bluuebunny/crossref_metadata_2025 huggingface dataset:
Seasonal Forecasting Skill of Sea‐Level Anomalies in a Multi‐Model Prediction Framework
Authors: Long Xiaoyu , Widlansky Matthew J. , Spillman Claire M. , Kumar Arun , Balmaseda Magdalena , Thompson Philip R. , Chikamoto Yoshimitsu , Smith Grant A. , Huang Bohua , Shin Chul‐Su , Merrifield Mark A. , Sweet William V. , Leuliette Eric , Annamalai H. S. , Marra John J. , Mitchum Gary
Published: May 2021

Coastal high water level events are increasing in frequency and severity as global sea‐levels rise, and are exposing coastlines to risks of flooding. Yet, operational seasonal forecasts of sea‐level anomalies are not made for most coastal regions. Advancements in forecasting climate variability using coupled ocean‐atmosphere global models provide the opportunity to predict the likelihood of future high water events several months in advance. However, the skill of these models to forecast seasonal sea‐level anomalies has not been fully assessed, especially in a multi‐model framework. Here, we construct a 10‐model ensemble of retrospective forecasts with future lead times of up to 11 months. We compare predicted sea levels from bias‐corrected forecasts with 20 years of observations from satellite‐based altimetry and shore‐based tide gauges. Forecast skill, as measured by anomaly correlation, tends to be highest in the tropical and subtropical open oceans, whereas the skill is lower in the higher latitudes and along some continental coasts. For most locations, multi‐model averaging produces forecast skill that is comparable to or better than the best performing individual model. We find that the most skillful predictions typically come from forecast systems with more accurate initializations of sea level, which is generally achieved by assimilating altimetry data. Having relatively higher horizontal resolution in the ocean is also beneficial, as such models seem to better capture dynamical processes necessary for successful forecasts. The multi‐model assessment suggests that skillful seasonal sea‐level forecasts are possible in many, though not all, parts of the global ocean.
The Arctic Polar Vortex Response to Volcanic Forcing of Different Strengths
Authors: Azoulay Alon , Schmidt Hauke , Timmreck Claudia
Published: May 2021

Tropical volcanic eruptions injecting sulfur into the stratosphere are assumed to not only scatter radiation and cool Earth's surface but also alter atmospheric circulation and in particular to strengthen the stratospheric polar vortex in boreal winter. The exact impact is difficult to estimate because of the small number of well observed eruptions and the high internal variability of the vortex. We use large (100‐member) ensembles of simulations with an Earth system model for idealized volcanic aerosol distributions resulting from sulfur injections between 2.5 and 20 Tg. We suggest the existence of a threshold somewhere between 2.5 and 5 Tg(S) below which the vortex does not show a detectable response to the injection. This nonlinearity is introduced partly through the infrared aerosol optical density which increases much stronger than linear with increasing particle size occurring for increasing injection amount. Additionally, the dynamical mechanism causing the vortex strengthening seems not to set in for small aerosol loading. Furthermore, we add to the recent discussion concerning a possible downward propagation of the circulation response leading to a winter warming in Northern Eurasia. At latitudes northward of about 50°N, our simulations do show such an average warming pattern that is statistically significant for injections of 10 Tg(S) or more.
Separating Long‐Term and Short‐Term Mass Changes of Antarctic Ice Drainage Basins: A Coupled State Space Analysis of Satellite Observations and Model Products
Authors: Willen M. O. , Broerse T. , Groh A. , Wouters B. , Kuipers Munneke P. , Horwath M. , van den Broeke M. R. , Schröder L.
Published: May 2021

Satellite gravimetry and altimetry measurements record gravity and elevation changes, respectively, which are useful for determining mass and volume change of the Antarctic Ice Sheet. Common methods employ products from regional climate modeling and firn modeling to aid interpretation and to link volume changes to mass changes. Estimating deterministic parameters over defined time periods is a conventional way to evaluate those changes. To overcome limitations of deterministic analyses with respect to time‐variable signals, we have developed a state‐space model framework. Therein, we jointly evaluate four mass and volume data sets by coupling of temporal signal variations. We identify long‐term signals of ice drainage basins that are observed by the satellite gravimetry mission GRACE and several satellite altimetry missions from April 2002 until August 2016. The degree to which we can separate long‐term and short‐term variations strongly depends on the similarity of the mass and volume change time series. For the drainage system of the Pine Island Glacier (West Antarctica), our results show noticeable variations of the long‐term trend with an acceleration of the contribution of ice dynamics to the mass balance from −11 ± 8 to −58 ± 8 Gt a−1. Our results in Dronning Maud Land (East Antarctica) show a positive long‐term contribution to the mass balance at almost a constant rate. The presented approach can fit time‐variable changes without artificial selection of periods of interest. Furthermore, because we only enforce common long‐term time variations between mass and volume data, differences in mean trend rates help to uncover model discrepancies.
Two Stages of Accelerated Exhumation in the Middle Reach of the Yarlung River, Southern Tibet Since the Mid‐Miocene
Authors: Dai Jin‐Gen , Fox Matthew , Han Xu , Tremblay Marissa M. , Xu Shi‐Ying , Shuster David L. , Liu Bo‐Rong , Zhang Jiawei , Wang Cheng‐Shan
Published: May 2021

Climate change and tectonic activity through erosion control Earth’s topography, much of which is shaped by river incision. The Yarlung River has dissected the Indian‐Asian Collision Zone, and is one of the Earth’s largest rivers. However, its erosion rate history and how it interacts with regional tectonics remain ambiguous. Here, we apply low‐temperature thermochronometry and thermal‐kinematic models for bedrock samples from the Yarlung River. Our analysis reveals two stages of relatively fast exhumation occurred in different parts of the middle reach of the Yarlung River followed by remarkedly slow exhumation rate. First, a mid‐Miocene period (15–9 Ma) of rapid exhumation occurred along much of the Yarlung River, including within wide portions of the valley and its tributaries. This period of rapid exhumation coincides with the stage of high precipitation rates recorded in the Asian marginal basins and the timing of the east‐west extensional faults. In combination with extensional faults, the enhanced precipitation due to the onset of Asian monsoon would increase river discharge and thus accelerate mid‐Miocene exhumation rates. Second, a Pliocene‐Pleistocene (5–2 Ma) period of accelerated exhumation limited to gorges occurred in response to north‐south normal faulting, implying local tectonics as a first‐order control. Our results highlight roles of climatic and tectonic processes in shaping fluvial topography and how these change with time.
Taking Flight to Study Clouds and Climate
Authors: Sorooshian Armin , Atkinson Joseph , Ferrare Richard , Hair Johnathan , Ziemba Luke
Published: May 2021

A new mission involving synchronized aircraft observations is collecting data vital for improving our understanding of how aerosol particles and clouds influence each other.
‘Oumuamua May Be an Icy Fragment of a Pluto-Like Exoplanet
Authors: Stanley Sarah
Published: May 2021

Researchers favor nitrogen ice as the most likely material for the mysterious interstellar object’s composition.
Tree Canopies Reflect Mycorrhizal Composition
Authors: Sousa Daniel , Fisher Joshua B. , Galvan Fernando Romero , Pavlick Ryan P. , Cordell Susan , Giambelluca Thomas W. , Giardina Christian P. , Gilbert Gregory S. , Imran‐Narahari Faith , Litton Creighton M. , Lutz James A. , North Malcolm P. , Orwig David A. , Ostertag Rebecca , Sack Lawren , Phillips Richard P.
Published: May 2021

Mycorrhizae alter global patterns of CO2 fertilization, carbon storage, and elemental cycling, yet knowledge of their global distributions is currently limited by the availability of forest inventory data. Here, we show that maps of tree‐mycorrhizal associations (hereafter “mycorrhizal maps”) can be improved by the novel technology of imaging spectroscopy because mycorrhizal signatures propagate up from plant roots to impact forest canopy chemistry. We analyzed measurements from 143 airborne imaging spectroscopy surveys over 112,975 individual trees collected across 13 years. Results show remarkable accuracy in capturing ground truth observations of mycorrhizal associations from canopy signals across disparate landscapes (R2 = 0.92, p < 0.01). Upcoming imaging spectroscopy satellite missions can reveal new insights into landscape‐scale variations in water, nitrogen, phosphorus, carotenoid/anthocyanin, and cellulose/lignin composition. Applied globally, this approach could improve the spatial precision of mycorrhizal distributions by a factor of roughly 104 and facilitate the incorporation of dynamic shifts in forest composition into Earth system models.
Investigation of Spontaneous Imbibition Behavior in a 3D Pore Space Under Reservoir Condition by Lattice Boltzmann Method
Authors: Zheng Jiangtao , Lei Wenhai , Ju Yang , Wang Moran
Published: May 2021

Spontaneous imbibition (SI) of the injected fluid into the pore space of a tight oil reservoir and replacing the crude oil therein has been considered as one of the possible mechanisms in increasing oil recovery. Such deeply buried reservoir rocks is usually under high‐pressure and high‐temperature conditions. Besides, their interior porous structures are usually characterized as irregular pore bodies and slit‐shaped pore throats. As a result, an accurate description of the SI behavior driven by capillary force in the real pore space under reservoir conditions is crucial to understand the process and uncover the controlling mechanisms. An improved multi‐component pseudo‐potential lattice Boltzmann method was developed to simulate the SI behavior in a representative 3D pore space extracted from a tight sandstone reservoir rock. Comparison of the SI behavior under ambient condition and reservoir condition showed that the latter case exhibited two times faster of the imbibition. Moreover, a snap‐off of the oil droplet phenomenon was observed in the pore bodies surrounded by slit‐shaped pore throats. The snap‐off oil droplets stuck in pore bodies accounted for 9.47% of the pore volume. These results indicated the importance of investigating the SI in a real porous structure and under actual reservoir condition. The proposed pore‐scale simulation method provides a useful tool in understanding the complex SI pattern and the resulted enhanced oil recovery.
Efficacy and safety of a novel dosing strategy for ruxolitinib in the treatment of patients with myelofibrosis and anemia: the REALISE phase 2 study
Authors: Cervantes Francisco , Ross David M. , Radinoff Atanas , Palandri Francesca , Myasnikov Alexandr , Vannucchi Alessandro M. , Zachee Pierre , Gisslinger Heinz , Komatsu Norio , Foltz Lynda , Mannelli Francesco , Passamonti Francesco , Gilotti Geralyn , Sadek Islam , Tiwari Ranjan , Zor Evren , Al-Ali Haifa Kathrin
Published: May 2021

Anemia is a frequent manifestation of myelofibrosis (MF) and there is an unmet need for effective treatments in anemic MF patients. The REALISE phase 2 study (NCT02966353) evaluated the efficacy and safety of a novel ruxolitinib dosing strategy with a reduced starting dose with delayed up-titration in anemic MF patients. Fifty-one patients with primary MF (66.7%), post-essential thrombocythemia MF (21.6%), or post-polycythemia vera MF (11.8%) with palpable splenomegaly and hemoglobin <10 g/dl were included. Median age was 67 (45–88) years, 41.2% were female, and 18% were transfusion-dependent. Patients received 10 mg ruxolitinib b.i.d. for the first 12 weeks, then up-titrations of up to 25 mg b.i.d. were permitted, based on efficacy and platelet counts. Overall, 70% of patients achieved a ≥50% reduction in palpable spleen length at any time during the study. The most frequent adverse events leading to dose interruption/adjustment were thrombocytopenia (17.6%) and anemia (11.8%). Patients who had a dose increase had greater spleen size and higher white blood cell counts at baseline. Median hemoglobin levels remained stable and transfusion requirements did not increase compared with baseline. These results reinforce the notion that it is unnecessary to delay or withhold ruxolitinib because of co-existent or treatment-emergent anemia.
Development of single-cell-level microfluidic technology for long-term growth visualization of living cultures of Mycobacterium smegmatis
Authors: Wang Han , Conover Gloria M. , Han Song-I , Sacchettini James C. , Han Arum
Published: May 2021

Analysis of growth and death kinetics at single-cell resolution is a key step in understanding the complexity of the nonreplicating growth phenotype of the bacterial pathogen Mycobacterium tuberculosis. Here, we developed a single-cell-resolution microfluidic mycobacterial culture device that allows time-lapse microscopy-based long-term phenotypic visualization of the live replication dynamics of mycobacteria. This technology was successfully applied to monitor the real-time growth dynamics of the fast-growing model strain Mycobacterium smegmatis (M. smegmatis) while subjected to drug treatment regimens during continuous culture for 48 h inside the microfluidic device. A clear morphological change leading to significant swelling at the poles of the bacterial membrane was observed during drug treatment. In addition, a small subpopulation of cells surviving treatment by frontline antibiotics was observed to recover and achieve robust replicative growth once regular culture media was provided, suggesting the possibility of identifying and isolating nonreplicative mycobacteria. This device is a simple, easy-to-use, and low-cost solution for studying the single-cell phenotype and growth dynamics of mycobacteria, especially during drug treatment.
High expression of PSMC2 promotes gallbladder cancer through regulation of GNG4 and predicts poor prognosis
Authors: Zhu Dawei , Gu Xing , Lin Zhengyu , Yu Dandan , Wang Jing
Published: May 2021

Gallbladder cancer (GBC) is a common malignant tumor of the biliary tract, which accounts for 80–95% of biliary tumors worldwide, and is the leading cause of biliary malignant tumor-related death. This study identified PSMC2 as a potential regulator in the development of GBC. We showed that PSMC2 expression in GBC tissues is significantly higher than that in normal tissues, while high PSMC2 expression was correlated with more advanced tumor grade and poorer prognosis. The knockdown of PSMC2 in GBC cells induced significant inhibition of cell proliferation, colony formation and cell motility, while the promotion of cell apoptosis. The construction and observation of the mice xenograft model also confirmed the inhibitory effects of PSMC2 knockdown on GBC development. Moreover, our mechanistic study recognized GNG4 as a potential downstream target of PSMC2, knockdown of which could aggravate the tumor suppression induced by PSMC2 knockdown in vitro and in vivo. In conclusion, for the first time, PSMC2 was revealed as a tumor promotor in the development of GBC, which could regulate cell phenotypes of GBC cells through the interaction with GNG4, and maybe a promising therapeutic target in GBC treatment.
Probiotics-induced changes in gut microbial composition and its effects on cognitive performance after stress: exploratory analyses
Authors: Bloemendaal Mirjam , Szopinska-Tokov Joanna , Belzer Clara , Boverhoff David , Papalini Silvia , Michels Franziska , van Hemert Saskia , Arias Vasquez Alejandro , Aarts Esther
Published: May 2021

Stress negatively affects cognitive performance. Probiotics remediate somatic and behavioral stress responses, hypothetically by acting on the gut microbiota. Here, in exploratory analyses, we assessed gut microbial alterations after 28-days supplementation of multi-strain probiotics (EcologicBarrier consisting of Lactobacilli, Lactococci, and Bifidobacteria in healthy, female subjects (probiotics group n = 27, placebo group n = 29). In an identical pre-session and post-session, subjects performed a working memory task before and after an acute stress intervention. Global gut microbial beta diversity changed over time, but we were not able to detect differences between intervention groups. At the taxonomic level, Time by Intervention interactions were not significant after multiple comparison correction; the relative abundance of eight genera in the probiotics group was higher (uncorrected) relative to the placebo group: Butyricimonas, Parabacteroides, Alistipes, Christensenellaceae_R-7_group, Family_XIII_AD3011_group, Ruminococcaceae_UCG-003, Ruminococcaceae_UCG-005, and Ruminococcaceae_UCG-010. In a second analysis step, association analyses were done only within this selection of microbial genera, revealing the probiotics-induced change in genus Ruminococcaceae_UCG-003 was significantly associated with probiotics’ effect on stress-induced working memory changes (rspearman(27) = 0.565; pFDR = 0.014) in the probiotics group only and independent of potential confounders (i.e., age, BMI, and baseline dietary fiber intake). That is subjects with a higher increase in Ruminococcaceae_UCG-003 abundance after probiotics were also more protected from negative effects of stress on working memory after probiotic supplementation. The bacterial taxa showing an increase in relative abundance in the probiotics group are plant fiber degrading bacteria and produce short-chain fatty acids that are known for their beneficial effect on gut and brain health, e.g., maintaining intestinal-barrier and blood–brain-barrier integrity. This study shows that gut microbial alterations, modulated through probiotics use, are related to improved cognitive performance in acute stress circumstances.
Transcriptomics identifies STAT3 as a key regulator of hippocampal gene expression and anhedonia during withdrawal from chronic alcohol exposure
Authors: Chen Wei-Yang , Chen Hu , Hamada Kana , Gatta Eleonora , Chen Ying , Zhang Huaibo , Drnevich Jenny , Krishnan Harish R. , Maienschein-Cline Mark , Grayson Dennis R. , Pandey Subhash C. , Lasek Amy W.
Published: May 2021

Alcohol use disorder (AUD) is highly comorbid with depression. Withdrawal from chronic alcohol drinking results in depression and understanding brain molecular mechanisms that drive withdrawal-related depression is important for finding new drug targets to treat these comorbid conditions. Here, we performed RNA sequencing of the rat hippocampus during withdrawal from chronic alcohol drinking to discover key signaling pathways involved in alcohol withdrawal-related depressive-like behavior. Data were analyzed by weighted gene co-expression network analysis to identify several modules of co-expressed genes that could have a common underlying regulatory mechanism. One of the hub, or highly interconnected, genes in module 1 that increased during alcohol withdrawal was the transcription factor, signal transducer and activator of transcription 3 (Stat3), a known regulator of immune gene expression. Total and phosphorylated (p)STAT3 protein levels were also increased in the hippocampus during withdrawal after chronic alcohol exposure. Further, pSTAT3 binding was enriched at the module 1 genes Gfap, Tnfrsf1a, and Socs3 during alcohol withdrawal. Notably, pSTAT3 and its target genes were elevated in the postmortem hippocampus of human subjects with AUD when compared with control subjects. To determine the behavioral relevance of STAT3 activation during alcohol withdrawal, we treated rats with the STAT3 inhibitor stattic and tested for sucrose preference as a measure of anhedonia. STAT3 inhibition alleviated alcohol withdrawal-induced anhedonia. These results demonstrate activation of STAT3 signaling in the hippocampus during alcohol withdrawal in rats and in human AUD subjects, and suggest that STAT3 could be a therapeutic target for reducing comorbid AUD and depression.
Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells
Authors: Fiskus Warren , Mill Christopher P. , Nabet Behnam , Perera Dimuthu , Birdwell Christine , Manshouri Taghi , Lara Bernardo , Kadia Tapan M. , DiNardo Courtney , Takahashi Koichi , Daver Naval , Bose Prithviraj , Masarova Lucia , Pemmaraju Naveen , Kornblau Steven , Borthakur Gautam , Montalban-Bravo Guillermo , Manero Guillermo Garcia , Sharma Sunil , Stubbs Matthew , Su Xiaoping , Green Michael R. , Coarfa Cristian , Verstovsek Srdan , Khoury Joseph D. , Vakoc Christopher R. , Bhalla Kapil N.
Published: May 2021

There is an unmet need to overcome nongenetic therapy-resistance to improve outcomes in AML, especially post-myeloproliferative neoplasm (MPN) secondary (s) AML. Studies presented describe effects of genetic knockout, degradation or small molecule targeted-inhibition of GFI1/LSD1 on active enhancers, altering gene-expressions and inducing differentiation and lethality in AML and (MPN) sAML cells. A protein domain-focused CRISPR screen in LSD1 (KDM1A) inhibitor (i) treated AML cells, identified BRD4, MOZ, HDAC3 and DOT1L among the codependencies. Our findings demonstrate that co-targeting LSD1 and one of these co-dependencies exerted synergistic in vitro lethality in AML and post-MPN sAML cells. Co-treatment with LSD1i and the JAKi ruxolitinib was also synergistically lethal against post-MPN sAML cells. LSD1i pre-treatment induced GFI1, PU.1 and CEBPα but depleted c-Myc, overcoming nongenetic resistance to ruxolitinib, or to BETi in post-MPN sAML cells. Co-treatment with LSD1i and BETi or ruxolitinib exerted superior in vivo efficacy against post-MPN sAML cells. These findings highlight LSD1i-based combinations that merit testing for clinical efficacy, especially to overcome nongenetic therapy-resistance in AML and post-MPN sAML.
Endocrine role of bone in the regulation of energy metabolism
Authors: Zhou Ruoyu , Guo Qiaoyue , Xiao Ye , Guo Qi , Huang Yan , Li Changjun , Luo Xianghang
Published: May 2021

Abstracts

Bone mainly functions as a supportive framework for the whole body and is the major regulator of calcium homeostasis and hematopoietic function. Recently, an increasing number of studies have characterized the significance of bone as an endocrine organ, suggesting that bone-derived factors regulate local bone metabolism and metabolic functions. In addition, these factors can regulate global energy homeostasis by altering insulin sensitivity, feeding behavior, and adipocyte commitment. These findings may provide a new pathological mechanism for related metabolic diseases or be used in the diagnosis, treatment, and prevention of metabolic diseases such as osteoporosis, obesity, and diabetes mellitus. In this review, we summarize the regulatory effect of bone and bone-derived factors on energy metabolism and discuss directions for future research.
TSP50 promotes the Warburg effect and hepatocyte proliferation via regulating PKM2 acetylation
Authors: Gao Feng , Zhang Xiaojun , Wang Shuyue , Zheng Lihua , Sun Ying , Wang Guannan , Song Zhenbo , Bao Yongli
Published: May 2021

Metabolic reprogramming is a hallmark of malignancy. Testes-specific protease 50 (TSP50), a newly identified oncogene, has been shown to play an important role in tumorigenesis. However, its role in tumor cell metabolism remains unclear. To investigate this issue, LC–MS/MS was employed to identify TSP50-binding proteins and pyruvate kinase M2 isoform (PKM2), a known key enzyme of aerobic glycolysis, was identified as a novel binding partner of TSP50. Further studies suggested that TSP50 promoted aerobic glycolysis in HCC cells by maintaining low pyruvate kinase activity of the PKM2. Mechanistically, TSP50 promoted the Warburg effect by increasing PKM2 K433 acetylation level and PKM2 acetylation site (K433R) mutation remarkably abrogated the TSP50-induced aerobic glycolysis, cell proliferation in vitro and tumor formation in vivo. Our findings indicate that TSP50-mediated low PKM2 pyruvate kinase activity is an important determinant for Warburg effect in HCC cells and provide a mechanistic link between TSP50 and tumor metabolism.
Epidermal chloroplasts are defense-related motile organelles equipped with plant immune components
Authors: Irieda Hiroki , Takano Yoshitaka
Published: May 2021

In addition to conspicuous large mesophyll chloroplasts, where most photosynthesis occurs, small epidermal chloroplasts have also been observed in plant leaves. However, the functional significance of this small organelle remains unclear. Here, we present evidence that Arabidopsis epidermal chloroplasts control the entry of fungal pathogens. In entry trials, specialized fungal cells called appressoria triggered dynamic movement of epidermal chloroplasts. This movement is controlled by common regulators of mesophyll chloroplast photorelocation movement, designated as the epidermal chloroplast response (ECR). The ECR occurs when the PEN2 myrosinase-related higher-layer antifungal system becomes ineffective, and blockage of the distinct steps of the ECR commonly decreases preinvasive nonhost resistance against fungi. Furthermore, immune components were preferentially localized to epidermal chloroplasts, contributing to antifungal nonhost resistance in the pen2 background. Our findings reveal that atypical small chloroplasts act as defense-related motile organelles by specifically positioning immune components in the plant epidermis, which is the first site of contact between the plant and pathogens. Thus, this work deepens our understanding of the functions of epidermal chloroplasts.
Continent-wide genomic signatures of adaptation to urbanisation in a songbird across Europe
Authors: Salmón Pablo , Jacobs Arne , Ahrén Dag , Biard Clotilde , Dingemanse Niels J. , Dominoni Davide M. , Helm Barbara , Lundberg Max , Senar Juan Carlos , Sprau Philipp , Visser Marcel E. , Isaksson Caroline
Published: May 2021

Urbanisation is increasing worldwide, and there is now ample evidence of phenotypic changes in wild organisms in response to this novel environment. Yet, the genetic changes and genomic architecture underlying these adaptations are poorly understood. Here, we genotype 192 great tits (Parus major) from nine European cities, each paired with an adjacent rural site, to address this major knowledge gap in our understanding of wildlife urban adaptation. We find that a combination of polygenic allele frequency shifts and recurrent selective sweeps are associated with the adaptation of great tits to urban environments. While haplotypes under selection are rarely shared across urban populations, selective sweeps occur within the same genes, mostly linked to neural function and development. Collectively, we show that urban adaptation in a widespread songbird occurs through unique and shared selective sweeps in a core-set of behaviour-linked genes.
Structural basis for allosteric regulation of Human Topoisomerase IIα
Authors: Vanden Broeck Arnaud , Lotz Christophe , Drillien Robert , Haas Léa , Bedez Claire , Lamour Valérie
Published: May 2021

The human type IIA topoisomerases (Top2) are essential enzymes that regulate DNA topology and chromosome organization. The Topo IIα isoform is a prime target for antineoplastic compounds used in cancer therapy that form ternary cleavage complexes with the DNA. Despite extensive studies, structural information on this large dimeric assembly is limited to the catalytic domains, hindering the exploration of allosteric mechanism governing the enzyme activities and the contribution of its non-conserved C-terminal domain (CTD). Herein we present cryo-EM structures of the entire human Topo IIα nucleoprotein complex in different conformations solved at subnanometer resolutions (3.6–7.4 Å). Our data unveils the molecular determinants that fine tune the allosteric connections between the ATPase domain and the DNA binding/cleavage domain. Strikingly, the reconstruction of the DNA-binding/cleavage domain uncovers a linker leading to the CTD, which plays a critical role in modulating the enzyme’s activities and opens perspective for the analysis of post-translational modifications.
40S ribosome profiling reveals distinct roles for Tma20/Tma22 (MCT-1/DENR) and Tma64 (eIF2D) in 40S subunit recycling
Authors: Young David J. , Meydan Sezen , Guydosh Nicholas R.
Published: May 2021

The recycling of ribosomes at stop codons for use in further rounds of translation is critical for efficient protein synthesis. Removal of the 60S subunit is catalyzed by the ATPase Rli1 (ABCE1) while removal of the 40S is thought to require Tma64 (eIF2D), Tma20 (MCT-1), and Tma22 (DENR). However, it remains unclear how these Tma proteins cause 40S removal and control reinitiation of downstream translation. Here we used a 40S ribosome footprinting strategy to directly observe intermediate steps of ribosome recycling in cells. Deletion of the genes encoding these Tma proteins resulted in broad accumulation of unrecycled 40S subunits at stop codons, directly establishing their role in 40S recycling. Furthermore, the Tma20/Tma22 heterodimer was responsible for a majority of 40S recycling events while Tma64 played a minor role. Introduction of an autism-associated mutation into TMA22 resulted in a loss of 40S recycling activity, linking ribosome recycling and neurological disease.
Multiscale influenza forecasting
Authors: Osthus Dave , Moran Kelly R.
Published: May 2021

Influenza forecasting in the United States (US) is complex and challenging due to spatial and temporal variability, nested geographic scales of interest, and heterogeneous surveillance participation. Here we present Dante, a multiscale influenza forecasting model that learns rather than prescribes spatial, temporal, and surveillance data structure and generates coherent forecasts across state, regional, and national scales. We retrospectively compare Dante’s short-term and seasonal forecasts for previous flu seasons to the Dynamic Bayesian Model (DBM), a leading competitor. Dante outperformed DBM for nearly all spatial units, flu seasons, geographic scales, and forecasting targets. Dante’s sharper and more accurate forecasts also suggest greater public health utility. Dante placed 1st in the Centers for Disease Control and Prevention’s prospective 2018/19 FluSight challenge in both the national and regional competition and the state competition. The methodology underpinning Dante can be used in other seasonal disease forecasting contexts having nested geographic scales of interest.
Interpretation of T cell states from single-cell transcriptomics data using reference atlases
Authors: Andreatta Massimo , Corria-Osorio Jesus , Müller Sören , Cubas Rafael , Coukos George , Carmona Santiago J.
Published: May 2021

Single-cell RNA sequencing (scRNA-seq) has revealed an unprecedented degree of immune cell diversity. However, consistent definition of cell subtypes and cell states across studies and diseases remains a major challenge. Here we generate reference T cell atlases for cancer and viral infection by multi-study integration, and develop ProjecTILs, an algorithm for reference atlas projection. In contrast to other methods, ProjecTILs allows not only accurate embedding of new scRNA-seq data into a reference without altering its structure, but also characterizing previously unknown cell states that “deviate” from the reference. ProjecTILs accurately predicts the effects of cell perturbations and identifies gene programs that are altered in different conditions and tissues. A meta-analysis of tumor-infiltrating T cells from several cohorts reveals a strong conservation of T cell subtypes between human and mouse, providing a consistent basis to describe T cell heterogeneity across studies, diseases, and species.
Data driven discovery of conjugated polyelectrolytes for optoelectronic and photocatalytic applications
Authors: Wan Yangyang , Ramirez Fernando , Zhang Xu , Nguyen Thuc-Quyen , Bazan Guillermo C. , Lu Gang
Published: May 2021

Conjugated polyelectrolytes (CPEs), comprised of conjugated backbones and pendant ionic functionalities, are versatile organic materials with diverse applications. However, the myriad of possible molecular structures of CPEs render traditional, trial-and-error materials discovery strategy impractical. Here, we tackle this problem using a data-centric approach by incorporating machine learning with high-throughput first-principles calculations. We systematically examine how key materials properties depend on individual structural components of CPEs and from which the structure–property relationships are established. By means of machine learning, we uncover structural features crucial to the CPE properties, and these features are then used as descriptors in the machine learning to predict the properties of unknown CPEs. Lastly, we discover promising CPEs as hole transport materials in halide perovskite-based optoelectronic devices and as photocatalysts for water splitting. Our work could accelerate the discovery of CPEs for optoelectronic and photocatalytic applications.
Cost-effectiveness analysis of COPD screening programs in primary care for high-risk patients in China
Authors: Qu Shuli , You Xuedan , Liu Tianyi , Wang Lijiao , Yin Zheng , Liu Yanjun , Ye Chong , Yang Ting , Huang Mao , Li Hongchao , Fang Liwen , Zheng Jinping
Published: May 2021

We built a decision-analytic model to compare the cost-effectiveness of using portable spirometer and questionnaire to screen chronic obstructive pulmonary diseases (COPD) with no screening (i.e. usual care) among chronic bronchitis patient in China. A lifetime horizon and a payer perspective were adopted. Cost data of health services including spirometry screening and treatment costs covered both maintenance and exacerbation. The result indicated that portable spirometer screening was cost-saving compared with questionnaire screening and no screening, with an incremental cost-effectiveness ratio (ICER) of −5026 and −1766 per QALY, respectively. Sensitivity analyses confirmed the robustness of the results. In summary, portable spirometer screening is likely the optimal option for COPD screening among chronic bronchitis patients China.
Rational design of innate defense regulator peptides as tumor vaccine adjuvants
Authors: Tian Yaomei , Hu Qiuyue , Zhang Rui , Zhou Bailing , Xie Daoyuan , Wang Yuanda , Zhang Xueyan , Yang Li
Published: May 2021

The development of adjuvants has been an empirical process. Efforts to develop a new design and evaluation system for novel adjuvants are not only desirable but also necessary. Moreover, composite adjuvants that contain two or more types of adjuvants to synergistically enhance the immune response are important for adjuvant and vaccine design. Innate defense regulator peptides (IDRs) are promising adjuvants for clinical immunotherapy because they exhibit multifaceted immunomodulatory capabilities. However, the rational design and discovery of IDRs that have improved immunomodulatory activities have been hampered by the lack of screening techniques and the great challenges in the identification of their interaction partners. Here, we describe a screening and evaluation system for IDR design. On the basis of in vitro screening, the optimized IDR DP7 recruited neutrophils, monocytes and macrophages to the site of infection. The adjuvant, comprising the DP7 and CpG oligonucleotide (CpG), induced chemokine/cytokine expression, enhanced the antigen uptake by dendritic cells and upregulated surface marker expression in dendritic cells. Vaccination with the NY-ESO-1 or OVA antigens combined with the adjuvant alum/CpG/DP7 strongly suppressed tumor growth in mice which was due to the improvement of antigen-specific humoral and cellular immunity. Regarding the mechanism of action, GPR35 may be the potential interaction partner of DP7. Our study revealed the potential application of the screening and evaluation system as a strategy for rationally designing effective IDRs or composite adjuvants and identifying their mechanism of action.
Metabolomics and computational analysis of the role of monoamine oxidase activity in delirium and SARS-COV-2 infection
Authors: Cuperlovic-Culf Miroslava , Cunningham Emma L. , Teimoorinia Hossen , Surendra Anuradha , Pan Xiaobei , Bennett Steffany A. L. , Jung Mijin , McGuiness Bernadette , Passmore Anthony Peter , Beverland David , Green Brian D.
Published: May 2021

Delirium is an acute change in attention and cognition occurring in ~ 65% of severe SARS-CoV-2 cases. It is also common following surgery and an indicator of brain vulnerability and risk for the development of dementia. In this work we analyzed the underlying role of metabolism in delirium-susceptibility in the postoperative setting using metabolomic profiling of cerebrospinal fluid and blood taken from the same patients prior to planned orthopaedic surgery. Distance correlation analysis and Random Forest (RF) feature selection were used to determine changes in metabolic networks. We found significant concentration differences in several amino acids, acylcarnitines and polyamines linking delirium-prone patients to known factors in Alzheimer’s disease such as monoamine oxidase B (MAOB) protein. Subsequent computational structural comparison between MAOB and angiotensin converting enzyme 2 as well as protein–protein docking analysis showed that there potentially is strong binding of SARS-CoV-2 spike protein to MAOB. The possibility that SARS-CoV-2 influences MAOB activity leading to the observed neurological and platelet-based complications of SARS-CoV-2 infection requires further investigation.
Med-BERT: pretrained contextualized embeddings on large-scale structured electronic health records for disease prediction
Authors: Rasmy Laila , Xiang Yang , Xie Ziqian , Tao Cui , Zhi Degui
Published: May 2021

Deep learning (DL)-based predictive models from electronic health records (EHRs) deliver impressive performance in many clinical tasks. Large training cohorts, however, are often required by these models to achieve high accuracy, hindering the adoption of DL-based models in scenarios with limited training data. Recently, bidirectional encoder representations from transformers (BERT) and related models have achieved tremendous successes in the natural language processing domain. The pretraining of BERT on a very large training corpus generates contextualized embeddings that can boost the performance of models trained on smaller datasets. Inspired by BERT, we propose Med-BERT, which adapts the BERT framework originally developed for the text domain to the structured EHR domain. Med-BERT is a contextualized embedding model pretrained on a structured EHR dataset of 28,490,650 patients. Fine-tuning experiments showed that Med-BERT substantially improves the prediction accuracy, boosting the area under the receiver operating characteristics curve (AUC) by 1.21–6.14% in two disease prediction tasks from two clinical databases. In particular, pretrained Med-BERT obtains promising performances on tasks with small fine-tuning training sets and can boost the AUC by more than 20% or obtain an AUC as high as a model trained on a training set ten times larger, compared with deep learning models without Med-BERT. We believe that Med-BERT will benefit disease prediction studies with small local training datasets, reduce data collection expenses, and accelerate the pace of artificial intelligence aided healthcare.
Mechanosensitive channel YnaI has lipid-bound extended sensor paddles
Authors: Hu Wenxin , Wang Zhiming , Zheng Hongjin
Published: May 2021

The general mechanism of bacterial mechanosensitive channels (MS) has been characterized by extensive studies on a small conductance channel MscS from Escherichia coli (E. coli). However, recent structural studies on the same channel have revealed controversial roles of various channel-bound lipids in channel gating. To better understand bacterial MscS-like channels, it is necessary to characterize homologs other than MscS. Here, we describe the structure of YnaI, one of the closest MscS homologs in E. coli, in its non-conducting state at 3.3 Å resolution determined by cryo electron microscopy. Our structure revealed the intact membrane sensor paddle domain in YnaI, which was stabilized by functionally important residues H43, Q46, Y50 and K93. In the pockets between sensor paddles, there were clear lipid densities that interact strongly with residues Q100 and R120. These lipids were a mixture of natural lipids but may be enriched in cardiolipin and phosphatidylserine. In addition, residues along the ion-conducting pathway and responsible for the heptameric assembly were discussed. Together with biochemical experiments and mutagenesis studies, our results provide strong support for the idea that the pocket lipids are functionally important for mechanosensitive channels.
Structural analysis of the SRP Alu domain from Plasmodium falciparum reveals a non-canonical open conformation
Authors: Soni Komal , Kempf Georg , Manalastas-Cantos Karen , Hendricks Astrid , Flemming Dirk , Guizetti Julien , Simon Bernd , Frischknecht Friedrich , Svergun Dmitri I. , Wild Klemens , Sinning Irmgard
Published: May 2021

The eukaryotic signal recognition particle (SRP) contains an Alu domain, which docks into the factor binding site of translating ribosomes and confers translation retardation. The canonical Alu domain consists of the SRP9/14 protein heterodimer and a tRNA-like folded Alu RNA that adopts a strictly ‘closed’ conformation involving a loop-loop pseudoknot. Here, we study the structure of the Alu domain from Plasmodium falciparum (PfAlu), a divergent apicomplexan protozoan that causes human malaria. Using NMR, SAXS and cryo-EM analyses, we show that, in contrast to its prokaryotic and eukaryotic counterparts, the PfAlu domain adopts an ‘open’ Y-shaped conformation. We show that cytoplasmic P. falciparum ribosomes are non-discriminative and recognize both the open PfAlu and closed human Alu domains with nanomolar affinity. In contrast, human ribosomes do not provide high affinity binding sites for either of the Alu domains. Our analyses extend the structural database of Alu domains to the protozoan species and reveal species-specific differences in the recognition of SRP Alu domains by ribosomes.
Silicon dioxide nanoparticles orchestrate carbon and nitrogen metabolism in pea seedlings to cope with broomrape infection
Authors: Shabbaj Ibrahim I. , Madany Mahmoud M. Y. , Tammar Abdurazag , Balkhyour Mansour A. , AbdElgawad Hamada
Published: May 2021

SiNPs orchestrate carbon and nitrogen metabolism and cell fortification in pea seedlings to cope withPhelipancheinfection.
RBC-derived nanosystem with enhanced ferroptosis triggered by oxygen-boosted phototherapy for synergized tumor treatment
Authors: Liu Wenjun , Zhang Jieyuan , Ding Liang , Ni Weifeng , Yuan Junjie , Xiao Haijun , Zhang Jingwei
Published: May 2021

RDV enriched with hemoglobin co-delivers Ce6 and SRF into cancer cells for boosting oxygen and providing iron, which leads to enhanced PDT and stronger ferroptosis therapy.
Proflavine and zinc chloride “team chemistry”: combining antibacterial agents via solid-state interaction
Authors: Fiore Cecilia , Shemchuk Oleksii , Grepioni Fabrizia , Turner Raymond J. , Braga Dario
Published: May 2021

Mechanochemical and solution reaction of ZnCl2 with proflavine yields the antimicrobials [HPF]2[ZnCl4]·H2O and ZnCl3(HPF), more active, with respect to the separate components and the AgNO3 standard, towards P. aeruginosa, E. coli and S. aureus.
Size-dependent strong metal–support interaction in Pd/ZnO catalysts for hydrogenation of CO2to methanol
Authors: Zhang Liangcai , Liu Xinyu , Wang Hengwei , Cao Lina , Huang Chenxi , Li Shang , Zhang Xiaohui , Guan Qiaoqiao , Shao Xiang , Lu Junling
Published: May 2021

Size-dependent strong metal–support interactions govern both the activity and selectivity decisively.
Nutritional targeting modification of silkworm pupae oil catalyzed by a smart hydrogel immobilized lipase
Authors: Wang Jin-Zheng , Wu Cheng-Kun , Yan Cheng-Hai , Chen Huan , You Shuai , Sheng Sheng , Wu Fu-An , Wang Jun
Published: May 2021

A brief description of the nutritional targeting design strategy for SPO. A microfluidic reactor with a smart hydrogel was first constructed and its application successfully improved the nutritional function of SPO by the decrease of PA.
Studies on the affinity of 6-[(n-(cyclo)aminoalkyl)oxy]-4H-chromen-4-ones for sigma 1/2 receptors
Authors: Deuther-Conrad Winnie , Diez-Iriepa Daniel , Iriepa Isabel , López-Muñoz Francisco , Martínez-Grau María Angeles , Gütschow Michael , Marco-Contelles José
Published: May 2021

Chromenone derivatives were identified as σ1and σ2receptor ligands (12,20) and multitarget small molecules (7).
Deciphering the architecture and interactome of hnRNP proteins and enigmRBPs
Authors: Wippel Helisa H. , Fioramonte Mariana , Chavez Juan D. , Bruce James E.
Published: May 2021

RNA-binding proteins (RBPs) have conserved domains and consensus sequences that interact with RNAs and other regulatory proteins forming ribonucleoprotein (RNP) complexes. Chemical crosslinking of proteins provides insights into RNP complexes interactome and protein conformations.
Nanoscale characterization of an all-oxide core–shell nanorod heterojunction using intermodulation atomic force microscopy (AFM) methods
Authors: Dobryden Illia , Borgani Riccardo , Rigoni Federica , Ghamgosar Pedram , Concina Isabella , Almqvist Nils , Vomiero Alberto
Published: May 2021

We introduce the application of advanced multifrequency ImAFM methods to probe the local electric properties of all-oxide core–shell ZnO–Co3O4 nanorod heterojunctions. These findings are important for the development of one-dimensional devices.
Progress in propylene homo- and copolymers using advanced transition metal catalyst systems
Authors: Mishra Anurag , Patil Harshad R. , Gupta Virendrakumar
Published: May 2021

Recent progress on advanced transition metal catalysts for propylene polymerization and copolymerization are reviewed.
Pure red phosphorescent iridium(iii) complexes containing phenylquinazoline ligands for highly efficient organic light-emitting diodes
Authors: Tian Houru , Liu Di , Li Jiuyan , Ma Mengyao , Lan Ying , Wei Wenkui , Niu Rui , Song Kai
Published: May 2021

By incorporating a methoxy group at the 6- and 7-sites of the quinazoline ring of phenylquinazoline cyclometalating ligands, the iridium complexes realize pure red phosphorescence. The PHOLED based on Ir2 achieves CIE of (0.65, 0.34) and a higher external quantum efficiency of 26.22%.
Copper-catalyzed asymmetric allylic C–H amination of alkenes using N-arylhydroxylamines
Authors: Murru Siva , Mokar Bhanudas D. , Bista Ramesh , Harakat Dominique , Le Bras Jean , Fronczek Frank , Nicholas Kenneth M. , Srivastava Radhey S.
Published: May 2021

The first Cu-catalyzed asymmetric allylic C–H amination of alkenes with N-aryl hydroxylamines has been developed. Metal-complexes isolation, ESI-MS analysis and the DFT calculations provided key insights on mechanistic pathway.
A dual-functional Ta/TaOx/Ru device with both nonlinear selector and resistive switching behaviors
Authors: Wang Rui , Shi Tuo , Zhang Xumeng , Wu Zuheng , Liu Qi
Published: May 2021

We presented a dual-functional Ta/TaOx/Ru device with both highly uniform nonlinear selector and stable resistive switching behaviors.
Effect of H2SiF6 modification of IM-5 on catalytic performance in benzene alkylation with ethylene
Authors: Zhai Yunping , Chen Junwen , Wang Yongrui , Luo Yibin , Shu Xingtian
Published: May 2021

IM-5 zeolite modified by H2SiF6 has superior activity, equivalent stability, higher DEB selectivity and a lower xylene selectivity in comparison of ZSM-5 with similar Si/Al2 ratio. The process provides a new way to make ethylbenzene in the vapor phase.