bluuebunny/crossref_metadata_2025 huggingface dataset:
The Politics of Change. Coalitional politics and labour market reforms during the sovereign debt crisis in Portugal
Authors: BRANCO RUI , CARDOSO DANIEL
Published: November 2020

This article describes and explains labour market reforms in Portugal during the sovereign debt crisis from 2011 to 2014. Policy outputs were not homogenous, but differentiated between a first phase where recalibration co-existed alongside hard liberalising measures and a second phase, from late 2012, where recalibration was dropped and liberalisation further deregulated employment protection and security and eroded collective bargaining. This variation is explained by the changing coalitional politics and blame allocation underpinning policymaking under conditionality. Initial reforms resulted from a broad informal political coalition spanning the governing centre-right parties, the main opposition party, a trade union and employer confederations; its breakdown in late 2012 led to the executive’s increasing centralisation, the shut down of social concertation, and more radical policy outputs. The article shows that cooperation between government and opposition and government and social partners is possible even under external conditionality, how coalition politics affects the nature and direction of reforms, and highlights how political dynamics of blame allocation drive the process of coalition building and breakdown.
The attrition of school-learned foreign languages: A multilingual perspective
Authors: Jessner Ulrike , Oberhofer Kathrin , Megens Manon
Published: November 2020

In the vast body of research on language learning, there is still surprisingly little work on the attrition or retention of second/foreign languages, particularly in multilinguals, once learning and/or use of these languages ceases. The present study focuses on foreign language attrition and examines lexical diversity and (dis)fluency in the oral productions of 114 multilingual young adults, first language German speakers who learned English as their first (FL1) and French or Italian as their second foreign language (FL2), shortly before and approximately 16 months after graduation from upper secondary school. The level of foreign language use after graduation was found to have a noticeable impact on the measured change in output quality in the FL2, but only little in the FL1, where participants’ initial proficiency was considerably higher. The amount of use in the FL1 had no visible connection with attrition/maintenance in a rarely used FL2. Those participants who felt their speaking skills in one of their foreign languages had improved were correct in their self-assessment, but the degree to which the remaining subjects felt their speaking skills had deteriorated was not reflected in their productions.
Ten Steps to Protect BIPOC Scholars in the Field
Authors: Anadu Joshua , Ali Hendratta , Jackson Christopher
Published: November 2020

Institutions should heed these recommendations to prepare faculty and students for discrimination and racialized violence before traveling and to protect them once in the field.
Lower‐Hybrid‐Drift Vortices in the Electron‐Scale Magnetic Reconnection Layer
Authors: Ng J. , Chen L.‐J. , Le A. , Stanier A. , Wang S. , Bessho N.
Published: November 2020

Lower‐hybrid‐drift waves driving vortical flows have recently been discovered in the electron current layer during magnetic reconnection in the terrestrial magnetotail. Yet, spacecraft measurements cannot address how pervasive the waves are. We perform three‐dimensional particle‐in‐cell simulations of guide field reconnection to demonstrate that electron vortices driven by the lower‐hybrid‐drift instability (LHDI) are excited immediately downstream from the electron jet reversal in 3‐D channels of enhanced electron outflow. The resulting fluctuations generate a series of alternating vortices, producing magnetic field perturbations opposing and enhancing the local guide field and causing kinking of the enhanced electron outflow and patches of increased current. Our results demonstrate for the first time that LHDI exists in the electron current layer and enhanced outflow channels, providing a conceptual breakthrough on the LHDI in reconnection.
Performance Evaluation of CMIP5 and CMIP6 Models on Heatwaves in Korea and Associated Teleconnection Patterns
Authors: Kim Maeng‐Ki , Yu Dae‐Geun , Oh Ji‐Seon , Byun Young‐Hwa , Boo Kyung‐On , Chung Il‐Ung , Park Jeong‐Soo , Park Doo‐Sun R. , Min Seung‐Ki , Sung Hyun Min
Published: November 2020

This study assesses the performance of the Coupled Model Intercomparison Project (CMIP) models for simulating summer heatwaves in Korea during a historical simulation period (1979–2014) using four diagnostic indices that represent the teleconnection mechanism of summer heatwaves in Korea. Four skill metrics are used for the model evaluation, namely, relative error (RE), interannual variability skill‐score (IVS), correlation coefficient (CC), and total ranking (TR) based on daily maximum temperature (TMAX) in Korea and the four diagnostic indices. The results show that the REs of CMIP5 models do not differ significantly from those of the CMIP6 models while the IVSs in the CMIP6 models are significantly improved compared with the CMIP5 models. Observations show that the heatwave circulation index (HWCI) contributes more to the interannual variability in TMAX in Korea than that of the Indian Monsoon Rainfall Index (IMRI), indicating that the teleconnection from the northwestern Pacific is more important than that from northwestern India. Interestingly, the CMIP6 models simulate this property better than the CMIP5 ensemble. The higher TR of CMIP6 models than CMIP5 supports that CMIP6 models are better overall in simulating heatwaves in Korea and the associated diagnostic indices.
Evaluation of spontaneous regional brain activity in weight-recovered anorexia nervosa
Authors: Seidel Maria , Geisler Daniel , Borchardt Viola , King Joseph A. , Bernardoni Fabio , Jaite Charlotte , Roessner Veit , Calhoun Vince , Walter Martin , Ehrlich Stefan
Published: November 2020

Whereas research using structural magnetic resonance imaging (sMRI) reports sizable grey matter reductions in patients suffering from acute anorexia nervosa (AN) to be largely reversible already after short-term weight gain, many task-based and resting-state functional connectivity (RSFC) studies suggest persistent brain alterations even after long-term weight rehabilitation. First investigations into spontaneous regional brain activity using voxel-wise resting-state measures found widespread abnormalities in acute AN, but no studies have compared intrinsic brain activity properties in weight-recovered individuals with a history of AN (recAN) with healthy controls (HCs). SMRI and RSFC data were analysed from a sample of 130 female volunteers: 65 recAN and 65 pairwise age-matched HC. Cortical grey matter thickness was assessed using FreeSurfer software. Fractional amplitude of low-frequency fluctuations (fALFFs), mean-square successive difference (MSSD), regional homogeneity (ReHo), voxel-mirrored homotopic connectivity (VHMC), and degree centrality (DC) were calculated. SMRI and RSFC data were analysed from a sample of 130 female volunteers: 65 recAN and 65 pairwise age-matched HCs. Cortical grey matter thickness was assessed using FreeSurfer software. Fractional amplitude of low-frequency fluctuations (fALFF), mean-square successive difference (MSSD), regional homogeneity (ReHo), voxel-mirrored homotopic connectivity (VHMC), and degree centrality (DC) were calculated. Abnormal regional homogeneity found in acute AN seems to normalize in recAN, supporting assumptions of a state rather than a trait marker. Aberrant fALFF values in the cerebellum and the infertior temporal gyrus could possibly hint towards trait factors or a scar (the latter, e.g., from prolonged periods of undernutrition), warranting further longitudinal research.
Correction: A human Myogenin promoter modified to be highly active in alveolar rhabdomyosarcoma drives an effective suicide gene therapy
Authors: Pruller Johanna , Hofer Isabella , Ganassi Massimo , Heher Philipp , Ma Michelle T. , Zammit Peter S.
Published: November 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Oncogenic role of lncRNA CRNDE in acute promyelocytic leukemia and NPM1-mutant acute myeloid leukemia
Authors: Ma Xuefei , Zhang Wei , Zhao Ming , Li Shufen , Jin Wen , Wang Kankan
Published: November 2020

The PML/RARα fusion protein acts in concert with cooperative genetic events in the development of acute promyelocytic leukemia (APL). However, oncogenic long non-coding RNAs (lncRNAs) cooperating with PML/RARα remain under-explored. Here, we first identified a set of pathogenesis-related lncRNAs, aberrantly expressed in APL using RNA-seq data from a large cohort of acute myeloid leukemia (AML) patients and normal counterparts. Among the pathogenesis-related lncRNAs, one of the evolutionarily conservative lncRNAs CRNDE (Colorectal Neoplasia Differentially Expressed) drew our attention. We found that CRNDE was highly expressed in the disease state but not in the preleukemic stage of APL, suggesting that CRNDE might be a secondary event coordinating with PML/RARα to promote APL development. Functional analysis showed that CRNDE knockdown induced differentiation and inhibited proliferation of APL cells, and prolonged survival of APL mice. Further mechanistic studies showed that CRNDE elicited its oncogenic effects through binding the miR-181 family and thereby regulating NOTCH2. Finally, we found that high CRNDE expression was also significantly correlated with NPM1 mutations and contributed to the differentiation block in NPM1-mutant AML. Collectively, our findings shed light on the importance of oncogenic lncRNAs in the development of AML and provide a promising target for AML therapy.
DNA nano-pocket for ultra-selective uranyl extraction from seawater
Authors: Yuan Yihui , Liu Tingting , Xiao Juanxiu , Yu Qiuhan , Feng Lijuan , Niu Biye , Feng Shiwei , Zhang Jiacheng , Wang Ning
Published: November 2020

Extraction of uranium from seawater is critical for the sustainable development of nuclear energy. However, the currently available uranium adsorbents are hampered by co-existing metal ion interference. DNAzymes exhibit high selectivity to specific metal ions, yet there is no DNA-based adsorbent for extraction of soluble minerals from seawater. Herein, the uranyl-binding DNA strand from the DNAzyme is polymerized into DNA-based uranium extraction hydrogel (DNA-UEH) that exhibits a high uranium adsorption capacity of 6.06 mg g−1 with 18.95 times high selectivity for uranium against vanadium in natural seawater. The uranium is found to be bound by oxygen atoms from the phosphate groups and the carbonyl groups, which formed the specific nano-pocket that empowers DNA-UEH with high selectivity and high binding affinity. This study both provides an adsorbent for uranium extraction from seawater and broadens the application of DNA for being used in recovery of high-value soluble minerals from seawater.
Comparing LAMA with LABA and LTRA as add-on therapies in primary care asthma management
Authors: Kaplan Alan , FitzGerald J. Mark , Buhl Roland , Vogelberg Christian , Hamelmann Eckard
Published: November 2020

The Global Initiative for Asthma recommends a stepwise approach to adjust asthma treatment to the needs of individual patients; inhaled corticosteroids (ICS) remain the core pharmacological treatment. However, many patients remain poorly controlled, and evidence-based algorithms to decide on the best order and rationale for add-on therapies are lacking. We explore the challenges of asthma management in primary care and review outcomes from randomised controlled trials and meta-analyses comparing the long-acting muscarinic antagonist (LAMA) tiotropium with long-acting β2-agonists (LABAs) or leukotriene receptor antagonists (LTRAs) as add-on to ICS in patients with asthma. In adults, LAMAs and LABAs provide a greater improvement in lung function than LTRAs as add-on to ICS. In children, results were positive and comparable between therapies, but data are scarce. This information could aid decision-making in primary care, supporting the use of add-on therapy to ICS to help improve lung function, control asthma symptoms and prevent exacerbations.
Progressive Cactus is a multiple-genome aligner for the thousand-genome era
Authors: Armstrong Joel , Hickey Glenn , Diekhans Mark , Fiddes Ian T. , Novak Adam M. , Deran Alden , Fang Qi , Xie Duo , Feng Shaohong , Stiller Josefin , Genereux Diane , Johnson Jeremy , Marinescu Voichita Dana , Alföldi Jessica , Harris Robert S. , Lindblad-Toh Kerstin , Haussler David , Karlsson Elinor , Jarvis Erich D. , Zhang Guojie , Paten Benedict
Published: November 2020

New genome assemblies have been arriving at a rapidly increasing pace, thanks to decreases in sequencing costs and improvements in third-generation sequencing technologies1–3. For example, the number of vertebrate genome assemblies currently in the NCBI (National Center for Biotechnology Information) database4increased by more than 50% to 1,485 assemblies in the year from July 2018 to July 2019. In addition to this influx of assemblies from different species, new human de novo assemblies5are being produced, which enable the analysis of not only small polymorphisms, but also complex, large-scale structural differences between human individuals and haplotypes. This coming era and its unprecedented amount of data offer the opportunity to uncover many insights into genome evolution but also present challenges in how to adapt current analysis methods to meet the increased scale. Cactus6, a reference-free multiple genome alignment program, has been shown to be highly accurate, but the existing implementation scales poorly with increasing numbers of genomes, and struggles in regions of highly duplicated sequences. Here we describe progressive extensions to Cactus to create Progressive Cactus, which enables the reference-free alignment of tens to thousands of large vertebrate genomes while maintaining high alignment quality. We describe results from an alignment of more than 600 amniote genomes, which is to our knowledge the largest multiple vertebrate genome alignment created so far.
A high-resolution map of reactive nitrogen inputs to China
Authors: Wang Sitong , Zhang Xiuming , Wang Chen , Zhang Xiuying , Reis Stefan , Xu Jianming , Gu Baojing
Published: November 2020

To feed an increasingly affluent population, reactive nitrogen (Nr) inputs to China’s lands and waters have substantially increased over the past century. Today, China’s Nr emissions account for over one third of global total emissions, leading to serious environmental pollution and health damages. Quantifying the spatial variability of Nr inputs is crucial for the identification of intervention points to mitigate Nr pollution, which, however, is not well known. Here, we present a database describing Nr inputs to China for the year 2017 with a 1 km × 1 km resolution, considering land use and Nr sources, compiled by using the CHANS model. Results show that the North China Plain, the Sichuan Basin and the Middle-Lower Yangtze River Plain are hotspots of Nr inputs, where per hectare Nr input is an order of magnitude higher than that in other regions. Cropland and surface water bodies receive much higher Nr inputs than other land use types. This unique database will provide basic data for research on environmental health and global change modelling.
NFKB1 gene rs28362491 ins/del variation is associated with higher susceptibility to myocardial infarction in a Chinese Han population
Authors: Luo Jun-Yi , Li Yan-Hong , Fang Bin-Bin , Tian Ting , Liu Fen , Li Xiao-Mei , Gao Xiao-Ming , Yang Yi-Ning
Published: November 2020

Myocardial infarction (MI), the leading cause of mortality and disability worldwide, is a disease in which multiple environmental and genetic factors are involved. Recently, researches suggested that insertion/deletion (ins/del) variation of NFKB1 gene rs28362491 is a functional polymorphism. In the present study, we aimed to explore the relation between variation of NFKB1 gene rs28362491 and MI by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) in 359 MI patients and 1085 control participants. Gensini score was used to evaluate the degree of coronary artery stenosis in MI patients. The plasma levels of interleukin-6 (IL-6), IL-8, malonaldehyde (MDA) and superoxide dismutase (SOD) were randomly measured by ELISA both in MI patients and control participants. We found that the detected frequencies of D allele (41.2% vs. 36.4%, P = 0.021) and DD genotype (17.5% vs. 12.0%, P = 0.022) were significantly higher in MI patients than in control participants. Compared with II or ID genotype carriers, the Gensini score in MI patients with DD genotype was 32–43% higher (both P < 0.001). Moreover, DD genotype carries had more diseased coronary arteries (P = 0.001 vs. II or ID genotype). Of note, IL-6 levels in MI patients carrying DD genotype were significantly higher than that in control participants and other genotype carriers in MI patients (both P < 0.05). In conclusion, NFKB1 gene rs28362491 DD genotype was associated with a higher risk of MI and more severe coronary artery lesion, which also had a potential influence on the level of inflammatory cytokine IL-6.
Seasonality and light phase-resetting in the mammalian circadian rhythm
Authors: Hannay Kevin M. , Forger Daniel B. , Booth Victoria
Published: November 2020

We study the impact of light on the mammalian circadian system using the theory of phase response curves. Using a recently developed ansatz we derive a low-dimensional macroscopic model for the core circadian clock in mammals. Significantly, the variables and parameters in our model have physiological interpretations and may be compared with experimental results. We focus on the effect of four key factors which help shape the mammalian phase response to light: heterogeneity in the population of oscillators, the structure of the typical light phase response curve, the fraction of oscillators which receive direct light input and changes in the coupling strengths associated with seasonal day-lengths. We find these factors can explain several experimental results and provide insight into the processing of light information in the mammalian circadian system. In particular, we find that the sensitivity of the circadian system to light may be modulated by changes in the relative coupling forces between the light sensing and non-sensing populations. Finally, we show how seasonal day-length, after-effects to light entrainment and seasonal variations in light sensitivity in the mammalian circadian clock are interrelated.
Recurring urothelial carcinomas show genomic rearrangements incompatible with a direct relationship
Authors: Marzouka Nour-Al-Dain , Lindgren David , Eriksson Pontus , Sjödahl Gottfrid , Bernardo Carina , Liedberg Fredrik , Axelson Håkan , Höglund Mattias
Published: November 2020

We used the fact that patients with non-muscle invasive bladder tumors show local recurrences and multiple tumors to study re-initiation of tumor growth from the same urothelium. By extensive genomic analyses we show that tumors from the same patient are clonal. We show that gross genomic chromosomal aberrations may be detected in one tumor, only to be undetected in a recurrent tumor. By analyses of incompatible changes i.e., genomic alterations that cannot be reversed, we show that almost all tumors from a single patient may show such changes, thus the tumors cannot have originated from each other. As recurring tumors share both genomic alterations and driver gene mutations, these must have been present in the urothelium in periods with no tumor growth. We present a model that includes a growing and evolving field of urothelial cells that occasionally, and locally, produce bursts of cellular growth leading to overt tumors.
Differentiation of low and high grade renal cell carcinoma on routine MRI with an externally validated automatic machine learning algorithm
Authors: Purkayastha Subhanik , Zhao Yijun , Wu Jing , Hu Rong , McGirr Aidan , Singh Sukhdeep , Chang Ken , Huang Raymond Y. , Zhang Paul J. , Silva Alvin , Soulen Michael C. , Stavropoulos S. William , Zhang Zishu , Bai Harrison X.
Published: November 2020

Pre-treatment determination of renal cell carcinoma aggressiveness may help guide clinical decision-making. We aimed to differentiate low-grade (Fuhrman I–II) from high-grade (Fuhrman III–IV) renal cell carcinoma using radiomics features extracted from routine MRI. 482 pathologically confirmed renal cell carcinoma lesions from 2008 to 2019 in a multicenter cohort were retrospectively identified. 439 lesions with information on Fuhrman grade from 4 institutions were divided into training and test sets with an 8:2 split for model development and internal validation. Another 43 lesions from a separate institution were set aside for independent external validation. The performance of TPOT (Tree-Based Pipeline Optimization Tool), an automatic machine learning pipeline optimizer, was compared to hand-optimized machine learning pipeline. The best-performing hand-optimized pipeline was a Bayesian classifier with Fischer Score feature selection, achieving an external validation ROC AUC of 0.59 (95% CI 0.49–0.68), accuracy of 0.77 (95% CI 0.68–0.84), sensitivity of 0.38 (95% CI 0.29–0.48), and specificity of 0.86 (95% CI 0.78–0.92). The best-performing TPOT pipeline achieved an external validation ROC AUC of 0.60 (95% CI 0.50–0.69), accuracy of 0.81 (95% CI 0.72–0.88), sensitivity of 0.12 (95% CI 0.14–0.30), and specificity of 0.97 (95% CI 0.87–0.97). Automated machine learning pipelines can perform equivalent to or better than hand-optimized pipeline on an external validation test non-invasively predicting Fuhrman grade of renal cell carcinoma using conventional MRI.
Diversity of secoiridoid glycosides in leaves of UK and Danish ash provide new insight for ash dieback management
Authors: Sidda John D. , Song Lijiang , Parker Jack L. , Studholme David J. , Sambles Christine , Grant Murray
Published: November 2020

Secoiridoid glycosides are anti-feeding deterrents of the Oleaceae family recently highlighted as potential biomarkers in Danish ash trees to differentiate between those tolerant and susceptible to the fungal disease ash dieback. With the knowledge that emerald ash borer has recently entered Europe from Russia, and that extensive selection trials are ongoing in Europe for ash dieback tolerant European ash (Fraxinus excelsior), we undertook comprehensive screening of secoiridoid glycosides in leaf extracts of trees tolerant and susceptible to ash dieback sampled from sites in the UK and Denmark. Here we report an unexpected diversity of secoiridoid glycosides in UK trees and higher levels of secoiridoid glycosides in the UK sample group. While it is unlikely that secoiridoid glycosides generally can serve as reliable markers for ash dieback susceptibility, there are differences between tolerant and susceptible groups for specific secoiridoids. We predict that the high levels—and structural diversity—of secoiridoids present in the UK group may provide a robust reservoir of anti-feeding deterrents to mitigate future herbivore threats such as the Emerald ash borer.
Step-like dependence of memory function on pulse width in spintronics reservoir computing
Authors: Yamaguchi Terufumi , Akashi Nozomi , Nakajima Kohei , Kubota Hitoshi , Tsunegi Sumito , Taniguchi Tomohiro
Published: November 2020

Physical reservoir computing is a type of recurrent neural network that applies the dynamical response from physical systems to information processing. However, the relation between computation performance and physical parameters/phenomena still remains unclear. This study reports our progress regarding the role of current-dependent magnetic damping in the computational performance of reservoir computing. The current-dependent relaxation dynamics of a magnetic vortex core results in an asymmetric memory function with respect to binary inputs. A fast relaxation caused by a large input leads to a fast fading of the input memory, whereas a slow relaxation by a small input enables the reservoir to keep the input memory for a relatively long time. As a result, a step-like dependence is found for the short-term memory and parity-check capacities on the pulse width of input data, where the capacities remain at 1.5 for a certain range of the pulse width, and drop to 1.0 for a long pulse-width limit. Both analytical and numerical analyses clarify that the step-like behavior can be attributed to the current-dependent relaxation time of the vortex core to a limit-cycle state.
Radiomics features of hippocampal regions in magnetic resonance imaging can differentiate medial temporal lobe epilepsy patients from healthy controls
Authors: Park Yae Won , Choi Yun Seo , Kim Song E. , Choi Dongmin , Han Kyunghwa , Kim Hwiyoung , Ahn Sung Soo , Kim Sol-Ah , Kim Hyeon Jin , Lee Seung-Koo , Lee Hyang Woon
Published: November 2020

To investigative whether radiomics features in bilateral hippocampi from MRI can identify temporal lobe epilepsy (TLE). A total of 131 subjects with MRI (66 TLE patients [35 right and 31 left TLE] and 65 healthy controls [HC]) were allocated to training (n = 90) and test (n = 41) sets. Radiomics features (n = 186) from the bilateral hippocampi were extracted from T1-weighted images. After feature selection, machine learning models were trained. The performance of the classifier was validated in the test set to differentiate TLE from HC and ipsilateral TLE from HC. Identical processes were performed to differentiate right TLE from HC (training set, n = 69; test set; n = 31) and left TLE from HC (training set, n = 66; test set, n = 30). The best-performing model for identifying TLE showed an AUC, accuracy, sensitivity, and specificity of 0.848, 84.8%, 76.2%, and 75.0% in the test set, respectively. The best-performing radiomics models for identifying right TLE and left TLE subgroups showed AUCs of 0.845 and 0.840 in the test set, respectively. In addition, multiple radiomics features significantly correlated with neuropsychological test scores (false discovery rate-corrected p-values < 0.05). The radiomics model from hippocampus can be a potential biomarker for identifying TLE.
Habenula kisspeptin retrieves morphine impaired fear memory in zebrafish
Authors: Sivalingam Mageswary , Ogawa Satoshi , Parhar Ishwar S.
Published: November 2020

The habenula is an evolutionarily conserved brain structure, which has recently been implicated in fear memory. In the zebrafish, kisspeptin (Kiss1) is predominantly expressed in the habenula, which has been implicated as a modulator of fear response. Hence, in the present study, we questioned whether Kiss1 has a role in fear memory and morphine-induced fear memory impairment using an odorant cue (alarm substances, AS)-induced fear avoidance paradigm in adult zebrafish, whereby the fear-conditioned memory can be assessed by a change of basal place preference (= avoidance) of fish due to AS-induced fear experience. Subsequently, to examine the possible role of Kiss1 neurons-serotonergic pathway, kiss1 mRNA and serotonin levels were measured. AS exposure triggered fear episodes and fear-conditioned place avoidance. Morphine treatment followed by AS exposure, significantly impaired fear memory with increased time-spent in AS-paired compartment. However, fish administered with Kiss1 (10–21 mol/fish) after morphine treatment had significantly lower kiss1 mRNA levels but retained fear memory. In addition, the total brain serotonin levels were significantly increased in AS- and Kiss1-treated groups as compared to control and morphine treated group. These results suggest that habenular Kiss1 might be involved in consolidation or retrieval of fear memory through the serotonin system.
Locked-in and living delta pathways in the Anthropocene
Authors: Santos Maria J. , Dekker Stefan C.
Published: November 2020

Delta systems are fundamental to the persistence of large human populations, food systems and ecosystem processes. Structural changes in natural and social components of deltas, emerging from past land-use changes, have led deltas to become locked-in loosing the ability to transform back into living deltas, and making them more at risk. We propose a framework to assess whether deltas become locked-in by changes in natural or social infrastructure, by examining the dynamic coupling between population and land-use development over 300 years for 48 deltas globally. We find that 46% of the deltas are defined as living, where population, irrigation, and cropland are correlated. Of the 54% locked-in deltas, 21% show changes in natural infrastructure to cropland (n = 6) or irrigation (n = 4), and 33% (n = 16) show changes in social infrastructure. Most locked-in deltas are in Europe but also in other continents due to decoupled development of population and cropland. While, locked-in deltas due to changes in natural infrastructure have highest average risks, those with changes in social infrastructure and the living deltas have highest risks from future relative sea level rise. These results show that deltas have varying natural and social components derived from a 300 years historical perspective, which are not taken into account in risk assessments for global deltas.
Oxidative stress induced by the anti-cancer agents, plumbagin, and atovaquone, inhibits ion transport through Na+/K+-ATPase
Authors: Alharbi Yousef , Kapur Arvinder , Felder Mildred , Barroilhet Lisa , Pattnaik Bikash R. , Patankar Manish S.
Published: November 2020

Oxidative stress inhibits Na+/K+-ATPase (NKA), the ion channel that maintains membrane potential. Here, we investigate the role of oxidative stress-mediated by plumbagin and atovaquone in the inhibition of NKA activity. We confirm that plumbagin and atovaquone inhibit the proliferation of three human (OVCAR-3, SKOV-3, and TYKNu) and one mouse (ID8) ovarian cancer cell lines. The oxygen radical scavenger, N-acetylcysteine (NAC), attenuates the chemotoxicity of plumbagin and atovaquone. Whole-cell patch clamping demonstrates that plumbagin and atovaquone inhibit outward and the inward current flowing through NKA in SKOV-3 and OVCAR-3. Although both drugs decrease cellular ATP; providing exogenous ATP (5 mM) in the pipet solution used during patch clamping did not recover NKA activity in the plumbagin or atovaquone treated SKOV-3 and OVCAR-3 cells. However, pretreatment of the cells with NAC completely abrogated the NKA inhibitory activity of plumbagin and atovaquone. Exposure of the SKOV-3 cells to either drug significantly decreases the expression of NKA. We conclude that oxidative stress caused by plumbagin and atovaquone degrades NKA, resulting in the inability to maintain ion transport. Therefore, when evaluating compounds that induce oxidative stress, it is important to consider the contribution of NKA inhibition to their cytotoxic effects on tumor cells.
Association of exhaled carbon monoxide with risk of cardio-cerebral-vascular disease in the China Kadoorie Biobank cohort study
Authors: Qiu Gaokun , Yu Kuai , Yu Canqing , Li Wending , Lv Jun , Guo Yu , Bian Zheng , Yang Ling , Chen Yiping , Chen Zhengming , Hu Frank B. , Li Liming , Wu Tangchun
Published: November 2020

Exhaled carbon monoxide (COex) level has been proposed as a noninvasive and easily-obtainable cardiovascular risk marker, however, with limited prospective evidence, and its association with stroke risk has been rarely explored. Measurements of COex were performed during 2004–2008 baseline examinations in the China Kadoorie Biobank study among 512,891 adults aged 30–79 years from 10 diverse study areas. After excluding participants with baseline cardiopulmonary diseases, stroke and cancer, 178,485 men and 267,202 women remained. Cox regression yielded hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of cardio-cerebral-vascular disease (CCVD) associated with COex levels, with sequential addition of adjustment for proxy variables for CO exposure, including study area indexing ambient CO variations at large, and smoking and solid fuel use, apart from adjusting for traditional cardiovascular risk factors. During 7-year follow-up, we documented 1744 and 1430 major coronary events (myocardial infarction plus fatal ischemic heart disease), 8849 and 10,922 ischemic strokes, and 2492 and 2363 hemorrhagic strokes among men and women, respectively. The HRs with 95% CIs comparing the highest with lowest COex quintile were 2.15 [1.72, 2.69] for major coronary events, 1.65 [1.50, 1.80] for ischemic stroke, and 1.35 [1.13, 1.61] for hemorrhagic stroke among men, while among women higher associated risk was only observed for major coronary events (1.64 [1.35, 2.00]) and ischemic stroke (1.87 [1.73, 2.01]). The elevated risks were consistent when COex level was over 3 ppm. However, these associations were all attenuated until null by sequential addition of stratification by study areas, and adjustments of smoking and solid fuel use. Nevertheless, the association with ischemic stroke was maintained among the subgroup of male smokers even with adjustment for the depth and amount of cigarette smoking (HR [95% CI]: 1.37 [1.06, 1.77]), while a negative association with hemorrhagic stroke also appeared within this subgroup. Higher COex level (over 3 ppm) was associated with elevated risk of ischemic CCVD, but not independently of CO exposure. Our finding suggests that, though not an independent risk factor, COex could potentially provide a cost-effective biomarker for ischemic cardio-cerebral-vascular risk, given that CO exposure is ubiquitous.
Schrenk spruce leaf litter decomposition varies with snow depth in the Tianshan Mountains
Authors: Gong Lu , Chen Xin , Zhang Xueni , Yang Xiaodong , Cai Yanjiang
Published: November 2020

Seasonal snowfall, a sensitive climate factor and the main form of precipitation in arid areas, is important for forest material circulation and surface processes and profoundly impacts litter decomposition and element turnover. However, how the thickness and duration of snow cover affect litter decomposition and element release remain unclear. Thus, to understand the effects of snow on litter decomposition, fiber degradation and their relationships with soil properties, a field litterbag experiment was conducted under no, thin, medium, and thick snow cover in a Schrenk spruce (Picea schrenkiana) forest gap in the Tianshan Mountains. The snow cover period exhibited markedly lower rates of decomposition than the snow-free period. The litter lignin, cellulose and N concentrations in the pregrowing season and middle growing season were significantly higher than those in the deep-freeze period, and the litter C and P concentrations were significantly higher during the onset of the freeze–thaw period, deep-freeze period and thaw period than in the late growing season. The litter cellulose, C and N concentrations were significantly higher under thick snow cover than under no snow cover in most stages. Moreover, the correlations among litter mass, cellulose, lignin/cellulose and soil bulk density varied with snow cover depth. The temporal variations and snow cover depth affected the decomposition process significantly. The former affected lignin, cellulose and P, and the latter affected cellulose, C and N and changed the litter-soil properties relationship. These differences provide references for understanding how winter conditions affect material cycling and other ecological processes under climate change.
Green fluorescent protein-based lactate and pyruvate indicators suitable for biochemical assays and live cell imaging
Authors: Harada Kazuki , Chihara Takami , Hayasaka Yuki , Mita Marie , Takizawa Mai , Ishida Kentaro , Arai Mary , Tsuno Saki , Matsumoto Mitsuharu , Ishihara Takeshi , Ueda Hiroshi , Kitaguchi Tetsuya , Tsuboi Takashi
Published: November 2020

Glycolysis is the metabolic pathway that converts glucose into pyruvate, whereas fermentation can then produce lactate from pyruvate. Here, we developed single fluorescent protein (FP)-based lactate and pyruvate indicators with low EC50 for trace detection of metabolic molecules and live cell imaging and named them “Green Lindoblum” and “Green Pegassos,” respectively. Green Lindoblum (EC50 of 30 µM for lactate) and Green Pegassos (EC50 of 70 µM for pyruvate) produced a 5.2- and 3.3-fold change in fluorescence intensity in response to lactate and pyruvate, respectively. Green Lindoblum measured lactate levels in mouse plasma, and Green Pegassos in combination with D-serine dehydratase successfully estimated D-serine levels released from mouse primary cultured neurons and astrocytes by measuring pyruvate level. Furthermore, live cell imaging analysis revealed their utility for dual-colour imaging, and the interplay between lactate, pyruvate, and Ca2+ in human induced pluripotent stem cell-derived cardiomyocytes. Therefore, Green Lindoblum and Green Pegassos will be useful tools that detect specific molecules in clinical use and monitor the interplay of metabolites and other related molecules in diverse cell types.
Changes in neuronal excitability and synaptic transmission in nucleus accumbens in a transgenic Alzheimer’s disease mouse model
Authors: Fernández-Pérez E. J. , Gallegos S. , Armijo-Weingart L. , Araya A. , Riffo-Lepe N. O. , Cayuman F. , Aguayo L. G.
Published: November 2020

Several previous studies showed that hippocampus and cortex are affected in Alzheimer’s disease (AD). However, other brain regions have also been found to be affected and could contribute with new critical information to the pathophysiological basis of AD. For example, volumetric studies in humans have shown a significant atrophy of the striatum, particularly in the nucleus Accumbens (nAc). The nAc is a key component of the limbic reward system and it is involved in cognition and emotional behaviors such as pleasure, fear, aggression and motivations, all of which are affected in neurodegenerative diseases such as AD. However, its role in AD has not been extensively studied. Therefore, using an AD mouse model, we investigated if the nAc was affected in 6 months old transgenic 2xTg (APP/PS1) mice. Immunohistochemistry (IHC) analysis in 2xTg mice showed increased intraneuronal Aβ accumulation, as well as occasional extracellular amyloid deposits detected through Thioflavin-S staining. Interestingly, the intracellular Aβ pathology was associated to an increase in membrane excitability in dissociated medium spiny neurons (MSNs) of the nAc. IHC and western blot analyses showed a decrease in glycine receptors (GlyR) together with a reduction in the pre- and post-synaptic markers SV2 and gephyrin, respectively, which correlated with a decrease in glycinergic miniature synaptic currents in nAc brain slices. Additionally, voltage-clamp recordings in dissociated MSNs showed a decrease in AMPA- and Gly-evoked currents. Overall, these results showed intracellular Aβ accumulation together with an increase in excitability and synaptic alterations in this mouse model. These findings provide new information that might help to explain changes in motivation, anhedonia, and learning in the onset of AD pathogenesis.
Clinical relevance and validity of TLICS system for thoracolumbar spine injury
Authors: Park Chan-Jin , Kim Sung-Kyu , Lee Tae-Min , Park Eric T.
Published: November 2020

In order to enhance the reliability of the application to clinical practice of the TLICS classification, we retrospectively reviewed the patients with thoracolumbar spine injuries who underwent magnetic resonance imaging (MRI) and analyzed the validity of the TLICS classification and the necessity of MRI. We enrolled 328 patients with thoracolumbar spine injury who underwent MRI. All patients were classified into conservative and operative treatment groups. The TLICS score of each group was analyzed and the degree of consistent with the recommended treatment through the TLICS classification was examined. Of the total 328 patients, 138 patients were treated conservatively and 190 patients were treated by surgery. Of the 138 patients who underwent conservative treatment, 131 patients (94.9%) had a TLICS score of 4 points or less, and matched with the recommendation score for conservative treatment according to the TLICS classification (match rate 94.9%, 131/138). Of the 190 patients who underwent operative treatment, 160 patients (84.2%) had a TLICS score of 4 points or more (match rate 84.2%, 160/190). All of 30 mismatched patients with a TLICS score of 3 points or less (15.8%) had stable burst fracture without neurological deficit. We retrospectively reviewed the validity of the TLICS classification for the injuries of the thoracolumbar spine, based on MRI in a large group of patients. Treatment with TLICS classification showed high validity, especially in conservative group, and MRI should be an essential diagnostic tool for accurate evaluation of posterior ligamentous complex injury.
SARS-CoV-2 receptor is co-expressed with elements of the kinin–kallikrein, renin–angiotensin and coagulation systems in alveolar cells
Authors: Sidarta-Oliveira Davi , Jara Carlos Poblete , Ferruzzi Adriano J. , Skaf Munir S. , Velander William H. , Araujo Eliana P. , Velloso Licio A.
Published: November 2020

SARS-CoV-2, the pathogenic agent of COVID-19, employs angiotensin converting enzyme-2 (ACE2) as its cell entry receptor. Clinical data reveal that in severe COVID-19, SARS-CoV-2 infects the lung, leading to a frequently lethal triad of respiratory insufficiency, acute cardiovascular failure, and coagulopathy. Physiologically, ACE2 plays a role in the regulation of three systems that could potentially be involved in the pathogenesis of severe COVID-19: the kinin–kallikrein system, resulting in acute lung inflammatory edema; the renin–angiotensin system, promoting cardiovascular instability; and the coagulation system, leading to thromboembolism. Here we assembled a healthy human lung cell atlas meta-analysis with ~ 130,000 public single-cell transcriptomes and show that key elements of the bradykinin, angiotensin and coagulation systems are co-expressed with ACE2 in alveolar cells and associated with their differentiation dynamics, which could explain how changes in ACE2 promoted by SARS-CoV-2 cell entry result in the development of the three most severe clinical components of COVID-19.
A novel Trypanosoma cruzi secreted antigen as a potential biomarker of Chagas disease
Authors: Nagarkatti Rana , Acosta David , Acharyya Nirmallya , de Araujo Fernanda Fortes , Elói-Santos Silvana Maria , Martins-Filho Olindo Assis , Teixeira-Carvalho Andréa , Debrabant Alain
Published: November 2020

Chagas drug discovery has been hampered by a lack of validated assays to establish treatment efficacy in pre-clinical animal models and in patients infected with T. cruzi. Reduced levels of parasite secreted antigens in the blood of infected hosts could be used to demonstrate treatment efficacy. A published proteomic study of parasite secreted antigens identified the hypothetical protein Tc_5171 as a secreted antigen. In this report, we developed Tc_5171 specific antibodies and showed that the native protein was expressed by the three life cycle stages of the parasite. Anti-peptide antibodies were able to detect the parasite antigen in blood of infected mice during the acute and the chronic phase of infection. Benznidazole treatment of infected mice significantly reduced their blood antigen levels. Of clinical significance, patients diagnosed with Chagas disease, either asymptomatic or with cardiac clinical symptoms had significantly higher Tc_5171 antigen levels compared to endemic controls. Pair-wise analysis, before and after Benznidazole treatment, of patients with asymptomatic Chagas disease showed a significant reduction in antigen levels post treatment. Taken together, our results indicate that Tc_5171 could be used as a novel biomarker of Chagas disease for diagnosis and to assess treatment efficacy.
Gene expression signatures associated with sensitivity to azacitidine in myelodysplastic syndromes
Authors: Kim Kyuryung , Park Silvia , Choi Hayoung , Kim Hye Joung , Kwon Yong-Rim , Ryu Daeun , Kim Myungshin , Kim Tae-Min , Kim Yoo-Jin
Published: November 2020

Allogeneic stem cell transplantation is currently the only curative treatment option for myelodysplastic syndromes (MDS). Pre-transplant debulking treatment have been employed for advanced MDS and we previously reported that marrow response (blast ≤ 5%) following the bridging therapy with hypomethylating agent was an independent favorable factor for survival; however, it is still not clear which patients will respond to hypomethylating agent and which genomic features can predict the response. In this study, we performed RNAseq for 23 MDS patients among which 14 (61%) and 9 (39%) patients showed marrow complete remission and primary resistance to azacitidine, respectively. Differential expression-based analyses of treatment-naive, baseline gene expression profiles revealed that molecular functions representing mitochondria and apoptosis were up-regulated in responders. In contrast, we identified genes involved in the Wnt pathway were relatively up-regulated in non-responders. In independent validation cohorts of MDS patients, the expression of gene sets specific to non-responders and responders distinguished the patients with favorable prognosis and those responded to azacitidine highlighting the prognostic and predictive implication. In addition, a systems biology approach identified genes involved in ubiquitination, such as UBC and PFDN2, which may be key players in the regulation of differential gene expression in treatment responders and non-responders. Taken together, identifying the gene expression signature may advance our understanding of the molecular mechanisms of azacitidine and may also serve to predict patient responses to drug treatment.
Exploring blood alterations in chronic kidney disease and haemodialysis using metabolomics
Authors: Gagnebin Yoric , Jaques David A. , Rudaz Serge , de Seigneux Sophie , Boccard Julien , Ponte Belén
Published: November 2020

Chronic kidney disease (CKD) is characterized by retention of uremic solutes. Compared to patients with non-dialysis dependent CKD, those requiring haemodialysis (HD) have increased morbidity and mortality. We wished to characterise metabolic patterns in CKD compared to HD patients using metabolomics. Prevalent non-HD CKD KDIGO stage 3b–4 and stage 5 HD outpatients were screened at a single tertiary hospital. Various liquid chromatography approaches hyphenated with mass spectrometry were used to identify 278 metabolites. Unsupervised and supervised data analyses were conducted to characterize metabolic patterns. 69 patients were included in the CKD group and 35 in the HD group. Unsupervised data analysis showed clear clustering of CKD, pre-dialysis (preHD) and post-dialysis (postHD) patients. Supervised data analysis revealed qualitative as well as quantitative differences in individual metabolites profiles between CKD, preHD and postHD states. An original metabolomics framework could discriminate between CKD stages and highlight HD effect based on 278 identified metabolites. Significant differences in metabolic patterns between CKD and HD patients were found overall as well as for specific metabolites. Those findings could explain clinical discrepancies between patients requiring HD and those with earlier stage of CKD.