bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oxygen False Positives on Habitable Zone Planets Around Sun‐Like Stars
Authors: Krissansen‐Totton Joshua , Fortney Jonathan J. , Nimmo Francis , Wogan Nicholas 
Published: April 2021

AbstractOxygen is a promising exoplanet biosignature due to the evolutionary advantage conferred by harnessing starlight for photosynthesis, and the apparent low likelihood of maintaining oxygen‐rich atmospheres without life. Hypothetical scenarios have been proposed for non‐biological oxygen accumulation on planets around late M‐dwarfs, where the extended pre‐main sequence may favor abiotic O2 accumulation. In contrast, abiotic oxygen accumulation on planets around F, G, and K‐type stars is seemingly less likely, provided they possess substantial non‐condensable gas inventories. The comparative robustness of oxygen biosignatures around larger stars has motivated plans for next‐generation telescopes capable of oxygen detection on planets around sun‐like stars. However, the general tendency of terrestrial planets to develop oxygen‐rich atmospheres across a broad range of initial conditions and evolutionary scenarios has not been explored. Here, we use a coupled thermal‐geochemical‐climate model of terrestrial planet evolution to illustrate three scenarios whereby significant abiotic oxygen can accumulate around sun‐like stars, even when significant noncondensable gas inventories are present. For Earth‐mass planets, we find abiotic oxygen can accumulate to modern levels if (1) the CO2:H2O ratio of the initial volatile inventory is high, (2) the initial water inventory exceeds ∼50 Earth oceans, or (3) the initial water inventory is very low (<0.3 Earth oceans). Fortunately, these three abiotic oxygen scenarios could be distinguished from biological oxygen with observations of other atmospheric constituents or characterizing the planetary surface. This highlights the need for broadly capable next‐generation telescopes that are equipped to constrain surface water inventories via time‐resolved photometry and search for temporal biosignatures or disequilibrium combination biosignatures to assess whether oxygen is biogenic.
Influence of Tide‐Induced Unstable Flow on Seawater Intrusion and Submarine Groundwater Discharge
Authors: Fang Yunhai , Zheng Tianyuan , Zheng Xilai , Yang Huiyu , Wang Huan , Walther Marc 
Published: April 2021

AbstractRecent studies have confirmed the instability of tide‐induced upper saline plume (USP) in tidal beach aquifers. A systematic understanding of how the unstable USP contributes to groundwater flow and salinity distribution is still lacking. Here we used laboratory experiments and numerical simulations to examine the responses of the salinity distribution and submarine groundwater discharge (SGD) to tide‐induced unstable flow. The results revealed that changes in physical forcing conditions (tides and inland freshwater input) drove the transition of the USP from stable to unstable states. Meanwhile, the phase‐averaged SGD and its components fluctuated over time, and their oscillation amplitudes depended on the physical forcing conditions. There was a correlation between USP instability and the fluctuation of water exchange across the aquifer‐sea interface. The fluxes across the aquifer‐sea interface under unstable conditions usually varied considerably over time with a lower frequency in comparison to stable conditions. The extent of seawater intrusion (SWI) measured by the total salt mass stored in the aquifer also varied over time, especially under unstable conditions. The vibration tendency of the total salt mass was opposite to that of the sum of inland freshwater discharge and tide‐induced circulation efflux. For coastal aquifers affected by tides, SWI was dominated by the sum of inland freshwater discharge and tide‐induced circulation efflux, followed by the sum of inland freshwater input and tide‐induced circulation influx. These findings lay the foundation for gaining a better understanding of tide‐induced unstable flow and its potential implications.
The roles of the inhibitory autophagy regulator Rubicon in the heart: A new therapeutic target to prevent cardiac cell death
Authors: Nah Jihoon , Zablocki Daniela , Sadoshima Junichi 
Published: April 2021

AbstractAutophagy contributes to the maintenance of cardiac homeostasis. The level of autophagy is dynamically altered in heart disease. Although autophagy is a promising therapeutic target, only a few selective autophagy activator candidates have been reported thus far. Rubicon is one of the few endogenous negative regulators of autophagy and a potential target for autophagy-inducing therapeutics. Rubicon was initially identified as a component of the Class III PI3K complex, and it has multiple functions, not only in canonical autophagy but also in endosomal trafficking and inflammatory responses. This review summarizes the molecular action of Rubicon in canonical and noncanonical autophagy. We discuss the roles of Rubicon in cardiac stress and the therapeutic potential of Rubicon in cardiac diseases through its modulation of autophagy.
Correction to: Spatial patterns in phage-Rhizobium coevolutionary interactions across regions of common bean domestication
Authors: Van Cauwenberghe Jannick , Santamaría Rosa I , Bustos Patricia , Juárez Soledad , Ducci Maria Antonella , Fleming Trinidad Figueroa , Etcheverry Angela Virginia , González Víctor 
Published: April 2021

Abstract
A Correction to this paper has been published: https://doi.org/10.1038/s41396-021-00963-5
Anticipated help-seeking for cancer symptoms before and after the coronavirus pandemic: results from the Onco-barometer population survey in Spain
Authors: Petrova Dafina , Pollán Marina , Rodriguez-Barranco Miguel , Garrido Dunia , Borrás Josep M. , Sánchez Maria-José 
Published: April 2021

Abstract
Background
The patient interval—the time patients wait before consulting their physician after noticing cancer symptoms—contributes to diagnostic delays. We compared anticipated help-seeking times for cancer symptoms and perceived barriers to help-seeking before and after the coronavirus pandemic.

Methods
Two waves (pre-Coronavirus: February 2020, N = 3269; and post-Coronavirus: August 2020, N = 1500) of the Spanish Onco-barometer population survey were compared. The international ABC instrument was administered. Pre–post comparisons were performed using multiple logistic and Poisson regression models.

Results
There was a consistent and significant increase in anticipated times to help-seeking for 12 of 13 cancer symptoms, with the largest increases for breast changes (OR = 1.54, 95% CI 1.22–1–96) and unexplained bleeding (OR = 1.50, 1.26–1.79). Respondents were more likely to report barriers to help-seeking in the post wave, most notably worry about what the doctor may find (OR = 1.58, 1.35–1.84) and worry about wasting the doctor’s time (OR = 1.48, 1.25–1.74). Women and older individuals were the most affected.

Conclusions
Participants reported longer waiting times to help-seeking for cancer symptoms after the pandemic. There is an urgent need for public interventions encouraging people to consult their physicians with symptoms suggestive of cancer and counteracting the main barriers perceived during the pandemic situation.
Directly targeting c-Myc contributes to the anti-multiple myeloma effect of anlotinib
Authors: Cao Yang , Shan Huizhuang , Liu Meng , Liu Jia , Zhang Zilu , Xu Xiaoguang , Liu Yue , Xu Hanzhang , Lei Hu , Yu Miao , Zhang Xingming , Liu Wanting , Bu Zhilei , Fang Zhixiao , Ji Yanjie , Yan Hua , Gu Weiying , Wu Yingli 
Published: April 2021

AbstractDespite the significant advances in the treatment of multiple myeloma (MM), this disease is still considered incurable because of relapse and chemotherapy resistance, underscoring the need to seek novel therapies with different mechanisms. Anlotinib, a novel multi-targeted tyrosine kinase inhibitor (TKI), has exhibited encouraging antitumor activity in several preclinical and clinical trials, but its effect on MM has not been studied yet. In this study, we found that anlotinib exhibits encouraging cytotoxicity in MM cells, overcomes the protective effect of the bone marrow microenvironment and suppresses tumor growth in the MM mouse xenograft model. We further examined the underlying molecular mechanism and found that anlotinib provokes cell cycle arrest, induces apoptosis and inhibits multiple signaling pathways. Importantly, we identify c-Myc as a novel direct target of anlotinib. The enhanced ubiquitin proteasomal degradation of c-Myc contributes to the cell apoptosis induced by anlotinib. In addition, anlotinib also displays strong cytotoxicity against bortezomib-resistant MM cells. Our study demonstrates the extraordinary anti-MM effect of anlotinib both in vitro and in vivo, which provides solid evidence and a promising rationale for future clinical application of anlotinib in the treatment of human MM.
Spine impairment in mice high-expressing neuregulin 1 due to LIMK1 activation
Authors: Chen Peng , Jing Hongyang , Xiong Mingtao , Zhang Qian , Lin Dong , Ren Dongyan , Wang Shunqi , Yin Dongmin , Chen Yongjun , Zhou Tian , Li Baoming , Fei Erkang , Pan Bing-Xing 
Published: April 2021

AbstractThe genes encoding for neuregulin1 (NRG1), a growth factor, and its receptor ErbB4 are both risk factors of major depression disorder and schizophrenia (SZ). They have been implicated in neural development and synaptic plasticity. However, exactly how NRG1 variations lead to SZ remains unclear. Indeed, NRG1 levels are increased in postmortem brain tissues of patients with brain disorders. Here, we studied the effects of high-level NRG1 on dendritic spine development and function. We showed that spine density in the prefrontal cortex and hippocampus was reduced in mice (ctoNrg1) that overexpressed NRG1 in neurons. The frequency of miniature excitatory postsynaptic currents (mEPSCs) was reduced in both brain regions of ctoNrg1 mice. High expression of NRG1 activated LIMK1 and increased cofilin phosphorylation in postsynaptic densities. Spine reduction was attenuated by inhibiting LIMK1 or blocking the NRG1–LIMK1 interaction, or by restoring NRG1 protein level. These results indicate that a normal NRG1 protein level is necessary for spine homeostasis and suggest a pathophysiological mechanism of abnormal spines in relevant brain disorders.
The ubiquitin ligase NEDD4-2/NEDD4L regulates both sodium homeostasis and fibrotic signaling to prevent end-stage renal disease
Authors: Manning Jantina A. , Shah Sonia S. , Nikolic Andrej , Henshall Tanya L. , Khew-Goodall Yeesim , Kumar Sharad 
Published: April 2021

AbstractKidney disease progression can be affected by Na+ abundance. A key regulator of Na+ homeostasis is the ubiquitin ligase NEDD4-2 and its deficiency leads to increased Na+ transport activity and salt-sensitive progressive kidney damage. However, the mechanisms responsible for high Na+ induced damage remain poorly understood. Here we show that a high Na+ diet compromised kidney function in Nedd4-2-deficient mice, indicative of progression toward end-stage renal disease. Injury was characterized by enhanced tubule dilation and extracellular matrix accumulation, together with sustained activation of both Wnt/β-catenin and TGF-β signaling. Nedd4-2 knockout in cortical collecting duct cells also activated these pathways and led to epithelial–mesenchymal transition. Furthermore, low dietary Na+ rescued kidney disease in Nedd4-2-deficient mice and silenced Wnt/β-catenin and TGF-β signaling. Our study reveals the important role of NEDD4-2-dependent ubiquitination in Na+ homeostasis and protecting against aberrant Wnt/β-catenin/TGF-β signaling in progressive kidney disease.
Honey-collecting in prehistoric West Africa from 3500 years ago
Authors: Dunne Julie , Höhn Alexa , Franke Gabriele , Neumann Katharina , Breunig Peter , Gillard Toby , Walton-Doyle Caitlin , Evershed Richard P. 
Published: April 2021

AbstractHoney and other bee products were likely a sought-after foodstuff for much of human history, with direct chemical evidence for beeswax identified in prehistoric ceramic vessels from Europe, the Near East and Mediterranean North Africa, from the 7thmillennium BC. Historical and ethnographic literature from across Africa suggests bee products, honey and larvae, had considerable importance both as a food source and in the making of honey-based drinks. Here, to investigate this, we carry out lipid residue analysis of 458 prehistoric pottery vessels from the Nok culture, Nigeria, West Africa, an area where early farmers and foragers co-existed. We report complex lipid distributions, comprisingn-alkanes,n-alkanoic acids and fatty acyl wax esters, which provide direct chemical evidence of bee product exploitation and processing, likely including honey-collecting, in over one third of lipid-yielding Nok ceramic vessels. These findings highlight the probable importance of honey collecting in an early farming context, around 3500 years ago, in West Africa.
Toward integrative approaches to study the causal role of neural oscillations via transcranial electrical stimulation
Authors: Beliaeva Valeriia , Savvateev Iurii , Zerbi Valerio , Polania Rafael 
Published: April 2021

AbstractDiverse transcranial electrical stimulation (tES) techniques have recently been developed to elucidate the role of neural oscillations, but critically, it remains questionable whether neural entrainment genuinely occurs and is causally related to the resulting behavior. Here, we provide a perspective on an emerging integrative research program across systems, species, theoretical and experimental frameworks to elucidate the potential of tES to induce neural entrainment. We argue that such an integrative agenda is a requirement to establish tES as a tool to test the causal role of neural oscillations and highlight critical issues that should be considered when adopting a translational approach.
Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice
Authors: Caballero Benjamin , Bourdenx Mathieu , Luengo Enrique , Diaz Antonio , Sohn Peter Dongmin , Chen Xu , Wang Chao , Juste Yves R. , Wegmann Susanne , Patel Bindi , Young Zapporah T. , Kuo Szu Yu , Rodriguez-Navarro Jose Antonio , Shao Hao , Lopez Manuela G. , Karch Celeste M. , Goate Alison M. , Gestwicki Jason E. , Hyman Bradley T. , Gan Li , Cuervo Ana Maria 
Published: April 2021

AbstractDisrupted homeostasis of the microtubule binding protein tau is a shared feature of a set of neurodegenerative disorders known as tauopathies. Acetylation of soluble tau is an early pathological event in neurodegeneration. In this work, we find that a large fraction of neuronal tau is degraded by chaperone-mediated autophagy (CMA) whereas, upon acetylation, tau is preferentially degraded by macroautophagy and endosomal microautophagy. Rerouting of acetylated tau to these other autophagic pathways originates, in part, from the inhibitory effect that acetylated tau exerts on CMA and results in its extracellular release. In fact, experimental blockage of CMA enhances cell-to-cell propagation of pathogenic tau in a mouse model of tauopathy. Furthermore, analysis of lysosomes isolated from brains of patients with tauopathies demonstrates similar molecular mechanisms leading to CMA dysfunction. This study reveals that CMA failure in tauopathy brains alters tau homeostasis and could contribute to aggravate disease progression.
Accelerated phase Ia/b evaluation of the malaria vaccine candidate PfAMA1 DiCo demonstrates broadening of humoral immune responses
Authors: Remarque Edmond J. , Faber Bart W. , Rodriguez Garcia Roberto , Oostermeijer Herman , Sirima Sodiomon B. , Nebie Ouedraogo Issa , Kara Leila , Launay Odile , Houard Sophie , Leroy Odile , Kocken Clemens H. M. 
Published: April 2021

AbstractPlasmodium falciparum apical membrane antigen 1 (PfAMA1) is a candidate malaria vaccine antigen expressed on merozoites and sporozoites. PfAMA1’s polymorphic nature impacts vaccine-induced protection. To address polymorphism, three Diversity Covering (DiCo) protein sequences were designed and tested in a staggered phase Ia/b trial. A cohort of malaria-naive adults received PfAMA1-DiCo adjuvanted with Alhydrogel® or GLA-SE and a cohort of malaria-exposed adults received placebo or GLA-SE adjuvanted PfAMA1 DiCo at weeks 0, 4 and 26. IgG and GIA levels measured 4 weeks after the third vaccination are similar in malaria-naive volunteers and placebo-immunised malaria-exposed adults, and have a similar breadth. Vaccination of malaria-exposed adults results in significant antibody level increases to the DiCo variants, but not to naturally occurring PfAMA1 variants. Moreover, GIA levels do not increase following vaccination. Future research will need to focus on stronger adjuvants and/or adapted vaccination regimens, to induce potentially protective responses in the target group of the vaccine.
Secondary structural choice of DNA and RNA associated with CGG/CCG trinucleotide repeat expansion rationalizes the RNA misprocessing in FXTAS
Authors: Ajjugal Yogeeshwar , Kolimi Narendar , Rathinavelan Thenmalarchelvi 
Published: April 2021

AbstractCGG tandem repeat expansion in the 5′-untranslated region of the fragile X mental retardation-1 (FMR1) gene leads to unusual nucleic acid conformations, hence causing genetic instabilities. We show that the number of G…G (in CGG repeat) or C…C (in CCG repeat) mismatches (other than A…T, T…A, C…G and G…C canonical base pairs) dictates the secondary structural choice of the sense and antisense strands of the FMR1 gene and their corresponding transcripts in fragile X-associated tremor/ataxia syndrome (FXTAS). The circular dichroism (CD) spectra and electrophoretic mobility shift assay (EMSA) reveal that CGG DNA (sense strand of the FMR1 gene) and its transcript favor a quadruplex structure. CD, EMSA and molecular dynamics (MD) simulations also show that more than four C…C mismatches cannot be accommodated in the RNA duplex consisting of the CCG repeat (antisense transcript); instead, it favors an i-motif conformational intermediate. Such a preference for unusual secondary structures provides a convincing justification for the RNA foci formation due to the sequestration of RNA-binding proteins to the bidirectional transcripts and the repeat-associated non-AUG translation that are observed in FXTAS. The results presented here also suggest that small molecule modulators that can destabilize FMR1 CGG DNA and RNA quadruplex structures could be promising candidates for treating FXTAS.
ENSO feedback drives variations in dieback at a marginal mangrove site
Authors: Hickey S. M. , Radford B. , Callow J. N. , Phinn S. R. , Duarte C. M. , Lovelock C. E. 
Published: April 2021

AbstractOcean–atmosphere climatic interactions, such as those resulting from El Niño Southern Oscillation (ENSO) are known to influence sea level, sea surface temperature, air temperature, and rainfall in the western Pacific region, through to the north-west Australian Ningaloo coast. Mangroves are ecologically important refuges for biodiversity and a rich store of blue carbon. Locations such as the study site (Mangrove Bay, a World Heritage Site within Ningaloo Marine Park and Cape Range National Park) are at the aridity range-limit which means trees are small in stature, forests small in area, and are potentially susceptible to climate variability such as ENSO that brings lower sea level and higher temperature. Here we explore the relationship between mangrove dieback, and canopy condition with climatic variables and the Southern Oscillation Index (SOI)—a measure of ENSO intensity, through remote sensing classification of Landsat satellite missions across a 29 year period at a north-west Australian site. We find that the SOI, and seasonal mean minimum temperature are strongly correlated to mangrove green canopy (as indicator of live canopy) area. This understanding of climate variations and mangrove temporal heterogeneity (patterns of abundance and condition) highlights the sensitivity and dynamics of this mangrove forest and recommends further research in other arid and semi-arid tropical regions at mangrove range-limits to ascertain the extent of this relationship.
The absence of the caffeine synthase gene is involved in the naturally decaffeinated status of Coffea humblotiana, a wild species from Comoro archipelago
Authors: Raharimalala Nathalie , Rombauts Stephane , McCarthy Andrew , Garavito Andréa , Orozco-Arias Simon , Bellanger Laurence , Morales-Correa Alexa Yadira , Froger Solène , Michaux Stéphane , Berry Victoria , Metairon Sylviane , Fournier Coralie , Lepelley Maud , Mueller Lukas , Couturon Emmanuel , Hamon Perla , Rakotomalala Jean-Jacques , Descombes Patrick , Guyot Romain , Crouzillat Dominique 
Published: April 2021

AbstractCaffeine is the most consumed alkaloid stimulant in the world. It is synthesized through the activity of three known N-methyltransferase proteins. Here we are reporting on the 422-Mb chromosome-level assembly of the Coffea humblotiana genome, a wild and endangered, naturally caffeine-free, species from the Comoro archipelago. We predicted 32,874 genes and anchored 88.7% of the sequence onto the 11 chromosomes. Comparative analyses with the African Robusta coffee genome (C. canephora) revealed an extensive genome conservation, despite an estimated 11 million years of divergence and a broad diversity of genome sizes within the Coffea genus. In this genome, the absence of caffeine is likely due to the absence of the caffeine synthase gene which converts theobromine into caffeine through an illegitimate recombination mechanism. These findings pave the way for further characterization of caffeine-free species in the Coffea genus and will guide research towards naturally-decaffeinated coffee drinks for consumers.
Enhancing the landscape of colorectal cancer using targeted deep sequencing
Authors: Lee Chul Seung , Song In Hye , Lee Ahwon , Kang Jun , Lee Yoon Suk , Lee In Kyu , Song Young Soo , Lee Sung Hak 
Published: April 2021

AbstractTargeted next-generation sequencing (NGS) technology detects specific mutations that can provide treatment opportunities for colorectal cancer (CRC) patients. We included 145 CRC patients who underwent surgery. We analyzed the mutation frequencies of common actionable genes and their association with clinicopathological characteristics and oncologic outcomes using targeted NGS. Approximately 97.9% (142) of patients showed somatic mutations. Frequent mutations were observed in TP53 (70%), APC (60%), and KRAS (49%). TP53 mutations were significantly linked to higher overall stage (p = 0.038) and lower disease-free survival (DFS) (p = 0.039). ATM mutation was significantly associated with higher tumor stage (p = 0.012) and shorter overall survival (OS) (p = 0.041). Stage 3 and 4 patients with ATM mutations (p = 0.023) had shorter OS, and FBXW7 mutation was significantly associated with shorter DFS (p = 0.002). However, the OS of patients with or without TP53, RAS, APC, PIK3CA, and SMAD4 mutations did not differ significantly (p = 0.59, 0.72, 0.059, 0.25, and 0.12, respectively). Similarly, the DFS between patients with RAS, APC, PIK3CA, and SMAD4 mutations and those with wild-type were not statistically different (p = 0.3, 0.79, 0.13, and 0.59, respectively). In multivariate Cox regression analysis, ATM mutation was an independent biomarker for poor prognosis of OS (p = 0.043). A comprehensive analysis of the molecular markers for CRC can provide insights into the mechanisms underlying disease progression and help optimize a personalized therapy.