bluuebunny/crossref_metadata_2025 huggingface dataset:
The ethanol extraction of prepared Psoralea corylifolia induces apoptosis and autophagy and alteres genes expression assayed by cDNA microarray in human prostate cancer PC‐3 cells
Authors: Lin Chia‐Hsin , Funayama Shinji , Peng Shu‐Fen , Kuo Chao‐Lin , Chung Jing‐Gung
Published: April 2018

Prostate cancer is the most common male reproductive system cancer. The prevalence of prostate cancer in Europe and the United States is higher than that in the Asian region. However, the treatment of prostate cancer remains unsatisfactory. Psoralea corylifolia has been used to cure this disease as Chinese medicine in the Asian region. In this study, we analyzed the components of ethanol extraction of unprepared and prepared P. corylifolia by HPLC. Psoralen and isopsoralen content from the prepared P. corylifolia is twofold higher than that from unprepared, so we use the prepared extraction in this study. However, the effects of the ethanol extraction of P. corylifolia (PCE) on PC‐3 human prostate cancer cells remain unclear. PC‐3 cells were treated with PCE for different time periods and cells were examined for cell morphological change and total viable cells by using contrast phase microscopy and flow cytometer, respectively. Results indicated that PCE induced cell morphological changes and cytotoxic effect in PC‐3 cells in dose‐dependent manners. PCE induced chromatin condensation of PC‐3 cells dose‐dependently. PCE also induced apoptosis and autophagy in PC‐3 by western blotting and acridine orange (AO) staining, respectively. Furthermore, a complementary DNA microarray analysis demonstrated that PCE treatment led to 944 genes upregulation and 872 genes downregulation. For example, the DNA damage‐associated gene DNA‐damage‐inducible transcript 3 (DDIT 3) had a 62.1‐fold upregulation and CDK1 2.68‐fold downregulation. The differential genes were classified according to the Gene Ontology. Furthermore, GeneGo software was used for the key genes involved and their possible interaction pathways. Those genes were affected by P. corylifolia, which provided information for the understanding of the antiprostate cancer mechanism at the genetic level and provide additional targets for the treatments of human prostate cancer.
Worldline quantization of field theory, effective actions and L∞ structure
Authors: Bonora L. , Cvitan M. , Prester P. Dominis , Giaccari S. , Paulišić M. , Štemberga T.
Published: April 2018

Abstract

We formulate the worldline quantization (a.k.a. deformation quantization) of a massive fermion model coupled to external higher spin sources. We use the relations obtained in this way to show that its regularized effective action is endowed with an L
∞ symmetry. The same result holds also for a massive scalar model.
Intrafamilial oocyte donation in classic galactosemia: ethical and societal aspects
Authors: Haskovic M. , Poot W. J. , van Golde R. J. T. , Benneheij S. H. , Oussoren E. , de Wert G. M. W. R. , Krumeich A. , Rubio‐Gozalbo M. Estela
Published: April 2018

Classic galactosemia is a rare inherited disorder of galactose metabolism. Primary ovarian insufficiency (POI) with subfertility affects > 80% of female patients and is an important concern for patients and their parents. Healthcare providers are often consulted for subfertility treatment possibilities. An option brought up by the families is intrafamilial oocyte donation (mother‐to‐daughter or sister‐to‐sister). In addition to POI, galactosemia patients can also present varying cognitive and neurological impairments, which may not be fully clear at the time when mother‐to‐daughter oocyte donation is considered. Ethical and societal aspects arise when exploring this option. This study aimed to provide guidance in aspects to consider based on the views of different groups involved in the oocyte donation process. A qualitative study using in‐depth semi‐structured interviews with > 50 participants (patients, family members, and healthcare providers) was conducted. From these interviews, themes of concern emerged, which are illustrated and reviewed: (1) family relations, (2) medical impact, (3) patients’ cognitive level, (4) agreements to be made in advance and organization of counseling, (5) disclosure to the child, and (6) need for follow‐up. We conclude that discussing and carrying out intrafamilial oocyte donation in galactosemia patients requires carefully addressing these themes. This study adds value to the already existing recommendations on intrafamilial oocyte donation in general, since it highlights important additional aspects from the perspectives of patients and their families.
Accelerating Alzheimer's disease drug innovations from the research pipeline to patients
Authors: Goldman Dana P. , Fillit Howard , Neumann Peter
Published: April 2018

In June 2017, a diverse group of experts in Alzheimer's disease convened to discuss how to accelerate getting new drugs to patients to both prevent and treat the disease. Participants concluded that we need a more robust, diversified drug development pipeline. Strategic policy measures can help keep new Alzheimer's disease therapies (whether to treat symptoms, prevent onset, or cure) affordable for patients while supporting innovation and facilitating greater information sharing among payers, providers, researchers, and the public, including a postmarket surveillance study system, disease registries, innovative payment approaches, harmonizing federal agency review requirements, allowing conditional coverage for promising therapeutics and technology while additional data are collected, and opening up channels for drug companies to communicate with payers (and each other) about data and outcomes. To combat reimbursement issues, policy makers should address the latency time between potential treatment—which may be costly and fall on private payers—and societal benefits that accrue elsewhere.
Secret digital coin mining and trading is a threat to your business
Authors: Sampson Jesse
Published: April 2018

Digital coin software could be infecting your desktops and servers with malware, opening the doors to hackers. They could be after your customer lists, your passwords, your databases. Or they could be looking to turn your computers and devices into bots. Jesse Sampson of Ziften explains the nature of the threat and what to do about it.

Bitcoin? Monero? Ethereum? It doesn't matter. Coin mining and trading activities by employees – or by hackers – is a huge security problem that every organisation needs to address.
Identity crisis: the disconnect between business and IT executives
Authors: Mansfield-Devine Steve
Published: April 2018

Perceptions about information security threats vary: what one person sees as a major menace another may view as little more than a nuisance. But while it might be normal for one company to regard the threat landscape differently from another, there can be problems when these mismatched perspectives exist within the same organisation. And as Barry Scott, CTO at Centrify EMEA, explains in this interview, if the C-suite is not getting the right picture, that can lead to dangerously skewed priorities and security strategies.
Evaluating an Information Campaign about Rural Development Policies in FYR Macedonia
Authors: Huber Martin , Kotevska Ana , Stojcheska Aleksandra Martinovska , Solovyeva Anna
Published: April 2018

This study investigates the effects of a local information campaign on farmers’ interest in a rural development programme (RDP) in the former Yugoslav Republic of Macedonia. The results suggest that while our intervention succeeded in informing farmers, it had a negative, albeit only marginally significant, effect on the reported possibility of using future RDP support. This puzzling result can be attributed to increased awareness of administrative burden associated with RDP participation. An additional heterogeneity analysis suggests the negative effect is driven by unprofitable farmers who are averse to any administrative encumbrance, for whom upfront cofinancing of an RDP is untenable.
ULTRASIM: Ultrasound in trauma simulation
Authors: McLean Devon , Hewitson Leanne , Atkinson Paul , Lewis David , Fraser Jacqueline , Verheul Glenn , Mekwan Jayanand , Robinson Bryn
Published: April 2018

Objective

This study sought to assess the effectiveness of ultrasound simulation as a component of high-fidelity trauma simulation, in training diagnostic capabilities of resident and attending physicians participating in simulated trauma scenarios.

Methods

Twelve residents and 20 attending physicians participated in 114 trauma simulations. Participants generated a ranked differential diagnosis list after a physical exam and subsequently after a simulated extended focused assessment with sonography for trauma (E-FAST) ultrasound scan. We compared reports to determine whether the addition of ultrasound improved diagnostic performance.

Results

The primary diagnosis accuracy improved significantly with the addition of simulated ultrasound (p<0.0001). Median diagnostic ranking scores also improved (p<0.0001). Further, participants reported a higher confidence in their diagnoses (p<0.0001) and narrowed their differential diagnosis list (p<0.0001).

Conclusion

We demonstrated that a low-cost ultrasound simulator can be successfully integrated into trauma simulations, resulting in an associated improvement in measures of diagnostic accuracy, confidence, and precision for participating resident and attending physicians.
A quantitative comparison of microfossil extraction methods from ice cores
Authors: BRUGGER SANDRA O. , GOBET E. , SCHANZ F. R. , HEIRI O. , SCHWÖRER C. , SIGL M. , SCHWIKOWSKI M. , TINNER W.
Published: April 2018

Microfossil records from ice archives allow vegetation, fire and land-use activity reconstructions on broad spatial scales. Samples typically contain low microfossil concentrations. Therefore, large ice volumes are often needed for palynology. Hence, it is crucial to extract maximum microfossil numbers through appropriate physical-chemical treatments. We compare six methods covering the main water reduction procedures: evaporation, filtration and centrifugation with snow samples. Adding a known number of Lycopodium marker spores prior to sample treatment and a second marker (Eucalyptus) after laboratory processing allows a quantitative microfossil loss assessment during pollen extraction. We applied the best-performing method (average loss of 22%) to high-alpine firn cores from Colle Gnifetti glacier for validation with a natural archive containing extremely low microfossil concentrations. We conclude that samples processed with different microfossil extraction protocols may give different results for pollen concentrations, percentages and ratios between different pollen types, especially if vesiculate conifer pollen is an important pollen assemblage component. We recommend a new evaporation-based method which delivers the smallest and least variable losses among the tested approaches. Since microfossil losses are inevitable during laboratory procedure, adding markers prior to sample processing is mandatory to achieve reliable microfossil concentration and influx estimates.
A cabinet of the ordinary: domesticating veterinary education, 1766–1799
Authors: HEINTZMAN KIT
Published: April 2018

In the late eighteenth century, the Ecole vétérinaire d'Alfort was renowned for its innovative veterinary education and for having one of the largest natural history and anatomy collections in France. Yet aside from a recent interest in the works of one particular anatomist, the school's history has been mostly ignored. I examine here the fame of the school in eighteenth-century travel literature, the historic connection between veterinary science and natural history, and the relationship between the school's hospital and its esteemed cabinet. Using the correspondence papers of veterinary administrators, state representatives and competing scientific institutions during the French Revolution, I argue that resource constraints and the management of anatomical and natural history specimens produced new disciplinary boundaries between natural history, veterinary medicine and human medicine, while reinforcing geographic divisions between the local and the foreign in the study of non-human animals. This paper reconstructs theAncien Régimereasoning that veterinary students would benefit from a global perspective on animality, and the Revolutionary government's rejection of that premise. Under republicanism, veterinary medicine became domestic.
Can the tea tree oil (Australian native plant:Melaleuca alternifolia Cheel) be an alternative treatment for human demodicosis on skin?
Authors: Lam Nelson Siu Kei , Long Xin Xin , Griffin Robert C , Chen Mu-Kai , Doery James CG
Published: April 2018

Australian tea tree oil (TTO) and its extract terpinen-4-ol (T4O) are found to be effective in moderating demodex-related diseases. Their possible effects are lowering the mite counts, relieving the demodex-related symptoms and modulating the immune system especially the inflammatory response. This review summarizes the topical treatments of TTO and T4O in human demodicosis, their possible mechanism of actions, side-effects and potential resistance in treating this condition. Although current treatments other than TTO and T4O are relatively effective in controlling the demodex mite population and the related symptoms, more research on the efficacy and drug delivery technology is needed in order to assess its potential as an alternative treatment with minimal side-effect profile, low toxicity and low risk of demodex resistance.
The king of dirt: public health and sanitation in late medieval Ghent
Authors: COOMANS JANNA
Published: April 2018

Taking the office of theconinc der ribaudenin Ghent as a case-study, this article reconstructs the enforcement of urban sanitation and preventative health practices during the fourteenth and fifteenth centuries. Theconincmanaged a wide range of issues perceived as potentially polluting, damaging or threatening to health. Banning waste and chasing pigs as well as prostitutes off the streets, the office implemented a governmental vision on communal well-being. Health interests, as part of a broader pursuit of the common good, therefore played an important yet hitherto largely overlooked role in medieval urban governance.
Caregiver perceptions of a fruit and vegetable prescription programme for low-income paediatric patients
Authors: Saxe-Custack Amy , Lofton Heather Claire , Hanna-Attisha Mona , Victor Colleen , Reyes Gwendolyn , Ceja Tiffany , LaChance Jenny
Published: April 2018

Objective

The physical and social environments that surround children should support good health. However, challenges with food security and access prevent many children from consuming a healthy diet, which is critical to proper growth and development. The present study sought to gain a better understanding of primary care initiatives to address these issues in a low-income setting.

Design

Following the relocation of a paediatric clinic to a farmers’ market building and the implementation of a fruit and vegetable prescription programme, researchers conducted thirty-two semi-structured interviews with caregivers. Researchers elicited caregivers’ perceptions of clinic co-location with the farmers’ market; experiences with the prescription programme; opinions of the farmers’ market; and perceived impact on child consumption of fresh produce. Interview recordings were transcribed for textual analysis. Using thematic analysis, researchers examined qualitative data to identify patterns across transcripts and formulate emerging themes. Researchers concluded when data saturation was reached.

Setting

Flint, Michigan, USA.

Subjects

The majority of participants were female (91 %) and African American (53 %).

Results

Four recurrent themes emerged during interviews: (i) convenience of relocation; (ii) attitude towards prescription programme; (iii) challenges with implementation; and (iv) perceived impact of combined interventions. Caregivers indicated that the co-location and prescription programme increased family shopping at the farmers’ market, improved access to high-quality produce and improved food security.

Conclusions

A fruit and vegetable prescription programme involving a partnership between a farmers’ market and paediatric clinic was perceived as effective in improving food security, food access and child consumption of fresh fruits and vegetables.
Antimicrobial resistance: from basic science to translational innovation
Authors: Lin Jun
Published: April 2018

The rise in antimicrobial resistance (AMR) poses a major threat to animal agriculture and human health. To summarize and update current and emerging AMR issues that are significant for animal health and food safety, this issue presents a virtual AMR symposium consisting of seven review papers. These reviews cover a newly described AMR mechanism in Campylobacter, effects of AMR and microbiome on Campylobacter infection, plasmid-mediated colistin resistance in food-producing animals, the impact of point source or antibiotic residues on the environmental resistome, and potential factors influencing horizontal gene transfer in the intestines of food animals. These papers also identify significant knowledge gaps in AMR research and provide new directions for the development of innovative and effective strategies to mitigate AMR in the animal production system.
Maternal intake of omega-3 and omega-6 polyunsaturated fatty acids during mid-pregnancy is inversely associated with linear growth
Authors: Al-Hinai M. , Baylin A. , Tellez-Rojo M. M. , Cantoral A. , Ettinger A. , Solano-González M. , Peterson K. E. , Perng W.
Published: April 2018

This study investigates relations of maternal N-3 and N-6 polyunsaturated fatty acids (PUFA) intake during pregnancy with offspring body mass index (BMI), height z-score and metabolic risk (fasting glucose, C-peptide, leptin, lipid profile) during peripuberty (8–14 years) among 236 mother–child pairs in Mexico. We used food frequency questionnaire data to quantify trimester-specific intake of N-3 alpha-linolenic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA); N-6 linoleic acid and arachidonic acid (AA); and N-6:N-3 (AA:EPA+DHA), which accounts for the fact that the two PUFA families have opposing effects on physiology. Next, we used multivariable linear regression models that accounted for maternal education and parity, and child’s age, sex and pubertal status, to examine associations of PUFA intake with the offspring outcomes. In models where BMI z-score was the outcome, we also adjusted for height z-score. We found that higher second trimester intake of EPA, DHA and AA were associated with lower offspring BMI and height z-score. For example, each 1-s.d.increment in second trimester EPA intake corresponded with 0.25 (95% CI: 0.03, 0.47) z-scores lower BMI and 0.20 (0.05, 0.36) z-scores lower height. Accounting for height z-score in models where BMI z-score was the outcome attenuated estimates [e.g., EPA: −0.16 (−0.37, 0.05)], suggesting that this relationship was driven by slower linear growth rather than excess adiposity. Maternal PUFA intake was not associated with the offspring metabolic biomarkers. Our findings suggest that higher PUFA intake during mid-pregnancy is associated with lower attained height in offspring during peripuberty. Additional research is needed to elucidate mechanisms and to confirm findings in other populations.
Maternal anxiety, depression and sleep disorders before and during pregnancy, and preschool ADHD symptoms in the NINFEA birth cohort study
Authors: Vizzini L. , Popovic M. , Zugna D. , Vitiello B. , Trevisan M. , Pizzi C. , Rusconi F. , Gagliardi L. , Merletti F. , Richiardi L.
Published: April 2018

Aims.

Maternal mental disorders have been associated with the risk of attention-deficit/hyperactivity disorder (ADHD) in children. Within the context of a mother–child cohort, we examined whether maternal anxiety, depression and sleep disorders are associated with pre-school ADHD symptoms.

Methods.

The study included 3634 singletons from the Italian NINFEA (Nascita e INFanzia: gli Effetti dell'Ambiente’) cohort. Maternal doctor-diagnosed anxiety, depression and sleep disorders before and during pregnancy were assessed from the questionnaires completed during pregnancy and 6 months after delivery. Mothers rated child ADHD symptoms at 4 years of age, according to the Diagnostic and Statistical Manual of Mental Disorders. Hyperactive–impulsive (ADHD-H), inattentive (ADHD-I) and total ADHD scores were analysed in the models adjusted for child's gender, first-born status, maternal age, education, alcohol consumption and smoking during pregnancy.

Results.

The total ADHD score at age 4 was associated with maternal lifetime anxiety (17.1% percentage difference in score compared with never; 95% CI 7.3–27.9%), sleep disorders (35.7%; 95% CI 10.7–66.5%) and depression (17.5%; 95% CI 3.2–33.8%). Similar positive associations were observed also for ADHD-H and ADHD-I traits, with slightly attenuated associations between maternal sleep disorders and child ADHD-I score, and maternal depression and both ADHD scores. All the estimates were enhanced when the disorders were active during pregnancy and attenuated for disorders active only during the pre-pregnancy period.

Conclusions.

Maternal anxiety, depression and sleep disorders are associated with a relative increase in the number of ADHD-H, ADHD-I and total ADHD symptoms in preschoolers.
The Routes of Intransigence:Mexico's ‘Spiritual Pilgrimage’ of 1874 and the Globalization of Ultramontane Catholicism
Authors: Stauffer Brian
Published: April 2018

In the fall of 1874, in the midst a particularly severe round of Church-state conflict, Mexico's archbishop, Pelagio Antonio Labastida y Dávalos, introduced a novel weapon in the Catholic Church's struggle against liberal anticlericalism. He had sought and obtained a special dispensation from Pope Pius IX for all Mexicans to participate in a “spiritual pilgrimage,” a month-long exercise of mental travel, prayer, and contemplation that would figuratively transport the faithful out of Mexico's anticlerical milieu and into the purified air of Jerusalem, Rome, and other Old World holy sites, where they would pray for divine intercession on behalf of the embattled Church. The practice had been inaugurated a year earlier by lay Catholics in Bologna, as a response to the prohibition of mass pilgrimages in the flesh in the former Papal States. Labastida y Dávalos felt that spiritual pilgrimage could be especially effective in Mexico, where the anticlerical government of Sebastián Lerdo de Tejada had embarked on a radical program of secularization. In fact, the recently codified Laws of Reform had likewise prohibited acts of public religiosity in Mexico, attempting thus to suppress the myriad local processions and mass pilgrimages that helped to define Mexican Catholicism.
Clara Porset in Mid Twentieth-Century Mexico:The Politics of Designing, Producing, and Consuming Revolutionary Nationalist Modernity
Authors: Sheppard Randal
Published: April 2018

In 2006, Mexico City's Museo Franz Meyer held an exhibition titled Creating a Modern Mexico, celebrating the furniture designs of Clara Porset y Dumas. This exhibition and a growing literature on her work by design historians during the first decades of the twenty-first century have helped establish Porset as the highest-profile pioneer of industrial and interior design in twentieth-century Mexico.
Epitaph of a Small Winner: My First 50 Years in Academe. An Interview with Judith Ewell
Authors: Lane Kris
Published: April 2018

Judith Ewell has been a major figure in modern Latin American history, both as a research scholar and as a teacher. Just before receiving her PhD at the University of New Mexico in 1972, Ewell began teaching at the College of William & Mary in Williamsburg, Virginia, from which she retired in 2004. Ewell's books include The Indictment of a Dictator: The Extradition and Trial of Marcos Pérez Jiménez (1981); Venezuela: A Century of Change (1984); and Venezuela and the United States: From Monroe's Hemisphere to Petroleum's Empire (1996, Spanish ed. 1998). Ewell has also published numerous articles and book chapters on modern Latin American history and women's history. She is co-editor of the much-loved biographical essay collection, The Human Tradition in Latin America (Nineteenth and Twentieth Centuries) with William H. Beezley, with whom she served on the editorial board of Scholarly Resources Press (now Rowman & Littlefield). Most importantly, Ewell served as chief editor of this journal, The Americas, from 1998 to 2003.
Rapid Changes in Anthropogenic Carbon Storage and Ocean Acidification in the Intermediate Layers of the Eurasian Arctic Ocean: 1996–2015
Authors: Ulfsbo Adam , Jones Elizabeth M. , Casacuberta Núria , Korhonen Meri , Rabe Benjamin , Karcher Michael , van Heuven Steven M.A.C.
Published: April 2018

The extended multiple linear regression technique is used to determine changes in anthropogenic carbon in the intermediate layers of the Eurasian Basin based on occupations from four cruises between 1996 and 2015. The results show a significant increase in basin‐wide anthropogenic carbon storage in the Nansen Basin (0.44–0.73 ± 0.14 mol C·m−2·year−1) and the Amundsen Basin (0.63–1.04 ± 0.09 mol C·m−2·year−1). Over the last two decades, inferred changes in ocean acidification (0.020–0.055 pH units) and calcium carbonate desaturation (0.05–0.18 units) are pronounced and rapid. These results, together with results from carbonate‐dynamic box model simulations and 129I tracer distribution simulations, suggest that the accumulation of anthropogenic carbon in the intermediate layers of the Eurasian Basin are consistent with increasing concentrations of anthropogenic carbon in source waters of Atlantic origin entering the Arctic Ocean followed by interior transport. The dissimilar distributions of anthropogenic carbon in the interior Nansen and Amundsen Basins are likely due to differences in the lateral ventilation of the intermediate layers by the return flows and ramifications of the boundary current along the topographic boundaries in the Eurasian Basin.
Automated Large‐Scale Full Seismic Waveform Inversion for North America and the North Atlantic
Authors: Krischer Lion , Fichtner Andreas , Boehm Christian , Igel Heiner
Published: April 2018

We present a new anisotropic seismic tomography model based on a multiscale full seismic waveform inversion for crustal and upper‐mantle structure from the western edge of North America across the North Atlantic and into Europe. The gradient‐based inversion strategy utilizes the adjoint state method coupled with an L‐BFGS quasi‐Newton optimization scheme. To improve the handling of large data quantities in the context of full seismic waveform inversions, we developed a workflow framework automating the procedure across all stages, enabling us to confidently invert for waveforms from 72 events recorded at 7,737 unique stations, resulting in a total of 144,693 raypaths, most of them with three‐component recordings. The final model after 20 iterations is able to explain complete waveforms including body as well as surface waves of earthquakes that were not used in the inversion down to periods of around 30 s. The model is complemented by a detailed resolution analysis in the form of 3‐D distributions of direction‐dependent resolution lengths.
Geological Evolution of Titan's Equatorial Regions: Possible Nature and Origin of the Dune Material
Authors: Brossier J. F. , Rodriguez S. , Cornet T. , Lucas A. , Radebaugh J. , Maltagliati L. , Le Mouélic S. , Solomonidou A. , Coustenis A. , Hirtzig M. , Jaumann R. , Stephan K. , Sotin C.
Published: April 2018

In 13 years, infrared observations from the Visual and Infrared Mapping Spectrometer onboard Cassini provided significant hints about the spectral and geological diversity of Titan's surface. The analysis of the infrared (IR) signature of spectral units enables constraining the surface composition, which is crucial for understanding possible interactions between Titan's interior, surface, and atmosphere. Here we investigate a selection of areas in the equatorial regions, imaged by Cassini's instruments, which exhibit an apparent transition from the Visual and Infrared Mapping Spectrometer IR‐bright to the IR‐blue and IR‐brown units (from false‐color composites using red: 1.57/1.27 μm, green: 2.01/1.27 μm, and blue: 1.27/1.08 μm). By applying an updated radiative transfer model, we extract the surface albedo of IR units identified in these regions. Then, we compare them with synthetic mixtures of two expected components on Titan's surface, namely, water ice and laboratory tholins. This allows us to reconnect the derived composition and grain size information to the geomorphology observed from Radio Detection and Ranging instrument (RADAR)/Synthetic Aperture Radar images. We interpret IR‐bright units as hills and plains coated by organic material and incised by fluvial networks. Erosion products are transported downstream to areas where IR‐blue units are seen near the IR‐bright units. These units, enriched in water ice, are most likely outwash plains hosting debris from fluvial erosion. Farther away from the IR‐bright units, the IR‐brown units are dominantly made of organics with varied grain sizes, ranging from dust‐ to sand‐sized particles that form the dune fields. The transition areas therefore exhibit trends in water ice content and grain size supported by geomorphological observations.
Useful pharmacodynamic endpoints in children: selection, measurement, and next steps
Authors: Kelly Lauren E , Sinha Yashwant , Barker Charlotte I S , Standing Joseph F , Offringa Martin
Published: April 2018

Pharmacodynamic (PD) endpoints are essential for establishing the benefit-to-risk ratio for therapeutic interventions in children and neonates. This article discusses the selection of an appropriate measure of response, the PD endpoint, which is a critical methodological step in designing pediatric efficacy and safety studies. We provide an overview of existing guidance on the choice of PD endpoints in pediatric clinical research. We identified several considerations relevant to the selection and measurement of PD endpoints in pediatric clinical trials, including the use of biomarkers, modeling, compliance, scoring systems, and validated measurement tools. To be useful, PD endpoints in children need to be clinically relevant, responsive to both treatment and/or disease progression, reproducible, and reliable. In most pediatric disease areas, this requires significant validation efforts. We propose a minimal set of criteria for useful PD endpoint selection and measurement. We conclude that, given the current heterogeneity of pediatric PD endpoint definitions and measurements, both across and within defined disease areas, there is an acute need for internationally agreed, validated, and condition-specific pediatric PD endpoints that consider the needs of all stakeholders, including healthcare providers, policy makers, patients, and families.
Author Correction: Angiotensin type 2 receptor activation promotes browning of white adipose tissue and brown adipogenesis
Authors: Than Aung , Xu Shaohai , Li Ru , Leow Melvin Khee-Shing , Sun Lei , Chen Peng
Published: April 2018

The original version of this Article incorrectly contained an error in author names, which was incorrectly given as ‘MelvinKhee-Shing Leow’, the correct authors name is Melvin Khee-Shing Leow and the initials should be Leow MK.
A Trib2-p38 axis controls myeloid leukaemia cell cycle and stress response signalling
Authors: Salomé Mara , Magee Aoife , Yalla Krisha , Chaudhury Shahzya , Sarrou Evgenia , Carmody Ruaidhrí J , Keeshan Karen
Published: April 2018

Trib2 pseudokinase is involved in the etiology of a number of cancers including leukaemia, melanoma, ovarian, lung and liver cancer. Both high and low Trib2 expression levels correlate with different types of cancer. Elevated Trib2 expression has oncogenic properties in both leukaemia and lung cancer dependent on interactions with proteasome machinery proteins and degradation of transcription factors. Here, we demonstrated that Trib2 deficiency conferred a growth and survival advantage both at steady state and in stress conditions in leukaemia cells. In response to stress, wild type leukaemia cells exited the cell cycle and underwent apoptosis. In contrast, Trib2 deficient leukaemia cells continued to enter mitosis and survive. We showed that Trib2 deficient leukaemia cells had defective MAPK p38 signalling, which associated with a reduced γ-H2Ax and Chk1 stress signalling response, and continued proliferation following stress, associated with inefficient activation of cell cycle inhibitors p21, p16 and p19. Furthermore, Trib2 deficient leukaemia cells were more resistant to chemotherapy than wild type leukaemia cells, having less apoptosis and continued propagation. Trib2 re-expression or pharmacological activation of p38 in Trib2 deficient leukaemia cells sensitised the cells to chemotherapy-induced apoptosis comparable with wild type leukaemia cells. Our data provide evidence for a tumour suppressor role of Trib2 in myeloid leukaemia via activation of p38 stress signalling. This newly identified role indicates that Trib2 may counteract the propagation and chemotherapy resistance of leukaemia cells.
Inhibition of cyclin-dependent kinase 4 as a potential therapeutic strategy for treatment of synovial sarcoma
Authors: Li Xiaoyang , Seebacher Nicole A. , Garbutt Cassandra , Ma Hangzhan , Gao Peng , Xiao Tao , Hornicek Francis J. , Duan Zhenfeng
Published: April 2018

Synovial sarcoma is a highly aggressive but rare form of soft tissue malignancy that primarily affects the extremities of the arms or legs, for which current chemotherapeutic agents have not been proven to be very effective. The cyclin-dependent kinase 4/6-retinoblastoma protein (CDK4/6-Rb) pathway of cell cycle control is known to be aberrant in a large proportion of cancers. Recently, CDK4 inhibitors have successfully been used pre-clinically for the treatment of many human cancers, and in 2015, following the success of clinical trials, the FDA approved the first selective CDK4/6 inhibitor, palbociclib, for the treatment of endocrine therapy resistant breast cancers. However, the expression and therapeutic potential of targeting CDK4 in synovial sarcoma remains unclear. In the present study, we report that CDK4 is highly expressed in human synovial sarcoma, and high CDK4 expressions are associated with poor prognosis in sarcomas patients and the clinical stage and the TNM grade in synovial sarcoma patients. Knockdown of CDK4 with specific small interference RNAs inhibits cell proliferation and enhances apoptotic effects in synovial sarcoma cells. CDK4 inhibitor palbociclib suppresses synovial sarcoma cell proliferation and growth in a dose and time-dependent manner. Palbociclib also inhibits the CDK4/6-Rb signaling pathway and promotes cell apoptosis without changing CDK4/6 protein levels, suggesting that palbociclib only represses the hyper-activation, not the expression of CDK4/6. Flow cytometry analysis reveals that palbociclib induces G1 cell-cycle arrest and apoptotic effects by targeting the CDK4/6-Rb pathway in synovial sarcoma cells. Furthermore, wound healing assays demonstrate that inhibition of the CDK4/6-Rb pathway by palbociclib significantly decreases synovial sarcoma cell migration in vitro. Our study highlights the importance of the CDK4/6-Rb pathway in human synovial sarcoma pathogenesis, and the role of the current selective CDK4/6 inhibitor, palbociclib, as a potential promising targeted therapeutic agent in the treatment of human synovial sarcoma.
Snord116-dependent diurnal rhythm of DNA methylation in mouse cortex
Authors: Coulson Rochelle L. , Yasui Dag H. , Dunaway Keith W. , Laufer Benjamin I. , Vogel Ciernia Annie , Zhu Yihui , Mordaunt Charles E. , Totah Theresa S. , LaSalle Janine M.
Published: April 2018

Rhythmic oscillations of physiological processes depend on integrating the circadian clock and diurnal environment. DNA methylation is epigenetically responsive to daily rhythms, as a subset of CpG dinucleotides in brain exhibit diurnal rhythmic methylation. Here, we show a major genetic effect on rhythmic methylation in a mouse Snord116 deletion model of the imprinted disorder Prader–Willi syndrome (PWS). More than 23,000 diurnally rhythmic CpGs are identified in wild-type cortex, with nearly all lost or phase-shifted in PWS. Circadian dysregulation of a second imprinted Snord cluster at the Temple/Kagami-Ogata syndrome locus is observed at the level of methylation, transcription, and chromatin, providing mechanistic evidence of cross-talk. Genes identified by diurnal epigenetic changes in PWS mice overlapped rhythmic and PWS-specific genes in human brain and are enriched for PWS-relevant phenotypes and pathways. These results support the proposed evolutionary relationship between imprinting and sleep, and suggest possible chronotherapy in the treatment of PWS and related disorders.
Structural basis for the activation of acid ceramidase
Authors: Gebai Ahmad , Gorelik Alexei , Li Zixian , Illes Katalin , Nagar Bhushan
Published: April 2018

Acid ceramidase (aCDase, ASAH1) hydrolyzes lysosomal membrane ceramide into sphingosine, the backbone of all sphingolipids, to regulate many cellular processes. Abnormal function of aCDase leads to Farber disease, spinal muscular atrophy with progressive myoclonic epilepsy, and is associated with Alzheimer’s, diabetes, and cancer. Here, we present crystal structures of mammalian aCDases in both proenzyme and autocleaved forms. In the proenzyme, the catalytic center is buried and protected from solvent. Autocleavage triggers a conformational change exposing a hydrophobic channel leading to the active site. Substrate modeling suggests distinct catalytic mechanisms for substrate hydrolysis versus autocleavage. A hydrophobic surface surrounding the substrate binding channel appears to be a site of membrane attachment where the enzyme accepts substrates facilitated by the accessory protein, saposin-D. Structural mapping of disease mutations reveals that most would destabilize the protein fold. These results will inform the rational design of aCDase inhibitors and recombinant aCDase for disease therapeutics.
Medical relevance of protein-truncating variants across 337,205 individuals in the UK Biobank study
Authors: DeBoever Christopher , Tanigawa Yosuke , Lindholm Malene E. , McInnes Greg , Lavertu Adam , Ingelsson Erik , Chang Chris , Ashley Euan A. , Bustamante Carlos D. , Daly Mark J. , Rivas Manuel A.
Published: April 2018

Protein-truncating variants can have profound effects on gene function and are critical for clinical genome interpretation and generating therapeutic hypotheses, but their relevance to medical phenotypes has not been systematically assessed. Here, we characterize the effect of 18,228 protein-truncating variants across 135 phenotypes from the UK Biobank and find 27 associations between medical phenotypes and protein-truncating variants in genes outside the major histocompatibility complex. We perform phenome-wide analyses and directly measure the effect in homozygous carriers, commonly referred to as “human knockouts,” across medical phenotypes for genes implicated as being protective against disease or associated with at least one phenotype in our study. We find several genes with strong pleiotropic or non-additive effects. Our results illustrate the importance of protein-truncating variants in a variety of diseases.
Epigenetic landscape influences the liver cancer genome architecture
Authors: Hama Natsuko , Totoki Yasushi , Miura Fumihito , Tatsuno Kenji , Saito-Adachi Mihoko , Nakamura Hiromi , Arai Yasuhito , Hosoda Fumie , Urushidate Tomoko , Ohashi Shoko , Mukai Wakako , Hiraoka Nobuyoshi , Aburatani Hiroyuki , Ito Takashi , Shibata Tatsuhiro
Published: April 2018

The accumulations of different types of genetic alterations such as nucleotide substitutions, structural rearrangements and viral genome integrations and epigenetic alterations contribute to carcinogenesis. Here, we report correlation between the occurrence of epigenetic features and genetic aberrations by whole-genome bisulfite, whole-genome shotgun, long-read, and virus capture sequencing of 373 liver cancers. Somatic substitutions and rearrangement breakpoints are enriched in tumor-specific hypo-methylated regions with inactive chromatin marks and actively transcribed highly methylated regions in the cancer genome. Individual mutation signatures depend on chromatin status, especially, signatures with a higher transcriptional strand bias occur within active chromatic areas. Hepatitis B virus (HBV) integration sites are frequently detected within inactive chromatin regions in cancer cells, as a consequence of negative selection for integrations in active chromatin regions. Ultra-high structural instability and preserved unmethylation of integrated HBV genomes are observed. We conclude that both precancerous and somatic epigenetic features contribute to the cancer genome architecture.
Warm summers during the Younger Dryas cold reversal
Authors: Schenk Frederik , Väliranta Minna , Muschitiello Francesco , Tarasov Lev , Heikkilä Maija , Björck Svante , Brandefelt Jenny , Johansson Arne V. , Näslund Jens-Ove , Wohlfarth Barbara
Published: April 2018

The Younger Dryas (YD) cold reversal interrupts the warming climate of the deglaciation with global climatic impacts. The sudden cooling is typically linked to an abrupt slowdown of the Atlantic Meridional Overturning Circulation (AMOC) in response to meltwater discharges from ice sheets. However, inconsistencies regarding the YD-response of European summer temperatures have cast doubt whether the concept provides a sufficient explanation. Here we present results from a high-resolution global climate simulation together with a new July temperature compilation based on plant indicator species and show that European summers remain warm during the YD. Our climate simulation provides robust physical evidence that atmospheric blocking of cold westerly winds over Fennoscandia is a key mechanism counteracting the cooling impact of an AMOC-slowdown during summer. Despite the persistence of short warm summers, the YD is dominated by a shift to a continental climate with extreme winter to spring cooling and short growing seasons.
Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer
Authors: McDevitt Michael R. , Thorek Daniel L. J. , Hashimoto Takeshi , Gondo Tatsuo , Veach Darren R. , Sharma Sai Kiran , Kalidindi Teja Muralidhar , Abou Diane S. , Watson Philip A. , Beattie Bradley J. , Timmermand Oskar Vilhemsson , Strand Sven-Erik , Lewis Jason S. , Scardino Peter T. , Scher Howard I. , Lilja Hans , Larson Steven M. , Ulmert David
Published: April 2018

Human kallikrein peptidase 2 (hK2) is a prostate specific enzyme whose expression is governed by the androgen receptor (AR). AR is the central oncogenic driver of prostate cancer (PCa) and is also a key regulator of DNA repair in cancer. We report an innovative therapeutic strategy that exploits the hormone-DNA repair circuit to enable molecularly-specific alpha particle irradiation of PCa. Alpha-particle irradiation of PCa is prompted by molecularly specific-targeting and internalization of the humanized monoclonal antibody hu11B6 targeting hK2 and further accelerated by inherent DNA-repair that up-regulate hK2 (KLK2) expression in vivo. hu11B6 demonstrates exquisite targeting specificity for KLK2. A single administration of actinium-225 labeled hu11B6 eradicates disease and significantly prolongs survival in animal models. DNA damage arising from alpha particle irradiation induces AR and subsequently KLK2, generating a unique feed-forward mechanism, which increases binding of hu11B6. Imaging data in nonhuman primates support the possibility of utilizing hu11B6 in man.
Policy review of the means of implementation targets and indicators for the sustainable development goal for water and sanitation
Authors: Bartram Jamie , Brocklehurst Clarissa , Bradley David , Muller Mike , Evans Barbara
Published: April 2018

The Sustainable Development Goals, adopted by the Member States of the United Nations in September 2016, contain both ‘Outcome’ and ‘Means of Implementation’ targets. However, there is generally weak evidence linking the Means of Implementation to outcomes, they are imperfectly conceptualised and inconsistently formulated, and tracking their largely qualitative indicators will be difficult. In this paper, we analyse and critique the Means of Implementation targets of the Sustainable Development Goal on water and sanitation (SDG6). Improvements are recommended that would reflect: the considerable investment needed to attain SDG6; the important role of the state, including government leadership and planning; the utility of disaggregating financial and capacity-building assistance; and the need for people to realise their rights to information, voice and remedy. Recommendations are also made for relevant indicators, including indicators that are applicable to governments in both aid-providing and aid-receiving countries.
Author Correction: Effect of compressibility and non-uniformity in flow on the scattering pattern of acoustic cloak
Authors: Ryoo Hyeonbin , Jeon Wonju
Published: April 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
Author Correction: Identification of oral cancer related candidate genes by integrating protein-protein interactions, gene ontology, pathway analysis and immunohistochemistry
Authors: Kumar Ravindra , Samal Sabindra K. , Routray Samapika , Dash Rupesh , Dixit Anshuman
Published: April 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
Author Correction: Selective 6H-SiC White Light Emission by Picosecond Laser Direct Writing
Authors: Wang Sicong , Ji Lingfei , Li Lin , Wu Yan , Zhang Yongzhe , Lin Zhenyuan
Published: April 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
Human mesenchymal stem cell basal membrane bending on gratings is dependent on both grating width and curvature
Authors: Zeng Yukai , Wong Sum Thai , Teo Soo Kng , Leong Kam W. , Chiam Keng-Hwee , Yim Evelyn K. F.
Published: April 2018

The topography of the extracellular substrate provides physical cues to elicit specific downstream biophysical and biochemical effects in cells. An example of such a topographical substrate is periodic gratings, where the dimensions of the periodic gratings influence cell morphology and directs cell differentiation. We first develop a novel sample preparation technique using Spurr’s resin to allow for cross-sectional transmission electron microscopy imaging of cells on grating grooves, and observed that the plasma membrane on the basal surface of these cells can deform and bend into grooves between the gratings. We postulate that such membrane bending is an important first step in eliciting downstream effects. Thus, we use a combination of image analysis and mathematical modeling to explain the extent of bending of basal membrane into grooves. We show that the extent to which the basal membrane bends into grooves depends on both groove width and angle of the grating ridge. Our model predicts that the basal membrane will bend into grooves when they are wider than 1.9 µm in width. The existence of such a threshold may provide an explanation for how the width of periodic gratings may bring about cellular downstream effects, such as cell proliferation or differentiation.