a series of costs and benefits while trying to maximize their fitness. For example, an individual may need to choose how much energy to allocate to reproduction versus growth, or how much time to spend on vigilance versus foraging. Their decisions depend on complex interactions between environmental conditions, behavioral plasticity, reproductive biology, and energetic demands. As animals respond to novel environmental conditions caused by climate change, the optimal decisions may shift. Stochastic dynamic programming provides a flexible modeling framework with which to explore these trade‐offs, but this method has not yet been used to study possible changes in optimal trade‐offs caused by climate change. We created a stochastic dynamic programming model capturing trade‐off decisions required by an individual adult female polar bear (Ursus maritimus) as well as the fitness consequences of her decisions. We predicted optimal foraging decisions throughout her lifetime as well as the energetic thresholds below which it is optimal for her to abandon a reproductive attempt. To explore the effects of climate change, we shortened the spring feeding period by up to 3 weeks, which led to predictions of riskier foraging behavior and higher reproductive thresholds. The resulting changes in fitness may be interpreted as a best‐case scenario, where bears adapt instantaneously and optimally to new environmental conditions. If the spring feeding period was reduced by 1 week, her expected fitness declined by 15%, and if reduced by 3 weeks, expected fitness declined by 68%. This demonstrates an effective way to explore a species' optimal response to a changing landscape of costs and benefits and highlights the fact that small annual effects can result in large cumulative changes in expected lifetime fitness.
Multiple KRAS mutations in the non‐mucinous epithelial lining in the majority of mucinous cystic neoplasms of the pancreas
Authors: An Soyeon , Kim Mi‐Ju , Kim Sung Joo , Sung You-Na , Kim Yeon Wook , Song Ki Byung , Hwang Dae Wook , Kim Song Cheol , Hruban Ralph H , Hong Seung‐Mo
Published: May 2019

Aims

Mucinous cystic neoplasms (MCNs) of the pancreas are cystic neoplasms lined by mucinous lining epithelium (MLE) with associated ovarian‐type stroma. Although a non‐MLE (NMLE) can be observed in some MCNs, whether cystic neoplasms with ovarian‐type stroma and NMLE should be classified as MCNs or separately designated is debated.

Methods and results

To test this, NMLEs were defined as flat or cuboidal epithelial cells without intracytoplasmic mucin. A total of 112 MCNs were reviewed, and the epithelium was classified as NMLE or MLE. A total of 110 females and two males with a mean age of 46.5 ± 12.3 years were included in this study. At least focal NMLE was noted in 76.8% (86/112) of MCNs. The mean percentage of the neoplastic epithelium that was NMLE in these 86 cases was 46%. NMLE was predominant (>50%) in 38.4% (43/112) of cases. MCNs with NMLE were smaller (42 ± 21 mm) than those with MLE (60 ± 36 mm, P < 0.001), and all NMLEs had low‐grade dysplasia. Twelve MCNs with NMLE or MLE were selected for KRAS mutation analysis with droplet digital polymerase chain reaction after laser capture microdissection. All 12 MCNs showed multiple types of KRAS mutation, which were detected in 92% (11/12) of NMLE foci and 89% (8/9) of MLE foci. Predominant NMLE was common in small MCNs with low‐grade dysplasia.

Conclusions

Clonal KRAS mutations were observed in both NMLE and MLE, supporting the hypothesis that MCNs with NMLE should be classified as MCNs.
Landscape‐mediated variation in diet is associated with egg size and maculation in a generalist forager
Authors: O'Hanlon Nina J. , Alonso Sarah , Miller Julie A. O. , McGill Rona A. R. , Nager Ruedi G.
Published: May 2019

Human impacts alter landscapes with consequences for the distribution and availability of high‐quality food resources to populations inhabiting those landscapes, which may impact on the reproductive output of individuals in those populations. The sensitivity of wild populations to changes in food resources may vary among stages of the annual cycle. For example, in birds, effects are likely to be greater during costly stages such as egg production. Here we compare assimilated diet (from stable isotope analysis of chick feathers) and egg traits (egg size, shape, eggshell colour and maculation, using pattern‐analysis software) in Herring GullsLarus argentatus, across seven colonies in southwest Scotland and Northern Ireland. The Herring Gull is an opportunistic, generalist forager on both marine and terrestrial resources which frequently exploits anthropogenic food sources such as fishery discards and human refuse. We found that larger eggs were laid in colonies where females consumed either a higher proportion of marine resources or terrestrial resources; smaller eggs were laid in colonies where females had an intermediate diet. In colonies where females consumed more marine items, they also laid eggs with higher maculation (intensity and size of spots) compared with colonies where females mainly consumed terrestrial food. We also found smaller and more pointed eggs, suggestive of resource shortages, in larger colonies. Generalist foragers are often thought to have the capacity to buffer themselves against changes in the food web, provided that enough alternative food is available. However, this study highlights that specializing on the most profitable or available resources has consequences for egg traits even in an opportunistic generalist forager exploiting a large range of habitats. If variation in egg traits is related to reproductive output, then understanding the impact of assimilated diet on reproduction early in the breeding season can provide important insights into how populations will respond to landscapes altered by human impact.
Fabrication and properties of porous anorthite/mullite ceramics with both high porosity and high strength
Authors: Wu Linghao , Li Cuiwei , Yang Jing , Li Hao
Published: May 2019

Porous anorthite/mullite ceramics with both high porosity and high strength have been successfully fabricated by foam‐gelcasting and pressureless sintering technology, using α‐Al2O3, SiO2, and CaCO3 as starting materials and MnO2 as sintering aids. The porous mullite ceramics prepared in this study had 83.3% porosity and 0.3 W/m·K thermal conductivity, exhibited compressive strength value as high as 6.1 MPa. The samples fabricated with mullite content of 30 mol% possessed 79.4% porosity and 5.9 MPa compressive strength showed thermal conductivity as low as 0.19 W/m·K. With the addition of MnO2, the properties of the prepared materials varied slightly when mullite content changed in a large scale. The results showed that the addition of MnO2 promoted the reaction, affected sintering and grain growth, and contributed to high strength and low‐thermal conductivity.
Straddling medical specialties: should we have more comprehensive advanced training?
Authors: Learoyd Diana L. , Clarke Stephen J.
Published: May 2019

Over careers spanning 35 years each, we have witnessed great advances in medicine especially in genetics, imaging, immunotherapies and targeted cancer therapies. Our respective specialties of endocrinology and medical oncology have come to overlap significantly necessitating better communication and skills across both specialties. We will highlight common scenarios that straddle endocrinology and medical oncology. The same broad issues apply to other closely related specialties, albeit with different clinical challenges. At present, we see expensive and inefficient cross‐referrals to other subspecialists or sometimes no referral at all, leading to significant clinical omissions. Opportunities for dual advanced training, or for more comprehensive single advanced training could more efficiently lead to enhanced patient care and communication.
Management of atrial fibrillation after cardiac surgery
Authors: Conte Sean M. , Florisson Daniel S. , De Bono Joshua A. , Davies Reece A. , Newcomb Andrew E.
Published: May 2019

A best evidence topic in cardiac surgery was written according to a structured protocol addressing the question ‘for post‐cardiac surgery atrial fibrillation (AF), do clinical outcomes differ between rate or rhythm control strategies?’ Altogether, 2174 papers were found using the reported searches, of which 5 represented the best evidence to answer the clinical question. Hospital length of stay ranged from 5.0 to 13.2 days for rate control and 5.2 to 10.3 days for rhythm control. Freedom from AF at follow up was achieved in 84.2–91 and 84.2–96% in rate and rhythm control groups respectively. Minimal serious adverse events were noted in all studies analysed and there was no difference between rate and rhythm control groups. We conclude that in the management of post‐cardiac surgery, AF, rate control and rhythm control are equivalent in terms of hospital length of stay, freedom from arrhythmia at follow up and complication rates.
Barriers and factors influencing communication between dental professionals and Child Welfare Services in their everyday work
Authors: Rønneberg Anne , Nordgarden Hilde , Skaare Anne B. , Willumsen Tiril
Published: May 2019

Background

Among various health professionals, general dental professionals (GDPs) screen children frequently, giving them a unique opportunity to act upon suspicion of child maltreatment. The dental team has received considerable attention regarding safeguarding children.

Aim

The aims of this study were to explore whether GDPs have mutual collaboration and communication with the Child Welfare Services (CWS), and potential barriers for reporting child maltreatment.

Design

An electronically pre‐coded questionnaire was sent to all GDPs (n = 131) in the Public Dental Health Service (PDHS) in Oslo. Frequency distributions and statistical analysis were carried out by chi‐squared statistics and multivariate logistic regression analysis.

Results

The response rate was 75%. Ninety per cent of GDPs had received requests from CWS to provide a child's dental chart. General dental professionals reported child maltreatment frequently (71%), but CWS only gave feedback in 55% of the cases. Uncertainty was the most common reason for not reporting and 33% of the GDPs had chosen not to send a report despite suspicion. Using guidelines increased frequency of reporting (OR 3.6).

Conclusions

Mutual collaboration and communication should be improved in the task of safeguarding children. Uncertainty and lack of guidelines may act as barriers for not reporting to the CWS.
Ancient habitat shifts and organismal diversification are decoupled in the African viper genus Bitis (Serpentes: Viperidae)
Authors: Barlow Axel , Wüster Wolfgang , Kelly Christopher M. R. , Branch William R. , Phelps Tony , Tolley Krystal A.
Published: May 2019

Aim

The expansion of open habitats during the mid‐Miocene has been hypothesized as a driver of allopatric speciation for many African taxa. This habitat‐dependent mode of diversification has been implicated in the shift from C3 (e.g. forest/woodland) to C4 dominated systems (i.e. open savanna, grasslands) in a number of African squamates. We examined this hypothesis using a genus of African viperid snakes (Bitis) with both open habitat and forest‐dwelling representatives.

Location

Africa.

Methods

A comprehensive multilocus dataset was used to generate a calibrated species tree using a multispecies coalescent model. Individual gene trees and patterns of nuclear allele sharing were used to assess species monophyly and isolation. To test the habitat‐dependent evolution hypothesis, we generated an ancestral character state reconstruction for open and closed habitats using the dated phylogeny. This was related to the timing of open habitat expansion and forest/woodland contraction in Africa.

Results

The genus Bitis originated in the Oligocene, with species level diversification in the late Miocene/Pliocene. Four well‐supported clades correspond to the recognized subgenera Bitis, Keniabitis, Macrocerastes and Calechidna. Several previously unrecognized lineages potentially represent cryptic species.

Main conclusions

Habitat‐dependent evolution does not appear to have been a main driver for generic level viperine diversification: the ancestral state for Bitis was open habitat and at least one clade moved into forest in the Miocene, long after forest had contracted and fragmented. Forest‐dependent species diversified only in the late Miocene, presumably as forest became further reduced in extent, fitting an allopatric model of speciation. Although our results do not favour a general pattern of habitat‐dependent diversification in Bitis, cladogenesis within the subgenus Calechidna for “arenicolous” species (Bitis caudalis complex) and “rupicolous” species (B. atropos‐cornuta complex), corresponds to the aridification of southwest Africa. This suggests there are subtleties not captured in the broad open habitat category, which are relevant for understanding the role of habitat‐dependent evolution.
The median eminence detects and responds to circulating prolactin in the male mouse
Authors: Kirk Siobhan E. , Grattan David R. , Bunn Stephen J.
Published: May 2019

In addition to its established lactational roles, prolactin acts on multiple target tissues and its circulating levels are responsive to a range of physiological stimuli. The present study used immunohistochemistry to demonstrate that systemic administration of prolactin activates target cells in the arcuate nucleus and median eminence of the male mouse. Prolactin receptor stimulation results in the phosphorylation and thus activation of the signal transducer and activator of transcription (STAT)5 pathway. Interestingly, although, in the arcuate nucleus, this response was localised to cell nuclei, the median eminence displayed both nuclear and diffuse, non‐nuclear, phospho‐STAT5 (pSTAT5) staining. Dual‐label immunostaining demonstrated that, although the majority of nuclear pSTAT5 within the median eminence was located within vimentin‐positive tanycytes, the non‐nuclear staining occurred primarily in neuronal (βIII tubulin immunoreactive) elements. This conclusion was supported by the marked reduction of this signal in prolactin‐treated mice lacking neuronal prolactin receptors. A smaller reduction was also seen in animals lacking prolactin receptors on GABAergic but not glutamatergic neurones. These findings identify a new prolactin target tissue and, in doing so, support the proposal that the median eminence has a sensory role in addition to its established secretory function. The physiological significance of this prolactin response is unknown, although its rapidity (maximum within 2 minutes of i.p. injection) suggests that it may enable the early detection of an increase in circulating prolactin. It is also possibile that non‐nuclear prolactin‐generated pSTAT5 in the median eminence may have a local, non‐transcriptional, action. To this end, we used Evans Blue dye to demonstrate that elevated prolactin appears to reduce median eminence permeability and also that this effect is lost in animals lacking neuronal prolactin receptors.
Poetics of Praise and Image‐Texts of Cinematic Encompassment
Authors: Nakassis Constantine V.
Published: May 2019

Developing the concept ofimage‐textout of Roman Jakobson's notion of aesthetic function and linguistic anthropology's discussion of entextualization,this paper shows how the tropology explored by the late Bernard Bate in twentieth‐century Dravidianist oratory is taken up and recontextualized in the late twentieth‐century Tamil films of the “mass hero” Rajinikanth. I trace a particular image‐text across the two major media of modern Tamil politics—oratory and cinema—showing how it threads an aesthetics of political power and representation in this part of south India. In doing so, the article theorizes what images are and how they circulate.
CCL2 promotes cell migration by inducing epithelial‐mesenchymal transition in oral squamous cell carcinoma
Authors: Ling Zihang , Yang Xi , Chen Xiaobin , Xia Juan , Cheng Bin , Tao Xiaoan
Published: May 2019

Background

Although a few studies suggested that the chemokine CCL2 might be involved in the development of oral squamous cell carcinoma (OSCC), the exact mechanism remains unclear. In this study, we aimed to determine the resource of CCL2 in lesions and explored a potential mechanism that CCL2 promotes tumor progression. The study was an effort to provide new insights into the pathological role of CCL2 in OSCC.

Methods

Specimens of OSCC and normal oral mucosa were stained using immunohistochemistry (IHC) to assess the CCL2 expression. Enzyme‐linked immunosorbent assay (ELISA) was used to detect the difference of CCL2 between OSCC and normal oral mucosa cell lines. In addition, we treated OSCC cells with exogenous rCCL2 combined with or without CCL2 neutralizing antibody and then determined the changes of in epithelial‐mesenchymal transition (EMT) markers and cell migration capacity using immunofluorescence, Western blotting, transwell migration, and wound healing assays.

Results

We have found that CCL2 expression was upregulated significantly in both lesions and cell culture supernatant of OSCC compared with controls. IHC staining demonstrated that CCL2 expression was primarily located in the cytoplasm and cell membrane of cells. We have also found that rCCL2 could effectively induce EMT through upregulating Snail in OSCC cells, which was demonstrated by the decrease of E‐cadherin and the increase of vimentin. In addition, we have found that CCL2 neutralizing antibody could block EMT induced by CCL2 in OSCC.

Conclusions

CCL2 secreted by cancer cells can promote cell migration by inducing EMT via paracrine or autocrine in OSCC.