bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractSubstitution 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

AbstractEML4–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

AbstractMany 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

AbstractMost 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

AbstractPolyclonal 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

AbstractThe 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

AbstractTranscriptomic 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

AbstractA 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

AbstractRealization 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

AbstractThe 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

AbstractThe 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

AbstractDespite 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

AbstractNon-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

AbstractLife 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

AbstractThe 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

AbstractHow 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.