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Article
| Open AccessAssessment of community efforts to advance network-based prediction of protein–protein interactions
Comprehensive understanding of the human protein-protein interaction network, aka the human interactome, can provide important insights into the molecular mechanisms of complex biological processes and diseases. Here the authors summarize the community efforts initiated by the International Network Medicine Consortium to benchmark the ability of 26 representative network-based methods to predict protein-protein interactions.
- Xu-Wen Wang
- , Lorenzo Madeddu
- & Yang-Yu Liu
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Article
| Open AccessPrecise programming of multigene expression stoichiometry in mammalian cells by a modular and programmable transcriptional system
Context-dependency of mammalian transcriptional elements has hindered the quantitative investigation of multigene expression stoichiometry and its biological functions. Here the authors present a host-orthogonal transcriptional system that drives tunable gene expression in mammalian cells, enabling predictive fine-tuning of multi-gene expression stoichiometry and the production optimization of virus-like particles from mammalian cells.
- Chenrui Qin
- , Yanhui Xiang
- & Chunbo Lou
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Article
| Open AccessA cybergenetic framework for engineering intein-mediated integral feedback control systems
Homeostasis and robust perfect adaptation are remarkable features of living cells. Here, to synthetically achieve this, the authors present a theoretical and experimental framework using inteins to implement compact biomolecular integral feedback controllers.
- Stanislav Anastassov
- , Maurice Filo
- & Mustafa Khammash
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Article
| Open AccessSize limits the sensitivity of kinetic schemes
Living things rely on extremely sensitive molecular circuits. Here, authors uncover a universal structural limit on kinetic scheme sensitivity, with implications for gene regulation & the functions of condensates.
- Jeremy A. Owen
- & Jordan M. Horowitz
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Article
| Open AccessPeriodic temperature changes drive the proliferation of self-replicating RNAs in vesicle populations
How primordial cells could achieve inheritance of encapsulated components is still an open question. Here, the authors show that ribozymes can assemble in active forms and replicate in populations of membrane vesicles thanks to freeze-thaw cycles.
- Elia Salibi
- , Benedikt Peter
- & Hannes Mutschler
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Article
| Open AccessAn optogenetic toolkit for light-inducible antibiotic resistance
Antibiotics are a key control mechanism for synthetic biology and microbiology. Here, using an optogenetic recombinase, the authors develop genetic constructs where antibiotic resistance levels in bacteria can be controlled using light.
- Michael B. Sheets
- , Nathan Tague
- & Mary J. Dunlop
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Article
| Open AccessFour-dimensional trapped ion mobility spectrometry lipidomics for high throughput clinical profiling of human blood samples
The circulatory lipidome is a valuable source for disease markers, but reliable marker discovery requires continuous development of lipidomic methods for large-scale clinical profiling. Here, the authors present a 4-dimensional lipidomics solution for confident and reproducible blood lipidome profiling.
- Raissa Lerner
- , Dhanwin Baker
- & Laura Bindila
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Article
| Open AccessParallelized multidimensional analytic framework applied to mammary epithelial cells uncovers regulatory principles in EMT
Epithelial-to-mesenchymal transition (EMT) is a complex process regulated at multiple molecular levels. Here, the authors implement an analytic framework - PAMAF - to integrate data from twelve distinct omics modalities, which they use to understand the molecular changes and regulation during EMT in vitro.
- Indranil Paul
- , Dante Bolzan
- & Andrew Emili
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Article
| Open AccessDNA-Aeon provides flexible arithmetic coding for constraint adherence and error correction in DNA storage
The extensive information capacity of DNA makes it an attractive alternative to traditional data storage. DNA-Aeon is a DNA data storage solution that can correct all error types commonly observed in DNA storage, while encoding data into sequences that meet user-defined constraints such as GC content, homopolymer length, and no undesired motifs.
- Marius Welzel
- , Peter Michael Schwarz
- & Dominik Heider
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Article
| Open AccessA split ribozyme that links detection of a native RNA to orthogonal protein outputs
RNA provides a unique readout of a cell’s identity, physiologic status, and phenotype. Here the authors deliver an RNA sensing system that can use the information contained within cellular RNA to selectively control the activity of genetic programs.
- Lauren Gambill
- , August Staubus
- & James Chappell
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Article
| Open AccessMapping lesion-specific response and progression dynamics and inter-organ variability in metastatic colorectal cancer
Understanding the heterogeneity of growth, response to therapy and progression dynamics in metastatic colorectal cancer (mCRC) remains critical. Here, the authors analyse lesion-specific response heterogeneity in 4,308 mCRC patients and find that organ-level progression sequence is associated with long-term survival.
- Jiawei Zhou
- , Amber Cipriani
- & Yanguang Cao
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Article
| Open AccessJag1-Notch cis-interaction determines cell fate segregation in pancreatic development
Notch signaling is crucial for pancreatic cell fate choice. With mathematical modeling and experiments, Xu et al. provides new insights into how different Notch ligands and Hes1 oscillation guide the spatial-temporal dynamics of cell differentiation.
- Xiaochan Xu
- , Philip Allan Seymour
- & Palle Serup
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Article
| Open AccessFinding shortest and nearly shortest path nodes in large substantially incomplete networks by hyperbolic mapping
Shortest paths between the nodes of complex networks are challenging to obtain if the information on network structure is incomplete. Here the authors show that the shortest paths are geometrically localized in hyperbolic representations of networks, and can be detected even if the large amount of network links are missing. The authors demonstrate the utility of geometric pathfinding in Internet routing and the reconstruction of cellular pathways.
- Maksim Kitsak
- , Alexander Ganin
- & Igor Linkov
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Article
| Open AccessEvidence that endosperm turgor pressure both promotes and restricts seed growth and size
Using computational simulations and experiments, the authors propose a mechanical model of seed growth where endosperm pressure directly induces growth but indirectly inhibits it through force-dependent testa wall stiffening.
- Audrey Creff
- , Olivier Ali
- & Benoit Landrein
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Article
| Open AccessBenchmarking tools for detecting longitudinal differential expression in proteomics data allows establishing a robust reproducibility optimization regression approach
Longitudinal proteomics holds great promise for biomarker discovery, but the data interpretation has remained a challenge. Here, the authors evaluate several tools to detect longitudinal differential expression in proteomics data and introduce RolDE, a robust reproducibility optimization approach.
- Tommi Välikangas
- , Tomi Suomi
- & Laura L. Elo
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Article
| Open AccessAccuracy and data efficiency in deep learning models of protein expression
Synthetic biology often involves engineering microbial strains to express high-value proteins. Here the authors build deep learning predictors of protein expression from sequence that deliver accurate models with fewer data than previously assumed, helping to lower costs of model-driven strain design.
- Evangelos-Marios Nikolados
- , Arin Wongprommoon
- & Diego A. Oyarzún
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Article
| Open AccessBiosynthesis of mushroom-derived type II ganoderic acids by engineered yeast
The biosynthetic pathway of type II ganoderic acids (GAs) in Ganoderma lucidum, a traditional medicinal mushroom, is unknown. Here, the authors assemble the genome of type II GAs accumulating accession, identify CYPs involving in type II GAs biosynthesis, and achieve their production in engineered baker’s yeast.
- Wei Yuan
- , Chenjian Jiang
- & Han Xiao
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Article
| Open AccessMolecular models of multiple sclerosis severity identify heterogeneity of pathogenic mechanisms
Multiple sclerosis (MS) changes the composition of the CSF. Here the authors use patient samples and aggregate CSF biomarkers into models that predict disability across all MS phenotypes, and identify potentially causal mechanisms and molecular disease heterogeneity.
- Peter Kosa
- , Christopher Barbour
- & Bibiana Bielekova
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Article
| Open AccessInterpretable and tractable models of transcriptional noise for the rational design of single-molecule quantification experiments
Here the authors explore the distributional differences expected from distinct biophysical models of transcription and show how measurements from single-cell genomics experiments can shed light on the underlying biological processes.
- Gennady Gorin
- , John J. Vastola
- & Lior Pachter
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Article
| Open AccessSlowest possible replicative life at frigid temperatures for yeast
It is unclear what constraints exist on cellular life in frigid environments. Here, the authors demonstrate that reactive oxygen species and gene-expression speed impose a barrier to replication at low temperatures in yeast, with lower levels enabling quicker replication, and develop a model to describe this phenomenon.
- Diederik S. Laman Trip
- , Théo Maire
- & Hyun Youk
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Article
| Open AccessIncreases in reef size, habitat and metacommunity complexity associated with Cambrian radiation oxygenation pulses
During the Cambrian Radiation, oxygenation occurred in a series of short pulses. Here, the authors quantify episodic changes in reef size, extent of habitat and in metacommunity ecological complexity associated with these oxygenation pulses by examining archaeocyath sponges.
- Andrey Yu. Zhuravlev
- , Emily G. Mitchell
- & Amelia Penny
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Article
| Open AccessIntegrated proteomic and transcriptomic landscape of macrophages in mouse tissues
Macrophage is located in different tissue to serve diverse functions. Here the authors use mass spectrometry and bulk RNA-sequencing to profile 11 mouse macrophage populations from 8 tissues, and combine their de novo data with public datasets to report an integrated proteomic and transcriptomic landscape of mouse macrophage as a valuable resource.
- Jingbo Qie
- , Yang Liu
- & Chen Ding
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Article
| Open AccessGenetically personalised organ-specific metabolic models in health and disease
Here, the authors present a method to build genetically personalised metabolic models across tissues to estimate individualised reaction fluxes. A fluxome-wide association study in UK Biobank identifies fluxes associated with metabolites and coronary artery disease.
- Carles Foguet
- , Yu Xu
- & Michael Inouye
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Article
| Open AccessEngineering receptors in the secretory pathway for orthogonal signalling control
Artificial receptors targeted to the secretory pathway often fail to exhibit the expected activity due to post-translational modifications and/or improper folding. Here, the authors engineer diverse synthetic receptors that reside in the cytoplasm, inside the endoplasmic reticulum, or on the plasma membrane through orientation adjustment of the receptor parts and by elimination of dysfunctional PTMs sites.
- Mohamed Mahameed
- , Pengli Wang
- & Martin Fussenegger
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Article
| Open AccessEnhanced access to the human phosphoproteome with genetically encoded phosphothreonine
Protein phosphorylation is a ubiquitous post-translational modification used to regulate cellular processes and proteome architecture by modulating protein-protein interactions. Here the authors optimize genetically encoded phosphothreonine to study the regulation of CHK2 kinase using large-scale DNA arrays that enable phosphoproteome expression techniques to identify sitespecific overlap between CHK2 substrates and 14-3-3 interactions.
- Jack M. Moen
- , Kyle Mohler
- & Jesse Rinehart
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Article
| Open AccessKinetics of mRNA nuclear export regulate innate immune response gene expression
The UCLA Ribonomics group reports that the nuclear export efficiency of innate immune mRNAs varies over a hundred-fold range such that for many genes only a small fraction of the newly synthesized premRNA reaches the cytoplasm. They show that nuclear export and cytoplasmic decay rates are correlated thereby ensuring similar expression levels of short-lived and long-lived mRNAs.
- Diane Lefaudeux
- , Supriya Sen
- & Sri Kosuri
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Article
| Open AccessMulti-omics signatures of the human early life exposome
Environmental exposures in early life can have lasting health effects, but the molecular mechanisms are not well understood. Here, the authors discover >1000 associations between exposure factors and child multi-omics profiles, revealing signatures for diet, toxic chemical compounds, essential trace elements, and weather conditions.
- Léa Maitre
- , Mariona Bustamante
- & Martine Vrijheid
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Article
| Open AccessAn atlas of amyloid aggregation: the impact of substitutions, insertions, deletions and truncations on amyloid beta fibril nucleation
By comprehensively mapping the impact that different classes of mutations (substitutions, insertions, deletions) have on the ability of the amyloid beta peptide to nucleate amyloids, the authors identify a large set of likely pathogenic variants of amyloid beta that are specifically enriched at its polar N-terminal region.
- Mireia Seuma
- , Ben Lehner
- & Benedetta Bolognesi
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Article
| Open AccessFeedforward growth rate control mitigates gene activation burden
Heterologous gene activation causes non-physiological burden on cellular resources that cells are unable to adjust to. Here the authors present a tunable, modular, and portable feedforward controller that allows dynamic modulation of a genes expression to possibly high-levels without substantially affecting growth rate.
- Carlos Barajas
- , Hsin-Ho Huang
- & Domitilla Del Vecchio
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Article
| Open AccessA Glb1-2A-mCherry reporter monitors systemic aging and predicts lifespan in middle-aged mice
Monitoring the aging process in vivo is challenging. Here the authors generate a Glb1+/m‒Glb1-2A-mCherry (GAC) reporter mouse model, where the GAC signal is consistently correlated with established biomarkers of cellular senescence, cardiac hypertrophy and shortened lifespan, which may prove helpful for studies developing anti-aging interventions.
- Jie Sun
- , Ming Wang
- & Baohua Liu
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Article
| Open AccessTwo simple movement mechanisms for spatial division of labour in social insects
Ant and honeybee workers specialize on certain tasks and also on zones within the nest; but how do they avoid straying into the wrong zone? The authors conduct automated tracking experiments following thousands of individuals, revealing that workers use context-dependent rules to navigate inside the nest.
- Thomas O. Richardson
- , Nathalie Stroeymeyt
- & Laurent Keller
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Article
| Open AccessTransposable elements orchestrate subgenome-convergent and -divergent transcription in common wheat
How subgenome-divergent and -convergent transcription is mediated and harmonized in hexaploid common wheat genome remains unclear. Here, via characterizing the cistrome maps, the authors reveal that transposon elements with transcription factor binding ability have the potential to make the contribution.
- Yuyun Zhang
- , Zijuan Li
- & Yijing Zhang
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Article
| Open AccessIntrinsic brain dynamics in the Default Mode Network predict involuntary fluctuations of visual awareness
The default mode network (DMN) is known to be involved in consciousness. Here the authors show intrinsic EEG oscillations in default mode network can predict upcoming involuntarily perceptual transitions.
- Dian Lyu
- , Shruti Naik
- & Emmanuel A. Stamatakis
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Article
| Open AccessIntegrase-mediated differentiation circuits improve evolutionary stability of burdensome and toxic functions in E. coli
Improving evolution stability of engineered functions is important for bioproduction and synthetic biology. Here, the authors developed an integrase-recombination-based terminal differentiation gene circuit in E. coli to improve the evolutionary stability of engineered function in a general manner.
- Rory L. Williams
- & Richard M. Murray
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Article
| Open AccessFormation of synthetic RNA protein granules using engineered phage-coat-protein -RNA complexes
Condensates composed of RNA and proteins are biologically vital but generally poorly understood. Here, the authors engineer synthetic RNA-protein condensates and show that gel-like condensates form as a result of liquid-gel phase separation in a specific and selective fashion.
- Naor Granik
- , Noa Katz
- & Roee Amit
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Article
| Open AccessSystematic characterization of cancer transcriptome at transcript resolution
Modification of transcribed mRNAs enables regulation of transcription but its extent in cancer cells is incompletely understood. Here, the authors analyse transcript assembly in over 1000 cancer cell lines and find unannotated transcripts are common, and are associated with drug sensitivity.
- Wei Hu
- , Yangjun Wu
- & Shengli Li
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Article
| Open AccessCircuit-guided population acclimation of a synthetic microbial consortium for improved biochemical production
Achieving stable production by co-culturing multiple microorganisms is often challenging due to difficulties in controlling its population. Here, the authors develop a “population guider” that can acclimate a population to higher production.
- Chae Won Kang
- , Hyun Gyu Lim
- & Gyoo Yeol Jung
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Article
| Open AccessInducible plasmid copy number control for synthetic biology in commonly used E. coli strains
The ability to externally control gene expression has been important for all areas of biological research, especially for synthetic biology. Here the authors present plasmid TULIP which offers DNA copy number control via chemical induction to accelerate the design, prototyping, and reuse of gene circuits in diverse contexts.
- Shivang Hina-Nilesh Joshi
- , Chentao Yong
- & Andras Gyorgy
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Article
| Open AccessAbsolute protein quantification using fluorescence measurements with FPCountR
A challenge in synthetic biology is the empirical characterisation of genetic parts. Here the authors present FPCountR, a validated method and accompanying R package that enables the precise quantification of fluorescent protein reporters per bacterial cell to be enumerated in ‘proteins per cell’ or nanomolar units without requiring protein purification.
- Eszter Csibra
- & Guy-Bart Stan
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Article
| Open AccessUnderstanding fibrosis pathogenesis via modeling macrophage-fibroblast interplay in immune-metabolic context
Renal fibrosis is a progressive process with complex etiopathology, causing organ failure. Here authors present a mathematical model, based on an in vitro system faithfully contemplating macrophage-fibroblast interaction and the metabolic-immunologic signals that are affecting kidney fibrosis, that is applicable to kidney transplant failure.
- Elisa Setten
- , Alessandra Castagna
- & Massimo Locati
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Article
| Open AccessRevealing β-TrCP activity dynamics in live cells with a genetically encoded biosensor
β-TrCP plays an important role in diverse cellular processes such as the cell cycle and inflammation. Here the authors develop a biosensor for β-TrCP activity and use it to investigate β-TrCP dynamics during the cell cycle, and to screen a small-molecule library for β-TrCP activators and inhibitors.
- Debasish Paul
- , Stephen C. Kales
- & Steven D. Cappell
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Article
| Open AccessMicro-scale functional modules in the human temporal lobe
The sensory cortices of many mammals consist of modules in the form of cortical columns. By analyzing functional connectivity and neural responses to visual stimuli, the authors show that this organization may extend to the human temporal lobe.
- Julio I. Chapeton
- , John H. Wittig Jr
- & Kareem A. Zaghloul
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Article
| Open AccessProteome effects of genome-wide single gene perturbations
Protein abundance is controlled at the transcriptional, translational and posttranslational levels. Here, Öztürk et al. determine proteome changes resulting from individual knockout of 3308 nonessential genes in the yeast S. pombe, infer gene functionality, and show that protein upregulation under stable transcript expression utilizes optimal codons.
- Merve Öztürk
- , Anja Freiwald
- & Falk Butter
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Article
| Open AccessA synthetic transcription platform for programmable gene expression in mammalian cells
Precise and scalable regulation of gene expression in mammalian cells is challenging. Here, the authors created a highly tunable CRISPR-based synthetic transcription system for programmable control of mammalian gene expression and cellular activity.
- William C. W. Chen
- , Leonid Gaidukov
- & Timothy K. Lu
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Article
| Open AccessIn vitro assembly, positioning and contraction of a division ring in minimal cells
Constructing a minimal protein machinery for self-division of membrane compartments is a major goal of bottom-up synthetic biology. Here, authors achieved the assembly, placement and onset of contraction of a minimal division ring in lipid vesicles.
- Shunshi Kohyama
- , Adrián Merino-Salomón
- & Petra Schwille
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Article
| Open AccessInferring differential subcellular localisation in comparative spatial proteomics using BANDLE
Changes in protein subcellular localization can be determined using mass spectrometry. Here, the authors present a statistical approach to determine relocalising proteins from spatial proteomics experiments.
- Oliver M. Crook
- , Colin T. R. Davies
- & Kathryn S. Lilley
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Article
| Open AccessDifferential nuclear import sets the timing of protein access to the embryonic genome
Here the authors address how embryos control the timing of specific gene activation in early frog development. They find transcription factors for early gene activation are maternally loaded and remain at constant levels, and rather that order of activation is based on their sequential entry into the nucleus based largely on their respective affinity to importins.
- Thao Nguyen
- , Eli J. Costa
- & Martin Wühr
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Article
| Open AccessHOXA9 has the hallmarks of a biological switch with implications in blood cancers
HOXA9 plays an important role in acute myeloid leukaemia (AML), but its relevance for other blood malignancies is unclear. Here, the authors show that HOXA9 has a binary switch function that can clinically stratify AML patients, and model how the interactions with JAK2, TET2 and NOTCH impact myeloproliferative neoplasms.
- Laure Talarmain
- , Matthew A. Clarke
- & Benjamin A. Hall
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Article
| Open AccessA deeper understanding of system interactions can explain contradictory field results on pesticide impact on honey bees
Pesticide impact on honey bees under field conditions remains elusive. Here, the authors combine a systems biology approach and laboratory experiments to show that the immune suppressive effect of the pathogen deformed wing virus can be responsible for the disparity amongst honey bee experiments.
- Dimitri Breda
- , Davide Frizzera
- & Francesco Nazzi
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