bluuebunny/crossref_metadata_2025 huggingface dataset:
Biotic interactions are more important at species’ warm vs. cool range-edges: a synthesis
Authors: Paquette Alexandra , Hargreaves Anna L.
Published: April 2021

Predicting which ecological factors constrain species distributions is a fundamental question in ecology and critical to forecasting geographic responses to global change. Darwin hypothesized that abiotic factors generally impose species’ high-latitude and high-elevation (typically cool) range limits, whereas biotic interactions more often impose species’ low-latitude/low-elevation (typically warm) limits, but empirical support has been mixed. Here, we clarify three predictions arising from Darwin’s hypothesis, and show that previously mixed support is partially due to researchers testing different predictions. Using a comprehensive literature review (886 range limits), we find that biotic interactions, including competition, predation, and parasitism, influenced species’ warm limits more often than species’ cool limits. At cool limits, abiotic factors were consistently more important than biotic interactions, but temperature contributed strongly to cool and warm limits. Our results suggest that most range limits will be sensitive to climate warming, but warm limit responses will depend strongly on biotic interactions.

“When we travel southward and see a species decreasing in numbers, we may feel sure that the cause lies quite as much in other species being favored, as in this one being hurt. (Whereas)… the number of species, and therefore of competitors, deceases northwards; hence in going northward or in ascending a mountain, we far oftener meet with stunted forms, due to the directly injurious action of climate”–Darwin 1859
Unbalanced dietary patterns contribute to the pathogenesis of precocious puberty by affecting gut microbiota and host metabolites
Authors: Wang Ying , Wu Dingfeng , Li Hongying , Liang Xiangrong , Jiao Na , Gao Wenxing , Zhao Lu , Yu Han , Wang Qian , Ge Yongsheng , Zhao Changying , Huo Meiling , Cao Ruifang , Gao Sheng , Tao Liwen , Ling Yunchao , Zhao Lingna , Lv Xin , Liu Yi , Zhang Lehai , Zhou Haokui , Zhang Guoqing , Zhao Guoping , Zhang Lei , Zhu Ruixin , Gai Zhongtao
Published: April 2021

Precocious puberty (PP) mostly stems from endocrine disorders. However, its triggering factors, especially for the early onset of partial PP, and the associated pathogenic mechanisms remain ambiguous. In this study, a systematic analysis in the form of a questionnaire of lifestyles, gut microbiome, and serum metabolome data was carried out to examine the pathogenesis of PP in a cohort comprised of 200 girls, with or without PP. The analysis revealed substantial alterations in gut microbiota, serum metabolites, as well as lifestyle patterns in the PP group, which were characterized by an elevated abundance of β-glucuronidase-producing and butyrate-producing bacteria, and excessive lipid concentration with decreased levels of organic nitrogen compounds in the serum of the participants. These differential microbes and metabolites tend to be reliable non-invasive diagnostic biomarkers aiding the early diagnosis of PP and exhibit a strong discriminative power (AUC = 0.93 and AUC = 0.97, respectively). Furthermore, the microbial biomarkers were confirmed in an independent validation cohort (n = 83, AUC = 0.85). Moreover, structural equation modeling revealed that unhealthy dietary habits were the primary contributors for the alteration of gut microbiota and serum metabolites, triggering the imbalance in the host hormones that leads to premature physical development. Our study determines a causal relationship among the gut microbiota, host metabolites, diet, and clinical characteristics of preadolescent girls who experienced early onset of PP, and formulates non-invasive diagnostic tools demonstrating excellent performance for the early detection of PP.
Combinatorial interactions between viral proteins expand the functional landscape of the viral proteome
Authors: Wang Liping , Tan Huang , Medina-Puche Laura , Wu Mengshi , Gómez Borja Garnelo , Gao Man , Shi Chaonan , Jimenez-Góngora Tamara , Fan Pengfei , Ding Xue , Zhang Dan , Yi Ding , Rosas-Diaz Tábata , Liu Yujing , Aguilar Emmanuel , Fu Xing , Lozano-Durán Rosa
Published: April 2021

As intracellular parasites, viruses need to manipulate the molecular machinery of their host cells in order to enable their own replication and spread. This manipulation is based on the activity of virus-encoded proteins. The reduced size of viral genomes imposes restrictions in coding capacity; how the action of the limited number of viral proteins results in the massive cell reprogramming observed during the viral infection is a long-standing conundrum in virology. In this work, we explore the hypothesis that combinatorial interactions expand the multifunctionality of viral proteins, which may exert different activities individually and when in combination, physical or functional. We show that the proteins encoded by a plant-infecting DNA virus physically associate with one another in an intricate network. Our results further demonstrate that these interactions can modify the subcellular localization of the viral proteins involved, and that co-expressed interacting viral proteins can exert novel biological functionsin plantathat go beyond the sum of their individual functions. Based on this, we propose a model in which combinatorial physical and functional interactions between viral proteins enlarge the functional landscape of the viral proteome, which underscores the importance of studying the role of viral proteins in the context of the infection.
Immunoprofiling of HTLV-1-infected individuals shows altered innate cell responsiveness in HAM/TSP patients
Authors: Rocamonde Brenda , Futsch Nicolas , Orii Noemia , Allatif Omran , Penalva de Oliveira Augusto Cesar , Mahieux Renaud , Caseb Jorge , Dutartre Hélène
Published: April 2021

The Human T-cell Leukemia Virus-1 (HTLV-1)-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is a devastating neurodegenerative disease with no effective treatment, which affects an increasing number of people in Brazil. A biological blood factor allowing the prediction of the disease occurrence is so far not available. In this study, we analyzed innate immunity responses at steady state and after blood cell stimulation using an agonist of the toll-like receptor (TLR)7/8-signaling pathway in blood samples from HTLV-1-infected volunteers, including asymptomatic carriers and HAM/TSP patients. We observed a lower responsiveness in dendritic cells to produce IFNα. Moreover, we found higher production of IL-12 and Mip-1α by monocytes together with higher levels of IFNγ produced by Natural Killer cells. These deregulations could represent a signature for progression towards HAM/TSP.
Fast and adaptive protein structure representations for machine learning
Authors: Durairaj Janani , Akdel Mehmet , Ridder Dick de , Dijk Aalt DJ van
Published: April 2021

The growing prevalence and popularity of protein structure data, both experimental and computationally modelled, necessitates fast tools and algorithms to enable exploratory and interpretable structure-based machine learning. Alignment-free approaches have been developed for divergent proteins, but proteins sharing func-tional and structural similarity are often better understood via structural alignment, which has typically been too computationally expensive for larger datasets. Here, we introduce the concept of rotation-invariant shape-mers to multiple structure alignment, creating a structure aligner that scales well with the number of proteins and allows for aligning over a thousand structures in 20 minutes. We demonstrate how alignment-free shape-mer counts and aligned structural features, when used in machine learning tasks, can adapt to different levels of functional hierarchy in protein kinases, pinpointing residues and structural fragments that play a role in catalytic activity.
bayesynergy: flexible Bayesian modelling of synergistic interaction effects in in-vitro drug combination experiments
Authors: Rønneberg Leiv , Cremaschi Andrea , Hanes Robert , Enserink Jorrit M. , Zucknick Manuela
Published: April 2021

The effect of cancer therapies is often tested pre-clinically viain-vitroexperiments, where the post-treatment viability of the cancer cell population is measured through assays estimating the number of viable cells. In this way, large libraries of compounds can be tested, comparing the efficacy of each treatment. Drug interaction studies focus on the quantification of the additional effect encountered when two drugs are combined, as opposed to using the treatments separately. In thebayesynergyR package, we implement a probabilistic approach for the description of the drug combination experiment, where the observed dose response curve is modelled as a sum of the expected response under a zero-interaction model and an additional interaction effect (synergistic or antagonistic). The interaction is modelled in a flexible manner, using a Gaussian process formulation. Since the proposed approach is based on a statistical model, it allows the natural inclusion of replicates, handles missing data and uneven concentration grids, and provides uncertainty quantification around the results. The model is implemented in the Stan programming language providing a computationally efficient sampler, a fast approximation of the posterior through variational inference, and features parallel processing for working with large drug combination screens.
Suppression of aminoglycoside-induced premature termination codon readthrough by the TRP channel inhibitor AC1903
Authors: Baradaran-Heravi Alireza , Bauer Claudia C. , Pickles Isabelle B. , Hosseini-Farahabadi Sara , Balgi Aruna D. , Choi Kunho , Linley Deborah M. , Beech David J. , Roberge Michel , Bon Robin S.
Published: April 2021

Nonsense mutations, which occur in ~11% of patients with genetic disorders, introduce premature termination codons (PTCs) that lead to truncated proteins and promote nonsense-mediated mRNA decay. Aminoglycosides such as gentamicin and G418 permit PTC readthrough and so may address this problem. However, their effects are variable between patients, making clinical use of aminoglycosides challenging. In this study, we addressed the hypothesis that TRP non-selective cation channels contribute to the variable effect of aminoglycosides by controlling their cellular uptake. To attempt to identify the channel type involved, we tested AC1903, a 2-aminobenzimidazole derivative recently reported to selectively inhibit TRPC5 cation channels. AC1903 consistently suppressed G418 uptake and G418-induced PTC readthrough in the DMS-114 cell line and patient-derived JEB01 keratinocytes. In an effort to validate the suggested role of TRPC5, we tested an independent and more potent inhibitor called Pico145, which affects channels containing TRPC1, TRPC4 and TRPC5 but not other TRPCs or other channels. Unexpectedly, Pico145 was completely without effect, suggesting that AC1903 may work through other or additional targets. Consistent with this suggestion, AC1903 inhibited multiple TRPC channels including homomeric TRPC3, TRPC4, TRPC5, TRPC6 as well as concatemeric TRPC4–C1 and TRPC5–C1 channels, all with low micromolar IC50values. It also inhibited TRPV4 channels but had weak or no effects on TRPV1 and no effect on another non-selective cation channel, PIEZO1. Overall, our study reveals a suppressor of aminoglycoside-mediated PTC readthrough (i.e., AC1903) but suggests that this compound has previously unrecognised effects. These effects require further investigation to determine the molecular mechanism by which AC1903 suppresses aminoglycoside uptake and PTC readthrough.
Land-use history impacts spatial patterns and composition of woody plant species across a 35-hectare temperate forest plot
Authors: Orwig D.A. , Aylward J.A. , Buckley H.L. , Case B.S. , Ellison A.M.
Published: April 2021

Land-use history is the template upon which contemporary plant and tree populations establish and interact with one another and exerts a legacy on the structure and dynamics of species assemblages and ecosystems. We use the first census (2010–2014) of a 35-ha forest-dynamics plot at the Harvard Forest in central Massachusetts to explore such legacies. The plot includes 108,632 live stems ≥ 1 cm in diameter (2215 individuals/ha) and 7,595 dead stems ≥ 5 cm in diameter. Fifty-one woody plant species were recorded in the plot, but two tree species—Tsuga canadensis(eastern hemlock) andAcer rubrum(red maple)—and one shrub—Ilex verticillata(winterberry)—comprised 56% of all stems. Live tree basal area averaged 42.25 m2/ha, of which 84% was represented byT. canadensis(14.0 m2/ ha),Quercus rubra(northern red oak; 9.6 m2/ ha),A. rubrum(7.2 m2/ ha) andPinus strobus(eastern white pine; 4.4 m2/ ha). These same four species also comprised 78% of the live aboveground biomass, which averaged 245.2 Mg/ ha, and were significantly clumped at distances up to 50 m within the plot. Spatial distributions ofA. rubrumandQ. rubrashowed negative intraspecific correlations in diameters up to at least a 150-m spatial lag, likely indicative of competition for light in dense forest patches. Bivariate marked point-pattern analysis showed thatT. canadensisandQ. rubradiameters were negatively associated with one another, indicating resource competition for light. Distribution and abundance of the common overstory species are predicted best by soil type, tree neighborhood effects, and two aspects of land-use history: when fields were abandoned in the late 19thcentury and the succeeding forest types recorded in 1908. In contrast, a history of intensive logging prior to 1950 and a damaging hurricane in 1938 appear to have had little effect on the distribution and abundance of present-day tree species.
Flight-induced compass representation in the monarch butterfly heading network
Authors: Beetz M. Jerome , Kraus Christian , Franzke Myriam , Dreyer David , Strube-Bloss Martin F. , Rössler Wolfgang , Warrant Eric J. , Merlin Christine , el Jundi Basil
Published: April 2021

For navigation, animals use a robust internal compass. Compass navigation is especially crucial for long-distance migrating animals like monarch butterflies, which use a sun compass to navigate every fall over 4,000 km to their overwintering sites. The central complex, a brain region equipped with sun-compass neurons, is proposed to control the butterfly’s heading. Although the activity of central-complex neurons exhibits a locomotor-dependent modulation in many insects, the consequences of such modulations for the coding of heading remain unexplored. Here, we developed tetrode recordings from tethered flying monarch butterflies to reveal how flight modulates heading representation. We found that during flight, heading-direction neurons change their tuning, transforming the central-complex network to function as a global compass. This compass coding is characterized by the dominance of steering feedback and allows for robust heading representation even under unreliable visual scenarios, an ideal strategy for maintaining a migratory heading over enormous distances.
morse: an R-package in support of Environmental Risk Assessment
Authors: Baudrot Virgile , Charles Sandrine
Published: April 2021

Packagemorseis devoted to the analysis of experimental data collected from standard toxicity tests. It provides ready-to-use functions to visualize a data set and to estimate several toxicity indices to be further used in support of environmental risk assessment in full compliance with regulatory requirements. Such toxicity indices are indeed classical requested by standardized regulatory guidelines on which national agencies base their evaluation of applications for marketing authorisation of chemical active substances.

Packagemorsecan be used to get estimates ofLCx(x% Lethal Concentration) orECx(x% Effective Concentration) by fitting standard exposure-response models on toxicity test data. Risk indicator estimates as well as model parameters are provided along with the quantification of their uncertainty. Packagemorsecan also be used to get estimates of theNEC(No Effect Concentration) by fitting a Toxicokinetic-Toxicodynamic (TKTD) model (namelyGUTSmodels, that isGeneral Unified Threshold models of Survival). UsingGUTSmodels also allow to get estimates ofLC(x,t)(whateverxandt) andLP(x,t), this later being defined by EFSA as the x% multiplication factor leading to an additional reduction of x% in survival at the end of the exposure profile. Above all,GUTSmodels can be used on data collected under time-variable exposure profiles.

This paper illustrates a typical use ofmorsewith survival data collected over time and at different increasing exposure concentrations, analysed with the reduced version of GUTS models based on the stochastic death hypothesis (namely, theGUTS-RED-SDmodel). This example can be followed step-by-step to analyse any new data set, as long as the data set format is respected.
Investigating a trade-off between the quality of nest grown feathers and pace of development in an altricial bird
Authors: Taff Conor C. , Johnson Brianna A. , Anker Allison T. , Rodriguez Alyssa M. , Houtz Jennifer L. , Uehling Jennifer J. , Vitousek Maren N.
Published: April 2021

Life history theory provides a framework for understanding how trade-offs generate negative trait associations. Among nestling birds, developmental rate, risk of predation, and lifespan covary, but some associations are only found within species while others are only observed between species. A recent comparative study suggests that allocation trade-offs may be alleviated by disinvestment in ephemeral traits, such as nest-grown feathers, that are quickly replaced. However, direct resource allocation trade-offs cannot be inferred from inter-specific trait-associations without complementary intra-specific studies. Here, we asked whether there is evidence for a within-species allocation trade-off between feather quality and developmental speed in tree swallows (Tachycineta bicolor). Consistent with the idea that ephemeral traits are deprioritized, nest-grown feathers had lower barb density than adult feathers. However, despite substantial variation in fledging age among nestlings, there was no evidence for a negative association between developmental pace and feather quality. Furthermore, accounting for differences in resource availability by considering provisioning rate and a nest predation treatment did not reveal a trade-off that was masked by variation in resources. Our results are most consistent with the idea that the inter-specific association between development and feather quality arises from adaptive specialization, rather than from a direct allocation trade-off.
Sex dependent glial-specific changes in the chromatin accessibility landscape in late-onset Alzheimer’s disease brains
Authors: Barrera Julio , Song Lingyun , Safi Alexias , Yun Young , Garrett Melanie E. , Gamache Julia , Premasinghe Ivana , Sprague Daniel , Chipman Danielle , Li Jeffrey , Fradin Hélène , Soldano Karen , Gordân Raluca , Ashley-Koch Allison E. , Crawford Gregory E. , Chiba-Falek Ornit
Published: April 2021

In the post-GWAS era, there is an unmet need to decode the underpinning genetic etiologies of late-onset Alzheimer’s disease (LOAD) and translate the associations to causation. Toward that goal, we conducted ATAC-seq profiling using neuronal nuclear protein (NeuN) sorted-nuclei from 40 frozen brain tissues to determine LOAD-specific changes in chromatin accessibility landscape in a cell-type specific manner. We identified 211 LOAD-specific differential chromatin accessibility sites in neuronal-nuclei, four of which overlapped with LOAD-GWAS regions (±100kb of SNP). While the non-neuronal nuclei did not show LOAD-specific differences, stratification by sex identified 842 LOAD-specific chromatin accessibility sites in females. Seven of these sex-dependent sites in the non-neuronal samples overlapped LOAD-GWAS regions including APOE. LOAD loci were functionally validated using single-nuclei RNA-seq datasets. In conclusion, using brain sorted-nuclei enabled the identification of sex-dependent cell type-specific LOAD alterations in chromatin structure. These findings enhance the interpretation of LOAD-GWAS discoveries, provide potential pathomechanisms, and suggest novel LOAD-loci. Furthermore, our results convey mechanistic insights into sex differences in LOAD risk and clinicopathology.

GRAPHICAL ABSTRACT
IL-22BP production is heterogeneously distributed in Crohn’s disease
Authors: Fantou Aurélie , Lagrue Eric , Laurent Thomas , Delbos Laurence , Blandin Stéphanie , Jarry Anne , Beriou Gaëlle , Braudeau Cécile , Salabert Nina , Marin Eros , Moreau Aurélie , Podevin Juliette , Bourreille Arnaud , Josien Régis , Martin Jérôme C
Published: April 2021

Crohn’s disease (CD), a form of inflammatory bowel disease (IBD), is characterized by impaired epithelial barrier functions and dysregulated mucosal immune responses. IL-22 binding protein (IL-22BP) is a soluble inhibitor regulating IL-22 bioactivity, a cytokine proposed to play protective roles during CD. We and others have shown that IL-22BP is produced in IBD inflamed tissues, hence suggesting a role in CD. In this work, we extended the characterization of IL-22BP production and distribution in CD tissues by applying enzyme-linked immunosorbent assays to supernatants obtained from the culture of endoscopic biopsies of patients, and reverse transcription-quantitative polymerase chain reaction on sorted immune cell subsets. We reveal that IL-22BP levels are higher in inflamed ileums than colons. We observe that in a cell-intrinsic fashion, populations of mononuclear phagocytes and eosinophils express IL-22BP at the highest levels in comparison to other sources of T cells. We suggest the enrichment of intestinal eosinophils could explain higher IL-22BP levels in the ileum. In inflamed colon, we reveal the presence of increased IL-22/IL22BP ratios compared to controls, and a strong correlation between IL-22BP and CCL24. We identify monocyte-derived dendritic cells (moDC) as a cellular subtype co-expressing both cytokines and validate our finding usingin vitroculture systems. We also show that retinoic acid induces the secretion of both IL-22BP and CCL24 by moDC. Finally, we report on higher IL-22BP levels in active smokers. In conclusion, our work provides new information relevant to therapeutic strategies modulating IL-22 bioactivity in CD, especially in the context of disease location.
The hexose transporter SWEET5 confers galactose sensitivity to Arabidopsis pollen germination via the galactokinase GALK
Authors: Wang Jiang , Yu Ya-Chi , Li Ye , Chen Li-Qing
Published: April 2021

Galactose is an abundant and essential sugar used for the biosynthesis of many macromolecules in different organisms, including plants. Galactose metabolism is tightly and finely controlled since excess galactose and derivatives are inhibitory. In Arabidopsis, root growth and pollen germination were strongly inhibited by excess galactose. However, the mechanism of galactose induced inhibition during pollen germination remains obscure. In this study, we characterized a plasma-membrane localized transporter, AtSWEET5, that transports glucose and galactose. SWEET5 protein level started to accumulate at the tricellular stage of pollen development and peaked in mature pollen before rapidly declining after pollen was germinated. SWEET5 levels are responsible for the dosage-dependent sensitivity of galactose and galactokinase (GALK) is essential for the inhibitory effects of galactose during pollen germination. Overall, SWEET5 and GALK contribute to the maintenance of galactose metabolic homeostasis during pollen germination. SWEET5 serves as a major low-affinity hexose transporter at the early stage of pollen germination.

One-sentence summary

SWEET5 mediates pollen galactose sensitivity via GALK that is required for efficient galactose uptake in pollen during pollen germination.
Detecting seabird responses to invasive species eradication
Authors: Bird Jeremy P. , Fuller Richard A. , Terauds Aleks , McInnes Julie C. , Pascoe Penelope P. , Travers Toby D. , Alderman Rachael , Shaw Justine D.
Published: April 2021

Maximising survey efficiency can help reduce the trade-off between spending limited conservation resources on evaluating performance of past interventions and directing those resources towards future interventions. Seabird responses to island eradications are often poorly evaluated owing to financial, logistical and methodological challenges associated with remote field work and species ecology. We surveyed an assemblage of threatened seabirds following the world’s largest island eradication of multiple invasive species, testing multiple survey designs and outputs. We compared the outcomes of two important choices made during survey design: 1) whether to use unbiased or targeted surveys; and 2) implementing design-based or model-based analyses. An unbiased whole-island stratified randomised survey design performed well in terms of confidence in the final population estimates for widespread species, but poorly for localised recolonising species. For widespread species, model-based analyses resulted in slightly lower population estimates with narrower confidence intervals than traditional design-based approaches but failed to capture the realised niches of recolonising species, resulting in population estimates three orders of magnitude higher than current best estimates. We conclude that a multi-method approach to survey design best captures the size and distribution of recovering populations when the study system is ecologically diverse—importantly our results suggest there is no single strategy for efficient surveys of diverse seabird communities following large island invasive species eradications.
Rapid, but limited, zooplankton adaptation to simultaneous warming and acidification
Authors: Dam Hans G. , deMayo James A. , Park Gihong , Norton Lydia , He Xuejia , Finiguerra Michael B. , Baumann Hannes , Brennan Reid S. , Pespeni Melissa H.
Published: April 2021

Predicting the response of marine metazoans to climate change is hampered by a lack of studies on evolutionary adaptation, particularly to combined ocean warming and acidification (OWA). We provide evidence for rapid adaptation to OWA in the foundational copepod species,Acartia tonsa, by assessing changes in population fitness based on a comprehensive suite of life-history traits, using an orthogonal experimental design of nominal temperature (18°C, 22°C) andpCO2(400, 2000 μatm) for 25 generations (~1 year). Egg production and hatching success initially decreased under OWA, resulting in a 56% reduction in fitness. However, both traits recovered by the third generation and average fitness was reduced thereafter by only 9%. Antagonistic interactions between warming and acidification in later generations decreased survival, thereby limiting full fitness recovery. Our results suggest such interactions constrain evolutionary rescue and add complexity to predictions of the responses of metazoan populations to climate change.
ATP dependent polymerization dynamics of bacterial actin proteins involved inSpiroplasmaswimming
Authors: Takahashi Daichi , Fujiwara Ikuko , Sasajima Yuya , Narita Akihiro , Imada Katsumi , Miyata Makoto
Published: April 2021

MreB is a bacterial protein belonging to the actin superfamily. It polymerises into an antiparallel double-stranded filament that generally functions in cell shape determination by maintaining cell wall synthesis.Spiroplasma eriocheiris, a helical wall-less bacterium, has five classes of MreB homologs (SpeMreB1-5) that are likely to be involved in swimming motility. Here, we investigated the structure, ATPase activity, and polymerisation dynamics of SpeMreB3 and SpeMreB5. SpeMreB3 polymerised into an antiparallel double-stranded filament, and SpeMreB5 formed sheets, including the antiparallel filament, upon the binding of a nucleotide. SpeMreB3 showed slow Pirelease owing to the lack of an amino acid motif conserved in the catalytic centre of MreB family proteins. Our crystal structures of SpeMreB3 and analyses of the mutant variants showed that the amino acid motif most likely plays a role in eliminating the proton of the nucleophilic water for ATP hydrolysis. Our sedimentation assay suggests that SpeMreB3 has a lower polymerisation activity than SpeMreB5, while their polymerisation dynamics are qualitatively similar to those of other actin superfamily proteins, in which ATP hydrolysis stabilises the filament, and Pirelease leads to depolymerisation.
RAMPs regulate signalling bias and internalisation of the GIPR
Authors: Harris Matthew , Mackie Duncan I. , Pawlak John B. , Carvalho Sabrina , Truong Tin T. , Safitri Dewi , Yeung Ho Yan , Routledge Sarah , Harper Matthew T. , Al-Zaid Bashaier , Soave Mark , Al-Sabah Suleiman , Inoue Asuka , Poyner David R. , Hill Stephen J. , Briddon Stephen J. , Sexton Patrick M. , Wootten Denise , Zhao Peishen , Caron Kathleen M. , Ladds Graham
Published: April 2021

Gastric inhibitory polypeptide (GIP) receptor is a class B1 GPCR, that responds to GIP and physiologically potentiates glucose-stimulated insulin secretion. Like most class B1 GPCRs, GIPR has been shown to interact with RAMPs, yet the effects of RAMPs on its signalling and trafficking remain poorly understood. We demonstrate that RAMPs modulate G protein activation and GIPR internalisation profiles. RAMP3 reduced GIPR Gsactivation and cAMP production but retained GIPR at the cell surface, and this was associated with prolonged ERK1/2 phosphorylation and β-arrestin association. By contrast, RAMP1/2 reduced Gq/11/15activation of the GIPR. Through knockout mice studies, we show that RAMP1 is important to the normal physiological functioning of GIPR to regulate blood glucose levels. Thus, RAMPs act on G protein/β-arrestin complexes, having both acute and chronic effects on GIPR function, while this study also raises the possibility of a more general role of RAMP3 to enhance GPCR plasma membrane localisation.
The Polar Night Shift: Annual Dynamics and Drivers of Microbial Community Structure in the Arctic Ocean
Authors: Wietz Matthias , Bienhold Christina , Metfies Katja , Torres-Valdés Sinhué , von Appen Wilken-Jon , Salter Ian , Boetius Antje
Published: April 2021

Change is a constant in the Arctic Ocean, with extreme seasonal differences in daylight, ice cover and temperature. The biodiversity and ecology of marine microbes across these extremes remain poorly understood. Here, using an array of autonomous samplers and sensors, we portray an annual cycle of microbial biodiversity, nutrient budgets and oceanography in the major biomes of the Fram Strait. In the ice-free West Spitsbergen Current, community turnover followed the solar cycle, with distinct separation of a productive summer state dominated by diatoms and carbohydrate-degrading bacteria, and a regenerative winter state dominated by heterotrophic Syndiniales, radiolarians, chemoautotrophic bacteria and archaea. Winter mixing of the water column replenishing nitrate, phosphate and silicate, and the onset of light were the major turning points. The summer succession ofPhaeocystis, GrammonemaandThalassiosiracoincided with ephemeral peaks ofFormosa, Polaribacterand NS clades, indicating metabolic relationships between phytoplankton and bacteria. In the East Greenland Current, ice cover and greater sampling depth coincided with weaker seasonality, featuring weaker bloom/decay events and an ice-related winter microbiome. Low ice cover and advection of Atlantic Water coincided with diminished abundances of chemoautotrophic bacteria whilePhaeocystisandFlavobacteriaceaeincreased, suggesting that Atlantification alters phytoplankton diversity and the biological carbon pump. Our findings promote the understanding of microbial seasonality in Arctic waters, illustrating the ecological importance of the polar night and providing an essential baseline of microbial dynamics in a region severely affected by climate change.
A Comparison of Persistence of SARS-CoV-2 Variants on Stainless Steel
Authors: Pottage Thomas , Garratt Isobel , Onianwa Okechukwu , Spencer Antony , Paton Susan , Dunning Jake , Bennett Allan
Published: April 2021

The survival of newer variants of SARS-CoV-2 on a representative surface has been compared to the established UK circulating isolate to determine whether enhanced environmental stability could play a part in their increased transmissibility. Stainless-steel coupons were inoculated with liquid cultures of the three variants, with coupons recovered over seven days and processed for recoverable viable virus using plaque assay. After drying, there was no significant difference in inactivation rates between variants. Indicating there is no increased environmental persistence from the new variants.
Polymersomes decorated with SARS-CoV-2 spike protein receptor binding domain elicit robust humoral and cellular immunity
Authors: Volpatti Lisa R. , Wallace Rachel P. , Cao Shijie , Raczy Michal M. , Wang Ruyi , Gray Laura T. , Alpar Aaron T. , Briquez Priscilla S. , Mitrousis Nikolaos , Marchell Tiffany M. , Sasso Maria Stella , Nguyen Mindy , Mansurov Aslan , Budina Erica , Solanki Ani , Watkins Elyse A. , Schnorenberg Mathew R. , Tremain Andrew C. , Reda Joseph W. , Nicolaescu Vlad , Furlong Kevin , Dvorkin Steve , Yu Shann S. , Manicassamy Balaji , LaBelle James L. , Tirrell Matthew V. , Randall Glenn , Kwissa Marcin , Swartz Melody A. , Hubbell Jeffrey A.
Published: April 2021

A diverse portfolio of SARS-CoV-2 vaccine candidates is needed to combat the evolving COVID-19 pandemic. Here, we developed a subunit nanovaccine by conjugating SARS-CoV-2 Spike protein receptor binding domain (RBD) to the surface of oxidation-sensitive polymersomes. We evaluated the humoral and cellular responses of mice immunized with these surface-decorated polymersomes (RBDsurf) compared to RBD-encapsulated polymersomes (RBDencap) and unformulated RBD (RBDfree), using monophosphoryl lipid A-encapsulated polymersomes (MPLA PS) as an adjuvant. While all three groups produced high titers of RBD-specific IgG, only RBDsurf elicited a neutralizing antibody response to SARS-CoV-2 comparable to that of human convalescent plasma. Moreover, RBDsurf was the only group to significantly increase the proportion of RBD-specific germinal center B cells in the vaccination-site draining lymph nodes. Both RBDsurf and RBDencap drove similarly robust CD4+ and CD8+ T cell responses that produced multiple Th1-type cytokines. We conclude that multivalent surface display of Spike RBD on polymersomes promotes a potent neutralizing antibody response to SARS-CoV-2, while both antigen formulations promote robust T cell immunity.
The impact of incongruence and exogenous gene fragments on estimates of the eukaryote root
Authors: Al Jewari Caesar , Baldauf Sandra L.
Published: April 2021

Phylogenomics uses multiple genetic loci to reconstruct evolutionary trees, under the stipulation that all combined loci share a common phylogenetic history,i.e., they are congruent. Congruence is primarily evaluated via single-gene trees, but these trees invariably lack sufficient signal to resolve deep nodes making it difficult to assess congruence at these levels. Two methods were developed to systematically assess congruence in multi-locus data. Protocol 1 uses gene jackknifing to measure deviation from a central mean to identify taxon-specific incongruencies in the form of persistent outliers. Protocol_2 assesses congruence at the sub-gene level using a sliding window. Both protocols were tested on a controversial data set of 76 mitochondrial proteins previously used in various combinations to assess the eukaryote root. Protocol_1 showed a concentration of outliers in under-sampled taxa, including the pivotal taxon Discoba. Further analysis of Discoba using Protocol_2 detected a surprising number of apparently exogenous gene fragments, some of which overlap with Protocol_1 outliers and others that do not. Phylogenetic analyses of the full data using the static LG-gamma evolutionary model support a neozoan-excavate root for eukaryotes (Discoba sister), which rises to 99-100% bootstrap support with data masked according to either Protocol_1 or Protocol_2. In contrast, site-heterogeneous (mixture) models perform inconsistently with these data, yielding all three possible roots depending on presence/absence/type of masking and/or extent of missing data. The neozoan-excavate root places Amorphea (including animals and fungi) and Diaphoretickes (including plants) as more closely related to each other than either is to Discoba (Jakobida, Heterolobosea, and Euglenozoa), regardless of the presence/absence of additional taxa.
The impact of viral mutations on recognition by SARS-CoV-2 specific T-cells
Authors: de Silva Thushan I. , Liu Guihai , B Lindsey Benjamin , Dong Danning , Shah Dhruv , J. Mentzer Alexander , Angyal Adrienn , Brown Rebecca , D. Parker Matthew , Ying Zixi , Yao Xuan , Turtle Lance , Dunachie Susanna ,   COVID-19 Genomics UK (COG-UK) Consortium, K. Maini Mala , Ogg Graham , Knight Julian C. , Peng Yanchun , Rowland-Jones Sarah L. , Dong Tao
Published: April 2021

We identify amino acid variants within dominant SARS-CoV-2 T-cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T-cells assessed by IFN-γ and cytotoxic killing assays. These data demonstrate the potential for T-cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T-cell as well as humoral immunity.
The causal role of transcranial alternating current stimulation at alpha frequency in boosting visual perceptual learning
Authors: He Qing , Yang Xin-Yue , Gong Baoqi , Bi Keyan , Fang Fang
Published: April 2021

Extensive training improves our ability to perceive visual contents around us, a phenomenon known as visual perceptual learning (VPL). Numerous studies have been conducted to understand the mechanisms of VPL, while the neural oscillatory mechanisms underpinning VPL has yet to be elucidated. To this end, we adopted transcranial alternating current stimulation (tACS), a neuromodulatory technique that can alter ongoing brain rhythms in a frequency-specific manner by applying external weak electric fields, to stimulate targeted cortical areas in human subjects while they performed an orientation discrimination learning task. Five groups of subjects undertook five daily training sessions to execute the task. Four groups received occipital tACS stimulation at 10 Hz (alpha band), 20 Hz (beta band), 40 Hz (gamma band), or sham 10 Hz (sham), and one group was stimulated at the sensorimotor regions by 10 Hz tACS. Compared with the sham stimulation, occipital tACS at 10 Hz, but not at 20 Hz or 40 Hz, increased both the learning rate and performance improvement. However, when 10 Hz tACS was delivered to the sensorimotor areas, the modulatory effects of tACS were absent, suggesting that tACS modulated the orientation discrimination learning in a frequency- and location-specific manner. Moreover, the tACS-induced enhancement lasted at least two months after the termination of training. Our findings provide strong evidence for the causal role of alpha oscillations in VPL and shed new light on the design of effective neuromodulation protocols that might facilitate rehabilitation for patients with neuro-ophthalmological disorders.

Significance Statement

Performance of visual tasks can be enhanced substantially by training, which is known as visual perceptual learning (VPL). However, little is known about the neural oscillatory mechanisms underlying VPL. To probe the causal link between a given oscillatory frequency band and VPL, transcranial alternating current stimulation (tACS) was applied while subjects performed an orientation discrimination learning task. Our results revealed that tACS modulates VPL in a frequency- and location-specific manner. Specifically, only training coupled with 10 Hz tACS over the occipital cortex speeded up the learning process and amplified the performance gain. Our findings demonstrate the causal role of alpha oscillations in VPL, and provide insight into developing more effective and efficient remediation protocols for clinical applications, e.g., amblyopia.
Functionalizing cell-free systems with CRISPR-associated proteins: Application to RNA-based circuit engineering
Authors: Lehr François-Xavier , Kuzembayeva Alina , Bailey Megan E. , Kleindienst Werner , Kabisch Johannes , Koeppl Heinz
Published: April 2021

Cell-free systems have become a compelling choice for the prototyping of synthetic circuits. Many robust protocols for preparing cell-free systems are now available along with toolboxes designed for a variety of applications. Thus far the production of cell-free extracts has often been decoupled from the production of functionalized proteins. Here, we leveraged the most recently published protocol for E. coli-based cell extracts with the endogenous production of two CRISPR-associated proteins, Csy4 and dCas9. We found pre-expression did not affect the resulting extract performance, and the final concentrations of the endonucleases matched the level required for synthetic circuit prototyping. We demonstrated the benefits and versatility of dCas9 and Csy4 through the use of RNA circuitry based on a combination of single guide RNAs, small transcriptional activator RNAs and toehold switches. For instance, we show that Csy4 processing increased fourfold the dynamic range of a previously published AND-logic gate. Additionally, blending the CRISPR-enhanced extracts enabled us to reduce leakage in a multiple inputs gate, and to extend the type of Boolean functions available for RNA-based circuits, such as NAND-logic. Finally, the use of dual transcriptional and translational reporters for the engineering of RNA-based circuits, allowed us to gain better insight into their underlying mechanisms. We hope this work will facilitate the adoption of advanced processing tools for RNA-based circuit prototyping in a cell-free environment.
Transient demographic approaches can drastically expand the toolbox of coral reef science
Authors: Cant James , Salguero-Gómez Roberto , Beger Maria
Published: April 2021

Coral communities are threatened by an increasing plethora of abiotic and biotic disturbances. Preventing the ensuing loss of coral coverage and diversity calls for a mechanistic understanding of resilience across coral species and populations that is currently lacking in coral reef science. Assessments into the dynamics of coral populations typically focus on their long-term (i.e. asymptotic) characteristics, tacitly assuming stable environments in which populations can attain their long-term characteristics. Instead, we argue that greater focus is needed on investigating thetransient(i.e.short-term) dynamics of coral populations to describe and predict their characteristics and trajectories within unstable environments. Applying transient demographic approaches to the evaluation and forecasting of the responses of coral populations to disturbance holds promise for expediting our capacity to predict and manage the resilience of coral populations, species, and communities.
Inhibition of LipopolysaccharideE. coli-induced acute lung injury by extractedAntidesma bunius(L.) Spreng fruits as compared to Fluticasone Propionate, a corticosteroid
Authors: Muñoz Maria Nilda M. , Lucero Jennifer , Benzon Kimberly Stacy Hope , Reyes Jerica Isabel L. , de Silva Charina , Delicana Reuel C. , Tejada Urdujah A. , Chatterjee Swapan , Watanabe Kozo
Published: April 2021

The hallmark of Acute Lung Injury/Acute Respiratory Distress Syndrome (ALI/ARDS) is inflammation-induced alveolar-vascular barrier destruction and neutrophilic infiltration that leads to the formation of cytokines and oxygen radicals. The objective of the study is to investigate the protective and toxicological effects ofAntidesma bunius(L.) Spreng [Bignay] in murine model of LipopolysaccharideE. coli(LPS)-induced ALI and compared with Fluticasone Propionate (FP), a synthetic corticosteroid. We showed that extracted Bignay fruits have high amount of phenols, steroids and flavonoids but insignificant amount of heavy metals and aflatoxins. BALB/c mice of either sex were divided into 4 groups in the ALI mouse model; Group 1: vehicle control; Group 2: LPS alone; Group 3: Bignay + LPS; and Group 4: FP + LPS. Bignay and FP were administered via intraperitoneal injection while LPS was given intra-tracheally. Biomarkers of ALI such as total lung inflammatory cell count, total lung protein content, lung edema and interleukin-6 (IL-6) secretion were measured 24 hrs after vehicle control or LPS treatment. Compared to vehicle controls, LPS caused significant increased in all measured biomarkers of ALI in samples collected from bronchoalveolar lavage fluid and were significantly attenuated by Bignay fruit extract or FP. Pulmonary vascular leakage caused by LPS was also evaluated after injection with Evans blue dye, an indication of lung injury. Extracted Bignay fruits or FP when given to mice 2 hrs after LPS administration substantially decreased the pulmonary vascular leak. Our findings are the first evidence demonstrating the preventive and non-toxic effects of extracted Bignay fruits in a murine model of LPS-induced ALI. The results could be attributed to the presence of active secondary metabolites such as flavonoids, phenols and steroids. It is also evident that extracted Bignay fruits are as effective as FP, well-established steroid, in blocking the biomarkers of ALI caused by LPS.
Genome-wide survey of the F-box/Kelch (FBK) members and molecular identification of a novel FBK geneTaAFRin wheat
Authors: Wei Chunru , Zhao Weiquan , Fan Runqiao , Meng Yuyu , Yang Yiming , Wang Xiaodong , Foroud Nora A. , Liu Daqun , Yu Xiumei
Published: April 2021

F-box proteins play critical roles in plant responses to biotic/abiotic stresses. In the present study, a total of 68 wheat F-box/Kelch (TaFBK) gene sequences encoding for 74 proteins were obtained in a genome-wide survey against EnsemblPlants. The 74 TaFBK proteins were divided into 5 categories based on their domain structures. The FBK proteins from wheat, Arabidopsis, and three other cereal species were grouped into 7 clades, and the number of Kelch domains present was their key clustering criterion. Sixty-eightTaFBKgenes were unevenly distributed on 21 chromosomes. Most of TaFBKs were predicted to localize in the nucleus and cytoplasm.In silicoanalysis of a digital PCR revealed thatTaFBKswere expressed at multiple developmental stages and tissues, and in response to drought and/or heat stresses. TheTaFBK19gene, a homologous to theAttenuated Far-Red Response(AFR) genes in other plant species, and hence namedTaAFR, was selected for further analysis. The gene was isolated from the wheat line TcLr15 and its expression evaluated by quantitative real-time PCR.TaAFRtranscripts were primarily detected in wheat leaves, and its expression was found to be regulated by various abiotic and biotic stresses as well as plant signaling hormones. Of particular interest,TaAFRexpression was differentially regulated in the compatiblevsincompatible wheat leaf rust reaction. Subcellular localization studies showed that TaAFR accumulates in the nucleus and cytoplasm. Three TaAFR-interacting proteins were identified experimentally: Skp1/ASK1-like protein (Skp1), ADP-ribosylation factor 2-like isoform X1 (ARL2) and phenylalanine ammonia-lyase (PAL). Further analysis revealed that the Skp1 protein interacted specifically with the F-box domain of TaAFR, while ARL2 and PAL were recognized by the Kelch domain. The data presented herein provides a solid foundation from which the function and metabolic network of TaAFR and other wheat FBKs can be further explored.