bluuebunny/crossref_metadata_2025 huggingface dataset:
A Comprehensive Phylogenomic Platform for Exploring the Angiosperm Tree of Life
Authors: Baker William J. , Bailey Paul , Barber Vanessa , Barker Abigail , Bellot Sidonie , Bishop David , Botigué Laura R. , Brewer Grace , Carruthers Tom , Clarkson James J. , Cook Jeffrey , Cowan Robyn S. , Dodsworth Steven , Epitawalage Niroshini , Françoso Elaine , Gallego Berta , Johnson Matthew G. , Kim Jan T. , Leempoel Kevin , Maurin Olivier , McGinnie Catherine , Pokorny Lisa , Roy Shyamali , Stone Malcolm , Toledo Eduardo , Wickett Norman J. , Zuntini Alexandre R. , Eiserhardt Wolf L. , Kersey Paul J. , Leitch Ilia J. , Forest Félix
Published: February 2021

The tree of life is the fundamental biological roadmap for navigating the evolution and properties of life on Earth, and yet remains largely unknown. Even angiosperms (flowering plants) are fraught with data gaps, despite their critical role in sustaining terrestrial life. Today, high-throughput sequencing promises to significantly deepen our understanding of evolutionary relationships. Here, we describe a comprehensive phylogenomic platform for exploring the angiosperm tree of life, comprising a set of open tools and data based on the 353 nuclear genes targeted by the universal Angiosperms353 sequence capture probes. This paper (i) documents our methods, (ii) describes our first data release and (iii) presents a novel open data portal, the Kew Tree of Life Explorer (https://treeoflife.kew.org). We aim to generate novel target sequence capture data for all genera of flowering plants, exploiting natural history collections such as herbarium specimens, and augment it with mined public data. Our first data release, described here, is the most extensive nuclear phylogenomic dataset for angiosperms to date, comprising 3,099 samples validated by DNA barcode and phylogenetic tests, representing all 64 orders, 404 families (96%) and 2,333 genera (17%). Using the multi-species coalescent, we inferred a “first pass” angiosperm tree of life from the data, which totalled 824,878 sequences, 489,086,049 base pairs, and 532,260 alignment columns. The tree is strongly supported and highly congruent with existing taxonomy, while challenging numerous hypothesized relationships among orders and placing many genera for the first time. The validated dataset, species tree and all intermediates are openly accessible via the Kew Tree of Life Explorer. This major milestone towards a complete tree of life for all flowering plant species opens doors to a highly integrated future for angiosperm phylogenomics through the systematic sequencing of standardised nuclear markers. Our approach has the potential to serve as a much-needed bridge between the growing movement to sequence the genomes of all life on Earth and the vast phylogenomic potential of the world’s natural history collections.
Conserved cell-lineage controlled epigenetic regulation in human and mouse glioblastoma stem cells determines functionally distinct subgroups
Authors: Lu Xi , Maturi Naga Prathyusha , Jarvius Malin , Zhao Linxuan , Xie Yuan , Tan E-Jean , Xing Pengwei , Fryknäs Mårten , Uhrbom Lene , Chen Xingqi
Published: February 2021

There is ample support for developmental regulation of glioblastoma stem cells (GSCs). To examine how cell lineage controls GSC function we have performed a cross-species epigenome analysis of mouse and human GSC cultures. We have analyzed and compared the chromatin-accessibility landscape of nine mouse GSC cultures of defined cell of origin and 60 patient-derived GSC cultures by assay for transposase-accessible chromatin using sequencing (ATAC-seq). This uncovered a variability of both mouse and human GSC cultures that was different from transcriptome analysis and better at predicting functional subgroups. In both species the chromatin accessibility-guided clusters were predominantly determined by distal regulatory element (DRE) regions, displayed contrasting sets of transcription factor binding motifs, and exhibited different functional and drug-response properties. Cross-species analysis of DRE regions in accessible chromatin revealed conserved epigenetic regulation of mouse and human GSCs. Human ATAC-seq data produced three distinct clusters with significant overlap to our previous mouse cell of origin- based stratification, where two of the clusters displayed significantly different patient survival. We conclude that epigenetic regulation of GSCs primarily is dictated by developmental origin which controls key GSC properties and affects therapeutic response.
Previously uncharacterized interactions between the folded and intrinsically disordered domains impart asymmetric effects on UBQLN2 phase separation
Authors: Zheng Tongyin , Castañeda Carlos A.
Published: February 2021

Shuttle protein UBQLN2 functions in protein quality control (PQC) by binding to proteasomal receptors and ubiquitinated substrates via its N-terminal ubiquitin-like (UBL) and C-terminal ubiquitin-associated (UBA) domains, respectively. Between these two folded domains are intrinsically disordered STI1-I and STI1-II regions, connected by disordered linkers. The STI1 regions bind other components, such as HSP70, that are important to the PQC functions of UBQLN2. We recently determined that the STI1-II region enables UBQLN2 to undergo liquid-liquid phase separation (LLPS) to form liquid dropletsin vitroand biomolecular condensates in cells. However, how the interplay between the folded (UBL/UBA) domains and the intrinsically-disordered regions mediates phase separation is largely unknown. Using engineered domain deletion constructs, we found that removing the UBA domain inhibits UBQLN2 LLPS while removing the UBL domain enhances LLPS, suggesting that UBA and UBL domains contribute asymmetrically in modulating UBQLN2 LLPS. To explain these differential effects, we interrogated the interactions that involve the UBA and UBL domains across the entire UBQLN2 molecule using NMR spectroscopy. To our surprise, aside from well-studied canonical UBL:UBA interactions, there also exist moderate and weak interactions between the UBL and STI1-I/STI1-II domains, and between the UBA domain and the linker connecting the two STI1 regions, respectively. Our findings are essential for the understanding of both the molecular driving forces of UBQLN2 LLPS and the effects of ligand binding to UBL, UBA, or STI1 domains on the phase behavior and physiological functions of UBQLN2.

Impact of Work Statement

Zheng and Castañeda show that interplay between the folded domains and intrinsically disordered regions regulates liquid-liquid phase separation behavior of UBQLN2, a protein quality control (PQC) shuttle protein. Despite their similar size, the folded UBL and UBA domains inhibit and promote phase separation, respectively, due to their previously uncharacterized, asymmetric interactions with the middle intrinsically-disordered region. These results strongly suggest that PQC components, including proteasomal receptors, are likely to modulate UBQLN2 phase separation behavior in cells.
Human immunodeficiency reveals GIMAP5 as lymphocyte-specific regulator of senescence
Authors: Park Ann Y. , Leney-Greene Michael , Lynberg Matthew , Xu Xijin , Zheng Lixin , Zhang Yu , Matthews Helen , Chao Brittany , Morawski Aaron , Jiang Ping , Aluri Jahnavi , Aydiner Elif Karakoc , Kiykim Ayca , Pascall John , Barlan Isil , Sari Sinan , Butcher Geoff , Rao V. Koneti , Lifton Richard , Baris Safa , Ozen Ahmet , Vilarinho Silvia , Su Helen , Lenardo Michael J.
Published: February 2021

Elucidating the molecular basis of immunodeficiency diseases is a powerful approach to discovering new immunoregulatory pathways in humans. Here we report 10 affected individuals from 4 families with a new immunodeficiency disease comprising of severe progressive lymphopenia, autoimmunity, immunodeficiency, and liver disease due to recessive loss of function variants in“GTPase of immunity-associated proteins” protein 5 (GIMAP5). We show that the disease involves the progressive loss of naïve T lymphocytes and a corresponding increase in antigen-experienced, but poorly functional and replicatively senescent T cells. In vivo treatment of Gimap5-deficient mice with rapamycin (an inhibitor of mTORC1) significantly restores the fraction of naïve T lymphocytes. Furthermore, a GIMAP5-deficient human patient who was treated with rapamycin (sirolimus) showed a remarkable reduction in spleen/lymph node size. Together, these observations reveal that GIMAP5 plays a critical role in lymphocyte metabolism which is essential for senescence prevention and immune competence, suggesting that an inhibitor of mTORC1 could be a valuable clinical intervention in treating patients deficient for GIMAP5.
Dependency of Lower Limb Joint Reaction Forces on Femoral Anteversion
Authors: Modenese Luca , Barzan Martina , Carty Christopher P
Published: February 2021

Background

Musculoskeletal (MSK) models based on literature data are meant to represent a generic anatomy and are a popular tool employed by biomechanists to estimate the internal loads occurring in the lower limb joints, such as joint reaction forces (JRFs). However, since these models are normally just linearly scaled to an individual’s anthropometry, it is unclear how their estimations would be affected by the personalization of key features of the MSK anatomy, one of which is the femoral anteversion angle.

Research Question

How are the lower limb JRF magnitudes computed through a generic MSK model affected by changes in the femoral anteversion?

Methods

We developed a bone-deformation tool in MATLAB (https://simtk.org/projects/bone_deformity) and used it to create a set of seven OpenSim models spanning from 2° femoral retroversion to 40° anteversion. We used these models to simulate the gait of an elderly individual with an instrumented prosthesis implanted at their knee joint (5thGrand Challenge dataset) and quantified both the changes in JRFs magnitude due to varying the skeletal anatomy and their accuracy against the correspondent in vivo measurements at the knee joint.

Results

Hip and knee JRF magnitudes were affected by the femoral anteversion with variations from the unmodified generic model up to 11.7±5.5% at the hip and 42.6±31.0% at the knee joint. The ankle joint was unaffected by the femoral geometry. The MSK models providing the most accurate knee JRFs (root mean squared error: 0.370±0.069 body weight, coefficient of determination: 0.764±0.104, largest peak error: 0.36±0.16 body weight) were those with the femoral anteversion angle closer to that measured on the segmented bone of the individual.

Significance

Femoral anteversion substantially affects hip and knee JRFs estimated with generic MSK models, suggesting that personalizing key MSK anatomical features might be necessary for accurate estimation of JRFs with these models.
Gradients of receptor expression in the macaque cortex
Authors: Froudist-Walsh Sean , Xu Ting , Niu Meiqi , Rapan Lucija , Margulies Daniel S. , Zilles Karl , Wang Xiao-Jing , Palomero-Gallagher Nicola
Published: February 2021

Dynamics and functions of neural circuits depend on synaptic interactions mediated by receptors. Therefore, a comprehensive map of receptor organization is needed to understand how different functions may emerge across distinct cortical regions. Here we usein-vitroreceptor autoradiography to measure the density of 14 neurotransmitter receptor types in 109 areas of macaque cortex. We integrate the receptor data with other anatomical, genetic and functional connectivity data into a common cortical space. We uncovered a principal gradient of increasing receptor expression per neuron aligned with cortical hierarchy from early sensory cortex to higher cognitive areas. A second gradient, primarily driven by 5-HT1Areceptors, peaks in the anterior and subcallosal cingulate, suggesting that the macaque may be a promising animal model for major depressive disorder. The receptor gradients may enable rapid, reliable information processing in sensory cortical areas and slow, flexible integration of information in higher cognitive areas.
Expression of CD49f defines subsets of human regulatory T cells with divergent transcriptional landscape and function that correlate with ulcerative colitis disease activity
Authors: Weerakoon Harshi , Straube Jasmin , Lineburg Katie , Cooper Leanne , Lane Steven , Smith Corey , Alabbas Saleh , Begun Jakob , Miles John J , Hill Michelle M , Lepletier Ailin
Published: February 2021

Objective

Adoptive regulatory T cell (Treg) therapy is being trialled for treatment of different autoimmune disorders, including inflammatory bowel diseases (IBD). In-depth understanding of the biological variability of Treg in the human blood may be required to improve IBD immune monitoring and treatment strategies.

Methods

Through a combination of quantitative proteomic, multiparametric flow cytometry, RNA-sequencing data analysis and functional assays on Treg enriched from the blood of ulcerative colitis (UC) patients and healthy controls, we investigated the association between CD49f expression, Treg phenotype and function, and UC disease activity.

Results

High-dimensional analysis and filtering defined two distinct subsets of human Treg based on the presence or absence of CD49f with divergent transcriptional landscape and functional activities. CD49f negative Treg are enriched for functional Treg markers and present significantly increased suppressive capacity. In contrast, CD49f high Treg display a pro-inflammatory Th17-like phenotype and accumulate in the blood of UC patients. Dysregulation on CD49f Treg subsets in UC patients correlate with disease activity.

Conclusion

Overall our findings uncover the importance of CD49f expression on Treg in physiological immunity and in pathological autoimmunity.
Protein-protein docking with large-scale backbone flexibility using coarse-grained Monte-Carlo simulations
Authors: Kurcinski Mateusz , Kmiecik Sebastian , Zalewski Mateusz , Kolinski Andrzej
Published: February 2021

Most of the protein-protein docking methods treat proteins as almost rigid objects. Only the side-chains flexibility is usually taken into account. The few approaches enabling docking with a flexible backbone typically work in two steps, in which the search for protein-protein orientations and structure flexibility are simulated separately. In this work, we propose a new straightforward approach for docking sampling. It consists of a single simulation step during which a protein undergoes large-scale backbone rearrangements, rotations, and translations. Simultaneously, the other protein exhibits small backbone fluctuations. Such extensive sampling was possible using the CABS coarse-grained protein model and Replica Exchange Monte Carlo dynamics at a reasonable computational cost. In our proof-of-concept simulations of 62 protein-protein complexes, we obtained acceptable quality models for a significant number of cases.
Targeting CoV-2 Spike RBD and ACE-2 Interaction with Flavonoids of Anatolian Propolis byin silicoandin vitroStudies in terms of possible COVID-19 therapeutics
Authors: Guler Halil Ibrahim , Ay Sal Fulya , Can Zehra , Kara Yakup , Yildiz Oktay , Belduz Ali Osman , Çanakci Sabriye , Kolayli Sevgi
Published: February 2021

Propolis is a multi-functional bee product with a rich in polyphenols. In this study, the inhibition effect of Anatolian propolis against SARS coronavirus-2 (SARS CoV-2) was investigated asin vitroandin silico. Raw and commercial of propolis samples were used in the study and it was found that both of were rich in caffeic acid, p-coumaric acid, ferulic acid, t-cinnamic acid, hesperetin, chrysin, pinocembrin and caffeic acid phenethyl ester (CAPE) by HPLC-UV analysis. The ethanolic propolis extracts (EPE) were used in the screening ELISA test against the spike S1 protein (SARS Cov-2): ACE-2 inhibition KIT forin vitrostudy. Binding energy constants of these polyphenols to the CoV-2 Spike S1 RBD and ACE-2proteinwere calculated separately as molecular docking study using AutoDock 4.2 molecular docking software. In addition, pharmacokinetics and drug-likeness properties of these eight polyphenols were calculated according to the SwissADME tool. Binding energy constant of pinocembrin was the highest for both of the receptors, followed by chrysin, CAPE and hesperetin.In silicoADME behavior of the eight polyphenols were found potential ability to work effectively as novel drugs. The findings of both studies showed that propolis has a high inhibitory potential against Covid-19 virus. However, further studies are needed.
Kynurenine pathway in post-mortem prefrontal cortex and cerebellum in schizophrenia: relationship with monoamines and symptomatology
Authors: Afia Amira Ben , Vila Èlia , MacDowell Karina S. , Ormazabal Aida , Leza Juan Carlos , Haro Josep Maria , Artuch Rafael , Ramos Belén , Garcia-Bueno Borja
Published: February 2021

Background

the cortico-cerebellar-thalamic-cortical circuit has been implicated in the emergence of psychotic symptoms in schizophrenia (SZ). The kynurenine pathway (KP) has been linked to alterations in glutamatergic and monoaminergic neurotransmission and to SZ symptomatology through the production of the metabolites quinolinic acid (QA) and kynurenic acid (KYNA).

Methods

this work describes alterations in KP in the post-mortem prefrontal cortex (PFC) and cerebellum (CB) of 15 chronic SZ patients and 14 control subjects in PFC and 13 control subjects in CB using immunoblot for protein levels and ELISA for interleukins and QA and KYNA determinations. Monoamine metabolites were analysed by High Performance Liquid Chromatography and SZ symptomatology was assessed by Positive and Negative Syndrome Scale (PANSS). The association of KP with inflammatory mediators, monoamine metabolism and SZ symptomatology was explored.

Results

in the PFC, the presence of the anti-inflammatory cytokine IL-10 together with IDO2 and KATII enzymes decreased in SZ, while TDO and KMO enzymes expression increased. A network interaction analysis showed that in the PFC IL-10 was coupled to the QA branch of the kynurenine pathway (TDO-KMO-QA), whereas IL-10 associated with KMO in CB. KYNA in the CB inversely correlated with negative and general PANSS psychopathology. Although there were no changes in monoamine metabolites content in the PFC in SZ, a network interaction analysis showed associations between dopamine and methoxyhydroxyphenylglycol degradation metabolite. Direct correlations were found between general PANSS psychopathology and the serotonin degradation metabolite, 5-hydroxyindoleacetic acid. Interestingly, KYNA in the CB inversely correlated with 5-hydroxyindoleacetic acid in the PFC.

Conclusions

thus, this work found alterations in KP in two brain areas belonging to the cortico-cerebellar-thalamic-cortical circuit associated with SZ symptomatology, with a possible impact across areas in 5-HT degradation.
Modeling SARS-CoV-2 infection and its individual differences with ACE2-expressing human iPS cells
Authors: Sano Emi , Sakamoto Ayaka , Mimura Natsumi , Hirabayashi Ai , Muramoto Yukiko , Noda Takeshi , Yamamoto Takuya , Takayama Kazuo
Published: February 2021

Genetic differences are a primary reason for differences in the susceptibility and severity of coronavirus disease 2019 (COVID-19). Because induced pluripotent stem (iPS) cells maintain the genetic information of the donor, they can be used to model individual differences in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectionin vitro. Notably, undifferentiated human iPS cells themselves cannot be infected bySARS-CoV-2. Using adenovirus vectors, here we found that human iPS cells expressing the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) (ACE2-iPS cells) can be infected with SARS-CoV-2. In infected ACE2-iPS cells, the expression of SARS-CoV-2 nucleocapsid protein, the budding of viral particles, the production of progeny virus, double membrane spherules, and double-membrane vesicles were confirmed. We also evaluated COVID-19 therapeutic drugs in ACE2-iPS cells and confirmed the strong antiviral effects of Remdesivir, EIDD-2801, and interferon-beta. In addition, we performed SARS-CoV-2 infection experiments on ACE2-iPS/ES cells from 8 individuals. Male iPS/ES cells were more capable of producing the virus as compared with female iPS/ES cells. These findings suggest that ACE2-iPS cells can not only reproduce individual differences in SARS-CoV-2 infectionin vitro, but they are also a useful resource to clarify the causes of individual differences in COVID-19 due to genetic differences.

Graphical Abstract
The Role of Interspecies recombinations in the evolution of antibiotic-resistant pneumococci
Authors: D’Aeth Joshua C. , van der Linden Mark P.G. , McGee Lesley , Lencastre Herminia De , Turner Paul , Song Jae-Hoon , Lo Stephanie W. , Gladstone Rebecca A. , Sá-Leão Raquel , Ko Kwan Soo , Hanage William P. , Beall Bernard , Bentley Stephen D. , Croucher Nicholas J. ,   The GPS Consortium
Published: February 2021

Abstract

The evolutionary histories of the antibiotic-resistantStreptococcus pneumoniaelineages PMEN3 and PMEN9 were reconstructed using global collections of genomes. In PMEN3, one resistant clade spread worldwide, and underwent 25 serotype switches, enabling evasion of vaccine-induced immunity. In PMEN9, only 9 switches were detected, and multiple resistant lineages emerged independently and circulated locally. In Germany, PMEN9’s expansion correlated significantly with the macrolide:penicillin consumption ratio. These isolates were penicillin sensitive but macrolide resistant, through a homologous recombination that integrated Tn1207.1into a competence gene, preventing further diversification via transformation. Analysis of a species-wide dataset found 183 acquisitions of macrolide resistance, and multiple gains of the tetracycline-resistant transposon Tn916, through homologous recombination, often originating in other streptococcal species. Consequently, antibiotic selection preserves atypical recom- bination events that cause sequence divergence and structural variation throughout theS. pneumoniaechromosome. These events reveal the genetic exchanges between species normally counter-selected until perturbed by clinical interventions.
Monitoring oxidative inflammatory processes in live cells and tissue with Hypocrates, a genetically encoded biosensor for hypochlorite
Authors: Kostyuk Alexander I. , Tossounian Maria-Armineh , Panova Anastasiya S. , Thauvin Marion , Wahni Khadija , Van Molle Inge , Raevskii Roman I. , Baranov Mikhail S. , Vriz Sophie , Messens Joris , Bilan Dmitry S. , Belousov Vsevolod V.
Published: February 2021

Hypochlorous acid, an aggressive oxidant, is important in immune defense against pathogens. The current lack of tools to monitor the dynamics of hypochlorous acid in live cells and tissue hinders a better understanding of inflammatory processes. We engineered a genetically encoded biosensor, Hypocrates, for the visualization of hypochlorous acid. Hypocrates consists of a circularly permuted yellow fluorescent protein integrated into the structure of the transcription repressor NemR fromE. coli. We determined sensitivity, selectivity, reaction rates, and the X-ray structure of this ratiometric redox biosensor, and tested the response of Hypocrates in HeLa Kyoto cells at varying hypochlorite concentrations. By combining Hypocrates with the biosensor HyperRed, we visualized the dynamics of hypochlorous acid and hydrogen peroxide in a zebrafish tail fin injury model.
Beneficial cumulative effects of old parental age on offspring fitness
Authors: Travers Laura. M. , Carlsson Hanne , Lind Martin I. , Maklakov Alexei A.
Published: February 2021

Old parental age is commonly associated with negative effects on offspring life-history traits. Such parental effect senescence is predicted to have a cumulative detrimental effect over successive generations. However, old parents may benefit from producing high-quality offspring when these compete for seasonal resources. Thus, old parents may choose to increase investment in their offspring, thereby producing fewer but larger and more competitive progeny. We show thatCaenorhabditis eleganshermaphrodites increase parental investment with advancing age, resulting in fitter offspring who reach their reproductive peak earlier. Remarkably, these effects increased over six successive generations of breeding from old parents and were subsequently reversed following a single generation of breeding from a young parent. These results contradict the theory that old parents transfer a cumulative detrimental “ageing factor” to their offspring. Instead, our findings support the hypothesis that offspring of old parents receive more resources and convert them into increasingly faster life-histories.
pyControl: Open source, Python based, hardware and software for controlling behavioural neuroscience experiments
Authors: Akam Thomas , Lustig Andy , Rowland James , Kapanaiah Sampath K.T. , Esteve-Agraz Joan , Panniello Mariangela , Marquez Cristina , Kohl Michael , Kätzel Dennis , Costa Rui M. , Walton Mark
Published: February 2021

Laboratory behavioural tasks are an essential research tool. As questions asked of behaviour and brain activity become more sophisticated, the ability to specify and run richly structured tasks becomes more important. An increasing focus on reproducibility also necessitates accurate communication of task logic to other researchers. To these ends we developed pyControl, a system of open source hardware and software for controlling behavioural experiments comprising; a simple yet flexible Python-based syntax for specifying tasks as extended state machines, hardware modules for building behavioural setups, and a graphical user interface designed for efficiently running high throughput experiments on many setups in parallel, all with extensive online documentation. These tools make it quicker, easier and cheaper to implement rich behavioural tasks at scale. As important, pyControl facilitates communication and reproducibility of behavioural experiments through a highly readable task definition syntax and self-documenting features.

Resources

Documentation:https://pycontrol.readthedocs.io

Repositories:https://github.com/pyControl

User support:https://groups.google.com/g/pycontrol
Genetic diversity and population history of eight Italian beef cattle breeds using measures of autozygosity
Authors: Fabbri Maria Chiara , Dadousis Christos , Tiezzi Francesco , Maltecca Christian , Lozada-Soto Emmanuel , Biffani Stefano , Bozzi Riccardo
Published: February 2021

In the present study, GeneSeek GGP-LDv4 33k single nucleotide polymorphism chip was used to detect runs of homozygosity (ROH) in eight Italian beef cattle breeds; six breeds with distribution limited to Tuscany (Calvana, Mucca Pisana, Pontremolese) or Sardinia (Sarda, Sardo Bruna and Sardo Modicana) and two cosmopolitan breeds (Charolais and Limousine). ROH detection analyses were used to estimate autozygosity and inbreeding and to identify genomic regions with high frequency of ROH, which might reflect selection signatures. Comparative analysis among breeds revealed differences in length and distribution of ROH and inbreeding levels. The Charolais, Limousine, Sarda, and Sardo Bruna breeds were found to have a high frequency of short ROH (30.000); Calvana and Mucca Pisana presented also runs longer than 16 Mbp. The highest level of average genomic inbreeding was observed in Tuscan breeds, around 0.3, while Sardinian and cosmopolitan breeds showed values around 0.2. The population structure and genetic distances were analyzed through principal component analysis and multidimensional scaling analysis, and resulted in a clear separation among the breeds, with clusters related to productive purposes and sample sizes. The frequency of ROH occurrence revealed eight breed-specific genomic regions where genes of potential selective and conservative interest are located (e.g.MYOG, Chitinases(BTA16),TIMELESS,APOF, Olfactory receptors,CACNG2(BTA5) and Collagens (BTA2)). In all breeds, we found the largest proportion of homozygous by descent segments to be those that represent inbreeding events that occurred around 32 generations ago; with Tuscan breeds also having a significant proportion of segments relating to more recent inbreeding.
Combined application of biochar with nitrogen fertilizer improves soil quality and reduces soil respiration whilst sustaining wheat grain yield in a semiarid environment
Authors: Yeboah Stephen , Jun Wu , Liqun Cai , Oteng-Darko Patricia , Renzhi Zhang
Published: February 2021

This study was conducted to investigate the effect of biochar, straw and N fertilizer on soil properties, soil respiration and grain yield of spring wheat (Triticum aestivumL.) in semi-arid Western Loess Plateau of northwestern China. The two carbon sources (straw and biochar) were applied alone or combined with nitrogen fertilizer (urea, 46% nitrogen [N]), whilst the soil without carbon is made up of nitrogen fertilizer applied at 0, 50 and 100 kg N/ha. The experiment was arranged in a randomized complete block design with three replicates and was conducted in 2014, 2015 and 2016 cropping season. Results showed that the greatest grain yields were found with 100 kg N ha−1fertilization rate under biochar, straw and soils without carbon, but the greatest effect occurred on the biochar amended soils. Biochar amendment produced the greatest grain yield at 1906 kg ha−1, followed by straw treated soils at 1643 kg ha−1, and soils without carbon the lowest at 1553 kg ha−1. This results is supported by the fact that, biochar amended soils (at 0–10 cm) increased soil organic C by 17.14% and 21.65% compared to straw treated soils and soils without carbon respectively. Seasonal soil respirations were between 19.05% and 23.67% lower in BN100compared with SN50and CN100. Soil respiration reduced with increasing N fertilization rates under all treatments, but the greatest effect occurred on biochar plots. Biochar amended soils decreased carbon emission by 26.80% and 9.54% compared to straw treated soils and soils without carbon amendment respectively. Increased grain yield and the decreased carbon emission in BN100translated into greater carbon emission efficiency (2.88 kg kg−1) which was significantly different compared with the other treatments. Combined application of biochar with 100 kg N ha−1in rainfed spring wheat was a suitable agricultural practice.
The non-benzodiazepine anxiolytic etifoxine limits the sensory-affective expression of pain following streptozotocin-induced diabetic neuropathy
Authors: Gazzo Géraldine , Ferrer Marlene Salgado , Poisbeau Pierrick
Published: February 2021

More than 450 million people worldwide suffer from diabetes, or 1 in 11 people. Chronic hyperglycemia degrades patients’ quality of life and the development of neuropathic pain contributes to the burden of this disease. In this study, we used the mouse model of streptozocin-induced diabetic type 1 neuropathy to assess the analgesic potential of etifoxine. Etifoxine is a prescribed anxiolytic that increases GABAAA receptor function through a direct positive allosteric modulation effect and, indirectly, by stimulating the production of endogenous GABAA receptor positive modulators such as allopregnanolone-type neurosteroids. We show that a curative or preventive treatment strongly and durably reduces mechanical hyperalgesia and anxiety in diabetic neuropathic mice. This analgesic and neuroprotective effect on painful symptoms and emotional comorbidities is promising and should now be clinically evaluated.
Regulation ofJacobaea vulgarisby varied cutting and restoration measures
Authors: Möhler Henrike , Diekötter Tim , Donath Tobias W.
Published: February 2021

The growth of the noxious grassland weedJacobaea vulgarisGaertn. in pastures is a threat to grazing animals. This is especially true when it dominates vegetation cover, which often occurs on non-intensively used pastures that are managed with the nature-conservation goal to maintain and promote biodiversity. Thus, we wanted to find management techniques to reduceJ. vulgariswithout harming the floral biodiversity on the pastures.

We tested six different mechanical and cultural methods to reduce the presence and spread ofJ. vulgaris. Seven study sites in Northern Germany (Schleswig-Holstein) were treated with various measurements, including: milling and seeding, hay transfer, mowing regimes at different times and frequencies, and combinations of mowing and seeding.

Our results show that cutting within the bloom of the plant at the end of June and again four weeks later, when the plant is in its second bloom was the most effective treatment in reducingJ. vulgarisabundance. This was the only treatment leading to a significant reduction in population growth rate and density without reducing surrounding plant species richness.

The study reveals that management ofJ. vulgarisin non-intensively used pastures is possible, while preserving species-rich grasslands.
Flanker: a tool for comparative genomics of gene flanking regions
Authors: Matlock William , Lipworth Samuel , Constantinides Bede , Peto Timothy E.A. , Sarah Walker A. , Crook Derrick , Hopkins Susan , Shaw Liam P. , Stoesser Nicole
Published: February 2021

Analysing the flanking sequences surrounding genes of interest is often highly relevant to understanding the role of mobile genetic elements (MGEs) in horizontal gene transfer, particular for antimicrobial resistance genes. Here, we present Flanker, a Python package which performs alignment-free clustering of gene flanking sequences in a consistent format, allowing investigation of MGEs without prior knowledge of their structure. These clusters, known as ‘flank patterns’, are based on Mash distances, allowing for easy comparison of similarity across sequences. Additionally, Flanker can be flexibly parameterised to finetune outputs by characterising upstream and downstream regions separately and investigating variable lengths of flanking sequence. We apply Flanker to two recent datasets describing plasmid-associated carriage of important carbapenemase genes (blaOXA-48 and blaKPC-2/3) and show that it successfully identifies distinct clusters of flank patterns, including both known and previously uncharacterised structural variants. For example, Flanker identified four Tn4401 profiles that could not be sufficiently characterised using TETyper or MobileElementFinder, demonstrating the utility of Flanker for flanking gene characterisation. Similarly, using a large (n=226) European isolate dataset, we confirm findings from a previous smaller study demonstrating association between Tn1999.2 andblaOXA-48upregulation and demonstrate 17 flank patterns (compared to the 5 previously identified). More generally the demonstration in this study that flank patterns are associated with to geographical regions and antibiotic susceptibility phenotypes suggests that they may be useful as epidemiological markers. Flanker is freely available under an MIT license athttps://github.com/wtmatlock/flanker.

Data Summary

NCBI accession numbers for all sequencing data used in this study is provided in Supplementary Table 1. The analysis performed in this manuscript can be reproduced in a binder environment provided on the Flanker Github page (https://github.com/wtmatlock/flanker).
DeepMotifSyn: a deep learning approach to synthesize heterodimeric DNA motifs
Authors: Lin Jiecong , Huang Lei , Chen Xingjian , Zhang Shixiong , Wong Ka-Chun
Published: February 2021

Motivation

The cooperativity of transcription factors (TFs) is a widespread phenomenon in the gene regulation system. However, the interaction patterns between TF binding motifs remain elusive. The recent high-throughput assays, CAP-SELEX, have identified over 600 composite DNA sites (i.e. heterodimeric motifs) bound by cooperative TF pairs. However, there are over 25,000 inferentially effective heterodimeric TFs in human cell. It is not practically feasible to validate all heterodimeric motifs due to cost and labour. Therefore, it is highly demanding to develop a fast and accurate computational tool for heterodimeric motif synthesis.

Results

We introduce DeepMotifSyn, a deep-learning-based tool for synthesizing heterodimeric motifs from monomeric motif pairs. Specifically, DeepMotifSyn is composed of heterodimeric motif generator and evaluator. The generator is a U-Net-based neural network that can synthesize heterodimeric motifs from aligned motif pairs. The evaluator is a machine-learning-based model that can score the generated heterodimeric motif candidates based on the motif sequence features. Systematic evaluations on CAP-SELEX data illustrates that DeepMotif-Syn significantly outperforms the current state-of-the-art predictors. In addition, DeepMotifSyn can synthesize multiple heterodimeric motifs with different orientation and spacing settings. Such a feature can address the shortcomings of previous models. We believe Deep-MotifSyn is a more practical and reliable model than current predictors on heterodimeric motif synthesis.

Availability and implementation

The software is freely available athttps://github.com/JasonLinjc/deepMotifSyn.
Resurrection of endogenous retroviruses during aging reinforces senescence
Authors: Liu Xiaoqian , Liu Zunpeng , Wu Zeming , Ren Jie , Fan Yanling , Sun Liang , Cao Gang , Niu Yuyu , Zhang Baohu , Ji Qianzhao , Jiang Xiaoyu , Wang Cui , Wang Qiaoran , Ji Zhejun , Li Lanzhu , Esteban Concepcion Rodriguez , Yan Kaowen , Li Wei , Cai Yusheng , Wang Si , Zheng Aihua , Zhang Yong E. , Tan Shengjun , Cai Yingao , Song Moshi , Lu Falong , Tang Fuchou , Ji Weizhi , Zhou Qi , Belmonte Juan Carlos Izpisua , Zhang Weiqi , Qu Jing , Liu Guang-Hui
Published: February 2021

Whether and how certain transposable elements with viral origins, such as endogenous retroviruses (ERVs) dormant in our genomes, can become awakened and contribute to the aging process are largely unknown. In human senescent cells, we found that HERVK (HML-2), the most recently integrated human ERVs, are unlocked to transcribe viral genes and produce retrovirus-like particles (RVLPs). These HERVK RVLPs constitute a transmissible message to elicit senescence phenotypes in young cells, which can be blocked by neutralizing antibodies. Activation of ERVs was also observed in organs of aged primates and mice, as well as in human tissues and serum from the elderly. Their repression alleviates cellular senescence and tissue degeneration and, to some extent, organismal aging. These findings indicate that the resurrection of ERVs is a hallmark and driving force of cellular senescence and tissue aging.

In brief

Liu and colleagues uncover the ways in which de-repression of human endogenous retrovirus triggers cellular senescence and tissue aging; the findings provide fresh insights into therapeutic strategies for alleviating aging.

Highlights

Derepression of the endogenous retrovirus contributes to programmed aging

Upregulation of HERVK triggers the innate immune response and cellular senescence

Extracellular HERVK retrovirus-like particles induce senescence in young cells

Endogenous retrovirus serves as a potential target to alleviate agings

Graphical abstract
BiSEK: a platform for a reliable differential expression analysis
Authors: Haas Roni , Light Dean , Festinger Yahav , Friedman Neta , Lamm Ayelet T.
Published: February 2021

Differential Expression Analysis (DEA) of RNA-sequencing data is frequently performed for detecting key genes, affected across different conditions. Although DEA-workflows are well established, preceding reliability-testing of the input material, which is crucial for consistent and strong results, is challenging and less straightforward. Here we present Biological Sequence Expression Kit (BiSEK), a graphical user interface-based platform for DEA, dedicated to a reliable inquiry. BiSEK is based on a novel algorithm to track discrepancies between the data and the statistical model design. Moreover, BiSEK enables differential-expression analysis of groups of genes, to identify affected pathways, without relying on the significance of genes comprising them. Using BiSEK, we were able to improve previously conducted analysis, aimed to detect genes affected by FUBP1 depletion in chronic myeloid leukemia cells of mice bone-marrow. We found affected genes that are related to the regulation of apoptosis, supporting in-vivo experimental findings. We further tested the host response following SARS-CoV-2 infection. We identified a substantial interferon-I reaction and low expression levels of TLR3, an inducer of interferon-III (IFN-III) production, upon infection with SARS-CoV-2 compared to other respiratory viruses. This finding may explain the low IFN-III response upon SARS-CoV-2 infection. BiSEK is open-sourced, available as a web-interface.
Levetiracetam treatment normalizes levels of the presynaptic endocytosis machinery and restores non-amyloidogenic APP processing inAppknock-in mice
Authors: Rao Nalini R. , Savas Jeffrey N.
Published: February 2021

Increasing evidence indicates that toxic amyloid-beta (Aβ) peptides, produced by sequential proteolytic cleavage of the Amyloid Precursor Protein (APP), induce neuronal circuit hyperexcitability in the early stages of Alzheimer’s disease (AD). As a result, treatments that modulate this early excitatory/inhibitory imbalance could act as potential AD therapies. Levetiracetam, an atypical antiepileptic drug, has garnered recent interest, despite the mechanism(s) of action remaining elusive. In this study, we set out to identify the pathways and mechanisms primarily affected by levetiracetam in diseased brains of amyloid pathology. Using theAppknock-in mouse models and multiplexed TMT-quantitative mass spectrometry-based proteomic analysis to determine how levetiracetam affects the proteome, our findings demonstrate that levetiracetam treatment selectively normalizes levels of presynaptic endocytosis proteins and is capable of lowering Aβ42levels by altering APP processing. These novel findings demonstrate a mechanism of action for how levetiracetam lowers Aβ42production.
Conformist social learning leads to self-organised prevention against adverse bias in risky decision making
Authors: Toyokawa Wataru , Gaissmaier Wolfgang
Published: February 2021

Given the ubiquity of potentially adverse behavioural bias owing to myopic trial-and-error learning, it seems paradoxical that improvements in decision-making performance through conformist social learning, a process widely considered to be bias amplification, still prevail in animal collective behaviour. Here we show, through model analyses and large-scale interactive behavioural experiments with 585 human subjects, that conformist influence can indeed promote favourable risk taking in repeated experience-based decision making, even though many individuals are systematically biased towards adverse risk aversion. Although strong positive feedback conferred by copying the majority’s behaviour could result in unfavourable informational cascades, our differential equation model of collective behavioural dynamics identified a key role for increasing exploration by negative feedback arising when a weak minority influence undermines the inherent behavioural bias. This ‘collective behavioural rescue’, emerging through coordination of positive and negative feedback, highlights a benefit of collective learning in a broader range of environmental conditions than previously assumed and resolves the ostensible paradox of adaptive collective behavioural flexibility under conformist influences.
Parallel processing of natural images by overlapping retinal neuronal ensembles
Authors: Pérez-Ortega Jesús , Araya Joaquín , Ibaceta Cristobal , Herzog Rubén , Escobar María-José , Peña-Ortega Fernando , Carrillo-Reid Luis , Palacios Adrian G.
Published: February 2021

Even though the retinal microcircuit organization has been described in detail at the single-cell level, little is known about how groups of retinal cells’ coordinated activity encode and process parallel information representing the spatial and temporal structure of changing environmental conditions. To describe the population dynamics of retinal neuronal ensembles, we used microelectrode array recordings that describe hundreds of retinal ganglion cells’ simultaneous activity in response to a short movie captured in the natural environment where our subject develops their visual behaviors. The vectorization of population activity allowed the identification of retinal neuronal ensembles that synchronize to specific segments of natural stimuli. These synchronous retinal neuronal ensembles were reliably activated by the same stimuli at different trials, indicating a robust population response of retinal microcircuits. The generation of asynchronous events required integrating a physiologically meaningful time window larger than 80 ms, demonstrating that retinal neuronal ensembles’ time integration filters non-structured visual information. Interestingly, individual neurons could be part of several ensembles indicating that parallel circuits could encode environmental conditions changes. We conclude that parallel neuronal ensembles could represent the functional unit of retinal computations and propose that the further study of retinal neuronal ensembles could reveal emergent properties of retinal circuits that individual cells’ activity cannot explain.
The Rise of West Nile Virus in Southern and Southeastern Europe: a spatial-temporal analysis investigating the combined effects of climate, land use and economic changes
Authors: Watts Matthew J. , Monteys Victor Sarto i , Mortyn P. Graham , Kotsila Panagiota
Published: February 2021

West Nile Virus (WNV) has recently emerged as a major public health concern in Europe, its recent expansion also coincided with some remarkable socio-economic and environmental changes, including an economic crisis and some of the warmest temperatures on record. Here we empirically investigate the drivers of this phenomenon at a European wide scale by constructing and analyzing a unique spatial-temporal data-set, that includes data on climate, land-use, the economy, and government spending on environmental related sectors. Drivers and risk factors of WNV were identified by building a conceptual framework, and relationships were tested using a Generalized Additive Model (GAM), which could capture complex non-linear relationships and also account for the spatial and temporal auto-correlation. Some of the key risk factors identified in our conceptual framework, such as a higher percentage of wetlands and arable land, climate factors (higher summer rainfall and higher summer temperatures) were positive predictors of WNV infections. Interestingly, winter temperatures of between 2 °C and 6 °C were among some of the strongest predictors of annual WNV infections, one possible explanation for this result is that successful overwintering of infected adult mosquitoes (likelyCulex pipiens) is key to the intensity of outbreaks for a given year. Furthermore, lower surface water extent over the summer is also associated with more more intense outbreaks, suggesting that drought, which is known to induce positive changes in WNV prevalence in mosquitoes is also contributing to the upward trend in WNV cases in affected regions. Our indicators representing the economic crisis were also strong predictors of WNV infections, suggesting there is an association between austerity and cuts to key sectors, which could have benefited vector species and the virus during this crucial period. These results, taken in the context of recent winter warming due to climate change, and more frequent droughts, may offer an explanation of why the virus has become so prevalent in Europe.