bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting cancer glycosylation repolarizes tumor-associated macrophages allowing effective immune checkpoint blockade
Authors: Stanczak Michal A. , Mantuano Natalia Rodrigues , Kirchhammer Nicole , Sanin David E. , Wang Jinyu , Trefny Marcel P. , Monaco Gianni , Gray Melissa A. , Petrone Adam , Kashyap Abhishek S. , Glatz Katharina , Kasenda Benjamin , Normington Karl , Broderick James , Peng Li , Pearce Oliver M.T. , Pearce Erika L. , Bertozzi Carolyn R. , Zippelius Alfred , Läubli Heinz 
Published: April 2021

AbstractImmune checkpoint blockade (ICB) has significantly improved the prognosis of cancer patients, but the majority experience limited benefit, evidencing the need for new therapeutic approaches. Upregulation of sialic acid-containing glycans, termed hypersialylation, is a common feature of cancer-associated glycosylation, driving disease progression and immune escape via the engagement of Siglec-receptors on tumor-infiltrating immune cells. Here, we show that tumor sialylation correlates with distinct immune states and reduced survival in human cancers. The targeted removal of Siglec-ligands in the tumor microenvironment, using an antibody-sialidase conjugate, enhances anti-tumor immunity and halts tumor progression in several mouse tumor models. Using single-cell RNA sequencing, we reveal desialylation mechanistically to repolarize tumor-associated macrophages (TAMs) and identify Siglec-E on TAMs as the main receptor for hypersialylation. Finally, we show genetic and therapeutic desialylation, as well as loss of Siglec-E, to synergize with ICB. Thus, therapeutic desialylation represents a novel immunotherapeutic approach, shaping macrophage phenotypes and augmenting the adaptive anti-tumor immune response.
An evidence-based 3D reconstruction of Asteroxylon mackiei the most complex plant preserved from the Rhynie chert
Authors: Hetherington Alexander J. , Bridson Siobhán L. , Jones Anna Lee , Hass Hagen , Kerp Hans , Dolan Liam 
Published: April 2021

AbstractThe 407-million-year-old Rhynie chert preserves the earliest terrestrial ecosystem and informs our understanding of early life on land. However, our knowledge of the 3D structure, and development of these plants is still rudimentary. Here we used digital 3D reconstruction techniques to produce the first complete reconstruction of the lycopsid Asteroxylon mackiei, the most complex plant in the Rhynie chert. The reconstruction reveals the organisation of the three distinct axes types – leafy shoot axes, root-bearing axes and rooting axes – in the body plan. Combining this reconstruction with developmental data from fossilised meristems, we demonstrate that the A. mackiei rooting axis – a transitional lycophyte organ between the rootless ancestral state and true roots – developed from root-bearing axes by anisotomous dichotomy. Our discovery demonstrates how this unique organ developed, and highlights the value of evidence-based reconstructions for understanding the development and evolution of the first complex plants on Earth.
Analysis of Conformational Exchange Processes using Methyl-TROSY-Based Hahn Echo Measurements of Quadruple-Quantum Relaxation
Authors: Waudby Christopher A. , Christodoulou John 
Published: April 2021

AbstractTransverse nuclear spin relaxation can be a sensitive probe of chemical exchange on timescales on the order of microseconds to milliseconds. Here we present an experiment for the simultaneous measurement of the relaxation rates of two four-spin transitions in selectively protonated methyl groups within perdeuterated biomacromolecules, alongside control experiments for measurement of1H and13C chemical shift anisotropies. We show that analysis of the static magnetic field dependence of zero-, double- and quadruple-quantum Hahn echo relaxation rates provides a robust indication of chemical exchange and determines the signed relative magnitudes of proton and carbon chemical shift differences between ground and excited states. The analysis can be combined with CPMG relaxation dispersion measurements to provide improved precision, particularly in the determination of1H chemical shift differences.
Cell Surface Multimeric Assemblies Regulate Canonical and Noncanonical EphA2 Receptor Tyrosine Kinase Signaling
Authors: Shi Xiaojun , Lingerak Ryan , Herting Cameron J. , Ge Yifan , Kim Soyeon , Toth Paul , Cuizon Carmelle , Zheng Ji , Chao Luke , Sossey-Alaoui Khalid , Buck Matthias , Singh Salendra , Varadan Vinay , Himanen Juha , Hambardzumyan Dolores , Nikolov Dimitar , Smith Adam W. , Wang Bingcheng 
Published: April 2021

ABSTRACTThe EphA2 receptor tyrosine kinase mediates ligand-induced canonical signaling associated with tumor suppression and ligand-independent noncanonical signaling implicated in tumor progression. Using time-resolved fluorescence spectroscopy in live cells, we find that unliganded EphA2 receptors pre-assemble into multimers, which is mediated by two symmetric and one asymmetric interfaces in the ectodomain. Upon ligand binding, EphA2 receptors are further assemble into large clusters that also requires the three interfaces. Functionally, disrupting either the symmetric or asymmetric contacts individually blocks the autorecycling of the EphA2 apo receptor. However, only symmetric contact disruption promotes noncanonical signaling and inhibits ligand-induced catalytic activation and endocytosis, which are associated with increased cell migrationin vitroand reduced survival in a syngeneic murine glioblastoma model. Our results reveal the pivotal role of EphA2 assembly in dictating canonical vs. noncanonical signaling, and identify the precise molecular interfaces that mediate the formation of the EphA2 signaling clusters.
Genetic Basis for Lentil Adaptation to Summer Cropping in Northern Temperate Environments
Authors: Haile Teketel A. , Stonehouse Robert , Weller James L. , Bett Kirstin E. 
Published: April 2021

ABSTRACTThe continued success of lentil (Lens culinarisMedik.) genetic improvement relies on the availability of broad genetic diversity and new alleles need to be identified and incorporated into the cultivated gene pool. Availability of robust and predictive markers greatly enhances the precise transfer of genomic regions from unadapted germplasm. Quantitative trait loci (QTLs) for key phenological traits in lentil were located using a recombinant inbreed line (RIL) population derived from a cross between an Ethiopian landrace (ILL 1704) and a northern temperate cultivar (CDC Robin). Field experiments were conducted at Sutherland research farm in Saskatoon and at Rosthern, Saskatchewan, Canada during 2018 and 2019. A linkage map was constructed using 21,634 SNPs located on seven linkage groups (LGs) which correspond to the seven haploid chromosomes of lentil. Eight QTL were identified for six phenological traits. Flowering related QTL were identified at two regions on LG6.FLOWERING LOCUS T(FT) genes were annotated within the flowering time QTL interval based on the lentil reference genome. Similarly, a major QTL for post-flowering developmental processes was located on LG5 with several senescence-associated genes annotated within the QTL interval. The flowering time QTL was validated in a different genetic background indicating the potential use of the identified markers for marker-assisted selection to precisely transfer genomic regions from exotic germplasm into elite crop cultivars without disrupting adaptation.Core IdeasStable QTL were located for key phenological traits in lentil that lead to regional adaptation.FTgenes are candidates for controlling flowering time in lentil grown in temperate environments.A major locus controlling post-flowering developmental processes was located on lentil LG5 with several senescence-associated genes annotated within the QTL interval.Markers identified in this study can be useful for marker-assisted selection to precisely transfer genomic regions from exotic germplasm into elite lentil cultivars without disrupting adaptation.
Vacuole phase-partitioning boosts mitochondria activity and cell lifespan through an inter-organelle lipid pipeline
Authors: Seo AY , Sarkleti F , Budin I , Chang C , King C , Kohlwein S-D , Sengupta P , Lippincott-Schwartz J 
Published: April 2021

SUMMARYFunctional linkage between mitochondria and lysosomes is crucial for survival under starvation and lifespan extension. Despite such co-dependency, the supportive pathways connecting mitochondria and lysosomes remain unclear. Here, we identify an inter-organelle lipid trafficking pathway linking yeast vacuole and mitochondria that results in increased mitochondria growth and respiratory activity under glucose starvation. The pathway depends on vacuolar phase-separated, lipid domains, which provide zones for: activation of the vacuolar proton pump; lipid droplet (LD) docking and internalization; and, lipid transfer from vacuole-to-ER-to-mitochondria. Partitioned vacuolar domains form through a specialized type of macro-autophagy, triggered only under acute glucose starvation, that delivers sterol-rich, endosomal-derived lipids to the vacuole. To balance this lipid influx, the vacuole reroutes lipids back to the ER to support both LD biogenesis and mitochondria growth and activity. Energy produced by enhanced mitochondrial activity then feeds back to support the inter-organelle lipid trafficking pathways to ensure survival under nutrient stress.
Direct and indirect pathway neurons in ventrolateral striatum differentially regulate licking movement and nigral responses
Authors: Chen Zhaorong , Zhang Zhi-Yu , Zhang Wen , Xie Taorong , Li Yaping , Xu Xiao-Hong , Yao Haishan 
Published: April 2021

SUMMARYDrinking behavior in rodents is characterized by stereotyped, rhythmic licking movement, which is regulated by the basal ganglia. It is unclear how direct and indirect pathways control the lick bout and individual spout contact. We find that inactivating D1 and D2 receptors-expressing medium spiny neurons (MSNs) in the ventrolateral striatum (VLS) oppositely alters the number of licks in a bout. D1- and D2-MSNs exhibit different patterns of lick sequence-related activity and different phases of oscillation time-locked to the lick cycle. On timescale of a lick cycle, transient inactivation of D1-MSNs during tongue protrusion reduces spout contact probability, whereas transiently inactivating D2-MSNs has no effect. On timescale of a lick bout, inactivation of D1-MSNs (D2-MSNs) causes rate increase (decrease) in a subset of basal ganglia output neurons that decrease firing during licking. Our results reveal the distinct roles of D1- and D2-MSNs in regulating licking at both coarse and fine timescales.
Gauge your phage: Benchmarking of bacteriophage identification tools in metagenomic sequencing data
Authors: Ho Siu Fung Stanley , Wheeler Nicole , Millard Andrew D. , van Schaik Willem 
Published: April 2021

AbstractBackgroundThe prediction of bacteriophage sequences in metagenomic datasets has become a topic of considerable interest, leading to the development of many novel bioinformatic tools. A comparative analysis of ten state-of-the-art phage identification tools was performed to inform their usage in microbiome research.MethodsArtificial contigs generated from complete RefSeq genomes representing phages, plasmids, and chromosomes, and a previously sequenced mock community containing four phage species, were used to evaluate the precision, recall and F1-scores of the tools. We also generated a dataset of randomly shuffled sequences to quantify false positive calls. In addition, a set of previously simulated viromes was used to assess diversity bias in each tool’s output.ResultsVirSorter2 achieved the highest F1 score (0.92) in the RefSeq artificial contigs dataset, with several other tools also performing well. Kraken2 had the highest F1 score (0.86) in the mock community benchmark by a large margin (0.3 higher than DeepVirFinder in second place), mainly due to its high precision (0.96). Generally, k-mer based tools performed better than reference similarity tools and gene-based methods. Several tools, most notably PPR Meta, called a high number of false positives in the randomly shuffled sequences. When analysing the diversity of the genomes that each tool predicted from a virome set, most tools produced a viral genome set that had similar alpha and beta diversity patterns to the original population, with Seeker being a notable exception.ConclusionsThis study provides key metrics used to assess performance of phage detection tools, offers a framework for further comparison of additional viral discovery tools, and discusses optimal strategies for using these tools. We highlight that the choice of tool for identification of phages in metagenomic datasets, as well as their parameters, can bias the results and provide pointers for different use case scenarios. We have also made our benchmarking dataset available for download in order to facilitate future comparisons of phage identification tools.
Ahead of Maturation: Enhanced Speech Envelope Training Boosts Rise Time Discrimination in Pre-Readers at Cognitive Risk for Dyslexia
Authors: Van Herck Shauni , Bempt Femke Vanden , Economou Maria , Vanderauwera Jolijn , Glatz Toivo , Dieudonné Benjamin , Vandermosten Maaike , Ghesquière Pol , Wouters Jan 
Published: April 2021

AbstractDyslexia has frequently been related to atypical auditory temporal processing and speech perception. Results of studies emphasizing speech onset cues and reinforcing the temporal structure of the speech envelope, i.e. envelope enhancement, demonstrated reduced speech perception deficits in individuals with dyslexia. The use of this strategy as an auditory intervention might thus reduce some of the deficits related to dyslexia. Importantly, interventions are most effective when they are provided during kindergarten and first grade. Hence, we provided a tablet-based 12-week preventive auditory and phonics-based intervention to pre-readers at cognitive risk for dyslexia and investigated the effect on auditory temporal processing with a rise time discrimination task. Ninety-one pre-readers at cognitive risk for dyslexia (aged 5-6) were assigned to two groups receiving a phonics-based intervention and playing a story listening game either with (n= 31) or without (n= 31) envelope enhancement or a third group playing control games and listening to non-enhanced stories (n= 29). Rise time discrimination was measured directly before, directly after and one year after the intervention. While the groups listening to non-enhanced stories mainly improved after the intervention during first grade, the group listening to enhanced stories improved during the intervention in kindergarten and subsequently remained stable during first grade. Hence, an envelope enhancement intervention improves auditory processing skills important for the development of phonological skills. This occurred before the onset of reading instruction, preceding the maturational improvement of these skills, hence giving at risk children a head start when learning to read.Research highlightsThe first investigation of speech envelope enhancement as a potential preventive intervention strategy in pre-readers at cognitive risk for dyslexiaSpeech envelope enhancement increases the rise time sensitivity of children at cognitive risk for dyslexiaRise time discrimination can be enhanced before formal reading instruction, a crucial period in development
Human Fronto-Striatal Connectivity is Organized into Discrete Functional Subnetworks
Authors: Gordon Evan M. , Laumann Timothy O. , Marek Scott , Newbold Dillan J. , Hampton Jacqueline M. , Seider Nicole A. , Montez David F. , Nielsen Ashley M. , Van Andrew N. , Zheng Annie , Miller Ryland , Siegel Joshua S. , Kay Benjamin P. , Snyder Abraham Z. , Greene Deanna J. , Schlaggar Bradley L. , Petersen Steven E. , Nelson Steven M. , Dosenbach Nico U.F. 
Published: April 2021

AbstractThe striatum is interconnected with the cerebral cortex via multiple recurrent loops that play a major role in many neuropsychiatric conditions. Primate cortico-striatal connections can be precisely mapped using invasive tract-tracing. However, noninvasive human research has not mapped these connections with anatomical precision, limited by the practice of averaging neuroimaging data across individuals. Here we utilized highly-sampled resting-state functional connectivity MRI for individually-specific precision functional mapping of cortico-striatal connections. We identified ten discrete, individual-specific subnetworks linking cortex—predominately frontal cortex—to striatum. These subnetworks included previously unknown striatal connections to the human language network. The discrete subnetworks formed a stepped rostral-caudal gradient progressing from nucleus accumbens to posterior putamen; this organization was strongest for projections from medial frontal cortex. The stepped gradient organization fit patterns of fronto-striatal connections better than a smooth, continuous gradient. Thus, precision subnetworks identify detailed, individual-specific stepped gradients of cortico-striatal connectivity that include human-specific language networks.
Revealing the threat of emerging SARS-CoV-2 mutations to antibody therapies
Authors: Chen Jiahui , Gao Kaifu , Wang Rui , Wei Guo-Wei 
Published: April 2021

AbstractThe ongoing massive vaccination and the development of effective intervention offer the long-awaited hope to end the global rage of the COVID-19 pandemic. However, the rapidly growing SARS-CoV-2 variants might compromise existing vaccines and monoclonal antibody (mAb) therapies. Although there are valuable experimental studies about the potential threats from emerging variants, the results are limited to a handful of mutations and Eli Lilly and Regeneron mAbs. The potential threats from frequently occurring mutations on the SARS-CoV-2 spike (S) protein receptor-binding domain (RBD) to many mAbs in clinical trials are largely unknown. We fill the gap by developing a topology-based deep learning strategy that is validated with tens of thousands of experimental data points. We analyze 261,348 genome isolates from patients to identify 514 non-degenerate RBD mutations and investigate their impacts on 16 mAbs in clinical trials. Our findings, which are highly consistent with existing experimental results about variants from the UK, South Africa, Brazil, US-California, and Mexico shed light on potential threats of 95 high-frequency mutations to mAbs not only from Eli Lilly and Regeneron but also from Celltrion and Rockefeller University that are in clinical trials. We unveil, for the first time, that high-frequency mutations R346K/S, N439K, G446V, L455F, V483F/A, E484Q/V/A/G/D, F486L, F490L/V/S, Q493L, and S494P/L might compromise some of mAbs in clinical trials. Our study gives rise to a general perspective about how mutations will affect current vaccines.
Cryptocurrency bubble risk and the FOMC announcements during COVID-19 black swan event
Authors: Jarboui Anis , Mnif Emna 
Published: April 2021

Purpose
After the COVID-19 outbreak, the Federal Reserve has undertaken several monetary policies to alleviate the pandemic consequences on the markets. This paper aims to evaluate the effects of the Federal Reserve monetary policy on the cryptocurrency dynamics during the COVID19 pandemic.

Design/methodology/approach
We examine the response and feedback effects via an event study methodology. For this purpose, abnormal returns (AR) and cumulative abnormal returns (CARs) around the first FOMC (Federal Open Market Committee) announcement related to the COVID-19 pandemic for the top five cryptocurrencies are explored. We, further investigate the effect of the eight FOMC statement announcements during the COVID19 pandemic on these cryptocurrencies (Bitcoin, Ethereum, Tether, Litecoin, and Ripple). In the above-mentioned crypto-currency markets, we investigate the presence of bubbles by using the PSY test. We then examine the concordance of the dates of these bubbles with the dates of the FOMC announcements.

Findings
The empirical results show that the first FOMC event has a negative significant effect after 4 days of the announcement date for all studied cryptocurrencies except Tether. The results also indicate that cumulative abnormal returns are significant during the event windows of (−3,8), (−3,9), and (−3,10). Besides, we find that Bitcoin, Ethereum and, Litecoin lived short bubbles lasting for a few days. However, Ripple and Tether markets present no bubbles and no explosive periods.

Research limitations/implications
This paper presents trained proof that FOMC announcements have a positive effect on volatility's predictive capacity. This work therefore promotes the study of the data quality of volatility in future research as well.

Practical implications
The justified effect of the FOMC announcements on cryptocurrency as a speculative asset has practical implications for investors in building their trading strategies in anticipation of the next FOMC announcement. Therefore, this study implies that the FOMC announcements contain very relevant information for investors in the cryptocurrency market. This research may not only encourage a better understanding of the evolution of the expectations of policymakers, but also facilitate a better understanding of how these expectations are developed.

Originality/value
The COVID-19 pandemic has disturbed the stability of financial markets, inciting the Fed to take some monetary regulations. To the best of our knowledge, this study is the first one that analyses the response of five major cryptocurrencies to FOMC announcements during COVID 19 pandemic and associates these dates with bubble occurrences.
Safari tourism and its role in sustainable poverty eradication in East Africa: the case of Kenya
Authors: Maingi Shem Wambugu 
Published: April 2021

Purpose
Globally, poverty has been a persistent problem despite decades of unprecedented growth. The purpose of this paper is to deliberate on a sustainable livelihoods and poverty eradication approach in an African context.

Design/methodology/approach
The paper aims to bridge the gaps in poverty eradication strategies in East Africa by examining recent literature on livelihoods approaches and poverty eradication approaches.

Findings
Safari tourism is one way of connecting poor communities in Kenya to the tourism industry. The development of community conservancies in Kenya presents yet more opportunities for communities to be integrated with the sector. The Africanization of the tourism sector in Kenya is a priority, as communities embrace tourism and poverty eradication measures.

Practical implications
There is a need for the Safari tourism sector to integrate the local community’s indigenous knowledge systems, community social capital and the community’s natural capital with tourism product development and diversification.

Originality/value
The paper draws on applied research and technical analysis of the unique opportunities for enhancing sustainable poverty eradication through the tourism sector in East Africa and, more particularly, a Kenyan context.