bluuebunny/crossref_metadata_2025 huggingface dataset:
Non-surface mass balance of glaciers in Iceland
Authors: Jóhannesson Tómas , Pálmason Bolli , Hjartarson Árni , Jarosch Alexander H. , Magnússon Eyjólfur , Belart Joaquín M. C. , Gudmundsson Magnús Tumi
Published: June 2020

Non-surface mass balance is non-negligible for glaciers in Iceland. Several Icelandic glaciers are in the neo-volcanic zone where a combination of geothermal activity, volcanic eruptions and geothermal heat flux much higher than the global average lead to basal melting close to 150 mm w.e. a−1for the Mýrdalsjökull ice cap and 75 mm w.e. a−1for the largest ice cap, Vatnajökull. Energy dissipation in the flow of water and ice is also rather large for the high-precipitation, temperate glaciers of Iceland resulting in internal and basal melting of 20–150 mm w.e. a−1. The total non-surface melting of glaciers in Iceland in 1995–2019 was 45–375 mm w.e. a−1on average for the main ice caps, and was largest for Mýrdalsjökull, the south side of Vatnajökull and Eyjafjallajökull. Geothermal melting, volcanic eruptions and the energy dissipation in the flow of water and ice, as well as calving, all contribute, and thus these components should be considered in mass-balance studies. For comparison, the average mass balance of glaciers in Iceland since 1995 is −500 to −1500 mm w.e. a−1. The non-surface mass balance corresponds to a total runoff contribution of 2.1 km3a−1of water from Iceland.
Ensuring safe growth of the geothermal energy sector in the Netherlands by proactively addressing risks and hazards
Authors: Jharap Graciela , van Leeuwen Laura P. , Mout Robert , van der Zee Wouter E. , Roos Femke M. , Muntendam-Bos Annemarie G.
Published: June 2020

The main objective of this paper is to give an overview of the risks seen in the exploration and production of geothermal energy from the viewpoint of the regulator. The risks are categorised as conventional risks, ultra-deep risks and enhancing factors. These risks are similar to those seen in the oil and gas industry, but the maturity of the geothermal sector in terms of managing such risks is much lower.

Another objective of this paper is to discuss how these risks are managed and mitigated by the sector and the supervisor, State Supervision of Mines (SodM). Portfolio operators developing multiple projects, using skilled employees and embracing continuous improvement are seen as the way forward for the sector to grow safely and sustainably.

This paper concludes that positive developments have started, but a lot of work still needs to be done to ensure safe growth of the geothermal energy sector.
Estimates for sums and gaps of eigenvalues of Laplacians on measure spaces
Authors: Deng Da-Wen , Ngai Sze-Man
Published: June 2020

For Laplacians defined by measures on a bounded domain in ℝn, we prove analogues of the classical eigenvalue estimates for the standard Laplacian: lower bound of sums of eigenvalues by Li and Yau, and gaps of consecutive eigenvalues by Payne, Pólya and Weinberger. This work is motivated by the study of spectral gaps for Laplacians on fractals.
Application of Thomson scattering to helicon plasma sources
Authors: Agnello R. , Andrebe Y. , Arnichand H. , Blanchard P. , De Kerchove T. , Furno I. , Howling A. A. , Jacquier R. , Sublet A.
Published: June 2020

The possibility of performing electron density and temperature measurements in a high power helicon plasma is a crucial issue in the framework of the AWAKE (Advanced WAKefield Experiment) project, which demonstrates acceleration of particles using

$\text{GeV}~\text{m}^{-1}$

electric fields in plasmas. For AWAKE, a helicon is currently envisaged as a candidate plasma source due to its capability for low electron and ion temperature, high electron density and production of an elongated plasma column. A plasma diagnostic to accurately determine the electron density in AWAKE regimes would be a valuable supporting tool. A demonstration Thomson scattering (TS) diagnostic was installed and successfully tested on the resonant antenna ion device (RAID) at the Swiss Plasma Center of Ecole Polytechnique Fédérale de Lausanne. RAID produces a helicon plasma column with characteristics similar to those of the AWAKE helicon source, and is therefore an optimal testbed for application to the AWAKE device. The spectrometer employed in RAID is based on polychromators which collect the light scattered by plasma electrons in spectrally filtered wavelength regions. Results from TS on RAID demonstrate conditions of electron density and temperature respectively of

$n_{e}=1.10\,(\pm 0.19)\times 10^{19}~\text{m}^{-3}$

and

$T_{e}=2.3\,(\pm 0.6)~\text{eV}$

in a steady-state discharge in an Ar plasma with 5 kW of RF power. If the same polychromator system is used for AWAKE, where the electron density attained is

$2\times 10^{20}~\text{m}^{-3}$

, the contribution to measurement error due to coherent scattering is

${\sim}2.5\,\%$

. Presented here are details of the TS diagnostic and the first tests in RAID, and the expectations for the system when employed on the AWAKE device.
SOFTWARE RELIABILITY BASED ON RENEWAL PROCESS MODELING FOR ERROR OCCURRENCE DUE TO EACH BUG WITH PERIODIC DEBUGGING SCHEDULE
Authors: Das Sudipta , Dewanji Anup , Kundu Subrata
Published: June 2020

The process of software testing usually involves the correction of a detected bug immediately upon detection. In this article, in contrast, we discuss continuous time testing of a software with periodic debugging in which bugs are corrected, instead of at the instants of their detection, at some pre-specified time points. Under the assumption of renewal distribution for the time between successive occurrence of a bug, maximum-likelihood estimation of the initial number of bugs in the software is considered, when the renewal distribution belongs to any general parametric family or is arbitrary. The asymptotic properties of the estimated model parameters are also discussed. Finally, we investigate the finite sample properties of the estimators, specially that of the number of initial number of bugs, through simulation.
Role of Policy in Best-Practice Dissemination: Informal Professional Advice Networks in Canadian Long-Term Care
Authors: Keefe Janice M. , Cranley Lisa , Berta Whitney B. , Taylor Deanne , Beacom Amanda M. , McAfee Erin , MacEachern Lauren E. , Boudreau Debra , Hall Jodi , Thompson Genevieve , Squires Janet E. , Wagg Adrian , Estabrooks Carole A.
Published: June 2020

This article examines provincial policy influence on long-term care (LTC) professionals’ advice-seeking networks in Canada’s Maritime provinces. The effects of facility ownership, geography, and region-specific political landscapes on LTC best-practice dissemination are examined. We used sociometric statistics and network sociograms, calculated from surveys with 169 senior leaders in LTC facilities, to identify advice-seeking network structures and to select 11 follow-up interview participants. Network structures were distinguished by density, sub-group number, opinion leader, and boundary spanner distribution. Network structure was affected by ownership model in Nova Scotia and Prince Edward Island, and by regional geography in New Brunswick. Political instability within each province’s LTC system negatively affected network actors’ capabilities to enact innovation. Moreover, provincial policy variations influence advice-seeking network structures, facilitating and constraining relationship development and networking. Consequently, local policy context is essential to informing dissemination strategy design or implementation.
Commentary: Whose suffering?
Authors: BUIJSEN MARTIN
Published: June 2020

Marije Brouwer et al. contend that collecting treatment experiences of newborns with life-threatening conditions can support both caregivers and parents in making difficult end-of-life decisions. They illustrate the importance of that understanding by narrating the heartbreaking story of the sisters Roos and Noor, two newborns in the last stage of their lives.1
ADDRESSING THE AUDIENCE: PAUL SAMUELSON, RADICAL ECONOMICS, AND TEXTBOOK MAKING, 1967–1973
Authors: Giraud Yann
Published: June 2020

Historians of economics rarely consider textbooks as more than passive receptacles of previously validated knowledge. Therefore, their active role in shaping the discipline and its image is seldom addressed. In this paper, I study the making of Paul Samuelson’s successive editions ofEconomicsfrom 1967 to 1973 as an instance of how textbooks stand at the crossroads between disciplinary knowledge, pedagogy, and larger political and societal concerns. In the mid-1960s, Economics, now at its sixth edition, was at the height of its success. Considered one cornerstone of modern economics, it was also at the center of a number of criticisms dealing with the current state of the economic discipline and its teaching in the universities. While the profession expressed its concern over the lack of relevance of economics to address the pressing issues of the day and pleaded for a new “problem-solving” approach to economic education, the late 1960s witnessed the emergence of a new generation of “radical” economists criticizing the economics orthodoxy. Their contention that mainstream theory had neglected the issues of class struggle and capitalist exploitation found a favorable echo among an increasingly politicized population. Using archival materials, I show how Samuelson, helped by his editorial team at McGraw-Hill, attempted to take into account these changes in order to ensure the continuing success of subsequent editions of his text in an increasingly competitive market. This study emphasizes Samuelson’s ambiguous attitude toward his contenders, revealing, on the one hand, his apparent openness to discussion and outsiders’ suggestions, and, on the other hand, his firm attachment to mildly liberal politics and aversion to Marxism, unchanged through revisions. It also helps refine a notion that is often invoked but never fully expounded in textbook studies: that of the audience.
Evolution as a Religion: Mary Midgley's Hopes and Fears
Authors: O'Hear Anthony
Published: June 2020

This paper considers Mary Midgley's views on evolution, especially as developed in her book Evolution as a Religion. In this she continues the critical campaign she waged against Dawkins’ notion of the selfish gene, but broadens her attack out to encompass many other thinkers (whom she calls the ‘Omega’ men), who are predicting dramatic and revolutionary futures for humanity, based supposedly on what evolutionary science tells us. Midgley argues that no such conclusions are scientifically warranted – hence evolution as a religion. Her own attempts to absolve Darwin himself from this sort of scientism, and to remove from him any taint of social Darwinism are criticised, particularly by reference to The Descent of Man. Something is then said about Midgley's own alternative view of nature and humanity, a more holistic view, which itself has religious overtones.
The Elusiveness of the Ethical: From Murdoch to Diamond
Authors: Lovibond Sabina
Published: June 2020

Cora Diamond is a powerful witness to the originality of Iris Murdoch's writings on ethics, showing how Murdoch is at variance with contemporary orthodoxy not just in respect of particular doctrines (no ‘ought’ from an ‘is’, etc.), but in her questioning of mainstream assumptions as to what constitutes the subject-matter of moral philosophy. Diamond celebrates Murdoch as an ally in her campaign against the ‘departmental’ conception of morality – the idea that moral thought is just one branch of thought among others – and highlights Murdoch's enduring belief in the ‘ubiquity of the moral quality inherent in consciousness’. In keeping with this belief, both philosophers affirm the value of general humanistic reflection on experience, an enterprise in which traditions of imaginative literature as well as of self-conscious theory can invite us to participate. While welcoming this vindication of the claims of ordinary (existentially embedded) moral intelligence, I will explore some difficulties flowing from the associated idea that ‘morality’ (in the guise of value-saturated human consciousness) is all-pervasive, and from the ‘perpetually-moralist’ account of our incentive to engage with fictional worlds.
Volunteers and Conscripts: Philippa Foot and the Amoralist
Authors: Krishna Nakul
Published: June 2020

Philippa Foot, like others of her philosophical generation, was much concerned with the status and authority of morality. How universal are its demands, and how dependent on the idiosyncrasies of individuals? In the early years of her career, she was persuaded that Kant and his twentieth-century followers had been wrong to insist on the centrality to morality of absolute and unconditionally binding moral imperatives. To that extent, she wrote, there was indeed ‘an element of deception in the official line about morality’. In this paper, I shall explore her early alternative: a system of merely ‘hypothetical’ imperatives, imperatives that depend on the motivations of particular individuals. Could so contingent a system deserve to be termed a morality? How revisionary a proposal was this, and how serious its costs? And how might we reconcile ourselves to a morality stripped of what she called the ‘fictions’ that surrounded it? Foot's early answer, tentative and exploratory, remains of interest, long after she herself abandoned it.
Depicting Human Form
Authors: Cumhaill Clare Mac
Published: June 2020

This paper involves constructive exegesis. I consider the contrast between morality and art as sketched in Philippa Foot's 1972 paper of the same name, ‘Morality and Art’. I then consider how her views might have shifted against the background of the conceptual landscape afforded by Natural Goodness (2001), though the topic of the relation of art and morality is not explicitly explored in that work. The method is to set out some textual fragments from Natural Goodness that can be arranged for a tentative Footian ‘aesthetics’. I bring them into conversation with some ideas from Iris Murdoch to elucidate what I think the import may be, for Foot, of depicting human form.
Using a citizens’ jury approach to determine a good nutrition resource for pregnant women
Authors: Coppell Kirsten J , Paterson Helen , Norton Joanna , Jeffs Emma , Hay-Smith E Jean C
Published: June 2020

Objective:

The development of user-friendly nutrition resources for pregnant women seldom involves end-users. This qualitative study used a citizens’ jury approach to determine if our modification of a longstanding, frequently used dietitian-informed diet and diabetes booklet was deemed to be a good healthy eating resource for pregnant women.

Design:

Midwives recruited thirteen first-time pregnant women not requiring specialist obstetric care or specialist dietetic advice for any reason. Participants were sent a copy of the modified healthy eating in pregnancy booklet prior to ‘jury day’. Five women were unable to attend the citizens’ jury citing reasons such as early labour. At the jury, five experts presented evidence. Participants adjourned, with an independent facilitator, to ‘deliberate’ as to whether the resource was suitable or not. The verdict was presented, and subsequent discussion was audio-recorded, transcribed and inductively content analysed.

Setting:

Southland, New Zealand.

Participants:

Pregnant women aged 19–35 years (n 8), of whom half had a household income <$NZ30 000.

Results:

The verdict was ‘Yes’; the resource was good. Three themes were derived: communication of health information, resource content and harm reduction in pregnancy. Based on these data, ways to enhance the quality and usability of the booklet were evident.

Conclusions:

Citizens’ juries can be used to obtain an independent assessment by end-users of health resources. Our modified diet and diabetes booklet was considered suitable for providing healthy eating advice to pregnant women. Inclusion of end-users’ perspectives is critical for end-user relevant content, comprehension and resource credibility.
Twins Reared Apart: Zygotic Division After Artificial Insemination/Twin Research Reviews: Selective Resuscitation of Premature Twins; Scientist Jailed for Editing Twins’ Genes; Sexual Arousal Patterns in MZ Twins Discordant for Sexual Orientation; MZ Twins With Jejuno-Ileal Atresia/Media Reports: Twin Girls’ Search for a Bone Marrow Donor; Puppy with a Possible Parasitic Twin; Twins in Silicon Valley; Surgical Separation of Craniopagus Twins; Twin-BasedNew Yorker MagazineCartoon; Twin Tragedies
Authors: Segal Nancy L.
Published: June 2020

This article opens with the brief life histories of reared-apart monozygotic (MZ) male twins. A New York City program that helped childless couples conceive via artificial insemination from the 1930s to the 1950s is examined as it related to these twins. The frequency with which pregnancies following assisted reproductive technology resulted in MZ twin pairs is also provided. Next, summaries of twin research concerning selective resuscitation, gene editing, sexual arousal and jejuno-ileal atresia are presented. The article ends with media reports of twin girls’ efforts to find a bone marrow donor for their father, possible parasitic twinning in a puppy, identical female twins’ business venture, the surgical separation of craniopagus twins, a twin-themed magazine cartoon and tragic events involving identical male twins.
Pricing Immigration
Authors: Hix Simon , Kaufmann Eric , Leeper Thomas J.
Published: June 2020

Immigration is highly salient for voters in Europe and the USA and has generated considerable academic debate about the causes of preferences over immigration. This debate centers around the relative influences of sociotropic or personal economic considerations, as well as noneconomic threats. We provide a test of the competing egocentric, sociotropic, and noneconomic paradigms using a novel constrained preference experiment in which respondents are asked to trade off preferred reductions in immigration levels with realistic estimates of the personal or societal costs associated with those reductions. This survey experiment, performed on a national sample of British YouGov panelists, allows us to measure the price-elasticity of the publicʼs preferences with regard to levels of European and non-European immigration. Respondents were willing to admit more immigrants when restriction carries economic costs, with egocentric considerations as important as sociotropic ones. People who voted for the UK to Leave the European Union in the 2016 referendum are less price-elastic than those voting Remain, indicating that noneconomic concerns are also important.1
Lagrangian Modeling of Mixing‐Limited Reactive Transport in Porous Media: Multirate Interaction by Exchange With the Mean
Authors: Sole‐Mari Guillem , Fernàndez‐Garcia Daniel , Sanchez‐Vila Xavier , Bolster Diogo
Published: June 2020

The presence of solute concentration fluctuations at spatial scales much below the scale of resolution is a major challenge for modeling reactive transport in porous media. Overlooking small‐scale fluctuations, which is the usual procedure, often results in strong disagreements between field observations and model predictions, including, but not limited to, the overestimation of effective reaction rates. Existing innovative approaches that account for local reactant segregation do not provide a general mathematical formulation for the generation, transport, and decay of these fluctuations and their impact on chemical reactions. We propose a Lagrangian formulation based on the random motion of fluid particles carrying solute concentrations whose departure from the local mean is relaxed through multirate interaction by exchange with the mean (MRIEM). We derive and analyze the macroscopic descriptionof the local concentration covariance that emerges from the model, showing its potential to simulate the dynamics of mixing‐limited processes. The action of hydrodynamic dispersion on coarse‐scale concentration gradients is responsible for the production of local concentration covariance, whereas covariance destruction stems from the local mixing process represented by the MRIEM formulation. The temporal evolution of integrated mixing metrics in two simple scenarios shows the trends that characterize fully resolved physical systems, such as a late‐time power law decay of the relative importance of incomplete mixing with respect to the total mixing. Experimental observations of mixing‐limited reactive transport are successfully reproduced by the model.
Removal of Ozone Air Pollution by Terrestrial Ecosystems
Authors: Clifton Olivia
Published: June 2020

Tropospheric ozone is removed at Earth’s surface through uptake by plant stomata and other nonstomatal deposition pathways, with impacts on air pollution, ecosystem health, and climate.
Neural responsivity to social rewards in autistic female youth
Authors: Lawrence Katherine E. , Hernandez Leanna M. , Eilbott Jeffrey , Jack Allison , Aylward Elizabeth , Gaab Nadine , Van Horn John D. , Bernier Raphael A. , Geschwind Daniel H. , McPartland James C. , Nelson Charles A. , Webb Sara J. , Pelphrey Kevin A. , Bookheimer Susan Y. , Dapretto Mirella ,   on behalf of the GENDAAR Consortium, Aylward Elizabeth , Bernier Raphael A. , Bookheimer Susan Y. , Dapretto Mirella , Gaab Nadine , Geschwind Daniel H. , Jack Allison , McPartland James C. , Nelson Charles A. , Pelphrey Kevin A. , Van Horn John D. , Webb Sara J. , Ankenman Katy , Corrigan Sarah , Depedro-Mercier Dianna , Guilford Desiree , Gupta Abha R. , Jacokes Zachary , Jeste Shafali , Keifer Cara M. , Kresse Anna , Libsack Erin , Lowe Jennifer K. , MacDonnell Erin , McDonald Nicole , Naples Adam , Neuhaus Emily , Sullivan Catherine A. W. , Tsapelas Heidi , Torgerson Carinna M. , Ventola Pamela , Welker Olivia , Wolf Julie
Published: June 2020

Autism is hypothesized to be in part driven by a reduced sensitivity to the inherently rewarding nature of social stimuli. Previous neuroimaging studies have indicated that autistic males do indeed display reduced neural activity to social rewards, but it is unknown whether this finding extends to autistic females, particularly as behavioral evidence suggests that affected females may not exhibit the same reduction in social motivation as their male peers. We therefore used functional magnetic resonance imaging to examine social reward processing during an instrumental implicit learning task in 154 children and adolescents (ages 8–17): 39 autistic girls, 43 autistic boys, 33 typically developing girls, and 39 typically developing boys. We found that autistic girls displayed increased activity to socially rewarding stimuli, including greater activity in the nucleus accumbens relative to autistic boys, as well as greater activity in lateral frontal cortices and the anterior insula compared with typically developing girls. These results demonstrate for the first time that autistic girls do not exhibit the same reduction in activity within social reward systems as autistic boys. Instead, autistic girls display increased neural activation to such stimuli in areas related to reward processing and salience detection. Our findings indicate that a reduced sensitivity to social rewards, as assessed with a rewarded instrumental implicit learning task, does not generalize to affected female youth and highlight the importance of studying potential sex differences in autism to improve our understanding of the condition and its heterogeneity.
No association between FKBP5 gene methylation and acute and long-term cortisol output
Authors: Alexander Nina , Kirschbaum Clemens , Stalder Tobias , Muehlhan Markus , Vogel Susanne
Published: June 2020

Prior studies identified DNA methylation (DNAM) changes in a regulatory region within the FK506 binding protein 5 (FKBP5) gene as a crucial mediator of long-term negative health outcomes following early adversity. A critical mechanism underlying this link, in turn, has been suggested to be epigenetically induced dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis. The purpose of this study was thus to investigate associations of FKBP5 DNAM with both acute and chronic cortisol output. Two hundred adults with differential exposure to childhood trauma (CT) were underwent a laboratory stressor (Trier Social Stress Test) and provided salivary samples for the analysis of acute cortisol stress responses. In addition, hair cortisol concentrations were determined as a valid measure of integrated long-term cortisol levels. Whole blood samples were drawn for DNAM analyses of FKBP5 intron 7 via bisulfite pyrosequencing. In contrast to most prior work, only healthy participants were included in order to disentangle the effects of trauma exposure per se from those related to mental disorders. First, our findings did not reveal strong evidence for a robust effect of CT on FKBP5 intron 7 DNAM status, even if genetic predisposition (rs1360780 genotype) was taken into account. Second, FKBP5 DNAM levels were found to be unrelated to acute cortisol stress reactivity and long-term cortisol concentration in hair. The failure to demonstrate a significant association between CT and FKBP5 DNAM in an exclusively healthy sample could be interpreted as suggesting that individuals’ mental health status may be a critical modulator of previously observed effects.
Δ-9-Tetrahydrocannabinol treatment during adolescence and alterations in the inhibitory networks of the adult prefrontal cortex in mice subjected to perinatal NMDA receptor antagonist injection and to postweaning social isolation
Authors: Garcia-Mompo Clara , Curto Yasmina , Carceller Hector , Gilabert-Juan Javier , Rodriguez-Flores Esther , Guirado Ramon , Nacher Juan
Published: June 2020

The prefrontal cortex (PFC) continues its development during adolescence and alterations in its structure and function, particularly of inhibitory networks, have been detected in schizophrenic patients. Since cannabis use during adolescence is a risk factor for this disease, our main objective was to investigate whether THC administration during this period might exacerbate alterations in prefrontocortical inhibitory networks in mice subjected to a perinatal injection of MK801 and postweaning social isolation. This double-hit model (DHM) combines a neurodevelopmental manipulation and the exposure to an aversive experience during early life; previous work has shown that DHM mice have important alterations in the structure and connectivity of PFC interneurons. In the present study we found that DHM had reductions in prepulse inhibition of the startle reflex (PPI), GAD67 expression and cingulate 1 cortex volume. Interestingly, THC by itself induced increases in PPI and decreases in the dendritic complexity of somatostatin expressing interneurons. Both THC and DHM reduced the density of parvalbumin expressing cells surrounded by perineuronal nets and, when combined, they disrupted the ratio between the density of puncta expressing excitatory and inhibitory markers. Our results support previous work showing alterations in parameters involving interneurons in similar animal models and schizophrenic patients. THC treatment does not modify further these parameters, but changes some others related also to interneurons and their plasticity, in some cases in the opposite direction to those induced by the DHM, suggesting a protective effect.
Impaired mitochondrial complex I function as a candidate driver in the biological stress response and a concomitant stress-induced brain metabolic reprogramming in male mice
Authors: Emmerzaal Tim L. , Preston Graeme , Geenen Bram , Verweij Vivienne , Wiesmann Maximilian , Vasileiou Elisavet , Grüter Femke , de Groot Corné , Schoorl Jeroen , de Veer Renske , Roelofs Monica , Arts Martijn , Hendriksen Yara , Klimars Eva , Donti Taraka R. , Graham Brett H. , Morava Eva , Rodenburg Richard J. , Kozicz Tamas
Published: June 2020

Mitochondria play a critical role in bioenergetics, enabling stress adaptation, and therefore, are central in biological stress responses and stress-related complex psychopathologies. To investigate the effect of mitochondrial dysfunction on the stress response and the impact on various biological domains linked to the pathobiology of depression, a novel mouse model was created. These mice harbor a gene trap in the first intron of the Ndufs4 gene (Ndufs4GT/GT mice), encoding the NDUFS4 protein, a structural component of complex I (CI), the first enzyme of the mitochondrial electron transport chain. We performed a comprehensive behavioral screening with a broad range of behavioral, physiological, and endocrine markers, high-resolution ex vivo brain imaging, brain immunohistochemistry, and multi-platform targeted mass spectrometry-based metabolomics. Ndufs4GT/GT mice presented with a 25% reduction of CI activity in the hippocampus, resulting in a relatively mild phenotype of reduced body weight, increased physical activity, decreased neurogenesis and neuroinflammation compared to WT littermates. Brain metabolite profiling revealed characteristic biosignatures discriminating Ndufs4GT/GT from WT mice. Specifically, we observed a reversed TCA cycle flux and rewiring of amino acid metabolism in the prefrontal cortex. Next, exposing mice to chronic variable stress (a model for depression-like behavior), we found that Ndufs4GT/GT mice showed altered stress response and coping strategies with a robust stress-associated reprogramming of amino acid metabolism. Our data suggest that impaired mitochondrial CI function is a candidate driver for altered stress reactivity and stress-induced brain metabolic reprogramming. These changes result in unique phenomic and metabolomic signatures distinguishing groups based on their mitochondrial genotype.
The lncRNA RUNX1-IT1 regulates C-FOS transcription by interacting with RUNX1 in the process of pancreatic cancer proliferation, migration and invasion
Authors: Liu Songsong , Zhang Junfeng , Yin Liangyu , Wang Xianxing , Zheng Yao , Zhang Yujun , Gu Jianyou , Yang Ludi , Yang Jiali , Zheng Ping , Jiang Yan , Shuai Ling , Cai Xiongwei , Wang Huaizhi
Published: June 2020

Numerous long noncoding RNAs (lncRNAs) are aberrantly expressed in pancreatic cancer (PC); however, their functions and mechanisms in cancer progression are largely unknown. In this study, we identified a novel PC-associated lncRNA, RUNX1-IT1, that was significantly upregulated in PC patient samples from multiple centers and associated with poor prognosis. In vitro and in vivo, alterations in RUNX1-IT1 expression markedly affected PC proliferation, migration and invasion. RUNX1-IT1 contributed to the progression of PC by interacting with the adjacent gene RUNX1. Rescue experiments showed that RUNX1 reduced the cancer-promoting effect of RUNX1-IT1. RNA-seq analysis after silencing RUNX1-IT1 and RUNX1 highlighted alterations in the common target C-FOS. Mechanistically, we demonstrated that RUNX1-IT1 was a trans-acting factor that participated in the proliferation, migration and invasion of PC by recruiting RUNX1 to the C-FOS gene promoter. Furthermore, RUNX1-IT1 enhanced the transcription of the RUNX1 gene, indicating its potential as a cis-regulatory RNA involved in the upstream regulation of RUNX1. Overall, RUNX1-IT1 is a crucial oncogenic lncRNA that activates C-FOS expression by regulating and recruiting RUNX1 and is a potential prognostic biomarker and therapeutic target for PC.
The Effect of Corrected Inflammation, Oxidative Stress and Endothelial Dysfunction on Fmd Levels in Patients with Selected Chronic Diseases: A Quasi-Experimental Study
Authors: Yilmaz Mahmut Ilker , Romano Micol , Basarali Mustafa Kemal , Elzagallaai Abdelbaset , Karaman Murat , Demir Zeynep , Demir Muhammet Fatih , Akcay Fatih , Seyrek Melik , Haksever Nuri , Piskin David , Cimaz Rolando , Rieder Michael J. , Demirkaya Erkan
Published: June 2020

While the pathophysiology of chronic disorders varies there are three basic mechanisms - inflammation, oxidative stress and endothelial dysfunction – that are common in many chronic diseases. However, the failure of these mechanisms to work synchronously can lead to morbidity complicating the course of many chronic diseases. We analyzed data of 178 patients from cohorts with selected chronic diseases in this quasi-experimental study. Endothelial dysfunction was determined by flow-mediated dilatation (FMD) and asymmetric dimethylarginine (ADMA) levels. Serum ADMA, high sensitive C-reactive protein (hs-CRP), serum PTX3, malondialdehyde (MDA), Cu/Zn-superoxide dismutase (Cu/Zn-SOD), glutathione peroxidase (GSH-Px) levels and FMD were studied in baseline and after 12 weeks of Morinda citrifolia (anti-atherosclerotic liquid- AAL), omega-3 (anti-inflammatory capsules- AIC) and extract with Alaskan blueberry (anti-oxidant liquid- AOL). Stepwise multivariate regression analysis was used to evaluate the association of FMD with clinical and serologic parameters. Serum ADMA, MDA, PTX3, hsCRP and albumin levels, and proteinuria were significantly decreased while CuZn-SOD, GSH-Px and FMD levels were significantly increased following AAL, AIC and AOL therapies. The FMD was negatively correlated with serum ADMA, MDA, PTX3, and hsCRP levels and positively correlated with CuZn-SOD and eGFR levels. ADMA and PTX3 levels were independently related to FMD both before and after AAL, AIC and AOL therapies. Our study shows that serum ADMA, MDA, PTX3 levels are associated with endothelial dysfunction in patients with selected chronic diseases. In addition, short-term AAL, AIC and AOL therapies significantly improves a number of parameters in our cohort and can normalize ADMA, PTX3, hsCRP and MDA levels.
A species-specific miRNA participates in biomineralization by targeting CDS regions of Prisilkin-39 and ACCBP in Pinctada fucata
Authors: Zhu Xuejing , Chen Yan , Zhang Zhen , Zhao Shuyan , Xie Liping , Zhang Rongqing
Published: June 2020

Biomineralization is a sophisticated biological process precisely regulated by multiple molecules and pathways. Accumulating miRNAs have been identified in invertebrates but their functions in biomineralization are poorly studied. Here, an oyster species-specific miRNA, novel_miR_1 was found to regulate biomineralization in Pinctada fucata. Target prediction showed that novel_miR_1 could target Prisilkin-39 and ACCBP by binding to their coding sequences (CDS). Tissue distribution analysis revealed that the expression level of novel_miR_1 was highest in the mantle, which was a key tissue participating in biomineralization. Gain-of-function assay in vivo showed that biomineralization-related genes including Prisilkin-39 and ACCBP were down-regulated and shell inner surfaces of both prismatic and nacreous layer were disrupted after the over-expression of novel_miR_1, indicating its dual roles in biomineralization. Furthermore, the shell notching results indicated that novel_miR_1 was involved in shell regeneration. Dual-luciferase reporter assay in vitro demonstrated that novel_miR_1 directly suppressed Prisilkin-39 and ACCBP genes by binding to the CDS regions. Taken together, these results suggest that novel_miR_1 is a direct negative regulator to Prisilkin-39 and ACCBP and plays an indispensable and important role in biomineralization in both prismatic and nacreous layer of P. fucata.
Sub-arctic palsa degradation and the role of climatic drivers in the largest coherent palsa mire complex in Sweden (Vissátvuopmi), 1955–2016
Authors: Olvmo Mats , Holmer Björn , Thorsson Sofia , Reese Heather , Lindberg Fredrik
Published: June 2020

Substantial palsa degradation has occurred in Fennoscandia, which is considered to be driven by global climate change. Deeper understanding of the role of different climatic drivers on palsa decay, however, is lacking. We use meteorological data and aerial photographs from 1955 to 2016 to statistically identify the most important climatic drivers affecting changes in lateral-temporal palsa decay rates in the largest coherent palsa complex in Sweden, Vissátvuopmi. We show that wetter, warmer and shorter winters are the main causes of large and rapid changes in lateral-palsa extent since the mid-1950s. By analyzing meteorological data from the 1880s to present, we show that average annual temperature conditions have been unfavourable for palsas for more than a century and average annual precipitation conditions have been unfavourable since the 1940s. The decay rates have likely been amplified over the past 50-60 years, and in particular over the most recent decades, due to the combined effect of adverse air temperature and precipitation conditions. Palsa loss is expected to continue, most likely at a higher rate than today, with serious ecological impacts as a consequence.
Vagus nerve stimulation (VNS)-induced layer-specific modulation of evoked responses in the sensory cortex of rats
Authors: Takahashi Hirokazu , Shiramatsu Tomoyo I. , Hitsuyu Rie , Ibayashi Kenji , Kawai Kensuke
Published: June 2020

Neuromodulation achieved by vagus nerve stimulation (VNS) induces various neuropsychiatric effects whose underlying mechanisms of action remain poorly understood. Innervation of neuromodulators and a microcircuit structure in the cerebral cortex informed the hypothesis that VNS exerts layer-specific modulation in the sensory cortex and alters the balance between feedforward and feedback pathways. To test this hypothesis, we characterized laminar profiles of auditory-evoked potentials (AEPs) in the primary auditory cortex (A1) of anesthetized rats with an array of microelectrodes and investigated the effects of VNS on AEPs and stimulus specific adaptation (SSA). VNS predominantly increased the amplitudes of AEPs in superficial layers, but this effect diminished with depth. In addition, VNS exerted a stronger modulation of the neural responses to repeated stimuli than to deviant stimuli, resulting in decreased SSA across all layers of the A1. These results may provide new insights that the VNS-induced neuropsychiatric effects may be attributable to a sensory gain mechanism: VNS strengthens the ascending input in the sensory cortex and creates an imbalance in the strength of activities between superficial and deep cortical layers, where the feedfoward and feedback pathways predominantly originate, respectively.
Demonstration of In Vitro to In Vivo Translation of a TYK2 Inhibitor That Shows Cross Species Potency Differences
Authors: Gerstenberger Brian S. , Banker Mary Ellen , Clark James D. , Dowty Martin E. , Fensome Andrew , Gifford Roger , Griffor Matthew C. , Hegen Martin , Hollingshead Brett D. , Knafels John D. , Lin Tsung H. , Smith James F. , Vajdos Felix F.
Published: June 2020

Translation of modulation of drug target activity to therapeutic effect is a critical aspect for all drug discovery programs. In this work we describe the profiling of a non-receptor tyrosine-protein kinase (TYK2) inhibitor which shows a functionally relevant potency shift between human and preclinical species (e.g. murine, dog, macaque) in both biochemical and cellular assays. Comparison of the structure and sequence homology of TYK2 between human and preclinical species within the ATP binding site highlights a single amino acid (I960 → V) responsible for the potency shift. Through TYK2 kinase domain mutants and a TYK2 980I knock-in mouse model, we demonstrate that this single amino acid change drives a functionally relevant potency difference that exists between human and all evaluated preclinical species, for a series of TYK2 inhibitors which target the ATP binding site.
Survey of drug resistance associated gene mutations in Mycobacterium tuberculosis, ESKAPE and other bacterial species
Authors: Ghosh Abhirupa , N. Saran , Saha Sudipto
Published: June 2020

Tuberculosis treatment includes broad-spectrum antibiotics such as rifampicin, streptomycin and fluoroquinolones, which are also used against other pathogenic bacteria. We developed Drug Resistance Associated Genes database (DRAGdb), a manually curated repository of mutational data of drug resistance associated genes (DRAGs) across ESKAPE (i.e. Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) pathogens, and other bacteria with a special focus on Mycobacterium tuberculosis (MTB). Analysis of mutations in drug-resistant genes listed in DRAGdb suggested both homoplasy and pleiotropy to be associated with resistance. Homoplasy was observed in six genes namely gidB, gyrA, gyrB, rpoB, rpsL and rrs. For these genes, drug resistance-associated mutations at codon level were conserved in MTB, ESKAPE and many other bacteria. Pleiotropy was exemplified by a single nucleotide mutation that was associated with resistance to amikacin, gentamycin, rifampicin and vancomycin in Staphylococcus aureus. DRAGdb data also revealed that mutations in some genes such as pncA, inhA, katG and embA,B,C were specific to Mycobacterium species. For inhA and pncA, the mutations in the promoter region along with those in coding regions were associated with resistance to isoniazid and pyrazinamide respectively. In summary, the DRAGdb database is a compilation of all the major MTB drug resistance genes across bacterial species, which allows identification of homoplasy and pleiotropy phenomena of DRAGs.
Comorbidities of epilepsy in low and middle-income countries: systematic review and meta-analysis
Authors: Muhigwa Aline , Preux Pierre-Marie , Gérard Daniel , Marin Benoit , Boumediène Farid , Ntamwira Charles , Tsai Chung-Huang
Published: June 2020

Epilepsy is a major public health concern in low and middle-income countries (LMICs) and comorbidities aggravate the burden associated with the disease. The epidemiology of these comorbidities has not been well described, although, identifying the main comorbidities of epilepsy, and their relative importance, is crucial for improving the quality of care. Comorbidities were defined as disorders coexisting with or preceding epilepsy, or else compounded or directly attributed to epilepsy or to its treatment. A meta-analysis of the proportion of main comorbidities by subcontinent as well as overall was also conducted. Out of the 2,300 papers identified, 109 from 39 countries were included in this systematic review. Four groups of comorbidities were identified: parasitic and infectious diseases (44% of comorbid conditions), somatic comorbidities (37%), psychosocial (11%), as well as psychiatric comorbidities (8%). Heterogeneity was statistically significant for most variables then random effect models were used. The most frequently studied comorbidities were: neurocysticercosis (comorbid proportion: 23%, 95% CI: 18–29), head trauma (comorbid proportion: 9%, 95% CI: 5–15) malnutrition (comorbid proportion: 16%, 95% CI: 28–40), stroke (comorbid proportion: 1.3%, 95% CI: 0.2–7.0), and discrimination for education (comorbid proportion: 34%, 95% CI: 28–40). Many comorbidities of epilepsy were identified in LMICs, most of them being infectious.
Body weight algorithm predicts humane endpoint in an intracranial rat glioma model
Authors: Helgers Simeon O. A. , Talbot Steven R. , Riedesel Ann-Kristin , Wassermann Laura , Wu Zhiqun , Krauss Joachim K. , Häger Christine , Bleich André , Schwabe Kerstin
Published: June 2020

Humane endpoint determination is fundamental in animal experimentation. Despite commonly accepted endpoint criteria for intracranial tumour models (20% body weight loss and deteriorated clinical score) some animals still die before being euthanized in current research. We here systematically evaluated other measures as surrogates for a more reliable humane endpoint determination. Adult male BDIX rats (n = 119) with intracranial glioma formation after BT4Ca cell-injection were used. Clinical score and body weight were assessed daily. One subgroup (n = 14) was assessed daily for species-specific (nesting, burrowing), motor (distance, coordination) and social behaviour. Another subgroup (n = 8) was implanted with a telemetric device for monitoring heart rate (variability), temperature and activity. Body weight and clinical score of all other rats were used for training (n = 34) and validation (n = 63) of an elaborate body weight course analysis algorithm for endpoint detection. BT4Ca cell-injection reliably induced fast-growing tumours. No behavioural or physiological parameter detected deteriorations of the clinical state earlier or more reliable than clinical scoring by experienced observers. However, the body weight course analysis algorithm predicted endpoints in 97% of animals without confounding observer-dependent factors. Clinical scoring together with the novel algorithm enables highly reliable and observer-independent endpoint determination in a rodent intracranial tumour model.
A Simple and Scalable Strategy for Analysis of Endogenous Protein Dynamics
Authors: Schwinn Marie K. , Steffen Leta S. , Zimmerman Kris , Wood Keith V. , Machleidt Thomas
Published: June 2020

The ability to analyze protein function in a native context is central to understanding cellular physiology. This study explores whether tagging endogenous proteins with a reporter is a scalable strategy for generating cell models that accurately quantitate protein dynamics. Specifically, it investigates whether CRISPR-mediated integration of the HiBiT luminescent peptide tag can easily be accomplished on a large-scale and whether integrated reporter faithfully represents target biology. For this purpose, a large set of proteins representing diverse structures and functions, some of which are known or potential drug targets, were targeted for tagging with HiBiT in multiple cell lines. Successful insertion was detected for 86% of the targets, as determined by luminescence-based plate assays, blotting, and imaging. In order to determine whether endogenously tagged proteins yield more representative models, cells expressing HiBiT protein fusions either from endogenous loci or plasmids were directly compared in functional assays. In the tested cases, only the edited lines were capable of accurately reproducing the anticipated biology. This study provides evidence that cell lines expressing HiBiT fusions from endogenous loci can be rapidly generated for many different proteins and that these cellular models provide insight into protein function that may be unobtainable using overexpression-based approaches.
Trends and causes of mortality in a population-based cohort of HIV-infected adults in Spain: comparison with the general population
Authors: Fontela Carmen , Aguinaga Aitziber , Moreno-Iribas Conchi , Repáraz Jesús , Rivero María , Gracia María , Floristán Yugo , Fresán Ujué , Miguel Ramón San , Ezpeleta Carmen , Castilla Jesús
Published: June 2020

Combination antiretroviral therapy reduces mortality of HIV-infected persons. In Spain, where this therapy is widely available, we aim to evaluate mortality trends and causes of death in HIV-infected adults, and to estimate the excess mortality compared to the general population. From 1999 to 2018 mortality by causes was analyzed in a population-based cohort of adults aged 25 to 74 years diagnosed with HIV infection in Spain. Observed deaths and expected deaths according mortality in the general population of the same sex and age were compared using standardized mortality ratios (SMRs). HIV-infected people increased from 839 in 1999–2003 to 1059 in 2014–2018, median age increased from 37 to 47 years, the annual mortality rate decreased from 33.5 to 20.7 per 1000 person-years and the proportion of HIV-related deaths declined from 64% to 35%. HIV-related mortality declined from 21.4 to 7.3 (p < 0.001), while non-HIV-related mortality remained stable: 12.1 and 13.4 per 1000, respectively. Mortality decreased principally in persons diagnosed with AIDS-defining events. In the last decade, 2009–2018, mortality was still 8.1 times higher among HIV-infected people than in the general population, and even after excluding HIV-related deaths, remained 4.8 times higher. Excess mortality was observed in non-AIDS cancer (SMR = 3.7), cardiovascular disease (SMR = 4.2), respiratory diseases (SMR = 7.9), liver diseases (SMR = 8.8), drug abuse (SMR = 47), suicide (SMR = 5.3) and other external causes (SMR = 6). In conclusion, HIV-related mortality continued to decline, while non-HIV-related mortality remained stable. HIV-infected people maintained important excess mortality. Prevention of HIV infections in the population and promotion of healthy life styles in HIV-infected people must be a priority.