bluuebunny/crossref_metadata_2025 huggingface dataset:
The Prediction for Development of COVID-19 in Global Major Epidemic Areas Through Empirical Trends in China by Utilizing State Transition Matrix Model
Authors: Zheng Zhong , Wu Ke , Yao Zhixian , Zheng Junhua , Chen Jian
Published: March 2020

Background

Since pneumonia caused by coronavirus disease 2019 (COVID-19) broke out in Wuhan, Hubei province, China, tremendous infected cases has risen all over the world attributed to high transmissibility. We managed to mathematically forecast the inflection point (IFP) of new cases in South Korea, Italy, and Iran, utilizing the transcendental model from Hubei and non-Hubei in China.

Methods

We extracted data from reports released by the National Health Commission of the People’s Republic of China (Dec 31, 2019 to Mar 5, 2020) and the World Health Organization (Jan 20, 2020 to Mar 5, 2020) as the training set to deduce the arrival of the IFP of new cases in Hubei and non-Hubei on subsequent days and the data from Mar 6 to Mar 9 as validation set. New close contacts, newly confirmed cases, cumulative confirmed cases, non-severe cases, severe cases, critical cases, cured cases, and death data were collected and analyzed. Using this state transition matrix model, the horizon of the IFP of time (the rate of new increment reaches zero) could be predicted in South Korean, Italy, and Iran. Also, through this model, the global trend of the epidemic will be decoded to allocate international medical resources better and instruct the strategy for quarantine.

Results

the optimistic scenario (non-Hubei model, daily increment rate of −3.87%), the relative pessimistic scenario (Hubei model, daily increment rate of −2.20%), and the relatively pessimistic scenario (adjustment, daily increment rate of −1.50%) were inferred and modeling from data in China. Matching and fitting with these scenarios, the IFP of time in South Korea would be Mar 6-Mar 12, Italy Mar 10-Mar 24, and Iran is Mar 10-Mar 24. The numbers of cumulative confirmed patients will reach approximately 20k in South Korea, 209k in Italy, and 226k in Iran under fitting scenarios, respectively. There should be room for improvement if these metrics continue to improve. In that case, the IFP will arrive earlier than our estimation. However, with the adoption of different diagnosis criteria, the variation of new cases could impose various influences in the predictive model. If that happens, the IFP of increment will be higher than predicted above.

Conclusion

We can affirm that the end of the burst of the epidemic is still inapproachable, and the number of confirmed cases is still escalating. With the augment of data, the world epidemic trend could be further predicted, and it is imperative to consummate the assignment of global medical resources to manipulate the development of COVID-19.
Combinatorial metabolic engineering platform enabling stable overproduction of lycopene from carbon dioxide by cyanobacteria
Authors: Taylor George M. , Heap John T.
Published: March 2020

Cyanobacteria are simple, efficient, genetically-tractable photosynthetic microorganisms representing ideal biocatalysts for CO2capture and conversion, in principle. In practice, genetic instability and low productivity are key, linked problems in engineered cyanobacteria. We took a massively parallel approach, generating and characterising libraries of synthetic promoters and RBSs for the cyanobacteriumSynechocystis, and assembling a sparse combinatorial library of millions of metabolic pathway-encoding construct variants. Laboratory evolution suppressed variants causing metabolic burden inSynechocystis, leading to expected genetic instability. Surprisingly however, in a single combinatorial round without iterative optimisation, 80% of variants chosen at random overproduced the valuable terpenoid lycopene from atmospheric CO2over many generations, apparently overcoming the trade-off between stability and productivity. This first large-scale parallel metabolic engineering of cyanobacteria provides a new platform for development of genetically stable cyanobacterial biocatalysts for sustainable light-driven production of valuable products directly from CO2, avoiding fossil carbon or competition with food production.
Disruption ofCYCLOPHILIN 38function reveals a photosynthesis-dependent systemic signal controlling lateral root emergence
Authors: Duan Lina , Pérez-Ruiz Juan Manuel , Cejudo Francisco Javier , Dinneny José R.
Published: March 2020

Photosynthesis in leaves generates the fixed-carbon resources and essential metabolites that support sink tissues, such as roots [1]. One of these products, sucrose, is known to promote primary root growth, but it is not clear what other molecules may be involved and whether other stages of root system development are affected by photosynthate levels [2]. Through a mutant screen to identify pathways regulating root system architecture, we identified a mutation in theCYCLOPHILIN 38(CYP38) gene, which causes an accumulation of pre-emergent stage lateral roots, with a minor effect on primary root growth. CYP38 was previously reported to maintain the stability of Photosystem II (PSII) in chloroplasts [3].CYP38expression is enriched in the shoot and grafting experiments show that the gene acts non-cell autonomously to promote lateral root emergence. Growth of wild-type plants under low light conditions phenocopied thecyp38lateral root emergence phenotype as did the inhibition of PSII-dependent electron transport or NADPH production. Importantly, thecyp38root phenotype is not rescued by exogenous sucrose, suggesting the involvement of another metabolite. Auxin (IAA) is an essential hormone promoting root growth and its biosynthesis from tryptophan is dependent on reductant generated during photosynthesis [4,5]. Both WT seedlings grown under low light andcyp38mutants have highly diminished levels of IAA in root tissues. Thecyp38lateral root defect is rescued by IAA treatment, revealing that photosynthesis promotes lateral root emergence partly through IAA biosynthesis. Metabolomic profiling shows that the accumulation of several defense-related metabolites are also photosynthesis-dependent, suggesting that the regulation of a number of energy-intensive pathways are down-regulated when light becomes limiting.
Red light controls adventitious root regeneration by modulating hormone homeostasis inPicea abiesseedlings
Authors: Alallaq Sanaria , Ranjan Alok , Brunoni Federica , Novák Ondřej , Lakehal Abdellah , Bellini Catherine
Published: March 2020

Vegetative propagation relies on the capacity of plants to regeneratede novoadventitious roots (ARs), a quantitative trait controlled by the interaction of endogenous factors such as hormones and environmental cues among which light plays a central role. However, the physiological and molecular components mediating light cues during AR initiation (ARI) remain largely elusive. We explored the effect of light spectral quality on ARI in de-rooted Norway spruce seedlings as well as on hormone metabolism with sensitive mass spectrometry-based methods. We coupled this to gene expression analysis to identify potential signaling pathways and to extensive anatomical characterization to investigate ARI at the cellular level. We showed that in contrast to white light and blue light, red light promoted ARI likely by reducing jasmonate (JA) and JA-isoleucine biosynthesis and repressing the accumulation of isopentyl-adenine-type cytokinins and abscisic acid. We confirmed that exogenously applied JA and/or CK inhibit ARI, and found that they possibly act in the same pathway. The negative effect of JA was confirmed at the histological level. We showed that JA represses the early events of ARI. In conclusion, RL promotes ARI by repressing the accumulation of the wound-induced phytohormones JA and CK.

Highlight

Blue and red light have an opposite effect on adventitious root initiation in Norway spruce hypocotyl, red light having a promoting effect by modulating hormone homeostasis.
Identification of m6A residues at single-nucleotide resolution using eCLIP and an accessible custom analysis pipeline
Authors: Roberts Justin T. , Porman Allison M. , Johnson Aaron M.
Published: March 2020

Methylation at the N6position of adenosine (m6A) is one of the most abundant RNA modifications found in eukaryotes, however accurate detection of specific m6A nucleotides within transcripts has been historically challenging due to m6A and unmodified adenosine having virtually indistinguishable chemical properties. While previous strategies such as methyl-RNA immunoprecipitation and sequencing (MeRIP-Seq) have relied on m6A-specific antibodies to isolate RNA fragments containing the modification, these methods do not allow for precise identification of individual m6A residues. More recently, modified cross-linking and immunoprecipitation (CLIP) based approaches that rely on inducing specific mutations during reverse transcription via UV crosslinking of the anti-m6A antibody to methylated RNA have been employed to overcome this limitation. However, the most utilized version of this approach, miCLIP, can be technically challenging to use for achieving high-complexity libraries. Here we present an improved methodology that yields high library complexity and allows for the straightforward identification of individual m6A residues with reliable confidence metrics. Based on enhanced CLIP (eCLIP), our m6A-eCLIP (meCLIP) approach couples the improvements of eCLIP with the inclusion of an input sample and an easy-to-use computational pipeline to allow for precise calling of m6A sites at true single nucleotide resolution. As the effort to accurately identify m6As in an efficient and straightforward way intensifies, this method is a valuable tool for investigators interested in unraveling the m6A epitranscriptome.
Autocrine IL11 cis-signaling in hepatocytes is an initiating nexus between lipotoxicity and non-alcoholic steatohepatitis
Authors: Dong Jinrui , Adami Eleonora , Chothani Sonia P. , Viswanathan Sivakumar , Ng Benjamin , Lim Wei Wen , Singh Brijesh K. , Zhou Jin , Ko Nicole SJ. , Shekeran Shamini G. , Tan Jessie , Lim Sze Yun , Wang Mao , Lio Pei Min , Yen Paul M. , Schafer Sebastian , Cook Stuart A. , Widjaja Anissa A.
Published: March 2020

Background and aims

IL11 signaling is important in non-alcoholic steatohepatitis (NASH) but how it contributes to NASH pathologies beyond fibrosis is not known. Here we investigate the role of IL11 signaling in hepatocyte lipotoxicity.

Methods

Hepatocytes were stimulated with IL6, IL11, HyperIL6, or HyperIL11 alone or in the presence of soluble gp130 (sgp130) or soluble IL11RA (sIL11RA), or loaded with palmitate in the presence of IgG or anti-IL11RA (X209) antibodies or sgp130. Effects were assessed using colorimetric ALT, GSH, or ELISA assays, immunoblots, and flow cytometry. The relative contributions of IL11cis-versus -transsignalingin vivowas assessed in two preclinical NASH models using a high fat methionine/choline deficient diet or a Western diet with liquid fructose in C57BL6/Ntac mice injected with AAV8-Alb-Cre, AAV8-Alb-sgp130, in mice with hepatocyte-specific deletion ofIl11ra(CKO), and in mice with global deletion ofIl11rainjected with AAV8-Alb-mIl11ra or AAV8-Alb-sIl11ra. Livers and serum were collected; serum samples were analyzed using biochemistry and liver tissues were analyzed by histology, qPCR, immunobloting, hydroxyproline, and GSH assays.

Results

We show that lipid-laden hepatocytes secrete IL11, which acts via autocrinecis-signaling to cause lipoapoptosis. IL11 causes lipotoxic hepatocyte death through activation of non-canonical signaling pathways and increased NOX4-derived reactive oxygen species. In two preclinical models, hepatocyte-specific deletion ofIl11ra1protects mice from all aspects of NASH with beneficial effects on body weight. In accordance, restoration of IL11cis-signaling in hepatocytes only in mice globally deleted forIl11ra1reconstitutes steatosis and inflammation. Throughout, we found no evidence to support the existence of IL6 or IL11trans-signaling in the liver.

Conclusion

We conclude that autocrine IL11-mediated cell death underlies hepatocyte lipotoxicity and that liver fibrosis and inflammation occur subsequently. These data highlight a new disease mechanism for the transition from compensated fatty liver disease to NASH.
PSP2, a gene encoding RGG-motif protein, is a novel suppressor of clathrin heavy chain deficiency
Authors: Roy Debadrita , Garg Mani , Rajyaguru Purusharth I
Published: March 2020

Clathrin, made up of the heavy- and light-chains, constitutes one of the most abundant protein in vesicles involved in intracellular protein trafficking and endocytosis.YPR129W, which encodes RGG-motif containing translation repressor was identified as a part of multi-gene construct (SCD6) that suppressed clathrin deficiency. However, the contribution ofYPR129Walone in suppressing clathrin deficiency has not been documented. In this study we identifyYPR129Was a necessary and sufficient gene in a multigene construct SCD6 that suppresses clathrin deficiency. Importantly, we identify cytoplasmic RGG-motif protein encoding genePSP2as a novel suppressor of clathrin deficiency. Three other RGG-motif protein encoding genesSBP1, DED1andGBP2do not suppress clathrin deficiency.DHH1, a DEAD-box RNA helicase with translation repression activity also fails to rescue clathrin deficiency. α-factor secretion assay suggests that suppression of clathrin deficiency bySCD6andPSP2is not mediated by the rescue of the trans-Golgi network (TGN) protein sorting defect observed in the absence ofCHC1. Detailed domain analysis of the two suppressors reveals that the RGG-motif of both Scd6 and Psp2 is important for suppressing clathrin deficiency. Additionally, the Lsm domain deletion as well as the arginine to alanine mutation in the arginine methylation defective (AMD) mutant render Scd6 defective in suppressing clathrin deficiency. Overall based on our results usingSCD6andPSP2proteins, we identify a novel role of RGG-motif in suppressing clathrin deficiency. Since both the suppressors are RNA-binding granule-resident proteins, this study opens an exciting avenue for exploring the connection between clathrin function and cytoplasmic RNA metabolism.
Discovery of a 382-nt deletion during the early evolution of SARS-CoV-2
Authors: Su Yvonne CF , Anderson Danielle E , Young Barnaby E , Zhu Feng , Linster Martin , Kalimuddin Shirin , Low Jenny GH , Yan Zhuang , Jayakumar Jayanthi , Sun Louisa , Yan Gabriel Z , Mendenhall Ian H , Leo Yee-Sin , Lye David Chien , Wang Lin-Fa , Smith Gavin JD
Published: March 2020

To date, the SARS-CoV-2 genome has been considered genetically more stable than SARS-CoV or MERS-CoV. Here we report a 382-nt deletion covering almost the entire open reading frame 8 (ORF8) of SARS-CoV-2 obtained from eight hospitalized patients in Singapore. The deletion also removes the ORF8 transcription-regulatory sequence (TRS), which in turn enhances the downstream transcription of the N gene. We also found that viruses with the deletion have been circulating for at least four weeks. During the SARS-CoV outbreak in 2003, a number of genetic variants were observed in the human population [1], and similar variation has since been observed across SARS-related CoVs in humans and bats. Overwhelmingly these viruses had mutations or deletions in ORF8, that have been associated with reduced replicative fitness of the virus [2]. This is also consistent with the observation that towards the end of the outbreak sequences obtained from human SARS cases possessed an ORF8 deletion that may be associated with host adaptation [1]. We therefore hypothesise that the major deletion revealed in this study may lead to an attenuated phenotype of SARS-CoV-2.
Revealing the polarity of actin filaments by cryo-electron tomography
Authors: Martins Bruno , Sorrentino Simona , Chung Wen-Lu , Tatli Meltem , Medalia Ohad , Eibauer Matthias
Published: March 2020

The actin cytoskeleton plays a fundamental role in numerous cellular processes, such as cell motility, cytokinesis, and adhesion to the extracellular matrix. Revealing the polarity of individual actin filaments in cells, would foster an unprecedented understanding of cytoskeletal processes and their associated mechanical forces. Cryo-electron tomography provides the means for high-resolution structural imaging of cells. However, the low signal-to-noise ratio of cryo-tomograms obscures the high frequencies and therefore the polarity of actin filaments cannot be directly measured. Here, we developed an approach that enables to determine the polarity of actin filaments in cellular cryo-tomograms. We applied it to reveal the actin polarity distribution in focal adhesions, and show a linear relation between actin polarity and distance from the apical boundary of the adhesion site.
Extracellular Ca2+-sensitive fluorescent protein biosensor based on a collagen-binding domain
Authors: Okkelman Irina A. , McGarrigle Ryan , O’Carroll Shane , Berrio Daniel Carvajal , Schenke-Layland Katja , Hynes James , Dmitriev Ruslan I.
Published: March 2020

The importance of extracellular gradients of biomolecules becomes increasingly appreciated in the processes of tissue development and regeneration, in health and disease. In particular, dynamics of extracellular calcium concentration is rarely studied. Here, we present low affinity Ca2+biosensor based on Twitch-2B fluorescent protein fused with the cellulose- and collagen-binding peptides. These recombinant chimeric proteins can bind cellulose and collagen scaffolds and enable for scaffold-based biosensing of Ca2+in proximity of live 3D tissue models. We found that the Twitch-2B mutant is compatible with intensity-based ratiometric and fluorescence lifetime imaging microscopy (FLIM) measurement formats, under one- and two-photon excitation modes. Furthermore, the donor fluorescence lifetime of ColBD-Twitch displays response to [Ca2+] over a range of ∼2-2.5 ns, making it attractive biosensor for multiplexed FLIM microscopy assays. To evaluate performance of this biosensor in physiological measurements, we applied ColBD-Twitch to the live Lgr5-GFP mouse intestinal organoid culture and measured its responses to the changes in extracellular Ca2+upon chelation with EGTA. When we combined it with spectrally resolved FLIM of lipid droplets using Nile Red dye, we observed changes in cytoplasmic and basal membrane-associated lipid droplet composition in response to the extracellular Ca2+depletion, suggesting that intestinal epithelium can respond to and compensate such treatment. Altogether, our results demonstrate ColBD-Twitch as a prospective Ca2+sensor for multiplexed FLIM analysis in a complex 3D tissue environment.
Plasticity as an Underlying Mechanism of Tumor Heterogeneity in Breast Cancer
Authors: Akbar Muhammad Waqas , Isbilen Murat , Kucukkaraduman Baris , Canli Secil Demirkol , Dedeoglu Ege , Azizolli Shila , Cela Isli , Akcay Abbas Guven , Hakanoglu Hasim , Gure Ali Osmay
Published: March 2020

Breast cancer shows plasticity in terms of classification. Upon drug treatment and metastasis some tumors switch to another subtype leading to loss of response to therapy. In this study, we ask the question which molecular subclasses of breast cancer are more switchable upon drug therapy and metastasis. We used in silico data to classify breast cancer tumors in PAM50 molecular classes before treatment and after treatment using gene expression data. Similar analysis was performed for primary tumors and their metastatic growth. Our analysis showed that in both scenarios some breast tumors shift from one class to another. This suggests that patients who underwent chemotherapy but resulted in relapse or/and metastasis should be retyped for molecular subclass so that treatment protocol should be adopted according to those subtypes. Additionally, 20 genes were identified as biomarkers for metastasis in breast cancer.
Molecular evolution and developmental expression of melanin pathway genes in Lepidoptera
Authors: Kuwalekar Muktai , Deshmukh Riddhi , Padvi Ajay , Kunte Krushnamegh
Published: March 2020

Pigmentation is involved in a wide array of biological functions across insect orders, including body patterning, thermoregulation, and immunity. The melanin pathway, in particular, has been characterized in several species. However, molecular evolution of the genes involved in this pathway is poorly characterized, and their roles in pigmentation of early developmental stages are just beginning to be explored in non-model organisms. We traced the molecular evolution of six melanin pathway genes in 53 species of Lepidoptera covering butterflies and moths, and representing over 100 million years of diversification. We compared the rates of synonymous and nonsynonymous substitutions within and between these genes to study signatures of selection at the level of individual sites, genes, and branches of the gene tree. We found that molecular evolution of all six genes was governed by strong purifying selection. Yet, a number of sites showed signs of being under positive selection, including in the highly conserved domain regions of three genes. Further, we traced the expression of these genes across developmental stages, tissues, and sexes in thePapilio polytesbutterfly using a developmental transcriptome dataset. We observed that the expression patterns of the genes inP. polyteslargely reflected their known tissue-specific function in other species. The expression of sequentially acting genes in the melanin pathway was correlated. Interestingly, four out of six melanin pathway genes (ebony, pale, aaNAT, andDDC) showed a sexually dimorphic pattern of developmental heterochrony; i.e., females showed peak activity much earlier in pupal development compared to that of males. Our evolutionary and developmental analyses suggest that the vast diversity of wing patterning and pigmentation in Lepidoptera may have been aided largely by differential developmental regulation of genes in a highly conserved pathway, in which the sequence evolution of individual genes is highly constrained.
Disruption of oncogenic targeting by ISWI via phosphorylation of a prion-like domain
Authors: Chen Mark , Foster Joseph P. , Lock Ian C. , Leisenring Nathan H. , Daniel Andrea R. , Floyd Warren , Xu Eric S. , Davis Ian J. , Kirsch David G.
Published: March 2020

Chromosomal translocations generate oncogenic fusion proteins in approximately one-third of sarcomas, but how these proteins promote tumorigenesis and the effect of cancer therapies on their function are not well understood. Here, we reveal a molecular mechanism by which the fusion oncoprotein FUS-CHOP promotes tumor maintenance that also explains the remarkable radiation sensitivity of myxoid liposarcomas. We identified novel interactions between FUS-CHOP and chromatin remodeling complexes that regulate sarcoma cell proliferation. One of these chromatin remodelers, SNF2H, co-localizes with FUS-CHOP genome-wide at active enhancers. Following ionizing radiation, DNA damage response kinases phosphorylate the prion-like domain of FUS-CHOP to impede these protein-protein interactions, which are required for transformation. Therefore, the DNA damage response after irradiation disrupts oncogenic targeting of chromatin remodelers required for FUS-CHOP-driven sarcomagenesis.

Significance

Prion-like domains translocated in cancer have been shown to drive global epigenetic changes that are oncogenic. However, some translocation-driven cancers exhibit dramatic clinical responses to therapy, though the mechanism for these responses are not well-understood. Here we show that ionizing radiation can disrupt oncogenic interactions between a fusion oncoprotein and a chromatin remodeling complex, ISWI. This mechanism of disruption links phosphorylation of the prion-like domain in an oncogenic fusion protein to DNA damage after ionizing radiation and reveals that a dependence on oncogenic chromatin remodeling underlies sensitivity to radiation therapy in myxoid liposarcoma.
Myelin water imaging depends on white matter fiber orientation in the human brain
Authors: Birkl Christoph , Doucette Jonathan , Fan Michael , Hernandez-Torres Enedino , Rauscher Alexander
Published: March 2020

The multiexponential T2decay of the magnetic resonance imaging (MRI) signal from cerebral white matter can be separated into short components sensitive to myelin water and long components related to intra- and extracellular water. In this study we investigated to what degree the myelin water fraction (MWF) depends on the angle between white matter fibers and the main magnetic filed. Maps of MWF were acquired using multi echo CPMG and GRASE sequences. The CPMG sequence was acquired with a TR of 1073 ms, 1500 ms and 2000 ms. The fiber orientation was mapped with diffusion tensor imaging. By angle-wise pooling the voxels across the brain’s white matter, an orientation dependent MWF curve was generated. We found that MWF varied between 25% and 35% across different fiber orientations. The orientation dependency of the MWF is characterized by a dipole-dipole interaction model. Furthermore, the selection of the TR influences the orientation dependent and global white matter MWF. White matter fiber orientation induces a strong systematic bias on the estimation of MWF. This finding has important implications for future research and the interpretation of MWI results in previously published studies.
A bottom-up approach for thede novodesign of functional proteins
Authors: Yang Che , Sesterhenn Fabian , Bonet Jaume , van Aalen Eva , Scheller Leo , Abriata Luciano A , Cramer Johannes T , Wen Xiaolin , Rosset Stéphane , Georgeon Sandrine , Jardetzky Theodore , Krey Thomas , Fussenegger Martin , Merkx Maarten , Correia Bruno E
Published: March 2020

De novoprotein design has enabled the creation of novel protein structures. To design novel functional proteins, state-of-the-art approaches use natural proteins or first design protein scaffolds that subsequently serve as templates for the transplantation of functional motifs. In these approaches, the templates are function-agnostic and motifs have been limited to those with regular secondary structure. Here, we present a bottom-up approach to buildde novoproteins tailored to structurally complex functional motifs. We applied a bottom-up strategy to design scaffolds for four different binding motifs, including one bi-functionalized protein with two motifs. Thede novoproteins were functional as biosensors to quantify epitope-specific antibody responses and as orthogonal ligands to activate a signaling pathway in engineered mammalian cells. Altogether, we present a versatile strategy for the bottom-up design of functional proteins, applicable to a wide range of functional protein design challenges.
Powerful detection of polygenic selection and evidence of environmental adaptation in US beef cattle
Authors: Rowan Troy N. , Durbin Harly J. , Seabury Christopher M. , Schnabel Robert D. , Decker Jared E.
Published: March 2020

Selection on complex traits can rapidly drive evolution, especially in stressful environments. This polygenic selection does not leave intense sweep signatures on the genome, rather many loci experience small allele frequency shifts, resulting in large cumulative phenotypic changes. Directional selection and local adaptation are actively changing populations; but, identifying loci underlying polygenic or environmental selection has been difficult. We use genomic data on tens of thousands of cattle from three populations, distributed over time and landscapes, in linear mixed models with novel dependent variables to map signatures of selection on complex traits and local adaptation. We identify 207 genomic loci associated with an animal’s birth date, representing ongoing selection for monogenic and polygenic traits. Additionally, hundreds of additional loci are associated with continuous and discrete environments, providing evidence for local adaptation. These candidate loci highlight the nervous system’s possible role in local adaptation. While advanced technologies have increased the rate of directional selection in cattle, it has likely been at the expense of historically generated local adaptation, which is especially problematic in changing climates. When applied to large, diverse cattle datasets, these selection mapping methods provide an insight into how selection on complex traits continually shapes the genome. Further, by understanding the genomic loci implicated in adaptation, may help us breed more adapted and efficient cattle and begin understanding the basis for mammalian adaptation, especially in changing climates. These selection mapping approaches help clarify selective forces and loci in evolutionary, model, and agricultural contexts.

Author Summary

Interest in mapping the impacts of selection and local adaptation on the genome is increasing due to the novel stressors presented by climate change. Until now, approaches have largely focused on mapping “sweeps” on large-effect loci. Highly powered datasets that are both temporally and geographically distributed have not existed. Recently, large numbers of beef cattle have been genotyped across the United States, including influential individuals with cryopreserved semen. This has created multiple powerful datasets distributed over time and landscapes. Here, we map the recent effects of selection and local adaptation in three cattle populations. The results provide insight into the biology of mammalian adaptation and generate useful tools for selecting and breeding better-adapted cattle for a changing environment.
Structural basis for capsid recruitment and coat formation during HSV-1 nuclear egress
Authors: Draganova Elizabeth B. , Zhang Jiayan , Zhou Z. Hong , Heldwein Ekaterina E.
Published: March 2020

During herpesvirus infection, egress of nascent viral capsids from the nucleus is mediated by the viral nuclear egress complex (NEC). NEC deforms the inner nuclear membrane (INM) around the capsid by forming a hexagonal array. However, how the NEC coat interacts with the capsid and how curved coats are generated to enable budding is yet unclear. Here, by structure-guided truncations, confocal microscopy, and cryoelectron tomography, we show that binding of the capsid protein UL25 promotes the formation of NEC pentagons rather than hexagons. We hypothesize that during nuclear budding, binding of UL25 situated at the pentagonal capsid vertices to the NEC at the INM promotes formation of NEC pentagons that would anchor the NEC coat to the capsid. Incorporation of NEC pentagons at the points of contact with the vertices would also promote assembly of the curved hexagonal NEC coat around the capsid, leading to productive egress of UL25-decorated capsids.
Three-dimensional genome structure and chromatin accessibility reorganization duringin vivoinduction of human T cell tolerance
Authors: Li Ruifeng , Guo Huidong , Hou Yingping , Liu Shuoshuo , Wang Ming , Peng Ting , Zhao Xiang-Yu , Lu Liming , Han Yali , Shao Yiming , Chang Ying-Jun , Li Cheng , Huang Xiao-Jun
Published: March 2020

Achieving T cell tolerance is a pivotal goal for the field of transplantation and autoimmune diseases. Here, we characterized the gene expression profiles, 3D genome architecture and chromatin accessibility in human steady-state and tolerant T cells, which had been induced in healthy donors by granulocyte-colony-stimulating factorin vivo. We provided the first high-resolution 3D genomic landscape of human tolerant T cellsin vivoand identified highly expressed suppressor of cytokine signaling 1 (SOCS1), which is essential for maintaining T cell tolerance and was validated byex vivoexperiments. Mechanistically, SOCS1 is activated by STAT3, which mediates a new interaction between theSOCS1locus and downstream super-enhancers and is accompanied by the disruption of the CTCF loop between theSOCS1locus and upstream heterochromatin. This competitive regulation pattern between STAT3 and CTCF is present in the whole genome. Our study defines a regulatory model of transcription factors and provides insight into the induction of immune tolerance.
ProNetView-ccRCC: A web-based portal to interactively explore clear cell renal cell carcinoma proteogenomics networks
Authors: Kalayci Selim , Petralia Francesca , Wang Pei , Gümüş Zeynep H.
Published: March 2020

To better understand the molecular basis of cancer, the NCI’s Clinical Proteomics Tumor Analysis Consortium (CPTAC) has been performing comprehensive large-scale proteogenomic characterizations of multiple cancer types. Gene/protein regulatory networks has subsequently been derived based on these proteogenomic profiles, which serve as useful tools to gain system-level understanding of the molecular regulatory factories underlying the diseases. On the other hand, it remains a challenge to effectively visualize and navigate the resulting network models, which capture higher order structures in the proteogenomic profiles. There is a pressing need to have a new open community resource tool for intuitive visual exploration, interpretation and communication of these gene/protein regulatory networks by the cancer research community. In this work, we introduce ProNetView-ccRCC (http://ccrcc.cptac-network-view.org/), an interactive web-based network exploration portal for investigating phosphopeptide co-expression network inferred based on the CPTAC clear cell renal cell carcinoma (ccRCC) phosphoproteomics data. ProNetView-ccRCC enables quick, user-intuitive visual interactions with the ccRCC tumor phosphoprotein co-expression network comprised of 3,614 genes, as well as 30 functional pathway-enriched network modules. Users can interact with the network portal and can conveniently query for association between abundance of each phosphopeptide in the network and clinical variables such as tumor grade.
Expression, purification and crystal structure determination of a ferredoxin reductase from the actinobacteriumThermobifida fusca
Authors: Rodriguez Buitrago Jhon Alexander , Klünemann Thomas , Blankenfeldt Wulf , Schallmey Anett
Published: March 2020

Ferredoxin reductase FdR9 fromThermobifida fusca, a member of the oxygenase-coupled NADH-dependent ferredoxin reductase (FNR) family, catalyzes electron transfer from NADH to its physiological electron acceptor ferredoxin. It forms part of a three-component cytochrome P450 monooxygenase system inT. fusca. Here, FdR9 was overexpressed and purified and its crystal structure was determined at 1.8 Å resolution. The overall structure of FdR9 is similar to other members of the FNR family and is composed of an FAD-binding domain, an NAD-binding domain and a C-terminal domain. Activity measurements with FdR9 confirmed a strong preference for NADH as the cofactor. Comparison of the FAD- and NAD-binding domains of FdR9 with other ferredoxin reductases revealed the presence of conserved sequence motifs in the FAD-binding domain as well as several highly conserved residues involved in FAD and NAD cofactor binding. Moreover, the NAD-binding site of FdR9 contains a modified Rossmann fold motif, GxSxxS, instead of the classical GxGxxG motif.
Biological activity ofAjuga ivaextracts against the African cotton leafwormSpodoptera littoralis
Authors: Taha-Salaime Leena , Lebedev Galina , Abo-Nassar Jackline , Marzouk Sally , Inbar Moshe , Ghanim Murad , Aly Radi
Published: March 2020

The African cotton leafwormSpodoptera littoralis, a major crop pest worldwide, is controlled by chemical insecticides, leading to serious resistance problems.Ajugaplants contain phytoecdysteroids (analogs of arthropod steroid hormones that regulate metamorphoses) and clerodanes (diterpenoids exhibiting antifeedant activity). We analyzed phytoecdysteroids and clerodanes in leaf extracts of the IsraeliAjuga ivaby LC-TOF-MS and TLC, and their efficiency at reducingS. littoralisfitness. Castor bean leaves were smeared with an aqueous suspension of dried methanolic crude extract of phytoecdysteroid and clerodanes fromA. ivaleaves (50, 100 and 250 µg/µl). First and third instars ofS. littoralislarvae were fed with 1 treated leaf for 3 and 4 days, respectively. Mortality, larval weight gain, relative growth rate and survival were compared to feeding on control leaves. To evaluate and localizeA. ivacrude leaf extract activity in the insect gut, we used DAPI and phalloidin staining. Crude extract ofA. ivaleaves (50, 100 and 250 µg/µl) significantly increased mortality of first instarS. littoralislarvae (36%, 70% and 87%, respectively) compared to controls (6%). Third instar larval weight gain decreased significantly (by 52%, 44% and 30%, respectively), as did relative growth rate (–0.05 g/g day, compared to the relevant controls).S. littoralislarvae were further affected at later stages, with few survivors. Insect-gut staining showed that 250 µg/µl crude leaf extract reduces gut size, with relocation of nuclei and abnormal actin-filament organization. Our results demonstrate the potential ofA. ivaextract for alternative, environmentally safe insect-pest control.

Key Message

Insects cause severe damage to numerous crops and their control relies on pesticides. Green control is becoming increasingly popular due to concerns about the negative impacts of pesticides on the environment. Phytoecdysteroids are found in Ajuga plants and affect a wide range of insects at very low concentrations. Here we demonstrate that crude extract fromAjuga ivaalters the development ofSpodoptera littoralis. Phytoecdysteroids may therefore be beneficial in IPM programs.
Year-to-year crop shifts promote weed diversity in tropical permanent rainfed cultivation
Authors: Neyret Margot , de Rouw Anneke , Colbach Nathalie , Robain Henri , Soulileuth Bounsamay , Valentin Christian
Published: March 2020

In the past decades, the expansion and modernisation of agriculture in the mountainous areas of Southeast Asia has had severe impacts on biodiversity, as the once species-rich forests were turned into homogeneous fields receiving ample external inputs. A common feature of permanent cropping with annual crops is the frequent change of crop choice, depending on market opportunities or other motives. However, the precise effect of crop shifts on weeds in tropical areas is largely unknown. In this study, we investigated the short-term effect of crop sequences on the diversity of weed communities in smallholder fields in Northern Thailand. Crop choices were upland rice, maize, fallow and young tree plantations with or without intercrop. We counted the number of crop shifts and the number of crops involved during a 3-years period preceding weed sampling. We showed that the number of crop shifts did not affect weed density and biomass. However, herbaceous species number and diversity (measured as Shannon index) increased by 36% and 46% respectively, while herbaceous species dominance decreased by 38%, in fields with yearly crop shifts compared to fields with no shifts in the previous three years. The effect of a particular crop on diversity, or the effect of intercropping with young trees, was weaker. It was likely due to the more variable resources (especially light) in fields with two crop shifts, allowing species with different niches to co-exist. Crop type and frequent crop shifts did not affect shrub and tree species number, diversity or dominance. Some species were strongly associated with fields with no crop shift in the sequence (e.g. the treeAntidesma velutinosum) or to fields with two crop shifts in the sequence (e.g. the herbCentella asiatica, the C4grassDigitaria radicosa). Overall, this study showed that in this agronomical system, maintaining yearly crop shifts does not significantly affect weed abundance, but supports in-field plant species diversity, which is likely to impact the services provisioned by tropical mountainous agro-ecosystems

Highlights

Frequent crop shifts in a crop sequence increased weed richness and diversity.

Crop shifts had a stronger effect on weed richness and diversity than the current crop.

The number of crop shifts did not affect weed biomass and density.

Graphical abstract
Minimizing the number of optimizations for efficient community dynamic flux balance analysis
Authors: Brunner James D. , Chia Nicholas
Published: March 2020

Dynamic flux balance analysis uses a quasi-steady state assumption to calculate an organism’s metabolic activity at each time-step of a dynamic simulation, using the well-know technique of flux balance analysis. For microbial communities, this calculation is especially costly and involves solving a linear constrained optimization problem for each member of the community at each time step. However, this is unnecessary and inefficient, as prior solutions can be used to inform future time steps. Here, we show that a basis for the space of internal fluxes can be chosen for each microbe in a community and this basis can be used to simulate forward by solving a relatively inexpensive system of linear equations at most time steps, instead of the full optimization problem. Using our method, we can use this solution as long as the resulting metabolic activity remains within the optimization problem’s constraints (i.e. the solution remains feasible). As the solution becomes infeasible, it first becomes a feasible but degenerate solution to the optimization problem, and we can solve a different but related optimization problem to choose an appropriate basis to continue forward simulation. We show using an eight species community that this is an efficient and robust method for computing dynamic flux balance analysis simulations, and so is capable of simulating communities of organisms. We demonstrate that the method gives an approximately 85% speed-up per organism over the standard and widely used method. Our method has been implemented in thePythonlanguage and source code is available athttps://github.com/jdbrunner/surfin_fbaand in the Python Package Index (PyPI) assurfinFBA.

Author summary

The standard method in the field for dynamic flux balance analysis carries a prohibitively high computational cost because it requires solving a linear optimization problem at each time-step. We have developed a novel method for producing solutions to this dynamical system which greatly reduces the number of optimization problems that must be solved. We prove mathematically that we can solve the optimization problem once and simulate the system forward as an ordinary differential equation for some time interval, and solutions to this ODE provide solutions to the optimization problem. Eventually, the system reaches an easily checkable condition which implies that another optimization problem must be solved. We compare our method with the classical method to validate that it provides equivalent solutions in much lower computational time.
Landmark navigation in a mantis shrimp
Authors: Patel Rickesh N. , Cronin Thomas W.
Published: March 2020

Mantis shrimp are predatory crustaceans that commonly occupy burrows in shallow, tropical waters worldwide. Most of these animals inhabit structurally complex, benthic environments where many potential landmarks are available. Mantis shrimp of the speciesNeogonodactylus oerstediireturn to their burrows between foraging excursions using path integration, a vector-based navigational strategy that is prone to accumulated error. Here we show thatN. oerstediican navigate using landmarks in parallel with their path integration system, offseting error generated when navigating using solely path integration. We also report that when the path integration and landmark navigation systems are placed in conflict,N. oerstediiwill orient using either system or even switch systems enroute. How they make the decision to trust one navigational system over another is unclear. These findings add to our understanding of the refined navigational toolkitN. oerstediirelies upon to efficiently navigate back to its burrow, complementing its robust, yet error prone, path integration system with landmark guidance.
Age-Dependent Changes in the Progenitor Translatome Coordinated in part byTsc1Increase Perception of Signaling Inputs to End Nephrogenesis
Authors: Brunskill Eric , Jarmas Alison , Chaturvedi Praneet , Kopan Raphael
Published: March 2020

Mammalian nephron endowment is determined by the coordinated cessation of nephrogenesis in independent niches. Here we report that in young niches, cellular Wnt agonists are poorly translated, Fgf20 levels are high and R-spondin levels are low, resulting in a pro self-renewal environment. By contrast, older niches are low in Fgf20 and high in R-spondin, with increased cellular translation of Wnt agonists, including the signalosome-promoting Tmem59. This suggests a hypothesis that the tipping point for nephron progenitor exit from the niche is controlled by the gradual increase in stability and clustering of Wnt/Fzd complexes in individual cells, enhancing the response to ureteric bud-derived Wnt9b inputs and driving differentiation. We showTsc1hemizygosity differentially promoted translation of Wnt antagonists over agonists, expanding a transitional (Six2+, Cited1+, Wnt4+) state and delaying the tipping point. As predicted by these findings, reducing Rspo3 dosage in nephron progenitors or Tmem59 globally increased nephron numbersin vivo.
Protein dynamics enables phosphorylation of buried residues in Cdk2/Cyclin A-bound p27
Authors: Henriques João , Lindorff-Larsen Kresten
Published: March 2020

Proteins carry out a wide range of functions that are tightly regulated in space and time. Protein phosphorylation is the most common post-translation modification of proteins and plays key roles in the regulation of many biological processes. The finding that many phosphorylated residues are not solvent exposed in the unphosphorylated state opens several questions for understanding the mechanism that underlies phosphorylation and how phosphorylation may affect protein structures. First, since kinases need access to the phosphorylated residue, how do such buried residues become modified? Second, once phosphorylated, what are the structural effects of phosphorylation of buried residues and do they lead to changed conformational dynamics. We have used the ternary complex between p27, Cdk2 and Cyclin A to study these questions using enhanced sampling molecular dynamics simulations. In line with previous NMR and single-molecule fluorescence experiments we observe transient exposure of Tyr88 in p27, even in its unphosphorylated state. Once Tyr88 is phosphorylated, we observe a coupling to a second site, thus making Tyr74 more easily exposed, and thereby the target for a second phosphorylation step. Our observations provide atomic details on how protein dynamics plays a role in modulating multi-site phosphorylation in p27, thus supplementing previous experimental observations. More generally, we discuss how the observed phenomenon of transient exposure of buried residues may play a more general role in regulating protein function.

Significance Statement

Protein phosphorylation is a common post-translation modification and is carried out by kinases. While many phosphorylation sites are located in disordered regions of proteins or in loops, a surprisingly large number of modification sites are buried inside folded domains. This observation led us to ask the question of how kinases gain access to such buried residues. We used the complex between p27, a regulator of cell cycle progression, and Cyclin-dependent kinase 2/Cyclin A to study this problem. We hypothesized that transient exposure of buried tyrosines in p27 to the solvent would make them accessible to kinases, explaining how buried residues get modified. We provide an atomic-level description of these dynamic processes revealing how protein dynamics plays a role in regulation.