bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identity and compatibility of reference genome resources
Authors: Stolarczyk Michał , Xue Bingjie , Sheffield Nathan C. 
Published: March 2021

Genome analysis relies on reference data like sequences, feature annotations, and aligner indexes. These data can be found in many versions from many sources, making it challenging to identify and assess compatibility among them. For example, how can you determine which indexes are derived from identical raw sequence files, or which annotations share a compatible coordinate system? Here, we describe a novel approach to establish identity and compatibility of reference genome resources. We approach this with three advances: First, we derive unique identifiers for each resource; second, we record parent-child relationships among resources; and third, we describe recursive identifiers that determine identity as well as compatibility of coordinate systems and sequence names. These advances facilitate portability, reproducibility, and re-use of genome reference data.Availabilityhttps://refgenie.databio.org
Reconstruction of Contemporary Human Stem Cell Dynamics with Oscillatory Molecular Clocks
Authors: Gabbutt Calum , Schenck Ryan O , Weisenberger Dan , Kimberley Christopher , Berner Alison , Househam Jacob , Lakatos Eszter , Robertson-Tessi Mark , Martin Isabel , Patel Roshani , Clark Sue , Latchford Andrew , Barnes Christopher , Leedham Simon J , Anderson Alexander RA , Graham Trevor A , Shibata Darryl 
Published: March 2021

AbstractMolecular clocks record cellular ancestry. However, currently used clocks ‘tick too slowly’ to measure the short-timescale dynamics of cellular renewal in adult tissues. Here we develop ‘rapidly oscillating DNA methylation clocks’ where ongoing (de)methylation causes the clock to ‘tick-tock’ back-and-forth between methylated and unmethylated states like a pendulum. We identify oscillators using standard methylation arrays and develop a mathematical modelling framework to quantitatively measure human adult stem cell dynamics from these data. Small intestinal crypts were inferred to contain slightly more stem cells than colon (6.5 ± 1.0 vs 5.8 ± 1.7 stem cells/crypt) with slower stem cell replacement in small intestine (0.79 ± 0.5 vs 1.1 ± 0.8 replacements/stem cell/year). GermlineAPCmutation increased the number of replacements per crypt (13.0 ± 2.4 replacements/crypt/year vs 6.9 ± 4.6 for healthy colon). In blood, we measure rapid expansion of acute leukaemia and slower growth of chronic disease. Rapidly oscillating molecular clocks are a new methodology to quantitatively measure human somatic cell dynamics.
Time series analysis of trial-to-trial variability of MEG power spectrum during rest state, unattented listening and frequency-modulated tones classification
Authors: Kipiński Lech , Kordecki Wojciech 
Published: March 2021

AbstractThe nonstationarity of EEG/MEG signals is important for understanding the functioning of human brain. From the previous research we know that even very short, i.e. 250—500ms MEG signals are variance-nonstationary. The covariance of stochastic process is mathematically associated with its spectral density, therefore we investigate how the spectrum of such nonstationary signals varies in time.We analyze the data from 148-channel MEG, that represent rest state, unattented listening and frequency-modulated tones classification. We transform short-time MEG signals to the frequency domain using the FFT algorithm and for the dominant frequencies 8—12 Hz we prepare the time series representing their trial-to-trial variability. Then, we test them for level- and trend-stationarity, unit root, heteroscedasticity and gaussianity and based on their properties we propose the ARMA-modelling for their description.The analyzed time series have the weakly stationary properties independently of the functional state of brain and localization. Only their small percentage, mostly related to the cognitive task, still presents nonstationarity. The obtained mathematical models show that the spectral density of analyzed signals depends on only 2—3 previous trials.The presented method has limitations related to FFT resolution and univariate models, but it is not computationally complicated and allows to obtain a low-complex stochastic models of the EEG/MEG spectrum variability.Although the physiological short-time MEG signals are in principle nonstationary in time domain, its power spectrum at the dominant frequencies varies as weakly stationary stochastic process. Described technique has the possible applications in prediction of the EEG/MEG spectral properties in theoretical and clinical neuroscience.
Spontaneous Eye Blink Rate during the Working Memory Delay Period Predicts Task Accuracy
Authors: Ortega Jefferson , Plaska Chelsea Reichert , Gomes Bernard A. , Ellmore Timothy M. 
Published: March 2021

AbstractSpontaneous eye blink rate (sEBR) has been linked to attention and memory, specifically working memory (WM). sEBR is also related to striatal dopamine (DA) activity with schizophrenia and Parkinson’s disease showing increases and decreases respectively in sEBR. A weakness of past studies of sEBR and WM is that correlations have been reported using blink rates taken at baseline either before or after performance of the tasks used to assess WM. The goal of the present study was to understand how fluctuations in sEBR during different phases of a visual WM task predict task accuracy. In two experiments, with recordings of sEBR collected inside and outside of a magnetic resonance imaging bore, we observed sEBR to be positively correlated with WM task accuracy during the WM delay period. We also found task-related modulation of sEBR, including higher sEBR during the delay period compared to rest, and lower sEBR during task phases (e.g., stimulus encoding) that place demands on visual attention. These results provide further evidence that sEBR could be an important predictor of WM task performance with the changes during the delay period suggesting a role in WM maintenance. The relationship of sEBR to DA activity and WM maintenance is discussed.
An integrative transcriptional logic model of hepatic insulin resistance
Authors: Kitamoto Takumi , Kuo Taiyi , Okabe Atsushi , Kaneda Atsushi , Accili Domenico 
Published: March 2021

ABSTRACTAbnormalities of lipid/lipoprotein and glucose metabolism are hallmarks of hepatic insulin resistance in type 2 diabetes. The former antedate the latter, but the latter become progressively refractory to treatment and contribute to therapeutic failures. It’s unclear whether the two processes share a common pathogenesis and what underlies their progressive nature. In this study, we investigated the hypothesis that genes in the lipid/lipoprotein pathway and those in the glucose metabolic pathway are governed by different transcriptional logics that affect their response to physiologic (fasting/refeeding) as well as pathophysiologic cues (insulin resistance and hyperglycemia). To this end, we obtained genomic and transcriptomic maps of the key insulin-regulated transcription factor, FoxO1, and integrated them with those of CREB, PPARα, and glucocorticoid receptor. We found an enrichment of glucose metabolic genes among those regulated by intergenic and promoter enhancers in a fasting-dependent manner, while lipid genes were enriched among fasting-dependent intron enhancers and fasting-independent enhancer-less introns. Glucose genes also showed a remarkable transcriptional resiliency, i.e., an enrichment of active marks at shared PPARα/FoxO1 regulatory elements when FoxO1 was inactivated. Surprisingly, the main features associated with insulin resistance and hyperglycemia were a “spreading” of FoxO1 binding to enhancers, and the emergence of target sites unique to this condition. We surmise that this unusual pattern correlates with the progressively intractable nature of hepatic insulin resistance. This transcriptional logic provides an integrated model to interpret the combined lipid and glucose abnormalities of type 2 diabetes.Significance StatementThe liver is a source of excess lipid, atherogenic lipoproteins, and glucose in patients with type 2 diabetes. These factors predispose to micro- and macrovascular complications. The underlying pathophysiology is not well understood, and mechanistic insight into it may provide better tools to prevent, treat, and reverse the disease. Here we propose an alternative explanation for this pathophysiologic conundrum by illustrating a transcriptional “logic” underlying the regulation of different classes of genes. These findings can be interpreted to provide an integrated stepwise model for the coexistence of lipid and glucose abnormalities in hepatic insulin resistance.HighlightsFoxo1 regulates liver metabolism through active enhancers, and hepatocyte maintenance through core promotersFoxo1 regulates glucose genes through fasting-dependent intergenic enhancersBipartite intron regulation of lipid genes is partly fasting-independentPparαcontributes to the transcriptional resiliency of Foxo1 metabolic targetsInsulin resistance causes de novo recruitment of Foxo1 to active enhancersA stepwise model of insulin resistance
Rationally designed immunogens enable immune focusing to the SARS-CoV-2 receptor binding motif
Authors: Hauser Blake M. , Sangesland Maya , Denis Kerri J. St. , Windsor Ian W. , Feldman Jared , Lam Evan C. , Kannegieter Ty , Balazs Alejandro B. , Lingwood Daniel , Schmidt Aaron G. 
Published: March 2021

ABSTRACTEliciting antibodies to surface-exposed viral glycoproteins can lead to protective responses that ultimately control and prevent future infections. Targeting functionally conserved epitopes may help reduce the likelihood of viral escape and aid in preventing the spread of related viruses with pandemic potential. One such functionally conserved viral epitope is the site to which a receptor must bind to facilitate viral entry. Here, we leveraged rational immunogen design strategies to focus humoral responses to the receptor binding motif (RBM) on the SARS-CoV-2 spike. Using glycan engineering and epitope scaffolding, we find an improved targeting of the serum response to the RBM in context of SARS-CoV-2 spike imprinting. Furthermore, we observed a robust SARS-CoV-2-neutralizing serum response with increased potency against related sarbecoviruses, SARS-CoV, WIV1-CoV, RaTG13-CoV, and SHC014-CoV. Thus, RBM focusing is a promising strategy to elicit breadth across emerging sarbecoviruses and represents an adaptable design approach for targeting conserved epitopes on other viral glycoproteins.One Sentence SummarySARS-CoV-2 immune focusing with engineered immunogens
Insights into the genetic architecture of complex traits in Napier grass (Cenchrus purpureus) and QTL regions governing forage biomass yield, water use efficiency and feed quality traits
Authors: Muktar Meki S. , Habte Ermias , Teshome Abel , Assefa Yilikal , Negawo Alemayehu T. , Lee Ki-Won , Zhang Jiyu , Jones Chris S. 
Published: March 2021

AbstractNapier grass is the most important perennial tropical grass native to Sub-Saharan Africa and widely grown in tropical and subtropical regions around the world, primarily as a forage crop for animal feed, but with potential as an energy crop and in a wide range of other areas. Genomic resources have recently been developed for Napier grass that need to be deployed for genetic improvement and molecular dissection of important agro-morphological and feed quality traits. From a diverse set of Napier grass genotypes assembled from two independent collections, a subset of 84 genotypes that best represents the genetic diversity of the collections were selected and evaluated for two years in dry (DS) and wet (WS) seasons under three soil moisture conditions: moderate water stress in DS (DS-MWS); severe water stress in DS (DS-SWS) and, under rainfed (RF) conditions in WS (WS-RF). Data for agro-morphological and feed quality traits, adjusted for the spatial heterogeneity in the experimental blocks, were collected over a two-year period from 2018 to 2020. A total of 135,706 molecular markers were filtered, after removing markers with missing values > 10% and a minor allele frequency (MAF) < 5 %, from the high-density genome-wide markers generated previously using the genotyping by sequencing (GBS) method of the DArTseq platform. A genome-wide association study (GWAS), using two different mixed linear model algorithms, identified more than 58 QTL regions and markers associated with agronomic, morphological and water-use efficiency traits. QTL regions governing purple pigmentation and feed quality traits were also identified. The identified markers will be useful in the genetic improvement of Napier grass through the application of marker-assisted selection and for further characterization and map-based cloning of the QTLs.
MCMICRO: A scalable, modular image-processing pipeline for multiplexed tissue imaging
Authors: Schapiro Denis , Sokolov Artem , Yapp Clarence , Muhlich Jeremy L. , Hess Joshua , Lin Jia-Ren , Chen Yu-An , Nariya Maulik K. , Baker Gregory J. , Ruokonen Juha , Maliga Zoltan , Jacobson Connor A. , Farhi Samouil L. , Abbondanza Domenic , McKinley Eliot T. , Betts Courtney , Regev Aviv , Coffey Robert J. , Coussens Lisa M. , Santagata Sandro , Sorger Peter K. 
Published: March 2021

ABSTRACTHighly multiplexed tissue imaging makes molecular analysis of single cells possible in a preserved spatial context. However, reproducible analysis of the underlying data poses a substantial computational challenge. Here we describe a modular and open-source computational pipeline (MCMICRO) for performing the sequential steps needed to transform large, multi-channel whole slide images into single-cell data. We demonstrate use of MCMICRO on images of different tissues and tumors acquired using multiple imaging platforms, thereby providing a solid foundation for the continued development of tissue imaging software.
Killed whole genome-reduced bacteria surface-expressed coronavirus fusion peptide vaccines protect against disease in a porcine model
Authors: Maeda Denicar Lina Nascimento Fabris , Tian Debin , Yu Hanna , Dar Nakul , Rajasekaran Vignesh , Meng Sarah , Mahsoub Hassan , Sooryanarain Harini , Wang Bo , Heffron C. Lynn , Hassebroek Anna , LeRoith Tanya , Meng Xiang-Jin , Zeichner Steven L. 
Published: March 2021

AbstractAs the coronavirus disease 2019 (COVID-19) pandemic rages on, it is important to explore new evolution-resistant vaccine antigens and new vaccine platforms that can produce readily scalable, inexpensive vaccines with easier storage and transport. We report here a synthetic biology-based vaccine platform that employs an expression vector with an inducible Gram-negative autotransporter to express vaccine antigens on surface of genome-reduced bacteria to enhance interaction of vaccine antigen with immune system. As a proof of principle, we utilized genome-reducedE. colito express SARS-CoV-2 and porcine epidemic diarrhea virus (PEDV) fusion peptide (FP) on the cell surface, and evaluated their use as a killed whole cell vaccine. The FP sequence is highly conserved across coronaviruses; the 6 FP core amino acid residues along with the 4 adjacent residues upstream and the 3 residues downstream the core are identical between SARS-CoV-2 and PEDV. We tested the efficacy of PEDV FP and SARS-CoV-2 FP vaccines in a PEDV challenge pig model. We demonstrated that both vaccines induced potent anamnestic responses upon virus challenge, potentiated IFN-γ responses, reduced viral RNA loads in jejunum tissue, and provided significant protection against clinical disease. However, neither vaccines elicited sterilizing immunity. Since SARS-CoV-2 FP and PEDV FP vaccines provided similar clinical protection, the coronavirus FP could be a target for a broadly-protective vaccine using any platform. Importantly, the genome-reduced bacterial surface-expressed vaccine platform, when using a vaccine appropriate bacterial vector, has potential utility as an inexpensive, readily manufactured, and rapid vaccine platform for other pathogens.Significance StatementWe report a new vaccine platform to express vaccine antigens on surface of genome-reduced bacteria to enhance vaccine immunogenicity. We demonstrated the utility of this vaccine platform by expressing the highly conserved fusion peptide (FP) of SARS-CoV-2 and porcine epidemic diarrhea virus on the surface ofE.colito produce killed whole cell bacterial vaccines. The vaccine primes a potent anamnestic response, potentiates IFN-γ responses, and provides significant protection in pigs against disease following virus challenge. The FP could be a target for a broadly-protective coronavirus vaccine since a Betacoronavirus SARS-CoV-2 FP vaccine provided cross-protection against Alphacoronavirus PEDV. When using a vaccine appropriate bacteria vector, this inexpensive new vaccine platform offers the potential for use in developing countries.
BREAKTHROUGH REPORT - Large scale measurement of protein synthesis rates over the diurnal cycle reveal pathway specific regulation of translation
Authors: Duncan Owen , Millar A. Harvey 
Published: March 2021

AbstractPlants have a diurnal separation of metabolic fluxes and a need for differential maintenance of protein machinery in the day and night. To directly assess aggregate protein translation and degradation for specific proteins and to estimate the ATP investment involved, the individual rates of synthesis and degradation of hundreds of different proteins were measured inArabidopsis thalianarosettes. This quantification of translation control through incorporation of heavy hydrogen into newly synthesised protein confirmed that most protein synthesis occurs during the day hours (~3:1 day:night), but revealed it was highly divergent across functional categories. Proteins involved in photosynthesis, especially components of the light harvesting complexes, were synthesized much faster in the day (~10:1), while the protein components of carbon metabolism and vesicle trafficking were translated at similar rates day or night. Comparison of aggregate translation with a range of comparable studies using polysomal loading of transcripts or transcript abundance suggests that translational control is a major contributor to effective gene expression over the diurnal cycle. Diurnal protein degradation rate was observed to be tightly coordinated with protein synthesis rate as few leaf proteins changed in abundance despite reduced translation rates during the night. The direct, quantitative and aggregate analysis of protein synthesis provides an integration of transcriptional, post-transcriptional and translational control of leaf proteome homeostasis and an opportunity to assess the ATP investments involved. The data reveals how the pausing of photosystem synthesis and degradation at night allows the redirection of a decreased energy budget to a selective night-time maintenance schedule.One sentence summaryAdvances in collection and processing of stable isotope incorporation data has allowed characterisation of differential protein synthesis rates over the diurnal cycle which reveal both global and specific translational regulation programs of core biochemical pathways.
Dynamic accumulation of a helper NLR at the plant-pathogen interface underpins pathogen recognition
Authors: Duggan Cian , Moratto Eleonora , Savage Zachary , Hamilton Eranthika , Adachi Hiroaki , Wu Chih-Hang , Leary Alexandre Y , Tumtas Yasin , Rothery Stephen M , Maqbool Abbas , Nohut Seda , Kamoun Sophien , Bozkurt Tolga Osman 
Published: March 2021

AbstractPlants employ sensor-helper pairs of NLR immune receptors to recognize pathogen effectors and activate immune responses. Yet the subcellular localization of NLRs pre- and post-activation during pathogen infection remains poorly known. Here we show that NRC4, from the ‘NRC’ solanaceous helper NLR family, undergoes dynamic changes in subcellular localization by shuttling to and from the plant-pathogen haustorium interface established during infection by the Irish potato famine pathogenPhytophthora infestans.Specifically, prior to activation, NRC4 accumulates at the extra-haustorial membrane (EHM), presumably to mediate response to perihaustorial effectors, that are recognized by NRC4-dependent sensor NLRs. However not all NLRs accumulate at the EHM, as the closely related helper NRC2, and the distantly related ZAR1, did not accumulate at the EHM. NRC4 required an intact N-terminal coiled coil domain to accumulate at the EHM, whereas the functionally conserved MADA motif implicated in cell death activation and membrane insertion was dispensable for this process. Strikingly, a constitutively autoactive NRC4 mutant did not accumulate at the EHM and showed punctate distribution that mainly associated with the plasma membrane, suggesting that post-activation, NRC4 probably undergoes a conformation switch to form clusters that do not preferentially associate with the EHM. When NRC4 is activated by a sensor NLR during infection however, NRC4 formed puncta mainly at the EHM and to a lesser extent at the plasma membrane. We conclude that following activation at the EHM, NRC4 may spread to other cellular membranes from its primary site of activation to trigger immune responses.Significance statementPlant NLR immune receptors function as intracellular sensors of pathogen virulence factors known as effectors. In resting state, NLRs localize to subcellular sites where the effectors they sense operate. However, the extent to which NLRs alter their subcellular distribution during infection remains elusive. We describe dynamic changes in spatiotemporal localization of an NLR protein in infected plant cells. Specifically, the NLR protein accumulates at the newly synthesized plant-pathogen interface membrane, where the corresponding effectors are deployed. Following immune recognition, the activated receptor re-organizes to form punctate structures that target the cell periphery. We propose that NLRs are not necessarily stationary immune receptors, but instead may spread to other cellular membranes from the primary site of activation to boost immune responses.
Plasma proteome analyses in individuals of European and African ancestry identifycis-pQTLs and models for proteome-wide association studies
Authors: Zhang Jingning , Dutta Diptavo , Köttgen Anna , Tin Adrienne , Schlosser Pascal , Grams Morgan E. , Harvey Benjamin ,   CKDGen Consortium, Yu Bing , Boerwinkle Eric , Coresh Josef , Chatterjee Nilanjan 
Published: March 2021

AbstractImproved understanding of genetic regulation of proteome can facilitate the identification of causal mechanisms for complex traits. We analyzed data on 4,657 plasma proteins from 7,213 European American (EA) and 1,871 African American (AA) individuals from the ARIC study, and further replicated findings on 467 AA individuals from the AASK study. Here we identified 2,004 proteins in EA and 1,618 in AA, with majority overlapping, which showed associations with common variants incis-regions. Availability of AA samples led to smaller credible sets and significant number of population-specificcis-pQTLs. Elastic-net produced powerful models for protein prediction in both populations. An application of proteome-wide association studies (PWAS) to serum urate and gout, implicated several proteins, includingIL1RN,revealing the promise of the drug anakinra to treat acute gout flares. Our study demonstrates the value of large and diverse ancestry study for genetic mechanisms of molecular phenotypes and their relationship with complex traits.