bluuebunny/crossref_metadata_2025 huggingface dataset:
Type of TP53 mutation influences oncogenic potential and spectrum of associated K‐ras mutations in lung‐specific transgenic mice
Authors: Duan Wenrui , Gao Li , Kalvala Arjun , Aguila Brittany , Brooks Christopher , Mo Xiaokui , Ding Haiming , Shilo Konstantin , Otterson Gregory A. , Villalona‐Calero Miguel A.
Published: March 2019

TP53 and K‐ras mutations are two of the major genetic alterations in human nonsmall cell lung cancers. The association between these two genes during lung tumorigenesis is unknown. We evaluated the potential of two common Type I (273H, contact) and Type II (175H, conformational) TP53 mutations to induce lung tumors in transgenic mice, as well as K‐ras status, and other driver mutations in these tumors. Among 516 (138 nontransgenic, 207 SPC‐TP53‐273H, 171 SPC‐TP53‐175H) mice analyzed, 91 tumors, all adenocarcinomas, were observed. Type II mutants developed tumors more frequently (as compared to nontransgenics, p = 0.0003; and Type I, p = 0.010), and had an earlier tumor onset compared to Type I (p = 0.012). K‐ras mutations occurred in 21 of 50 (42%) of murine lung tumors sequenced. For both the nontransgenic and the SPC‐TP53‐273H transgenics, tumor K‐ras codon 12–13 mutations occurred after 13 months with a peak incidence at 16–18 months. However, for the SPC‐TP53‐175H transgenics, K‐ras codon 12–13 mutations were observed as early as 6 months, with a peak incidence between the ages of 10–12 months. Codons 12–13 transversion mutations were the predominant changes in the SPC‐TP53‐175H transgenics, whereas codon 61 transition mutations were more common in the SPC‐TP53‐273H transgenics. The observation of accelerated tumor onset, early appearance and high frequency of K‐ras codon 12–13 mutations in the Type II TP53‐175H mice suggests an enhanced oncogenic function of conformational TP53 mutations, and gains in early genetic instability for tumors containing these mutations compared to contact mutations.
Understanding the gap in emergency obstetric and neonatal care in Ghana through the PREventing Maternal And Neonatal Deaths (PREMAND) study
Authors: Kaselitz Elizabeth , James Katherine H. , Aborigo Raymond A. , Agorinya Isaiah , Moyer Cheryl A. , Williams John
Published: March 2019

Objective

To explore basic and comprehensive emergency obstetric service provision across four districts in rural northern Ghana, and whether women were more likely to deliver at facilities with more skilled care.

Methods

Field workers geo‐coded all health facilities in East Mamprusi, Sissala East, Kassena Nankana Municipal, and Kassena Nankana West districts, and administered surveys to assess providers and emergency obstetric care available. Data were also prospectively collected on delivery locations of women and neonates who died, or nearly died (near misses), between September 1, 2015 and April 30, 2017.

Results

There were 14 physicians for a population of nearly 360 000 women. Six (6%) facilities could provide basic emergency care, and 3 (3%) could provide comprehensive care. Services were distributed unequally, with 6 (67%) of the emergency facilities located in the least populated district. Among the sample of women and neonates who died or nearly died, 175 (39%) delivered at locations unable to provide basic emergency services.

Conclusion

Access to emergency obstetric and neonatal care was distributed inequitably across these districts, suggesting the need to revisit geographic placement of facilities relative to population. The study also raised the question of how to ensure facilities are equipped to respond to emergencies.
miR‐4458 regulates cell proliferation and apoptosis through targeting SOCS1 in triple‐negative breast cancer
Authors: Liu Xiaomeng , Wang Jianling , Zhang Guochao
Published: March 2019

Our previous study has suggested suppressor of cytokine signaling 1 (SOCS1) is associated with clinical progression and functions as an oncogenic role to regulate cell proliferation and apoptosis in triple‐negative breast cancer (TNBC). Several microRNA‐messenger RNA (miRNA‐mRNA) relationship databases show SOCS1 is identified as a direct target gene of miRNA‐4458 (miR‐4458). The purpose of this study was to study the relationship between miR‐4458 and SOCS1 in TNBC. In our results, miR‐4458 expression was decreased in TNBC tissues and cells compared with adjacent normal tissues and normal mammary epithelial cell line, respectively. Moreover, miR‐4458 directly bound to SOCS1, and negatively regulated SOCS1 mRNA and protein expression. Furthermore, miR‐4458 suppressed cell proliferation and promote cell apoptosis through regulating SOCS1 in TNBC. Besides, levels of miR‐4458 expression in patients with advanced clinical stage were obviously lower than in patients with early clinical stage. In conclusion, miR‐4458 mediates SOCS1 to play a tumor‐suppressive role in TNBC.
Cationic liposome codelivering PI3K pathway regulator improves the response of BRCA1‐deficient breast cancer cells to PARP1 inhibition
Authors: Zhang Haipeng , Yu Na , Chen Yan , Yan Kaowen , Wang Xiaozhen
Published: March 2019

Although some progresses have been made in breast cancer therapy, effective treatment for BRCA1‐deficient breast cancer remains to be a great challenge. It has been demonstrated that the PI3K pathway is inappropriately activated in BRCA1‐deficient breast cancers which can be downregulated by microRNA 451 (miR‐451). In addition, although PARP1 inhibitors showed relatively positive results in both preclinical and clinical studies, additional efforts to decrease drug resistance as well as reduce systematic toxicity need to be addressed. To this end, by encapsulating the miR‐451 mimic and PARP1 inhibitor in the same cationic liposome, we examined the potential of enhancing the response of PARP1 inhibition on BRCA1‐deficient breast cancer by regulating the PI3K pathway. Our results revealed that in BRCA1‐deficient human breast cancer cell line, PARP1 inhibition resulted in DNA damage with viability decrease, G2/M arrest as well as apoptosis. In contrast, single PI3K inhibition induced G1 arrest along with retarded cell proliferation. However, it was noted that combination of PARP inhibitor and PI3K regulator could exert synergetic function to evidently decrease cell proliferation compared with PARP inhibition alone, which was also confirmed by in vivo antitumor assay using xenograft tumor models. Collectively, our results offer an alternative but superior strategy for the therapy of BRCA1‐deficient human breast cancers which may benefit the clinical applications.
Acute effect of an amino acid mixture in the rat glycemic profile
Authors: Pena Maria J. , Guerreiro Susana G. , Rocha Júlio C. , Morais Tiago , Pereira Sofia S. , Monteiro Mariana P. , Borges Nuno
Published: March 2019

Amino acid mixtures (AAM) are protein substitutes used for phenylketonuria treatment, but their metabolic effects have not been well characterized. The objective of this study was to compare the acute glycemic response to free amino acids (free AA) from AAM with the response to intact protein (iProtein). Male Wistar rats (n = 14) were administered by gavage a bolus of free AA (n = 7) or iProtein as albumin (n = 7) containing equivalent amounts of nitrogen. Blood glucose and insulin levels were measured at baseline and 15, 30, 60 and 120 minutes later, when gut GLP‐1 content and pancreatic insulin, GLP‐1 receptor and Ki67 expression were quantified at 120 minutes time point. After AAM, glucose area under the curve (free AA vs iProtein; P < 0.01), serum insulin levels at 120 minutes (free AA vs iProtein;
P < 0.05), colon GLP‐1 content (free AA vs iProtein;
P < 0.01), pancreatic GLP‐1 receptor (free AA vs iProtein;
P < 0.01) and insulin expression (free AA vs iProtein;
p < 0.01) were significantly lower as compared with iProtein. AAM increased Ki67 expression in pancreatic islets (free AA vs iProtein;
P < 0.05). In conclusion, this study demonstrated that acute response to AAM differs from iProtein and is characterized by a lower glucose excursion, along with a decrease in gut GLP‐1 and pancreatic GLP‐1 receptor and insulin. This data suggests the modulation of glycemia by free AA is mediated by the incretin axis.
A comparison of noninvasive methods for early detection of hemorrhage: Inferior vena cava ultrasonography and spectrophotometric hemoglobin levels
Authors: Yamanoglu Adnan , Celebi Yamanoglu Nalan Gokce , Sogut Ozgur , Yigit Mehmet , Tas Demet , Saclı Neslihan , Topal Fatih Esad
Published: March 2019

Objectives

Blood hemoglobin concentration measurements using a spectrophotometric method (SpHb), and inferior vena cava ultrasonography (IVC‐US) are noninvasive methods used to follow‐up hemorrhages. We compared their efficacy using voluntary blood donation as a model of moderate (approx. 500 mL) blood loss.

Methods

In this prospective observational study enrolling blood‐donor volunteers (BD) and matched controls, we recorded SpHb, IVC diameters, and vital signs. Changes in variables from baseline were compared between BD and controls using the paired t test and Wilcoxon signed rank test.

Results

We included 118 subjects in the BD group and 95 healthy subjects in the control group. Changes in IVC maximum diameter, IVC minimum diameter, pulse rate, mean arterial pressure, pulse pressure, and shock index, but not in other variables, were significantly different in the BD and the control group (P < 0.05). IVCmax ≥1.1 mm yielded a 74% sensitivity and 77% specificity (PPV 79.8%, NPV 70.2%) in detecting early hemorrhage. With these cutoff values, IVCmax or PR reached a 90% sensitivity, while IVCmin and PR reached 98% specificity.

Conclusions

IVC ultrasound may be superior to SpHb in predicting blood loss and may be useful in addition to vital signs for its follow‐up.
Investigating GABA concentrations measured with macromolecule suppressed and unsuppressed MEGA‐PRESS MR spectroscopy and their relationship with BOLD responses in the occipital cortex
Authors: Duncan Niall W. , Zhang Jianfeng , Northoff Georg , Weng Xuchu
Published: March 2019

Background

A combination of magnetic resonance spectroscopy (MRS) and functional (f)MRI is a promising method for studying brain activity. Negative results have, however, produced uncertainty as to the validity of the approach. Using a MEGA‐PRESS sequence adapted to suppress the macromolecule signal (GABA–) has been suggested as a key methodological improvement, but there is some doubt as to the relationship between such estimates and those from the standard sequence (GABA+), making interpretation difficult.

Purpose

To investigate the relationship between GABA+ and GABA– estimates from the posterior cingulate and occipital cortices. The second aim was to test for a correlation between occipital GABA and blood oxygenation level‐dependent (BOLD) responses in the visual cortex to establish which of the two MEGA‐PRESS sequences was more related to the functional responses.

Study Type

Prospective.

Subjects

Thirty‐one healthy participants.

Field Strength/Sequence

3T/single‐voxel 1H‐MRS and gradient‐echo echo planar imaging (EPI).

Assessment

GABA estimates were made using the Gannet toolbox. fMRI data were analyzed with FSL and Python scripts.

Statistical Test

Relationships between different variables were tested with Pearson's correlation.

Results

GABA+ and GABA– concentrations were found to be correlated in both regions (r = 0.52, 95% confidence interval [CI] = 0.35 0.66, pFDR = 0.002). No relationship was found between either the GABA+ or the GABA– concentrations and the amplitude of the BOLD response in the occipital cortex (GABA+, r = –0.14, pFDR > 0.1; GABA–, r = –0.29, pFDR >0.1). However, adding these results to those of prior studies in a meta‐analysis of correlation coefficients did provide overall support for a negative correlation between GABA and BOLD response amplitudes (r = –0.39, 95% CI = –0.15–0.64).

Data Conclusion

The current findings highlight potential methodological issues that continue to interfere with relating MRS GABA estimates with fMRI responses but, taken in sum, provide support for this general approach.

Level of Evidence: 1

Technical Efficacy: Stage 1

J. Magn. Reson. Imaging 2019;50:1285–1294.
Can shared value and entrepreneurship contribute to SME development within rural locations?
Authors: Blanchard Kevin , Gray David
Published: March 2019

The study tests the view that shared value indices are or similar to that of entrepreneurial awareness, both in their tacit and strategic decision‐making abilities. A survey of 23 rural and remote rural businesses was carried in order to examine how and why they made specific judgments within their daily and longer‐term business decision making. The literature indicates that both concepts do have similar traits/characteristically, and also that the two areas may be both mutually similar and have synergies founded within their desired outcomes and centered on the business community. The concept of shared value as a mechanism for profit generating is accepted, but this is tempered with the ability to bring together visions of a shared nature within both customer base and business. In such circumstances the synergistic effect of such strategies becomes blurred and transcends into other business disciplines, which may have very similar outcomes. The survey found that both areas of test shared a high level of similarity, but geographical location had no effect on the level of application.
Cover Image, Volume 99, Issue 6
Authors: Su Ruihua , Li Tangfei , Fan Daming , Huang Jianlian , Zhao Jianxin , Yan Bowen , Zhou Wenguo , Zhang Wenhai , Zhang Hao
Published: March 2019

The cover image is based on the Research Article The inhibition mechanism of Є‐polylysine against Bacillus cereus emerging in surimi gel during refrigerated storage by Ruihua Su et al., DOI: 10.1002/jsfa.9505.

image
Characterization of permethrin resistance in a Musca domestica strain: resistance development, cross‐resistance potential and realized heritability
Authors: Khan Hafiz Azhar Ali
Published: March 2019

Background

Permethrin (a pyrethroid) has been recommended for the management of a number of insect pests, including Musca domestica. Recently, resistance to permethrin has been reported from the Punjab province, Pakistan, which necessitates the need to manage the resistance problem. For this reason, a field strain of M. domestica was selected with permethrin for ten consecutive generations (G1–G10) to determine the risk assessment, the rapidity with which permethrin resistance can develop, and the presence or absence of the cross‐resistance phenomenon.

Results

The results revealed that permethrin resistance increased very quickly in response to selection experiments. The resistance ratio (RR) value increased by 16.04‐ to 605.92‐fold and the LD50 value increased by 100.22 to 3787.08 ng fly−1 after selection experiments. Moreover, the increase in LD50 value remained stable when the selected strain (Perm‐SEL) was cultured in the absence of permethrin for the next five generations (G11–G15). The results revealed the possibility of minor cross‐resistance in the Perm‐SEL strain with β‐cyfluthrin and deltamethrin, and lack of cross‐resistance with imidacloprid and spinosad. The realized heritability (h2) value for the Perm‐SEL strain was 0.23. Assuming a mean slope value of 1.27 and an h2 value of 0.23, then ten to four generations would be estimated for a 10‐fold increase in the LD50 values at 50–90% selection intensity, respectively.

Conclusion

The results of present study revealed high risk for permethrin resistance development under continuous selection pressure. Permethrin resistance developed very quickly under laboratory conditions, which might reflect the likelihood of resistance evolution in field conditions if permethrin selection pressure holds for a long time. © 2019 Society of Chemical Industry
Modulation of the urban boundary‐layer heat budget by a heatwave
Authors: Wang Liang , Li Dan
Published: March 2019

Previous studies on urban heatwaves (HWs) often focused on the surface and near‐surface thermal conditions, but the urban boundary layer under HW conditions is less studied. This study examines the urban boundary‐layer heat budget over the Phoenix metropolitan area throughout a HW event in June 2016 using the Weather Research and Forecasting (WRF) model. The simulations are first validated against a wide range of observational data, including radiosonde, aircraft, weather station, and flux tower measurements. Then the boundary‐layer heat budget integrated over the urban area is examined. It is found that the surface sensible‐heat flux plays a major role in heating the urban boundary layer during daytime. The warming rate of the urban boundary layer is modulated by the large‐scale subsidence and the horizontal advection throughout the HW period, which however largely cancel each other due to the mass balance constraint. Our findings suggest that the traditional one‐dimensional convective boundary‐layer model may be more applicable than its original derivation implies.
Get an insider's glimpse into potential impact of esports
Authors: McCarthy Claudine
Published: March 2019

CLEARWATER, FLA. — Brace for the reverberating impact of esports on your college campus. Whether you recognize it or not, esports have already taken up residence in the life of your campus community. And while there's nothing you can do to prevent esports' influence, you can play a role in forming your school's relationship to esports to make the most of the opportunities while limiting the detrimental effects of this emerging sport — but only if you take action now.
Honeycomb‐Inspired Heterogeneous Bimetallic Co–Mo Oxide Nanoarchitectures for High‐Rate Electrochemical Lithium Storage
Authors: Mei Jun , Liao Ting , Spratt Henry , Ayoko Godwin A. , Zhao X. S. , Sun Ziqi
Published: March 2019

Nanostructure engineering has been proved to be an efficient approach for improving electrochemical properties for energy storage by accommodating volume changes, facilitating rapid mass transport paths, and enlarging ion storage sites and interfaces. The well‐designed fine nanostructures, unfortunately, are usually destroyed during long‐term cycles and ultimately lose their structural advantages. Herein, stimulated by the extraordinary structural stability, robust mechanical properties, and salient ventilation capacity of natural honeycomb species, bioinspired heterogeneous bimetallic Co–Mo oxide (CoMoOx) nanoarchitectures assembled from 2D nanounits are successfully fabricated via a molybdenum‐mediated self‐assembly strategy for improving the rate capability of electrochemical lithium storage devices. Owing to the robust structural stability and the ultrathin 2D wall structure, CoMoOx nanostructures present well‐maintained honeycomb‐like structure, rapid capacitive insertion–desertion behaviors, and thus significantly enhanced lithium ion storage performance at high rates (5.0 A g−1). It is also revealed that the reversible transition of cobalt and molybdenum phases closely associated with the ultrathin 2D wall structures greatly contribute to the outstanding electrochemical lithium storage performances. This attractive integration of structural and functional advantages achieved by learning from nature offers new insights into the design of cost‐effective electrode materials for high‐performance energy devices.
Scaling limits of dS vacua and the swampland
Authors: Banlaki Andreas , Chowdhury Abhishek , Roupec Christoph , Wrase Timm
Published: March 2019

Abstract

We discuss the properties of massive type IIA flux compactifications. In particular, we investigate in which case one can obtain dS vacua at large volume and small coupling. We support a general discussion of scaling symmetries with the analysis of a concrete example. We find that the large volume and weak coupling limit requires a large number of O6-planes. Since these are bound for any given compactification space one cannot get arbitrarily good control over α′ and string loop corrections.
Enhanced n-body annihilation of dark matter and its indirect signatures
Authors: Namjoo Mohammad Hossein , Slatyer Tracy R. , Wu Chih-Liang
Published: March 2019

Abstract

We examine the possible indirect signatures of dark matter annihilation processes with a non-standard scaling with the dark matter density, and in particular the case where more than two dark matter particles participate in the annihilation process. We point out that such processes can be strongly enhanced at low velocities without violating unitarity, similar to Sommerfeld enhancement in the standard case of two-body annihilation, potentially leading to visible signals in indirect searches. We study in detail the impact of such multi-body annihilations on the ionization history of the universe and consequently the cosmic microwave background, and find that unlike in the two-body case, the dominant signal can naturally arise from the end of the cosmic dark ages, after the onset of structure formation. We examine the complementary constraints from the Galactic Center, Galactic halo, and galaxy clusters, and outline the circumstances under which each search would give rise to the strongest constraints. We also show that if there is a population of ultra-compact dense dark matter clumps present in the Milky Way with sufficiently steep density profile, then it might be possible to detect point sources illuminated by multi-body annihilation, even if there is no large low-velocity enhancement. Finally, we provide a case study of a model where 3-body annihilation dominates the freezeout process, and in particular the resonant regime where a large low-velocity enhancement is naturally generated.
The propagator seagull: general evaluation of a two loop diagram
Authors: Kol Barak , Shir Ruth
Published: March 2019

Abstract

We study a two loop diagram of propagator type with general parameters through the Symmetries of Feynman Integrals (SFI) method. We present the SFI group and equation system, the group invariant in parameter space and a general representation as a line integral over simpler diagrams. We present close form expressions for three sectors, each with three or four energy scales, for any spacetime dimension d as well as the ϵ expansion. We determine the singular locus and the diagram’s value on it.
dS/dS and $$ T\overline{T} $$
Authors: Gorbenko Victor , Silverstein Eva , Torroba Gonzalo
Published: March 2019

Abstract

The

$$ T\overline{T} $$

T

T
¯

deformation of a conformal field theory has a dual description as a cutoff AdS
3 spacetime, at least at the level of pure 3d gravity. We generalize this deformation in such a way that it builds up a patch of bulk dS
3 spacetime instead. At each step along the trajectory in the space of 2d theories, the theory is deformed by a specific combination of

$$ T\overline{T} $$

T

T
¯

and the two-dimensional cosmological constant. This provides a concrete holographic dual for the warped throat on the gravity side of the dS/dS duality, at leading order in large central charge. We also analyze a sequence of excitations of this throat on both sides of the duality, as well as the entanglement entropy. Our results point toward a mechanism for obtaining de Sitter solutions starting from seed conformal field theories with AdS duals.
Youth and young adult dating relationship dynamics and subsequent abusive outcomes
Authors: Mumford Elizabeth A. , Liu Weiwei , Taylor Bruce G.
Published: March 2019

Introduction

In order to prevent youth and young adult partner abuse, it is necessary to have a better understanding of dating relationship dynamics as the context for potential abusive interactions.

Methods

Youth and young adults (ages 10–18 at baseline) were surveyed along with a matched parent/caregiver. Data, including parent and youth responses (n = 437 youth/parent dyads), are drawn from the nationally representative Survey on Teen Relationships and Intimate Violence (STRiV).

Results

Applying latent class analytic techniques with seven different positive and problematic descriptors of dating relationships, this study found four classes of relationship dynamics representing healthy, unhealthy, intense, and disengaged relationships. The intense relationship dynamic class exhibits the strongest associations with reports of any youth and young adult partner abuse, as well as distinctly with the subtypes of psychological, physical, and sexual victimization and perpetration.

Conclusions

Results demonstrate the importance of clinicians, parents and other responsible adults attending to an array of youth and young adult dating relationship dynamics rather than single indicators, to assess youth and young adult risk for involvement in abusive relationships.
Advances in reducing cardiovascular risk in the management of patients with type 2 diabetes mellitus
Authors: Hu Ying
Published: March 2019

Treatment intended to lower cardiovascular (CV) risk in patients with diabetes has always been a primary goal of diabetes treatment. Due to the subdued effects of reducing hemoglobin A1c (HbA1c) on macrovascular complications, controlling other CV risk factors such as hypertension and hyperlipidemia instead of hyperglycemia has been the mainstay treatment to improve CV outcome in patients with type 2 diabetes mellitus (T2DM) until recent years. This review is intended to summarize and compare the results from the available cardiovascular outcome trials (CVOTs) for the two classes of glucose lowering drug: sodium‐glucose co‐transporter 2 inhibitor (SGLT2i) and glucagon‐like peptide‐1 receptor agonist (GLP‐1 RA). The results including the EMPA‐REG, CANVAS program and DECLARE‐TIMI 58 trials for SGLT2i, and the ELIXA, LEADER, SUSTAIN‐6, EXSCEL and HARMONY trials for GLP‐1 RA were summarized. The potential mechanisms of these CV beneficial effects and the optimal CV risk reduction treatment in patients with T2DM based on patient risk stratification and evidence from these CVOTs in real‐world setting were discussed.
Autonomous soaring using a simplified MPC approach
Authors: Pogorzelski G. , Silvestre F. J.
Published: March 2019

The need for efficient propulsion systems allied to increasingly more challenging fixed-wing UAV mission requirements has led to recent research on the autonomous thermal soaring field with promising results. As part of that effort, the feasibility and advantages of model predictive control (MPC)-based guidance and control algorithms capable of extracting energy from natural occurring updrafts have already been demonstrated numerically. However, given the nature of the dominant atmospheric phenomena and the amplitude of the required manoeuvres, a non-linear optimal control problem results. Depending on the adopted prediction horizon length, it may be of large order, leading to implementation and real-time operation difficulties. Knowing that, an alternative MPC-based autonomous thermal soaring controller is presented herein. It is designed to yield a simple and small non-linear programming problem to be solved online. In order to accomplish that, linear prediction schemes are employed to impose the differential constraints, thus no extra variables are added to the problem and only linear bound restrictions result. For capturing the governing non-linear effects during the climb phase, a simplified representation of the aircraft kinematics with quasi-steady corrections is used by the controller internal model. Flight simulation results using a 3 degree-of-freedom model subjected to a randomly generated time varying thermal environment show that the aircraft is able to locate and exploit updrafts, suggesting that the proposed algorithm is a feasible MPC strategy to be employed in a practical application.
Influences of forested and grassland vegetation on late Quaternary ecosystem development as recorded in lacustrine sediments
Authors: McLauchlan Kendra K. , Lascu Ioan , Mellicant Emily , Scharping Robert J. , Williams Joseph J.
Published: March 2019

Geosphere-biosphere interactions are ubiquitous features of the Earth surface, yet the development of interactions between newly exposed lithologic surfaces and colonizing plants during primary succession after glaciation are lacking temporal detail. To assess the nature, rate, and magnitude of vegetation influence on parent material and sediment delivery, we analyzed ecosystem and geochemical proxies from lacustrine sediment cores at a grassland site and a forested site in the northern United States. Over time, terrigenous inputs declined at both sites, with increasing amounts of organic inputs toward present. The similarities between sites were striking given that the grassland sequence began in the Early Holocene, and the forested sequence began after the last glacial maximum. Multiple mechanisms of chemical weathering, hydrologic transport, and changes in source material potentially contribute to this pattern. Although there were strong links between vegetation composition and nitrogen cycling at each site, it appears that changes in forest type, or from oak woodland to grassland, did not exert a large influence on elemental (K, Ti, Si, Ca, Fe, Mn, and S) abundance in the sedimentary sequences. Rather, other factors in the catchment-lake system determined the temporal sequence of elemental abundance.
Cost-Effectiveness of Pain Management Strategies in Advanced Cancer
Authors: Meads David M. , O'Dwyer John L. , Hulme Claire T. , Lopez Rocio Rodriguez , Bennett Michael I.
Published: March 2019

Objectives

Uncontrolled pain in advanced cancer is a common problem and has significant impact on individuals’ quality of life and use of healthcare resources. Interventions to help manage pain at the end of life are available, but there is limited economic evidence to support their wider implementation. We conducted a case study economic evaluation of two pain self-management interventions (PainCheck and Tackling Cancer Pain Toolkit [TCPT]) compared with usual care.

Methods

We generated a decision-analytic model to facilitate the evaluation. This modelled the survival of individuals at the end of life as they moved through pain severity categories. Intervention effectiveness was based on published meta-analyses results. The evaluation was conducted from the perspective of the U.K. health service provider and reported cost per quality-adjusted life-year (QALY).

Results

PainCheck and TCPT were cheaper (respective incremental costs -GBP148 [-EUR168.53] and -GBP474 [-EUR539.74]) and more effective (respective incremental QALYs of 0.010 and 0.013) than usual care. There was a 65 percent and 99.5 percent chance of cost-effectiveness for PainCheck and TCPT, respectively. Results were relatively robust to sensitivity analyses. The most important driver of cost-effectiveness was level of pain reduction (intervention effectiveness). Although cost savings were modest per patient, these were considerable when accounting for the number of potential intervention beneficiaries.

Conclusions

Educational and monitoring/feedback interventions have the potential to be cost-effective. Economic evaluations based on estimates of effectiveness from published meta-analyses and using a decision modeling approach can support commissioning decisions and implementation of pain management strategies.
Music, the Realist Conception of Art and the Materialist Conception of History
Authors: HAMMEL STEPHAN
Published: March 2019

Our fraught political moment is a propitious one for renewing the Marxist approach to music. Because that approach has consistently been folded into a more general Marxist discourse on art and aesthetics, any attempt must begin by revisiting what is essential to that discourse. I take its keystone to be the realist conception of art. This conception holds that artworks are a means by which at least some of their appreciators come to know truths about the world outside consciousness. Insofar as they are representational, painting, fiction, music, and drama potentially constitute vehicles for coming to understand the real world. Artistic representation on this view is understood to be analogous to mental representation.

Previous studies of Marxist aesthetics have followed Maurice Merleau-Ponty in making a sharp distinction between ‘Eastern’ and ‘Western’ branches of the tradition. The Eastern, beleaguered by the exigencies of Communist Party rule is often presented as the corrupt twin of the Western. The latter, developed in relative freedom and informed by a Hegelian legacy suppressed by Stalinism, alone commands theoretical, rather than merely historical, interest. This article departs from this Cold War framework in arguing that the Hegelian strand in Marxist aesthetics grows out of its Bolshevik predecessor and, crucially, shares with it a realist conception of art. After reconstructing the emergence and development of this conception (paying special attention to how music is directly addressed in the literature), I evaluate the compatibility of the realist conception of art with the materialist conception of history as it is found in Marx and Engels. I ultimately argue that moving past the realist conception of art is key to renewing the Marxist approach to music for our time.
1968: Mythology Matters
Authors: HILL SARAH
Published: March 2019

We are now reaching the last flurry of half-century commemorations of the 1960s. What is striking in these backwards glances – most recently, fifty years since 1967’s Summer of Love, and fifty years since ‘1968’ – is the truncation of events, the conflation of ideas, the simplification of meaning. Years and eras are impossible to encapsulate in sound bites or longer narratives of public memorialization, so music often serves as a convenient shorthand; yet popular songs of 1967 and 1968 only occasionally spoke to contemporary events, and more often skated over the surface of deep cultural rifts and political upheaval. What we now retain is a sort of shared mythology – 1967 was peaceful, 1968 was violent – that complicates our ability to see the past in the present. As I aim to show here, the 1960s continue to resonate today in ways that force us to confront history, for as William Faulkner wrote, ‘the past is never dead. It's not even past.’
From a model of peace to a model of conflict: The effect of architectural modernization on the Syrian urban and social make-up
Authors: Al-Sabouni Marwa
Published: March 2019

From a land called the “Cradle of Civilizations” to one that is now described as “apocalyptic” and “one of the most dangerous places on Earth”, Syria may have no more critical moment than the current crisis to reflect on what is taking it down this terrifyingly dark path. We resort to history in order to decipher the mysteries of the present, and there is no more honest and direct history than that of the built environment: a concrete object that tells the narratives not only of the winners, the wealthy and the powerful, but also of those who were brushed aside, cut apart and walked over.

This Opinion Note argues that reversing the process which led to the loss of home and the loss of urban fabric is the foundation of reclaiming these as essential elements of recovery after war and destruction. It examines four areas of transformation where modern urban planning and architecture have left their marks on the Levantine city, to give a clearer understanding of the role of architecture and where to begin in the rebuilding.
Mitigation of Extreme Ocean Anoxic Event Conditions by Organic Matter Sulfurization
Authors: Hülse D. , Arndt S. , Ridgwell A.
Published: March 2019

Past occurrences of widespread and severe anoxia in the ocean have frequently been associated with abundant geological evidence for free hydrogen sulfide (H2S) in the water column, so‐called euxinic conditions. Free H2S may react with, and modify, the chemical structure of organic matter settling through the water column and in marine sediments, with hypothesized implications for carbon sequestration. Here, taking the example of Ocean Anoxic Event 2, we explore the potential impact of organic matter sulfurization on marine carbon and oxygen cycling by means of Earth system modeling. Our model experiments demonstrate that rapid sulfurization (ksulf≥ = 105 M−1 year−1) of organic matter in the water column can drive a more than 30% enhancement of organic carbon preservation and burial in marine sediments and hence help accelerate climate cooling and Ocean Anoxic Event 2 recovery. As a consequence of organic matter sulfurization, we also find that H2S can be rapidly scavenged and the euxinic ocean volume reduced by up to 80%—helping reoxygenate the ocean as well as reducing toxic H2S emissions to the atmosphere, with potential implications for the kill mechanism at the end‐Permian. Finally, we find that the addition of organic matter sulfurization induces a series of additional feedbacks, including further atmospheric CO2 drawdown and ocean reoxygenation by the creation of a previously unrecognized net source of alkalinity to the ocean as H2S is scavenged and buried.
Endogenous dopamine release under transcranial direct-current stimulation governs enhanced attention: a study with positron emission tomography
Authors: Fukai Mina , Bunai Tomoyasu , Hirosawa Tetsu , Kikuchi Mitsuru , Ito Shigeru , Minabe Yoshio , Ouchi Yasuomi
Published: March 2019

Transcranial direct-current stimulation (tDCS) to the dorsolateral prefrontal cortex (DLPFC) has been established as an effective and noninvasive method to modulate cognitive function. Nevertheless, the mechanisms causing those cognitive changes under the tDCS remain largely unknown. We strove to elucidate the cognito-biological relation under the tDCS condition by examining whether the dopamine system activated by tDCS is involved in cognitive changes in human participants, or not. To evaluate the dopamine system, we used [11C]-raclopride positron emission tomography (PET) scanning: 20 healthy men underwent two [11C]-raclopride PET scans and subsequent neuropsychological tests. One scan was conducted after tDCS to the DLPFC. One was conducted after sham stimulation (control). Results of [11C]-raclopride PET measurements demonstrate that tDCS to the DLPFC caused dopamine release in the right ventral striatum. Neuropsychological tests for attentiveness revealed that tDCS to the DLPFC-enhanced participants’ accuracy. Moreover, this effect was correlated significantly with dopamine release. This finding provides clinico-biological evidence, demonstrating that enhancement of dopamine signaling by tDCS in the ventral striatum is associated with attention enhancement.
ATG5-mediated autophagy suppresses NF-κB signaling to limit epithelial inflammatory response to kidney injury
Authors: Peng Xuan , Wang Yating , Li Huiyan , Fan Jinjin , Shen Jiani , Yu Xueqing , Zhou Yi , Mao Haiping
Published: March 2019

G2/M-arrested proximal tubular epithelial cells (TECs) after renal injury are linked to increased cytokines production. ATG5-mediated autophagy in proximal TECs has recently been shown to protect against G2/M cell cycle arrest and renal fibrosis. However, the impacts of autophagy in regulating inflammatorily response mounted by injured TECs remains largely unknown. In the present study, we investigated whether ATG5 acts as an innate immune suppressor in proximal TECs during kidney injury. Using the unilateral ureteric obstruction model in proximal tubule-specific autophagy-deficient mice, we demonstrated that ablation of epithelial ATG5 genes markedly impaired autophagy, resulting in enhanced nuclear factor κB (NF-κB) activation, macrophage and lymphocyte infiltration, and proinflammatory cytokines production in obstructed kidneys, as compared with wild-type mice. Following stimulation with angiotensin II (Ang II), siRNA silencing of ATG5 in cultured HK-2 cells or ATG5-deficient primary proximal TECs produced more cytokines, including IL-1β, IL-6, and TNF-α than did their control cells. Overexpressed ATG5, but not the autophagy-incompetent ATG5 mutant K130R in HK-2 cells, rendered resistant to Ang II-induced inflammatory response. Immunofluorescence assay indicated that ATG5 and p65 colocalized in the nucleus and cytoplasm, and their interaction was verified in immunoprecipitation assay from HEK-293T cell extracts. Genetic downregulation of endogenous ATG5 increased Ang II-induced phosphorylation and nuclear translocation of p65 and transcriptional activity of NF-κB, whereas the overexpressed ATG5, rather than ATG5 mutant K130R, hampered activation of NF-κB signaling, suggest an autophagy-dependent anti-inflammatory effect of ATG5. Further, pharmacological manipulation of autophagy yielded similar results both in vivo and in vitro. Additionally, JSH-23, a specific inhibitor of NF-κB nuclear translocation, rescued Ang II-driven IL-1β production in ATG5 siRNA-treated cells and decreased the proportion of cells in G2/M phase. In conclusion, ATG5-mediated autophagy in tubules targets NF-κB signaling to protect against renal inflammation.
RBCK1 promotes p53 degradation via ubiquitination in renal cell carcinoma
Authors: Yu Sifan , Dai Jie , Ma Meng , Xu Tianxiao , Kong Yan , Cui Chuanliang , Chi Zhihong , Si Lu , Tang Huan , Yang Lu , Sheng Xinan , Guo Jun
Published: March 2019

Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies, and the incidence of RCC continues to rise worldwide. Although RCC can be treated with surgery at an early stages, the five-year survival rates have been observed to decline dramatically in patients with advanced disease. Most patients with RCC treated with cytotoxic or targeted drugs will develop resistance at some point during therapy. Thus, it is necessary to identify novel therapeutic targets for RCC. Here, we found that RANBP2-type and C3HC4-type zinc finger-containing 1 (RBCK1) expression was upregulated in human RCC samples. Analysis of multiple public databases revealed the correlation between RBCK1 expression and poor prognosis in RCC patients. Subsequently, we performed RBCK1 depletion experiments in RCC cells that severely affected the in vivo and in vitro proliferation of renal cancer cells. The effects of RBCK1 on cell proliferation could be rescued with p53 expression knockdown in two cell lines expressing wild-type p53. Further experiments demonstrated that RBCK1 could facilitate p53 poly-ubiquitination and degradation by direct interaction with p53. Together, our results show that RBCK1 may serve as a promising target for RCC therapy by restoring p53 functions.
Sulforaphane metabolites inhibit migration and invasion via microtubule-mediated Claudins dysfunction or inhibition of autolysosome formation in human non-small cell lung cancer cells
Authors: Zheng Zhongnan , Lin Kai , Hu Yabin , Zhou Yan , Ding Xiaoyan , Wang Yalin , Wu Wei
Published: March 2019

Both sulforaphane-cysteine (SFN-Cys) and sulforaphane-N-acetyl-l-cysteine (SFN-NAC) inhibited cancer migration and invasion, but the underlying mechanisms were not clear. Here we uncovered via tissue microarray assay that high expression of invasion-associated Claudin-5 was correlated to malignant grades in human non-small cell lung cancer (NSCLC) cells. Further, SFN-Cys (10 µM) induced the accumulated phosphorylation of ERK1/2, leading to downregulation of Claudin-5 and upregulation of Claudin-7, and the decrease of Claudin-1 in SK-1 cells and increase of Claudin-1 in A549 cells; knockdown of Claudin-5 significantly reduced invasion, whereas knockdown of Claudin-7 increased invasion; knockdown of Claudin-1 reduced invasion in SK-1 cells, whereas it increased invasion in A549 cells, indicating that SFN-Cys regulated Claudins and inhibited invasion depending on Claudin isotypes and cell types. Furthermore, immunofluorescence staining showed that SFN-Cys triggered microtubule disruption and knockdown of α-tubulin downregulated Claudin-1, 5, and 7, and inhibited migration and invasion, indicating that microtubule disruption contributed to invasive inhibition. Co-immunoprecipitation and confocal microscopy observation showed that SFN-Cys lowered the interaction between α-tubulin and Claudin-1 or 5, or 7. Meanwhile, Western blotting and immunofluorescence staining showed that SFN-NAC (15 µM) downregulated α-tubulin resulting in microtubule disruption; knockdown of α-tubulin increased SFN-NAC-induced LC3 II accumulation in SK-1 cells. Combined with the inhibitor of autolysosome formation, Bafilomycin A1 (100 nM), SFN-NAC inhibited invasion via accumulating LC3 II and blocking formation of autolysosome. Further, SFN-NAC upregulated microtubule-stabilizing protein Tau; knockdown of Tau reduced LC3 II/LC3 I inhibiting migration and invasion. These results indicated that SFN-Cys inhibited invasion via microtubule-mediated Claudins dysfunction, but SFN-NAC inhibited invasion via microtubule-mediated inhibition of autolysosome formation in human NSCLC cells.
HSP70 is a negative regulator of NLRP3 inflammasome activation
Authors: Martine Pierre , Chevriaux Angélique , Derangère Valentin , Apetoh Lionel , Garrido Carmen , Ghiringhelli François , Rébé Cédric
Published: March 2019

The NOD-leucine rich repeat and pyrin containing protein 3 (NLRP3) inflammasome is a multi-protein complex, aimed at producing IL-1β in response to danger signals which must be tightly regulated. Here we investigated the importance of the stress sensor, Heat Shock Protein 70 (HSP70) on NLRP3 inflammasome activation. HSP70 deficiency leads to the worsening of NLRP3-dependent peritonitis in mice. HSP70 deficiency also enhances caspase-1 activation and IL-1β production in murine Bone Marrow-Derived Macrophages (BMDMs) under NLRP3 activator treatment in vitro. This observation is associated with an increased number and size of Apoptosis associated Speck-like protein containing a CARD domain (ASC)/NLRP3 specks. Conversely, the overexpression of HSP70 in BMDMs decreases caspase-1 activation and IL-1β production under NLRP3 activator treatment. HSP70 interacts with NLRP3 and this interaction is lost upon NLRP3 inflammasome activation. Heat shock inhibits NLRP3 inflammasome activation in vitro and inhibits peritonitis in mice. Therefore this study provides evidence on the inhibitory role of HSP70 on NLRP3 inflammasome and open the possibility of treating inflammatory diseases via HSP70 induction and/or by hyperthermia.
Retraction Note: Vibrio parahaemolyticus RhsP represents a widespread group of pro-effectors for type VI secretion systems
Authors: Jiang Nan , Tang Le , Xie Ruiqiang , Li Zhi , Burkinshaw Brianne , Liang Xiaoye , Sosa Dylan , Aravind L. , Dong Tao , Zhang Dapeng , Zheng Jun
Published: March 2019

This paper has been retracted.
Pervasive function and evidence for selection across standing genetic variation in S. cerevisiae
Authors: Jakobson Christopher M. , She Richard , Jarosz Daniel F.
Published: March 2019

Quantitative genetics aims to map genotype to phenotype, often with the goal of understanding how organisms evolved. However, it remains unclear whether the genetic variants identified are exemplary of evolution. Here we analyzed progeny of two wild Saccharomyces cerevisiae isolates to identify 195 loci underlying complex metabolic traits, resolving 107 to single polymorphisms with diverse molecular mechanisms. More than 20% of causal variants exhibited patterns of emergence inconsistent with neutrality. Moreover, contrary to drift-centric expectation, variation in diverse wild yeast isolates broadly exhibited this property: over 30% of shared natural variants exhibited phylogenetic signatures suggesting that they are not neutral. This pattern is likely attributable to both homoplasy and balancing selection on ancestral polymorphism. Variants that emerged repeatedly were more likely to have done so in isolates from the same ecological niche. Our results underscore the power of super-resolution mapping of ecologically relevant traits in understanding adaptation and evolution.
Author Correction: Universality of defect-skyrmion interaction profiles
Authors: Fernandes Imara Lima , Bouaziz Juba , Blügel Stefan , Lounis Samir
Published: March 2019

The original version of this Article contained an error in the Acknowledgements, which incorrectly omitted from the end the following: ‘We acknowledge the computing time granted by the JARA-HPC Vergabegremium and VSR commission on the supercomputer JURECA at Forschungszentrum Jülich.’ This has been corrected in both the PDF and HTML versions of the Article.