bluuebunny/crossref_metadata_2025_split huggingface dataset:
Concurrent Measurements of Soil and Ecosystem Respiration in a Mature Eucalypt Woodland: Advantages, Lessons, and Questions
Authors: Renchon A. A. , Drake J. E. , Macdonald C. A. , Sihi D. , Hinko‐Najera N. , Tjoelker M. G. , Arndt S. K. , Noh N. J. , Davidson E. , Pendall E. 
Published: February 2021

AbstractUnderstanding seasonal and diurnal dynamics of ecosystem respiration (Reco) in forests is challenging, because Reco can only be measured directly during night‐time by eddy‐covariance flux towers. Reco is the sum of soil respiration (Rsoil) and above‐ground respiration (in theory, RAG = Reco − Rsoil). Rsoil can be measured day and night and can provide a check of consistency on Reco, as the difference in magnitude and time dynamic between Reco and Rsoil should be explained by RAG. We assessed the temporal patterns and climatic drivers of Rsoil and Reco in a mature eucalypt woodland, using continuous measurements (only at night for Reco) at half‐hourly resolution over 4 years (2014–2017). Our data showed large seasonal and diurnal (overnight) variation of Reco, while Rsoil had a low diurnal amplitude and their difference (Reco − Rsoil, or RAG) had a low seasonal amplitude. This result implies at first glance that seasonal variation of Reco was mainly influenced by Rsoil while its diurnal variation was mainly influenced by RAG. However, our analysis suggests that the night‐time Reco decline cannot realistically be explained by a decline of RAG. Chamber measurements of autotrophic components at half‐hourly time resolution are needed to quantify how much of the Reco decline overnight is due to declines in leaf or stem respiration, and how much is due to missing storage or advection, which may create a systematic bias in Reco measurements. Our findings emphasize the need for reconciling bottom‐up (via components measured with chambers) and direct estimates of Reco (via eddy‐covariance method).
Genetic analysis of 20 patients with hypomyelinating leukodystrophy by trio-based whole-exome sequencing
Authors: Yan Huifang , Ji Haoran , Kubisiak Thomas , Wu Ye , Xiao Jiangxi , Gu Qiang , Yang Yanling , Xie Han , Ji Taoyun , Gao Kai , Li Dongxiao , Xiong Hui , Shi Zhen , Li Ming , Zhang Yuehua , Duan Ruoyu , Bao Xinhua , Jiang Yuwu , Burmeister Margit , Wang Jingmin 
Published: February 2021

AbstractHypomyelinating leukodystrophies (HLDs) are a rare group of disorders characterized by myelin deficit of the brain-based on MRI. Here, we studied 20 patients with unexplained HLD to uncover their genetic etiology through whole-exome sequencing (WES). Trio-based WES was performed for 20 unresolved HLDs families after genetic tests for the PLP1 duplication and a panel of 115 known leukodystrophy-related genes. Variants in both known genes that related to HLDs and promising candidate genes were analyzed. Minigene splicing assay was conducted to confirm the effect of splice region variant. All 20 patients were diagnosed with HLDs clinically based on myelin deficit on MRI and impaired motor ability. Through WES, in 11 of 20 trios, 15 causative variants were detected in seven genes TUBB4A, POLR1C, POLR3A, SOX10, TMEM106B, DEGS1, and TMEM63A. The last three genes have just been discovered. Of 15 variants, six were novel. Using minigene splicing assay, splice variant POLR3A c.1770 + 5 G > C was proved to disrupt the normal splicing of intron 13 and led to a premature stop codon at position 618 (p.(P591Vfs*28)). Our analysis determined the molecular diagnosis of 11 HLDs patients. It emphasizes the heterogenicity of HLDs, the diagnostic power of trio-based WES for HLDs. Comprehensive analysis including a focus on candidate genes helps to discover novel disease-causing genes, determine the diagnosis for the first time, and improve the yield of WES. Moreover, novel mutations identified in TUBB4A, POLR3A, and POLR1C expand the mutation spectrum of these genes.
Analysis of transient membrane protein interactions by single-molecule diffusional mobility shift assay
Authors: Jeong Min Gyu , Zhou Kai , Park Soyeon , An HyeongJeon , Kwon Yonghoon , Chang Yeonho , Kim Do-Hyeon , Ryu Sung Ho 
Published: February 2021

AbstractVarious repertoires of membrane protein interactions determine cellular responses to diverse environments around cells dynamically in space and time. Current assays, however, have limitations in unraveling these interactions in the physiological states in a living cell due to the lack of capability to probe the transient nature of these interactions on the crowded membrane. Here, we present a simple and robust assay that enables the investigation of transient protein interactions in living cells by using the single-molecule diffusional mobility shift assay (smDIMSA). Utilizing smDIMSA, we uncovered the interaction profile of EGFR with various membrane proteins and demonstrated the promiscuity of these interactions depending on the cancer cell line. The transient interaction profile obtained by smDIMSA will provide critical information to comprehend the crosstalk among various receptors on the plasma membrane.
Sorafenib or placebo in patients with newly diagnosed acute myeloid leukaemia: long-term follow-up of the randomized controlled SORAML trial
Authors: Röllig Christoph , Serve Hubert , Noppeney Richard , Hanoun Maher , Krug Utz , Baldus Claudia D. , Brandts Christian H. , Kunzmann Volker , Einsele Hermann , Krämer Alwin , Müller-Tidow Carsten , Schäfer-Eckart Kerstin , Neubauer Andreas , Burchert Andreas , Giagounidis Aristoteles , Krause Stefan W. , Mackensen Andreas , Aulitzky Walter , Herbst Regina , Hänel Mathias , Frickhofen Norbert , Kullmer Johannes , Kaiser Ulrich , Kiani Alexander , Link Hartmut , Geer Thomas , Reichle Albrecht , Junghanß Christian , Repp Roland , Meinhardt Achim , Dürk Heinz , Klut Ina-Maria , Bornhäuser Martin , Schaich Markus , Parmentier Stefani , Görner Martin , Thiede Christian , von Bonin Malte , Platzbecker Uwe , Schetelig Johannes , Kramer Michael , Berdel Wolfgang E. , Ehninger Gerhard ,   for the Study Alliance Leukaemia (SAL)
Published: February 2021

AbstractEarly results of the randomized placebo-controlled SORAML trial showed that, in patients with newly diagnosed acute myeloid leukaemia (AML), sorafenib led to a significant improvement in event-free (EFS) and relapse-free survival (RFS). In order to describe second-line treatments and their implications on overall survival (OS), we performed a study after a median follow-up time of 78 months. Newly diagnosed fit AML patients aged ≤60 years received sorafenib (n = 134) or placebo (n = 133) in addition to standard chemotherapy and as maintenance treatment. The 5-year EFS was 41 versus 27% (HR 0.68; p = 0.011) and 5-year RFS was 53 versus 36% (HR 0.64; p = 0.035). Allogeneic stem cell transplantation (allo SCT) was performed in 88% of the relapsed patients. Four years after salvage allo SCT, the cumulative incidence of relapse was 54 versus 35%, and OS was 32 versus 50%. The 5-year OS from randomization in all study patients was 61 versus 53% (HR 0.82; p = 0.282). In conclusion, the addition of sorafenib to chemotherapy led to a significant prolongation of EFS and RFS. Although the OS benefit did not reach statistical significance, these results confirm the antileukaemic activity of sorafenib.
Small molecule induces mitochondrial fusion for neuroprotection via targeting CK2 without affecting its conventional kinase activity
Authors: Zeng Ke-Wu , Wang Jing-Kang , Wang Li-Chao , Guo Qiang , Liu Ting-Ting , Wang Fu-Jiang , Feng Na , Zhang Xiao-Wen , Liao Li-Xi , Zhao Mei-Mei , Liu Dan , Jiang Yong , Tu Pengfei 
Published: February 2021

AbstractMitochondrial fusion/fission dynamics plays a fundamental role in neuroprotection; however, there is still a severe lack of therapeutic targets for this biological process. Here, we found that the naturally derived small molecule echinacoside (ECH) significantly promotes mitochondrial fusion progression. ECH selectively binds to the previously uncharacterized casein kinase 2 (CK2) α′ subunit (CK2α′) as a direct cellular target, and genetic knockdown of CK2α′ abolishes ECH-mediated mitochondrial fusion. Mechanistically, ECH allosterically regulates CK2α′ conformation to recruit basic transcription factor 3 (BTF3) to form a binary protein complex. Then, the CK2α′/BTF3 complex facilitates β-catenin nuclear translocation to activate TCF/LEF transcription factors and stimulate transcription of the mitochondrial fusion gene Mfn2. Strikingly, in a mouse middle cerebral artery occlusion (MCAO) model, ECH administration was found to significantly improve cerebral injuries and behavioral deficits by enhancing Mfn2 expression in wild-type but not CK2α′+/− mice. Taken together, our findings reveal, for the first time, that CK2 is essential for promoting mitochondrial fusion in a Wnt/β-catenin-dependent manner and suggest that pharmacologically targeting CK2 is a promising therapeutic strategy for ischemic stroke.
Host genotype and genetic diversity shape the evolution of a novel bacterial infection
Authors: Ekroth Alice K E , Gerth Michael , Stevens Emily J , Ford Suzanne A , King Kayla C 
Published: February 2021

Abstract
Pathogens continue to emerge from increased contact with novel host species. Whilst these hosts can represent distinct environments for pathogens, the impacts of host genetic background on how a pathogen evolves post-emergence are unclear. In a novel interaction, we experimentally evolved a pathogen (Staphylococcus aureus) in populations of wild nematodes (Caenorhabditis elegans) to test whether host genotype and genetic diversity affect pathogen evolution. After ten rounds of selection, we found that pathogen virulence evolved to vary across host genotypes, with differences in host metal ion acquisition detected as a possible driver of increased host exploitation. Diverse host populations selected for the highest levels of pathogen virulence, but infectivity was constrained, unlike in host monocultures. We hypothesise that population heterogeneity might pool together individuals that contribute disproportionately to the spread of infection or to enhanced virulence. The genomes of evolved populations were sequenced, and it was revealed that pathogens selected in distantly-related host genotypes diverged more than those in closely-related host genotypes. S. aureus nevertheless maintained a broad host range. Our study provides unique empirical insight into the evolutionary dynamics that could occur in other novel infections of wildlife and humans.
The neural basis underlying impaired attentional control in problematic smartphone users
Authors: Choi Jihye , Cho Hyun , Choi Jung-Seok , Choi In Young , Chun Ji-Won , Kim Dai-Jin 
Published: February 2021

AbstractAs a portable media device that enables ubiquitous access to friends and entertainment, smartphones are inextricably linked with our lives. Although there is growing concern about the detrimental effect of problematic smartphone use on attentional control, the underlying neural mechanisms of impaired attentional control in problematic smartphone users (PSU) has yet to be investigated. Using a modified cognitive conflict task, we examined behavioral performance in the presence of distracting words during functional magnetic resonance imaging in 33 PSU and 33 control participants (CON). Compared with the CON group, the PSU group demonstrated impaired performance that was accompanied by constantly enhanced but not differentiated activation in the frontoparietal regions across all conditions, regardless of distractor saliency. The inferior parietal lobule (IPL) activation in the PSU group, in particular, showed an association with performance deficits in the distractor conditions. Furthermore, the PSU group exhibited decreased functional connectivity of the right IPL with the right superior temporal gyrus of the ventral attention system in the attention-demanding condition relative to the easiest condition, which was associated with the severe dependence on smartphone use. Our findings suggest that greater distractibility in the PSU group during the attentional control task may be associated with inefficient recruitment of the ventral attention network involved in bottom-up attentional processing, as indicated by hyperactivation but less coherence within the network. The present study provides evidence for understanding the neural mechanisms underlying the impaired ability to keep attention from being oriented to task-irrelevant stimuli observed in PSU.
From warrior genes to translational solutions: novel insights into monoamine oxidases (MAOs) and aggression
Authors: Mentis Alexios-Fotios A. , Dardiotis Efthimios , Katsouni Eleni , Chrousos George P. 
Published: February 2021

AbstractThe pervasive and frequently devastating nature of aggressive behavior calls for a collective effort to understand its psychosocial and neurobiological underpinnings. Regarding the latter, diverse brain areas, neural networks, neurotransmitters, hormones, and candidate genes have been associated with antisocial and aggressive behavior in humans and animals. This review focuses on the role of monoamine oxidases (MAOs) and the genes coding for them, in the modulation of aggression. During the past 20 years, a substantial number of studies using both pharmacological and genetic approaches have linked the MAO system with aggressive and impulsive behaviors in healthy and clinical populations, including the recent discovery ofMAALIN, a long noncoding RNA (lncRNA) regulating theMAO-Agene in the human brain. Here, we first provide an overview of the MAOs and their physiological functions, we then summarize recent key findings linking MAO-related enzymatic and gene activity and aggressive behavior, and, finally, we offer novel insights into the mechanisms underlying this association. Using the existing experimental evidence as a foundation, we discuss the translational implications of these findings in clinical practice and highlight what we believe are outstanding conceptual and methodological questions in the field. Ultimately, we propose that unraveling the specific role of MAO in aggression requires an integrated approach, where this question is pursued by combining psychological, radiological, and genetic/genomic assessments. The translational benefits of such an approach include the discovery of novel biomarkers of aggression and targeting the MAO system to modulate pathological aggression in clinical populations.
Ibrutinib and venetoclax target distinct subpopulations of CLL cells: implication for residual disease eradication
Authors: Lu Pin , Wang Shengchun , Franzen Carrie A. , Venkataraman Girish , McClure Rebecca , Li Lei , Wu Wenjun , Niu Nifang , Sukhanova Madina , Pei Jianming , Baldwin Donald A. , Nejati Reza , Wasik Mariusz A. , Khan Nadia , Tu Yifan , Gao Juehua , Chen Yihua , Ma Shuo , Larson Richard A. , Wang Y. Lynn 
Published: February 2021

AbstractIbrutinib inhibits Bruton tyrosine kinase while venetoclax is a specific inhibitor of the anti-apoptotic protein BCL2. Both drugs are highly effective as monotherapy against chronic lymphocytic leukemia (CLL), and clinical trials using the combination therapy have produced remarkable results in terms of rate of complete remission and frequency of undetectable minimal residual disease. However, the laboratory rationale behind the success of the drug combination is still lacking. A better understanding of how these two drugs synergize would eventually help develop other rational combination strategies. Using an ex vivo model that promotes CLL proliferation, we show that modeled ibrutinib proliferative responses, but not viability responses, correlate well with patients’ actual clinical responses. Importantly, we demonstrate for the first time that ibrutinib and venetoclax act on distinct CLL subpopulations that have different proliferative capacities. While the dividing subpopulation of CLL responds to ibrutinib, the resting subpopulation preferentially responds to venetoclax. The combination of these targeted therapies effectively reduced both the resting and dividing subpopulations in most cases. Our laboratory findings help explain several clinical observations and contribute to the understanding of tumor dynamics. Additionally, our proliferation model may be used to identify novel drug combinations with the potential of eradicating residual disease.
The Y chromosome ancestry marker R1b1b2: a surrogate of the SARS-CoV-2 population affinity
Authors: Ibrahim Muntaser , Salih Abdalhameed 
Published: February 2021

AbstractIndividual and population susceptibilities to disease remain a murky area of investigation, clouded by past bias based on ideological differences and wars. The current SARS-CoV-2 pandemic, the largest in living memory, brought this matter to forefront as the disparity in disease burden became apparent. A timeline analysis of the pandemic revealed the presence of country clusters that display a marked preponderance of disease among populations carrying the ancestry marker R1b1b2, notably associated with both infection and mortality. This marker is a relic of past human expansions from western Asia and subsequently Europe and the rest of the world, which may have been accompanied by peculiar biological events rendering these populations vulnerable to SARS-CoV-2.
Scaling advantage over path-integral Monte Carlo in quantum simulation of geometrically frustrated magnets
Authors: King Andrew D. , Raymond Jack , Lanting Trevor , Isakov Sergei V. , Mohseni Masoud , Poulin-Lamarre Gabriel , Ejtemaee Sara , Bernoudy William , Ozfidan Isil , Smirnov Anatoly Yu. , Reis Mauricio , Altomare Fabio , Babcock Michael , Baron Catia , Berkley Andrew J. , Boothby Kelly , Bunyk Paul I. , Christiani Holly , Enderud Colin , Evert Bram , Harris Richard , Hoskinson Emile , Huang Shuiyuan , Jooya Kais , Khodabandelou Ali , Ladizinsky Nicolas , Li Ryan , Lott P. Aaron , MacDonald Allison J. R. , Marsden Danica , Marsden Gaelen , Medina Teresa , Molavi Reza , Neufeld Richard , Norouzpour Mana , Oh Travis , Pavlov Igor , Perminov Ilya , Prescott Thomas , Rich Chris , Sato Yuki , Sheldan Benjamin , Sterling George , Swenson Loren J. , Tsai Nicholas , Volkmann Mark H. , Whittaker Jed D. , Wilkinson Warren , Yao Jason , Neven Hartmut , Hilton Jeremy P. , Ladizinsky Eric , Johnson Mark W. , Amin Mohammad H. 
Published: February 2021

AbstractThe promise of quantum computing lies in harnessing programmable quantum devices for practical applications such as efficient simulation of quantum materials and condensed matter systems. One important task is the simulation of geometrically frustrated magnets in which topological phenomena can emerge from competition between quantum and thermal fluctuations. Here we report on experimental observations of equilibration in such simulations, measured on up to 1440 qubits with microsecond resolution. By initializing the system in a state with topological obstruction, we observe quantum annealing (QA) equilibration timescales in excess of one microsecond. Measurements indicate a dynamical advantage in the quantum simulation compared with spatially local update dynamics of path-integral Monte Carlo (PIMC). The advantage increases with both system size and inverse temperature, exceeding a million-fold speedup over an efficient CPU implementation. PIMC is a leading classical method for such simulations, and a scaling advantage of this type was recently shown to be impossible in certain restricted settings. This is therefore an important piece of experimental evidence that PIMC does not simulate QA dynamics even for sign-problem-free Hamiltonians, and that near-term quantum devices can be used to accelerate computational tasks of practical relevance.
Predicting mammalian hosts in which novel coronaviruses can be generated
Authors: Wardeh Maya , Baylis Matthew , Blagrove Marcus S. C. 
Published: February 2021

AbstractNovel pathogenic coronaviruses – such as SARS-CoV and probably SARS-CoV-2 – arise by homologous recombination between co-infecting viruses in a single cell. Identifying possible sources of novel coronaviruses therefore requires identifying hosts of multiple coronaviruses; however, most coronavirus-host interactions remain unknown. Here, by deploying a meta-ensemble of similarity learners from three complementary perspectives (viral, mammalian and network), we predict which mammals are hosts of multiple coronaviruses. We predict that there are 11.5-fold more coronavirus-host associations, over 30-fold more potential SARS-CoV-2 recombination hosts, and over 40-fold more host species with four or more different subgenera of coronaviruses than have been observed to date at >0.5 mean probability cut-off (2.4-, 4.25- and 9-fold, respectively, at >0.9821). Our results demonstrate the large underappreciation of the potential scale of novel coronavirus generation in wild and domesticated animals. We identify high-risk species for coronavirus surveillance.
A game theoretic approach reveals that discretizing clinical information can reduce antibiotic misuse
Authors: Diamant Maya , Baruch Shoham , Kassem Eias , Muhsen Khitam , Samet Dov , Leshno Moshe , Obolski Uri 
Published: February 2021

AbstractThe overuse of antibiotics is exacerbating the antibiotic resistance crisis. Since this problem is a classic common-goods dilemma, it naturally lends itself to a game-theoretic analysis. Hence, we designed a model wherein physicians weigh whether antibiotics should be prescribed, given that antibiotic usage depletes its future effectiveness. The physicians’ decisions rely on the probability of a bacterial infection before definitive laboratory results are available. We show that the physicians’ equilibrium decision rule of antibiotic prescription is not socially optimal. However, we prove that discretizing the information provided to physicians can mitigate the gap between their equilibrium decisions and the social optimum of antibiotic prescription. Despite this problem’s complexity, the effectiveness of the discretization solely depends on the type of information available to the physician to determine the nature of infection. This is demonstrated on theoretic distributions and a clinical dataset. Our results provide a game-theory based guide for optimal output of current and future decision support systems of antibiotic prescription.
Tumour gene expression signature in primary melanoma predicts long-term outcomes
Authors: Garg Manik , Couturier Dominique-Laurent , Nsengimana Jérémie , Fonseca Nuno A. , Wongchenko Matthew , Yan Yibing , Lauss Martin , Jönsson Göran B. , Newton-Bishop Julia , Parkinson Christine , Middleton Mark R. , Bishop D. Timothy , McDonald Sarah , Stefanos Nikki , Tadross John , Vergara Ismael A. , Lo Serigne , Newell Felicity , Wilmott James S. , Thompson John F. , Long Georgina V. , Scolyer Richard A. , Corrie Pippa , Adams David J. , Brazma Alvis , Rabbie Roy 
Published: February 2021

AbstractAdjuvant systemic therapies are now routinely used following resection of stage III melanoma, however accurate prognostic information is needed to better stratify patients. We use differential expression analyses of primary tumours from 204 RNA-sequenced melanomas within a large adjuvant trial, identifying a 121 metastasis-associated gene signature. This signature strongly associated with progression-free (HR = 1.63, p = 5.24 × 10−5) and overall survival (HR = 1.61, p = 1.67 × 10−4), was validated in 175 regional lymph nodes metastasis as well as two externally ascertained datasets. The machine learning classification models trained using the signature genes performed significantly better in predicting metastases than models trained with clinical covariates (pAUROC = 7.03 × 10−4), or published prognostic signatures (pAUROC < 0.05). The signature score negatively correlated with measures of immune cell infiltration (ρ = −0.75, p < 2.2 × 10−16), with a higher score representing reduced lymphocyte infiltration and a higher 5-year risk of death in stage II melanoma. Our expression signature identifies melanoma patients at higher risk of metastases and warrants further evaluation in adjuvant clinical trials.