bluuebunny/crossref_metadata_2025 huggingface dataset:
The Relative Importance of Phytoplankton Light Absorption and Ecosystem Complexity in an Earth System Model
Authors: Asselot Rémy , Lunkeit Frank , Holden Philip B. , Hense Inga
Published: May 2021

We investigate the relative importance of ecosystem complexity and phytoplankton light absorption for climate studies. While the complexity of Earth System models (ESMs) with respect to marine biota has increased over the past years, the relative importance of biological processes in driving climate‐relevant mechanisms such as the biological carbon pump and phytoplankton light absorption is still unknown. The climate effects of these mechanisms have been studied separately, but not together. To shed light on the role of biologically mediated feedbacks, we performed different model experiments with the EcoGENIE ESM. The model experiments have been conducted with and without phytoplankton light absorption and with two or 12 plankton functional types. For a robust comparison, all simulations are tuned to have the same primary production. Our model experiments show that phytoplankton light absorption changes ocean physics and biogeochemistry. Higher sea surface temperature decreases the solubility of CO2 which in turn increases the atmospheric CO2 concentration, and finally the atmospheric temperature rises by 0.45°C. An increase in ecosystem complexity increases the export production of particulate organic carbon but decreases the amount of dissolved organic matter. These changes in the marine carbon cycling, however, hardly reduces the atmospheric CO2 concentrations and slightly decreases the atmospheric temperature by 0.034°C. Overall we show that phytoplankton light absorption has a higher impact on the carbon cycle and on the climate system than a more detailed representation of the marine biota.
Using Chemical Affinities to Understand Disequilibrium Textures of Plagioclase Preserved in Magmatic Systems
Authors: Huggins Ellyn G. , Ruprecht Philipp , Ghiorso Mark S.
Published: May 2021

Volcanic textures are strongly related to magma ascent histories. Degassing of a volatile‐rich magma can drive plagioclase microlite growth on eruptive timescales, but such growth can be inhibited when ascent is sufficiently fast. Thus, the absence of microlites is used to determine the minimum ascent rates. However, open‐system processes, such as magma recharge, prior to decompression can also suppress microlite growth, possibly extending the timescales for ascent. Here, we explore the trade‐offs between degassing‐driven growth and reheating‐driven suppression of microlite formation. We develop a quantitative model on the basis of the chemical affinity that accounts for disequilibrium driving crystal growth or dissolution. We test decompression scenarios to understand how net‐crystallization varies with different pressure‐temperature ascent histories for the 2008 Chaitén eruption. Degassing‐driven growth and reheating‐driven dissolution are balanced for ascent rates of 0.002–0.006 MPa/s (∼0.08–0.25 m/s) from 200 MPa storage depth and reheating by 50 °C–70 °C, significantly reducing the minimum ascent rates.
MAVEN Survey of Magnetic Flux Rope Properties in the Martian Ionosphere: Comparison With Three Types of Formation Mechanisms
Authors: Bowers C. F. , Slavin J. A. , DiBraccio G. A. , Poh G. , Hara T. , Xu S. , Brain D. A.
Published: May 2021

Flux ropes are a magnetic field phenomenon characterized by a filament of twisted, helical magnetic field around an axial core. They form in the Martian ionosphere via three distinct mechanisms: Boundary wave instabilities (BWI), external reconnection (ER) between the interplanetary magnetic field and the crustal anomalies, and internal reconnection (IR) of the crustal anomalies themselves. We have identified 121 magnetic flux ropes (FR) from 1900 orbits using plasma and magnetic field measurements measured by the Mars Atmosphere and Volatile EvolutioN (MAVEN) spacecraft, and separate FR into categories based on formation mechanism by analyzing electron signatures. We find evidence for flux ropes formed via BWI, ER, and IR mechanisms which comprise 9%, 34%, and 57% of our data‐set, respectively. FR formed via different mechanisms exhibit differences in location and force‐free radius, indicating the formation mechanism of a FR impacts their influence on the Martian plasma environment.
Cold Pools Observed by Uncrewed Surface Vehicles in the Central and Eastern Tropical Pacific
Authors: Wills Samantha M. , Cronin Meghan F. , Zhang Dongxiao
Published: May 2021

New in situ observations collected by Saildrones, a novel uncrewed surface vehicle (USV), are used to investigate atmospheric cold pools during three 6‐month missions to the central and eastern (∼140°W–125°W) tropical Pacific. Cold pool fronts in the atmospheric boundary layer are identified by a −1.5°C air temperature drop occurring in 10 min or less. While cold pool events were observed in the central Pacific as far north as 30°N and within the equatorial band, the majority of observed cold pools occurred within the convective, low‐wind shear environment of the Intertropical Convergence Zone. Composite time series analysis of measurements during the 382 cold pool events reveals new insights on high‐frequency variations in air temperature, wind speed, humidity, pressure, and sea surface temperature and salinity associated with cold pool fronts. The results highlight the unique capabilities of Saildrone USVs to resolve small spatial and temporal scales of variability over observationally sparse ocean regions.
Energy Modulations of Magnetospheric Ions Induced by Foreshock Transient‐Driven Ultralow‐Frequency Waves
Authors: Wang Boyi , Zhang Hui , Liu Zhiyang , Liu Terry , Li Xingyu , Angelopoulos Vassilis
Published: May 2021

Although foreshock transients can generate strong magnetospheric Pc5 ultralow‐frequency (ULF) waves, whether they can modulate the energy of magnetospheric ions is still poorly understood. In this study, we analyze the strong magnetospheric ion energy modulations in a foreshock transient event on October 30, 2008, based on the magnetospheric observations by the time history of events and macroscale interactions during substorms A and D in the prenoon sector. ULF wave‐induced drift accelerated the cold ions up to ∼10 keV and the enhanced ion fluxes have wave‐like patterns. There is another portion of enhanced ion fluxes from ∼0.8 to ∼10 keV but with strong energy dispersions in this event. By comparing the observations and the theoretical prediction, we for the first time found that the drift‐bounce resonances played a major role in modulating the energy of those ions with energy dispersions, during the interactions between the ions and the foreshock transient‐driven Pc5 ULF wave with growing and damping effects.
Second allogeneic transplants for multiple myeloma: a report from the EBMT Chronic Malignancies Working Party
Authors: Hayden Patrick J. , Eikema Dirk-Jan , de Wreede Liesbeth C. , Koster Linda , Kröger Nicolaus , Einsele Hermann , Minnema Monique , Dominietto Alida , Potter Michael , Passweg Jacob , Bermúdez Arancha , Nguyen-quoc Stephanie , Platzbecker Uwe , Tischer Johanna , Ciceri Fabio , Veelken Joan Hendrik , Ljungman Per , Schaap Nicolaas , Forcade Edouard , Carella Angelo Michele , Gandemer Virginie , Arcese William , Bloor Adrian , Olivieri Attilio , Vincent Laure , Beksac Meral , Schönland Stefan , Yakoub-Agha Ibrahim
Published: May 2021

The EBMT Chronic Malignancies Working Party performed a retrospective analysis of 215 patients who underwent a second allo-HCT for myeloma between 1994 and 2017, 159 for relapse and 56 for graft failure. In the relapse group, overall survival (OS) was 38% (30–46%) at 2 years and 25% (17–32%) at 5 years. Patients who had a HLA-identical sibling (HLAid-Sib) donor for their first and second transplants had superior OS (5 year OS: HLAid-Sib/HLAid-Sib: 35% (24–46%); Others 9% (0–17%), p < 0.001). There was a significantly higher incidence of acute grade II-IV GvHD in those patients who had also developed GvHD following their initial HLA-identical sibling allo-HCT (HLAid-Sib/HLAid-Sib: 50% (33–67%); Other 22% (8–36%), p = 0.03). More as opposed to fewer than 2 years between transplants was associated with superior 5-yr OS (31% (21–40%) vs. 10% (1–20%), P = 0.005). On multivariate analysis, consecutive HLA-identical sibling donor transplants conferred a significant OS advantage (0.4 (0.24–0.67), p < 0.001). In the graft failure group, OS was 41% at 2 years. In summary, a second allo-HCT using a HLA-identical sibling donor, if available, provides the best transplant outcomes for relapsed myeloma in this setting.
Correction to: Build-UPS and break-downs: metabolism impacts on proteostasis and aging
Authors: Ottens Franziska , Franz André , Hoppe Thorsten
Published: May 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41418-021-00800-4
Knockout RAGE alleviates cardiac fibrosis through repressing endothelial-to-mesenchymal transition (EndMT) mediated by autophagy
Authors: Zhang Lu , He Jiaqi , Wang Junyan , Liu Jing , Chen Zixin , Deng Bo , Wei Lan , Wu Hanqin , Liang Birong , Li Huan , Huang Yusheng , Lu Lu , Yang Zhongqi , Xian Shaoxiang , Wang Lingjun
Published: May 2021

Endothelial-to-mesenchymal transition (EndMT) has been shown to contribute to cardiac fibrosis and heart failure (HF). Recent studies have demonstrated that EndMT is regulated by autophagy, and we previously showed suppression of excessive autophagy and alleviation of cardiac fibrosis in HF mice with inactivated receptor for advanced glycation end products (RAGE). Thus, we investigated whether reduced cardiac fibrosis due to RAGE knockout occurred by inhibiting EndMT mediated by excessive autophagy. We found a decrease in endothelial cells (CD31+/VE-Cadherin+) and an increase in cells co-expressing CD31 and α-smooth muscle actin (α-SMA, myofibroblast marker) at 8 weeks in heart tissue of mice subjected to transverse aortic constriction (TAC), which implied EndMT. Knockout RAGE decreased EndMT accompanied by decreased expression of autophagy-related proteins (LC3BII/I and Beclin 1), and alleviated cardiac fibrosis and improved cardiac function in TAC mice. Moreover, 3-methyladenine (3-MA) and chloroquine (CQ), inhibitors of autophagy, attenuated EndMT, and cardiac fibrosis in TAC mice. Importantly, EndMT induced by AGEs could be blocked by autophagy inhibitor in vivo and in vitro. These results suggested that AGEs/RAGE-autophagy-EndMT axis involved in the development of cardiac fibrosis and knockout RAGE ameliorated cardiac fibrosis through decreasing EndMT regulated by autophagy, which could be a promising therapeutic strategy for HF.
Cryo-EM structure of SETD2/Set2 methyltransferase bound to a nucleosome containing oncohistone mutations
Authors: Liu Yingying , Zhang Yanjun , Xue Han , Cao Mi , Bai Guohui , Mu Zongkai , Yao Yanli , Sun Shuyang , Fang Dong , Huang Jing
Published: May 2021

Substitution of lysine 36 with methionine in histone H3.3 (H3.3K36M) is an oncogenic mutation that inhibits SETD2-mediated histone H3K36 tri-methylation in tumors. To investigate how the oncohistone mutation affects the function of SETD2 at the nucleosome level, we determined the cryo-EM structure of human SETD2 associated with an H3.3K36M nucleosome and cofactor S-adenosylmethionine (SAM), and revealed that SETD2 is attached to the N-terminal region of histone H3 and the nucleosome DNA at superhelix location 1, accompanied with the partial unwrapping of nucleosome DNA to expose the SETD2-binding site. These structural features were also observed in the previous cryo-EM structure of the fungal Set2–nucleosome complex. By contrast with the stable association of SETD2 with the H3.3K36M nucleosome, the EM densities of SETD2 could not be observed on the wild-type nucleosome surface, suggesting that the association of SETD2 with wild-type nucleosome might be transient. The linker histone H1, which stabilizes the wrapping of nucleosome DNA at the entry/exit sites, exhibits an inhibitory effect on the activities of SETD2 and displays inversely correlated genome distributions with that of the H3K36me3 marks. Cryo-EM analysis of yeast H3K36 methyltransferase Set2 complexed with nucleosomes further revealed evolutionarily conserved structural features for nucleosome recognition in eukaryotes, and provides insights into the mechanism of activity regulation. These findings have advanced our understanding of the structural basis for the tumorigenesis mechanism of the H3.3K36M mutation and highlight the effect of nucleosome conformation on the regulation of histone modification.
Phase separation of EML4–ALK in firing downstream signaling and promoting lung tumorigenesis
Authors: Qin Zhen , Sun Honghua , Yue Meiting , Pan Xinwen , Chen Liang , Feng Xinhua , Yan Xiumin , Zhu Xueliang , Ji Hongbin
Published: May 2021

EML4–ALK fusion, observed in about 3%–7% of human lung adenocarcinoma, is one of the most important oncogenic drivers in initiating lung tumorigenesis. However, it still remains largely unknown about how EML4–ALK fusion exactly fires downstream signaling and drives lung cancer formation. We here find that EML4–ALK variant 1 (exon 1–13 of EML4 fused to exon 20–29 of ALK) forms condensates via phase separation in the cytoplasm of various human cancer cell lines. Using two genetically engineered mouse models (GEMMs), we find that EML4–ALK variant 1 can drive lung tumorigenesis and these murine tumors, as well as primary tumor-derived organoids, clearly show the condensates of EML4–ALK protein, further supporting the findings from in vitro study. Mutation of multiple aromatic residues in EML4 region significantly impairs the phase separation of EML4–ALK and dampens the activation of the downstream signaling pathways, especially the STAT3 phosphorylation. Importantly, it also significantly decreases cancer malignant transformation and tumor formation. These data together highlight an important role of phase separation in orchestrating EML4–ALK signaling and promoting tumorigenesis, which might provide new clues for the development of clinical therapeutic strategies in treating lung cancer patients with the EML4–ALK fusion.
On the use of plume models to estimate the flux in volcanic gas plumes
Authors: Woitischek Julia , Mingotti Nicola , Edmonds Marie , Woods Andrew W.
Published: May 2021

Many of the standard volcanic gas flux measurement approaches involve absorption spectroscopy in combination with wind speed measurements. Here, we present a new method using video images of volcanic plumes to measure the speed of convective structures combined with classical plume theory to estimate volcanic fluxes. We apply the method to a nearly vertical gas plume at Villarrica Volcano, Chile, and a wind-blown gas plume at Mount Etna, Italy. Our estimates of the gas fluxes are consistent in magnitude with previous reported fluxes obtained by spectroscopy and electrochemical sensors for these volcanoes. Compared to conventional gas flux measurement techniques focusing on SO2, our new model also has the potential to be used for sulfur-poor plumes in hydrothermal systems because it estimates the H2O flux.
FUT8-mediated aberrant N-glycosylation of B7H3 suppresses the immune response in triple-negative breast cancer
Authors: Huang Yun , Zhang Hai-Liang , Li Zhi-Ling , Du Tian , Chen Yu-Hong , Wang Yan , Ni Huan-He , Zhang Kai-Ming , Mai Jia , Hu Bing-Xin , Huang Jun-Hao , Zhou Li-Huan , Yang Dong , Peng Xiao-Dan , Feng Gong-Kan , Tang Jun , Zhu Xiao-Feng , Deng Rong
Published: May 2021

Most patients with triple negative breast cancer (TNBC) do not respond to anti-PD1/PDL1 immunotherapy, indicating the necessity to explore immune checkpoint targets. B7H3 is a highly glycosylated protein. However, the mechanisms of B7H3 glycosylation regulation and whether the sugar moiety contributes to immunosuppression are unclear. Here, we identify aberrant B7H3 glycosylation and show that N-glycosylation of B7H3 at NXT motif sites is responsible for its protein stability and immunosuppression in TNBC tumors. The fucosyltransferase FUT8 catalyzes B7H3 core fucosylation at N-glycans to maintain its high expression. Knockdown of FUT8 rescues glycosylated B7H3-mediated immunosuppressive function in TNBC cells. Abnormal B7H3 glycosylation mediated by FUT8 overexpression can be physiologically important and clinically relevant in patients with TNBC. Notably, the combination of core fucosylation inhibitor 2F-Fuc and anti-PDL1 results in enhanced therapeutic efficacy in B7H3-positive TNBC tumors. These findings suggest that targeting the FUT8-B7H3 axis might be a promising strategy for improving anti-tumor immune responses in patients with TNBC.
Genomic analyses of Mycobacterium tuberculosis from human lung resections reveal a high frequency of polyclonal infections
Authors: Moreno-Molina Miguel , Shubladze Natalia , Khurtsilava Iza , Avaliani Zaza , Bablishvili Nino , Torres-Puente Manuela , Villamayor Luis , Gabrielian Andrei , Rosenthal Alex , Vilaplana Cristina , Gagneux Sebastien , Kempker Russell R. , Vashakidze Sergo , Comas Iñaki
Published: May 2021

Polyclonal infections occur when at least two unrelated strains of the same pathogen are detected in an individual. This has been linked to worse clinical outcomes in tuberculosis, as undetected strains with different antibiotic resistance profiles can lead to treatment failure. Here, we examine the amount of polyclonal infections in sputum and surgical resections from patients with tuberculosis in the country of Georgia. For this purpose, we sequence and analyse the genomes of Mycobacterium tuberculosis isolated from the samples, acquired through an observational clinical study (NCT02715271). Access to the lung enhanced the detection of multiple strains (40% of surgery cases) as opposed to just using a sputum sample (0–5% in the general population). We show that polyclonal infections often involve genetically distant strains and can be associated with reversion of the patient’s drug susceptibility profile over time. In addition, we find different patterns of genetic diversity within lesions and across patients, including mutational signatures known to be associated with oxidative damage; this suggests that reactive oxygen species may be acting as a selective pressure in the granuloma environment. Our results support the idea that the magnitude of polyclonal infections in high-burden tuberculosis settings is underestimated when only testing sputum samples.
A network linking scene perception and spatial memory systems in posterior cerebral cortex
Authors: Steel Adam , Billings Madeleine M. , Silson Edward H. , Robertson Caroline E.
Published: May 2021

The neural systems supporting scene-perception and spatial-memory systems of the human brain are well-described. But how do these neural systems interact? Here, using fine-grained individual-subject fMRI, we report three cortical areas of the human brain, each lying immediately anterior to a region of the scene perception network in posterior cerebral cortex, that selectively activate when recalling familiar real-world locations. Despite their close proximity to the scene-perception areas, network analyses show that these regions constitute a distinct functional network that interfaces with spatial memory systems during naturalistic scene understanding. These “place-memory areas” offer a new framework for understanding how the brain implements memory-guided visual behaviors, including navigation.
Overcoming false-positive gene-category enrichment in the analysis of spatially resolved transcriptomic brain atlas data
Authors: Fulcher Ben D. , Arnatkeviciute Aurina , Fornito Alex
Published: May 2021

Transcriptomic atlases have improved our understanding of the correlations between gene-expression patterns and spatially varying properties of brain structure and function. Gene-category enrichment analysis (GCEA) is a common method to identify functional gene categories that drive these associations, using gene-to-category annotation systems like the Gene Ontology (GO). Here, we show that applying standard GCEA methodology to spatial transcriptomic data is affected by substantial false-positive bias, with GO categories displaying an over 500-fold average inflation of false-positive associations with random neural phenotypes in mouse and human. The estimated false-positive rate of a GO category is associated with its rate of being reported as significantly enriched in the literature, suggesting that published reports are affected by this false-positive bias. We show that within-category gene–gene coexpression and spatial autocorrelation are key drivers of the false-positive bias and introduce flexible ensemble-based null models that can account for these effects, made available as a software toolbox.
Programming gene expression in multicellular organisms for physiology modulation through engineered bacteria
Authors: Gao Baizhen , Sun Qing
Published: May 2021

A central goal of synthetic biology is to predictably and efficiently reprogram living systems to perform computations and carry out specific biological tasks. Although there have been many advances in the bio-computational design of living systems, these advances have mainly been applied to microorganisms or cell lines; programming animal physiology remains challenging for synthetic biology because of the system complexity. Here, we present a bacteria-animal symbiont system in which engineered bacteria recognize external signals and modulate animal gene expression, twitching phenotype, and fat metabolism through RNA interference toward gfp, sbp-1, and unc-22 gene in C. elegans. By using genetic circuits in bacteria to control these RNA expressions, we are able to program the physiology of the model animal Caenorhabditis elegans with logic gates. We anticipate that engineered bacteria can be used more extensively to program animal physiology for agricultural, therapeutic, and basic science applications.
Molecular engineering of piezoelectricity in collagen-mimicking peptide assemblies
Authors: Bera Santu , Guerin Sarah , Yuan Hui , O’Donnell Joseph , Reynolds Nicholas P. , Maraba Oguzhan , Ji Wei , Shimon Linda J. W. , Cazade Pierre-Andre , Tofail Syed A. M. , Thompson Damien , Yang Rusen , Gazit Ehud
Published: May 2021

Realization of a self-assembled, nontoxic and eco-friendly piezoelectric device with high-performance, sensitivity and reliability is highly desirable to complement conventional inorganic and polymer based materials. Hierarchically organized natural materials such as collagen have long been posited to exhibit electromechanical properties that could potentially be amplified via molecular engineering to produce technologically relevant piezoelectricity. Here, by using a simple, minimalistic, building block of collagen, we fabricate a peptide-based piezoelectric generator utilising a radically different helical arrangement of Phe-Phe-derived peptide, Pro-Phe-Phe and Hyp-Phe-Phe, based only on proteinogenic amino acids. The simple addition of a hydroxyl group increases the expected piezoelectric response by an order of magnitude (d35 = 27 pm V−1). The value is highest predicted to date in short natural peptides. We demonstrate tripeptide-based power generator that produces stable max current >50 nA and potential >1.2 V. Our results provide a promising device demonstration of computationally-guided molecular engineering of piezoelectricity in peptide nanotechnology.
The impact of stopping and starting indoor residual spraying on malaria burden in Uganda
Authors: Namuganga Jane F. , Epstein Adrienne , Nankabirwa Joaniter I. , Mpimbaza Arthur , Kiggundu Moses , Sserwanga Asadu , Kapisi James , Arinaitwe Emmanuel , Gonahasa Samuel , Opigo Jimmy , Ebong Chris , Staedke Sarah G. , Shililu Josephat , Okia Michael , Rutazaana Damian , Maiteki-Sebuguzi Catherine , Belay Kassahun , Kamya Moses R. , Dorsey Grant , Rodriguez-Barraquer Isabel
Published: May 2021

The scale-up of malaria control efforts has led to marked reductions in malaria burden over the past twenty years, but progress has slowed. Implementation of indoor residual spraying (IRS) of insecticide, a proven vector control intervention, has been limited and difficult to sustain partly because questions remain on its added impact over widely accepted interventions such as bed nets. Using data from 14 enhanced surveillance health facilities in Uganda, a country with high bed net coverage yet high malaria burden, we estimate the impact of starting and stopping IRS on changes in malaria incidence. We show that stopping IRS was associated with a 5-fold increase in malaria incidence within 10 months, but reinstating IRS was associated with an over 5-fold decrease within 8 months. In areas where IRS was initiated and sustained, malaria incidence dropped by 85% after year 4. IRS could play a critical role in achieving global malaria targets, particularly in areas where progress has stalled.
Snapshots into carbon dots formation through a combined spectroscopic approach
Authors: Rigodanza Francesco , Burian Max , Arcudi Francesca , Đorđević Luka , Amenitsch Heinz , Prato Maurizio
Published: May 2021

The design of novel carbon dots with ad hoc properties requires a comprehensive understanding of their formation mechanism, which is a complex task considering the number of variables involved, such as reaction time, structure of precursors or synthetic protocol employed. Herein, we systematically investigated the formation of carbon nanodots by tracking structural, chemical and photophysical features during the hydrothermal synthesis. We demonstrate that the formation of carbon nanodots consists of 4 consecutive steps: (i) aggregation of small organic molecules, (ii) formation of a dense core with an extended shell, (iii) collapse of the shell and (iv) aromatization of the core. In addition, we provide examples of routes towards tuning the core-shell design, synthesizing five novel carbon dots that all consist of an electron-dense core covered by an amine rich ligand shell.
SARS-CoV-2 gene content and COVID-19 mutation impact by comparing 44 Sarbecovirus genomes
Authors: Jungreis Irwin , Sealfon Rachel , Kellis Manolis
Published: May 2021

Despite its clinical importance, the SARS-CoV-2 gene set remains unresolved, hindering dissection of COVID-19 biology. We use comparative genomics to provide a high-confidence protein-coding gene set, characterize evolutionary constraint, and prioritize functional mutations. We select 44 Sarbecovirus genomes at ideally-suited evolutionary distances, and quantify protein-coding evolutionary signatures and overlapping constraint. We find strong protein-coding signatures for ORFs 3a, 6, 7a, 7b, 8, 9b, and a novel alternate-frame gene, ORF3c, whereas ORFs 2b, 3d/3d-2, 3b, 9c, and 10 lack protein-coding signatures or convincing experimental evidence of protein-coding function. Furthermore, we show no other conserved protein-coding genes remain to be discovered. Mutation analysis suggests ORF8 contributes to within-individual fitness but not person-to-person transmission. Cross-strain and within-strain evolutionary pressures agree, except for fewer-than-expected within-strain mutations in nsp3 and S1, and more-than-expected in nucleocapsid, which shows a cluster of mutations in a predicted B-cell epitope, suggesting immune-avoidance selection. Evolutionary histories of residues disrupted by spike-protein substitutions D614G, N501Y, E484K, and K417N/T provide clues about their biology, and we catalog likely-functional co-inherited mutations. Previously reported RNA-modification sites show no enrichment for conservation. Here we report a high-confidence gene set and evolutionary-history annotations providing valuable resources and insights on SARS-CoV-2 biology, mutations, and evolution.
Neural network aided approximation and parameter inference of non-Markovian models of gene expression
Authors: Jiang Qingchao , Fu Xiaoming , Yan Shifu , Li Runlai , Du Wenli , Cao Zhixing , Qian Feng , Grima Ramon
Published: May 2021

Non-Markovian models of stochastic biochemical kinetics often incorporate explicit time delays to effectively model large numbers of intermediate biochemical processes. Analysis and simulation of these models, as well as the inference of their parameters from data, are fraught with difficulties because the dynamics depends on the system’s history. Here we use an artificial neural network to approximate the time-dependent distributions of non-Markovian models by the solutions of much simpler time-inhomogeneous Markovian models; the approximation does not increase the dimensionality of the model and simultaneously leads to inference of the kinetic parameters. The training of the neural network uses a relatively small set of noisy measurements generated by experimental data or stochastic simulations of the non-Markovian model. We show using a variety of models, where the delays stem from transcriptional processes and feedback control, that the Markovian models learnt by the neural network accurately reflect the stochastic dynamics across parameter space.
Molecular evolution and the decline of purifying selection with age
Authors: Cheng Changde , Kirkpatrick Mark
Published: May 2021

Life history theory predicts that the intensity of selection declines with age, and this trend should impact how genes expressed at different ages evolve. Here we find consistent relationships between a gene’s age of expression and patterns of molecular evolution in two mammals (the human Homo sapiens and the mouse Mus musculus) and two insects (the malaria mosquito Anopheles gambiae and the fruit fly Drosophila melanogaster). When expressed later in life, genes fix nonsynonymous mutations more frequently, are more polymorphic for nonsynonymous mutations, and have shorter evolutionary lifespans, relative to those expressed early. The latter pattern is explained by a simple evolutionary model. Further, early-expressed genes tend to be enriched in similar gene ontology terms across species, while late-expressed genes show no such consistency. In humans, late-expressed genes are more likely to be linked to cancer and to segregate for dominant disease-causing mutations. Last, the effective strength of selection (Nes) decreases and the fraction of beneficial mutations increases with a gene’s age of expression. These results are consistent with the diminishing efficacy of purifying selection with age, as proposed by Medawar’s classic hypothesis for the evolution of senescence, and provide links between life history theory and molecular evolution.
Origin of ammoniated phyllosilicates on dwarf planet Ceres and asteroids
Authors: Singh Santosh K. , Bergantini Alexandre , Zhu Cheng , Ferrari Marco , De Sanctis Maria Cristina , De Angelis Simone , Kaiser Ralf I.
Published: May 2021

The surface mineralogy of dwarf planet Ceres is rich in ammonium (NH4+) bearing phyllosilicates. However, the origin and formation mechanisms of ammoniated phyllosilicates on Ceres’s surface are still elusive. Here we report on laboratory simulation experiments under astrophysical conditions mimicking Ceres’ physical and chemical environments with the goal to better understand the source of ammoniated minerals on Ceres’ surface. We observe that thermally driven proton exchange reactions between phyllosilicates and ammonia (NH3) could trigger at low temperature leading to the genesis of ammoniated-minerals. Our study revealed the thermal (300 K) and radiation stability of ammoniated-phyllosilicates over a timescale of at least some 500 million years. The present experimental investigations corroborate the possibility that Ceres formed at a location where ammonia ices on the surface would have been stable. However, the possibility of Ceres’ origin near to its current location by accreting ammonia-rich material cannot be excluded.
Immune cellular networks underlying recovery from influenza virus infection in acute hospitalized patients
Authors: Nguyen Thi H. O. , Koutsakos Marios , van de Sandt Carolien E. , Crawford Jeremy Chase , Loh Liyen , Sant Sneha , Grzelak Ludivine , Allen Emma K. , Brahm Tim , Clemens E. Bridie , Auladell Maria , Hensen Luca , Wang Zhongfang , Nüssing Simone , Jia Xiaoxiao , Günther Patrick , Wheatley Adam K. , Kent Stephen J. , Aban Malet , Deng Yi-Mo , Laurie Karen L. , Hurt Aeron C. , Gras Stephanie , Rossjohn Jamie , Crowe Jane , Xu Jianqing , Jackson David , Brown Lorena E. , La Gruta Nicole , Chen Weisan , Doherty Peter C. , Turner Stephen J. , Kotsimbos Tom C. , Thomas Paul G. , Cheng Allen C. , Kedzierska Katherine
Published: May 2021

How innate and adaptive immune responses work in concert to resolve influenza disease is yet to be fully investigated in one single study. Here, we utilize longitudinal samples from patients hospitalized with acute influenza to understand these immune responses. We report the dynamics of 18 important immune parameters, related to clinical, genetic and virological factors, in influenza patients across different severity levels. Influenza disease correlates with increases in IL-6/IL-8/MIP-1α/β cytokines and lower antibody responses. Robust activation of circulating T follicular helper cells correlates with peak antibody-secreting cells and influenza heamaglutinin-specific memory B-cell numbers, which phenotypically differs from vaccination-induced B-cell responses. Numbers of influenza-specific CD8+or CD4+T cells increase early in disease and retain an activated phenotype during patient recovery. We report the characterisation of immune cellular networks underlying recovery from influenza infection which are highly relevant to other infectious diseases.
Low cost exoskeleton manipulator using bidirectional triboelectric sensors enhanced multiple degree of freedom sensory system
Authors: Zhu Minglu , Sun Zhongda , Chen Tao , Lee Chengkuo
Published: May 2021

Rapid developments of robotics and virtual reality technology are raising the requirements of more advanced human-machine interfaces for achieving efficient parallel control. Exoskeleton as an assistive wearable device, usually requires a huge cost and complex data processing to track the multi-dimensional human motions. Alternatively, we propose a triboelectric bi-directional sensor as a universal and cost-effective solution to a customized exoskeleton for monitoring all of the movable joints of the human upper limbs with low power consumption. The corresponding movements, including two DOF rotations of the shoulder, twisting of the wrist, and the bending motions, are detected and utilized for controlling the virtual character and the robotic arm in real-time. Owing to the structural consistency between the exoskeleton and the human body, further kinetic analysis offers additional physical parameters without introducing other types of sensors. This exoskeleton sensory system shows a great potential of being an economic and advanced human-machine interface for supporting the manipulation in both real and virtual worlds, including robotic automation, healthcare, and training applications.
Androgen signaling uses a writer and a reader of ADP-ribosylation to regulate protein complex assembly
Authors: Yang Chun-Song , Jividen Kasey , Kamata Teddy , Dworak Natalia , Oostdyk Luke , Remlein Bartlomiej , Pourfarjam Yasin , Kim In-Kwon , Du Kang-Ping , Abbas Tarek , Sherman Nicholas E. , Wotton David , Paschal Bryce M.
Published: May 2021

Androgen signaling through the androgen receptor (AR) directs gene expression in both normal and prostate cancer cells. Androgen regulates multiple aspects of the AR life cycle, including its localization and post-translational modification, but understanding how modifications are read and integrated with AR activity has been difficult. Here, we show that ADP-ribosylation regulates AR through a nuclear pathway mediated by Parp7. We show that Parp7 mono-ADP-ribosylates agonist-bound AR, and that ADP-ribosyl-cysteines within the N-terminal domain mediate recruitment of the E3 ligase Dtx3L/Parp9. Molecular recognition of ADP-ribosyl-cysteine is provided by tandem macrodomains in Parp9, and Dtx3L/Parp9 modulates expression of a subset of AR-regulated genes. Parp7, ADP-ribosylation of AR, and AR-Dtx3L/Parp9 complex assembly are inhibited by Olaparib, a compound used clinically to inhibit poly-ADP-ribosyltransferases Parp1/2. Our study reveals the components of an androgen signaling axis that uses a writer and reader of ADP-ribosylation to regulate protein-protein interactions and AR activity.
Genetic risk factors for colorectal cancer in multiethnic Indonesians
Authors: Yusuf Irawan , Pardamean Bens , Baurley James W. , Budiarto Arif , Miskad Upik A. , Lusikooy Ronald E. , Arsyad Arham , Irwan Akram , Mathew George , Suriapranata Ivet , Kusuma Rinaldy , Kacamarga Muhamad F. , Cenggoro Tjeng W. , McMahan Christopher , Joyner Chase , Pardamean Carissa I.
Published: May 2021

Colorectal cancer is a common cancer in Indonesia, yet it has been understudied in this resource-constrained setting. We conducted a genome-wide association study focused on evaluation and preliminary discovery of colorectal cancer risk factors in Indonesians. We administered detailed questionnaires and collecting blood samples from 162 colorectal cancer cases throughout Makassar, Indonesia. We also established a control set of 193 healthy individuals frequency matched by age, sex, and ethnicity. A genome-wide association analysis was performed on 84 cases and 89 controls passing quality control. We evaluated known colorectal cancer genetic variants using logistic regression and established a genome-wide polygenic risk model using a Bayesian variable selection technique. We replicate associations for rs9497673, rs6936461 and rs7758229 on chromosome 6; rs11255841 on chromosome 10; and rs4779584, rs11632715, and rs73376930 on chromosome 15. Polygenic modeling identified 10 SNP associated with colorectal cancer risk. This work helps characterize the relationship between variants in the SCL22A3, SCG5, GREM1, and STXBP5-AS1 genes and colorectal cancer in a diverse Indonesian population. With further biobanking and international research collaborations, variants specific to colorectal cancer risk in Indonesians will be identified.
Evaluation of changes in intestinal microbiota in Crohn’s disease patients after anti-TNF alpha treatment
Authors: Sanchis-Artero Laura , Martínez-Blanch Juan Francisco , Manresa-Vera Sergio , Cortés-Castell Ernesto , Valls-Gandia Marina , Iborra Marisa , Paredes-Arquiola Jose Maria , Boscá-Watts Maia , Huguet Jose Maria , Gil-Borrás Rafael , Rodríguez-Morales Josefa , Cortés-Rizo Xavier
Published: May 2021

Intestinal dysbiosis is key in the onset and development of Crohn’s disease (CD). We evaluated the microbiota changes in CD patients before and after a six-month anti-TNF treatment, comparing these changes with the microbiota of healthy subjects. This prospective multicenter observational study involved 27 CD patients initiating anti-TNF treatment and 16 healthy individuals. Inflammatory activity was determined at baseline, 3 and 6 months, classifying patients into responders and non-responders. Fecal microbiota was analyzed by massive genomic sequencing thought 16S rRNA amplicon sequencing before and after six months of anti-TNF treatment. The CD cohort showed a decrease in genera of the class Clostridia, short-chain fatty acid producers, and an increase in the phylum Proteobacteria (p < 0.01) versus the healthy cohort. After anti-TNF treatment, the phylum Proteobacteria also increased in non-responders versus responders (13/27) (p < 0.005), with the class Clostridia increasing. In addition, alpha diversity increased in responders versus non-responders (p < 0.01), tending towards eubiosis. An association was found (p < 0.001) in the F.prausnitzii/E.coli ratio between responders and non-responders. The F/E ratio was the most accurate biomarker of anti-TNF response (area under the curve 0.87). Thus, anti-TNF treatment allows partial restoration of intestinal microbiota in responders and the F.prausnitzii/E.coli ratio can provide a reliable indicator of response to anti-TNF in CD.
Augmented reality navigation method for recontouring surgery of craniofacial fibrous dysplasia
Authors: Liu Kai , Gao Yuan , Abdelrehem Ahmed , Zhang Lei , Chen Xi , Xie Le , Wang Xudong
Published: May 2021

The objective of this study is to introduce the application of augmented reality (AR) navigation system developed by the authors in recontouring surgery of craniofacial fibrous dysplasia. Five consecutive patients with craniofacial fibrous dysplasia were enrolled. Through three-dimensional (3D) simulation, a virtual plan was designed to reconstruct the normal anatomical contour of the deformed region. Surgical recontouring was achieved with the assistance of the AR navigation system. The accuracy of the surgical procedure was assessed by superimposing the post-operative 3D craniomaxillofacial model onto the virtual plan. The pre-operative preparation time and operation time were also counted. In all patients, AR navigation was performed successfully, with a mean ± SD of the errors of 1.442 ± 0.234 mm. The operative time of the patients ranged from 60 to 80 min. The pre-operative preparation time was 20 min for each patient. All the patients showed uneventful healing without any complications, in addition to satisfaction with the post-operative aesthetics. Using our AR navigation system in recontouring surgery can provide surgeons with a comprehensive and intuitive view of the recontouring border, as well as the depth, in real time. This method could improve the efficiency and safety of craniofacial fibrous dysplasia recontouring procedures.
PhosIDP: a web tool to visualize the location of phosphorylation sites in disordered regions
Authors: Nicolaou Sonia T. , Hebditch Max , Jonathan Owen J. , Verma Chandra S. , Warwicker Jim
Published: May 2021

Charge is a key determinant of intrinsically disordered protein (IDP) and intrinsically disordered region (IDR) properties. IDPs and IDRs are enriched in sites of phosphorylation, which alters charge. Visualizing the degree to which phosphorylation modulates the charge profile of a sequence would assist in the functional interpretation of IDPs and IDRs. PhosIDP is a web tool that shows variation of charge and fold propensity upon phosphorylation. In combination with the displayed location of protein domains, the information provided by the web tool can lead to functional inferences for the consequences of phosphorylation. IDRs are components of many proteins that form biological condensates. It is shown that IDR charge, and its modulation by phosphorylation, is more tightly controlled for proteins that are essential for condensate formation than for those present in condensates but inessential.
Synthesis and in vitro PDT evaluation of red emission polymer dots (R-CPDs) and pyropheophorbide-α conjugates
Authors: Sajjad Faiza , Yan Yi-Jia , Margetić Davor , Chen Zhi-Long
Published: May 2021

Carbon based polymer dots have piqued attention of researchers because of excellent biocompatibility, and good solubility. Most of the p-dots are able to generate ROS which is effective for photodynamic therapy for the treatment of cancer while some photosensitizers such as porphyrins possess some drawbacks such as hydrophobicity, and dark toxicity. Therefore in this study we conjugated red emission carbon based polymer with pyropheophorbide-α through amide condensation and π–π stacking. One pot synthesis of the conjugate was successfully achieved. Their photophysiological properties were studied and structures were characterized by FT-IR, TEM and 1HNMR. pH- sensitivity of the conjugates was confirmed using fluorescence and UV–vis spectroscopy. Photo toxicity and dark toxicity of the prepared conjugates were evaluated in human esophageal cancer cell line (Eca-109). Hemocompatibility of the synthesized conjugates was evaluated and proved that the conjugates are safe to use for the treatment of tumor. Our results showed the PS doped p-dots had less dark toxicity and increased light toxicity as well as ROS generation was high as compared to precursor drug. Therefore, incorporation of p-dots to porphyrin improved biocompatibility and enhanced the photodynamic effect.
Alkalinity of diverse water samples can be altered by mercury preservation and borosilicate vial storage
Authors: Mos Benjamin , Holloway Ceylena , Kelaher Brendan P. , Santos Isaac R. , Dworjanyn Symon A.
Published: May 2021

We compared the effects of preservation and storage methods on total alkalinity (AT) of seawater, estuarine water, freshwater, and groundwater samples stored for 0–6 months. Water samples, untreated or treated with HgCl2, 0.45 µm filtration, or filtration plus HgCl2, were stored in polypropylene or borosilicate glass vials for 0, 1, or 6 months. Mean AT of samples treated with HgCl2 was reduced by as much as 49.1 µmol kg−1 (1.3%). Borosilicate glass elevated AT, possibly due to dissolving silicates. There was little change in AT of control and filtered samples stored in polypropylene, except for untreated groundwater (~ 4.1% reduction at 6 months). HgCl2 concentrations of 0.02–0.05% reduced the AT of fresh, estuarine, and ground water samples by as much as 35.5 µmol kg−1 after 1 month, but had little effect on the AT of seawater. Adding glucose as a carbon source for microbial growth resulted in no AT changes in 0.45 µm-filtered samples. We suggest water samples intended for AT analyses can be filtered to 0.45 µm, and stored in polypropylene vials at 4 °C for at least 6 months. Borosilicate glassware and HgCl2 can be avoided to prevent analytical uncertainties and reduce risks related to use of Hg2+.
Genome-wide identification and expression pattern analysis of lipoxygenase gene family in banana
Authors: Liu Fan , Li Hua , Wu Junwei , Wang Bin , Tian Na , Liu Jiapeng , Sun Xueli , Wu Huan , Huang Yuji , Lü Peitao , Cheng Chunzhen
Published: May 2021

The LOX genes have been identified and characterized in many plant species, but studies on the banana LOX genes are very limited. In this study, we respectively identified 18 MaLOX, 11 MbLOX, and 12 MiLOX genes from the Musa acuminata, M. balbisiana and M. itinerans genome data, investigated their gene structures and characterized the physicochemical properties of their encoded proteins. Banana LOXs showed a preference for using and ending with G/C and their encoded proteins can be classified into 9-LOX, Type I 13-LOX and Type II 13-LOX subfamilies. The expansion of the MaLOXs might result from the combined actions of genome-wide, tandem, and segmental duplications. However, tandem and segmental duplications contribute to the expansion of MbLOXs. Transcriptome data based gene expression analysis showed that MaLOX1, 4, and 7 were highly expressed in fruit and their expression levels were significantly regulated by ethylene. And 11, 12 and 7 MaLOXs were found to be low temperature-, high temperature-, and Fusarium oxysporum f. sp. Cubense tropical race 4 (FocTR4)-responsive, respectively. MaLOX8, 9 and 13 are responsive to all the three stresses, MaLOX4 and MaLOX12 are high temperature- and FocTR4-responsive; MaLOX6 and MaLOX17 are significantly induced by low temperature and FocTR4; and the expression of MaLOX7 and MaLOX16 are only affected by high temperature. Quantitative real-time PCR (qRT-PCR) analysis revealed that the expression levels of several MaLOXs are regulated by MeJA and FocTR4, indicating that they can increase the resistance of banana by regulating the JA pathway. Additionally, the weighted gene co-expression network analysis (WGCNA) of MaLOXs revealed 3 models respectively for 5 (MaLOX7-11), 3 (MaLOX6, 13, and 17), and 1 (MaLOX12) MaLOX genes. Our findings can provide valuable information for the characterization, evolution, diversity and functionality of MaLOX, MbLOX and MiLOX genes and are helpful for understanding the roles of LOXs in banana growth and development and adaptations to different stresses.