RIKEN Center for Computational Science

Regulated transcription controls the diversity, developmental pathways and spatial organization of the hundreds of cell types that make up a mammal. Using single-molecule cDNA sequencing, we mapped transcription start sites (TSSs) and their usage in human and mouse primary cells, cell lines and tissues to produce a comprehensive overview of mammalian gene expression across the human body. We find that few genes are truly ‘housekeeping’, whereas many mammalian promoters are composite entities composed of several closely separated TSSs, with independent cell-type-specific expression profiles. TSSs specific to different cell types evolve at different rates, whereas promoters of broadly expressed genes are the most conserved. Promoter-based expression analysis reveals key transcription factors defining cell states and links them to binding-site motifs. The functions of identified novel transcripts can be predicted by coexpression and sample ontology enrichment analyses. The functional annotation of the mammalian genome 5 (FANTOM5) project provides comprehensive expression profiles and functional annotation of mammalian cell-type-specific transcriptomes with wide applications in biomedical research. A study from the FANTOM consortium using single-molecule cDNA sequencing of transcription start sites and their usage in human and mouse primary cells, cell lines and tissues reveals insights into the specificity and diversity of transcription patterns across different mammalian cell types. FANTOM5 (standing for functional annotation of the mammalian genome 5) is the fifth major stage of a major international collaboration that aims to dissect the transcriptional regulatory networks that define every human cell type. Two Articles in this issue of Nature present some of the project's latest results. The first paper uses the FANTOM5 panel of tissue and primary cell samples to define an atlas of active, in vivo bidirectionally transcribed enhancers across the human body. These authors show that bidirectional capped RNAs are a signature feature of active enhancers and identify more than 40,000 enhancer candidates from over 800 human cell and tissue samples. The enhancer atlas is used to compare regulatory programs between different cell types and identify disease-associated regulatory SNPs, and will be a resource for studies on cell-type-specific enhancers. In the second paper, single-molecule sequencing is used to map human and mouse transcription start sites and their usage in a panel of distinct human and mouse primary cells, cell lines and tissues to produce the most comprehensive mammalian gene expression atlas to date. The data provide a plethora of insights into open reading frames and promoters across different cell types in addition to valuable annotation of mammalian cell-type-specific transcriptomes.

Although fluorescence microscopy provides a crucial window into the physiology of living specimens, many biological processes are too fragile, are too small, or occur too rapidly to see clearly with existing tools. We crafted ultrathin light sheets from two-dimensional optical lattices that allowed us to image three-dimensional (3D) dynamics for hundreds of volumes, often at subsecond intervals, at the diffraction limit and beyond. We applied this to systems spanning four orders of magnitude in space and time, including the diffusion of single transcription factor molecules in stem cell spheroids, the dynamic instability of mitotic microtubules, the immunological synapse, neutrophil motility in a 3D matrix, and embryogenesis in Caenorhabditis elegans and Drosophila melanogaster. The results provide a visceral reminder of the beauty and the complexity of living systems.

The recent chemical exfoliation of layered MAX phase compounds to novel two-dimensional transition metal carbides and nitrides, the so-called MXenes, has brought a new opportunity to materials science and technology.

Here, using further optimized 3D culture that allows highly selective induction and long-term growth of human ES cell (hESC)-derived cortical neuroepithelium, we demonstrate unique aspects of self-organization in human neocorticogenesis. Self-organized cortical tissue spontaneously forms a polarity along the dorsocaudal-ventrorostral axis and undergoes region-specific rolling morphogenesis that generates a semispherical structure. The neuroepithelium self-forms a multilayered structure including three neuronal zones (subplate, cortical plate, and Cajal-Retzius cell zones) and three progenitor zones (ventricular, subventricular, and intermediate zones) in the same apical-basal order as seen in the human fetal cortex in the early second trimester. In the cortical plate, late-born neurons tend to localize more basally to early-born neurons, consistent with the inside-out pattern seen in vivo. Furthermore, the outer subventricular zone contains basal progenitors that share characteristics with outer radial glia abundantly found in the human, but not mouse, fetal brain. Thus, human neocorticogenesis involves intrinsic programs that enable the emergence of complex neocortical features.

The Hippo signaling pathway plays an important role in regulation of cell proliferation. Cell density regulates the Hippo pathway in cultured cells; however, the mechanism by which cells detect density remains unclear. In this study, we demonstrated that changes in cell morphology are a key factor. Morphological manipulation of single cells without cell-cell contact resulted in flat spread or round compact cells with nuclear or cytoplasmic Yap, respectively. Stress fibers increased in response to expanded cell areas, and F-actin regulated Yap downstream of cell morphology. Cell morphology- and F-actin-regulated phosphorylation of Yap, and the effects of F-actin were suppressed by modulation of Lats. Our results suggest that cell morphology is an important factor in the regulation of the Hippo pathway, which is mediated by stress fibers consisting of F-actin acting upstream of, or on Lats, and that cells can detect density through their resulting morphology. This cell morphology (stress-fiber)-mediated mechanism probably cooperates with a cell-cell contact (adhesion)-mediated mechanism involving the Hippo pathway to achieve density-dependent control of cell proliferation.

Microelectrode arrays and microprobes have been widely utilized to measure neuronal activity, both in vitro and in vivo. The key advantage is the capability to record and stimulate neurons at multiple sites simultaneously. However, unlike the single-cell or single-channel resolution of intracellular recording, microelectrodes detect signals from all possible sources around the sensor. Here, we review the current understanding of microelectrode signals and the techniques for analyzing them. We introduce the ongoing advancements in microelectrode technology, with focus on achieving higher resolution and quality of recordings by means of monolithic integration with on-chip circuitry. We show how recent advanced microelectrode array measurement methods facilitate the understanding of single neurons as well as network function.

Specialized computational chemistry packages have permanently reshaped the landscape of chemical and materials science by providing tools to support and guide experimental efforts and for the prediction of atomistic and electronic properties. In this regard, electronic structure packages have played a special role by using first-principle-driven methodologies to model complex chemical and materials processes. Over the past few decades, the rapid development of computing technologies and the tremendous increase in computational power have offered a unique chance to study complex transformations using sophisticated and predictive many-body techniques that describe correlated behavior of electrons in molecular and condensed phase systems at different levels of theory. In enabling these simulations, novel parallel algorithms have been able to take advantage of computational resources to address the polynomial scaling of electronic structure methods. In this paper, we briefly review the NWChem computational chemistry suite, including its history, design principles, parallel tools, current capabilities, outreach, and outlook.

refers to the microscale processes that affect cloud and precipitation particles and is a key linkage among the various components of Earth's atmospheric water and energy cycles. The representation of microphysical processes in models continues to pose a major challenge leading to uncertainty in numerical weather forecasts and climate simulations. In this paper, the problem of treating microphysics in models is divided into two parts: (i) how to represent the population of cloud and precipitation particles, given the impossibility of simulating all particles individually within a cloud, and (ii) uncertainties in the microphysical process rates owing to fundamental gaps in knowledge of cloud physics. The recently developed Lagrangian particle-based method is advocated as a way to address several conceptual and practical challenges of representing particle populations using traditional bulk and bin microphysics parameterization schemes. For addressing critical gaps in cloud physics knowledge, sustained investment for observational advances from laboratory experiments, new probe development, and next-generation instruments in space is needed. Greater emphasis on laboratory work, which has apparently declined over the past several decades relative to other areas of cloud physics research, is argued to be an essential ingredient for improving process-level understanding. More systematic use of natural cloud and precipitation observations to constrain microphysics schemes is also advocated. Because it is generally difficult to quantify individual microphysical process rates from these observations directly, this presents an inverse problem that can be viewed from the standpoint of Bayesian statistics. Following this idea, a probabilistic framework is proposed that combines elements from statistical and physical modeling. Besides providing rigorous constraint of schemes, there is an added benefit of quantifying uncertainty systematically. Finally, a broader hierarchical approach is proposed to accelerate improvements in microphysics schemes, leveraging the advances described in this paper related to process modeling (using Lagrangian particle-based schemes), laboratory experimentation, cloud and precipitation observations, and statistical methods.

After the first report of induced pluripotent stem cells (iPSCs), considerable efforts have been made to develop more efficient methods for generating iPSCs without foreign gene insertions. Here we show that Sendai virus vector, an RNA virus vector that carries no risk of integrating into the host genome, is a practical solution for the efficient generation of safer iPSCs. We improved the Sendai virus vectors by introducing temperature-sensitive mutations so that the vectors could be easily removed at nonpermissive temperatures. Using these vectors enabled the efficient production of viral/factor-free iPSCs from both human fibroblasts and CD34(+) cord blood cells. Temperature-shift treatment was more effective in eliminating remaining viral vector-related genes. The resulting iPSCs expressed human embryonic stem cell markers and exhibited pluripotency. We suggest that generation of transgene-free iPSCs from cord blood cells should be an important step in providing allogeneic iPSC-derived therapy in the future.

Abstract We review lattice results related to pion, kaon, D -meson, B -meson, and nucleon physics with the aim of making them easily accessible to the nuclear and particle physics communities. More specifically, we report on the determination of the light-quark masses, the form factor $$f_+(0)$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:msub> <mml:mi>f</mml:mi> <mml:mo>+</mml:mo> </mml:msub> <mml:mrow> <mml:mo>(</mml:mo> <mml:mn>0</mml:mn> <mml:mo>)</mml:mo> </mml:mrow> </mml:mrow> </mml:math> arising in the semileptonic $$K \rightarrow \pi $$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:mi>K</mml:mi> <mml:mo>→</mml:mo> <mml:mi>π</mml:mi> </mml:mrow> </mml:math> transition at zero momentum transfer, as well as the decay constant ratio $$f_K/f_\pi $$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:msub> <mml:mi>f</mml:mi> <mml:mi>K</mml:mi> </mml:msub> <mml:mo>/</mml:mo> <mml:msub> <mml:mi>f</mml:mi> <mml:mi>π</mml:mi> </mml:msub> </mml:mrow> </mml:math> and its consequences for the CKM matrix elements $$V_{us}$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msub> <mml:mi>V</mml:mi> <mml:mrow> <mml:mi>us</mml:mi> </mml:mrow> </mml:msub> </mml:math> and $$V_{ud}$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msub> <mml:mi>V</mml:mi> <mml:mrow> <mml:mi>ud</mml:mi> </mml:mrow> </mml:msub> </mml:math> . Furthermore, we describe the results obtained on the lattice for some of the low-energy constants of $$SU(2)_L\times SU(2)_R$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:mi>S</mml:mi> <mml:mi>U</mml:mi> <mml:msub> <mml:mrow> <mml:mo>(</mml:mo> <mml:mn>2</mml:mn> <mml:mo>)</mml:mo> </mml:mrow> <mml:mi>L</mml:mi> </mml:msub> <mml:mo>×</mml:mo> <mml:mi>S</mml:mi> <mml:mi>U</mml:mi> <mml:msub> <mml:mrow> <mml:mo>(</mml:mo> <mml:mn>2</mml:mn> <mml:mo>)</mml:mo> </mml:mrow> <mml:mi>R</mml:mi> </mml:msub> </mml:mrow> </mml:math> and $$SU(3)_L\times SU(3)_R$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:mi>S</mml:mi> <mml:mi>U</mml:mi> <mml:msub> <mml:mrow> <mml:mo>(</mml:mo> <mml:mn>3</mml:mn> <mml:mo>)</mml:mo> </mml:mrow> <mml:mi>L</mml:mi> </mml:msub> <mml:mo>×</mml:mo> <mml:mi>S</mml:mi> <mml:mi>U</mml:mi> <mml:msub> <mml:mrow> <mml:mo>(</mml:mo> <mml:mn>3</mml:mn> <mml:mo>)</mml:mo> </mml:mrow> <mml:mi>R</mml:mi> </mml:msub> </mml:mrow> </mml:math> Chiral Perturbation Theory. We review the determination of the $$B_K$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msub> <mml:mi>B</mml:mi> <mml:mi>K</mml:mi> </mml:msub> </mml:math> parameter of neutral kaon mixing as well as the additional four B parameters that arise in theories of physics beyond the Standard Model. For the heavy-quark sector, we provide results for $$m_c$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msub> <mml:mi>m</mml:mi> <mml:mi>c</mml:mi> </mml:msub> </mml:math> and $$m_b$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msub> <mml:mi>m</mml:mi> <mml:mi>b</mml:mi> </mml:msub> </mml:math> as well as those for the decay constants, form factors, and mixing parameters of charmed and bottom mesons and baryons. These are the heavy-quark quantities most relevant for the determination of CKM matrix elements and the global CKM unitarity-triangle fit. We review the status of lattice determinations of the strong coupling constant $$\alpha _s$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msub> <mml:mi>α</mml:mi> <mml:mi>s</mml:mi> </mml:msub> </mml:math> . We consider nucleon matrix elements, and review the determinations of the axial, scalar and tensor bilinears, both isovector and flavor diagonal. Finally, in this review we have added a new section reviewing determinations of scale-setting quantities.

Embryonic stem (ES) cells are pluripotent cells derived from the inner cell mass (ICM) and the epiblast, and have been suggested to be a homogeneous population with characteristics intermediate between them. These cells express Oct3/4 and Rex1 genes, which have been used as markers to indicate the undifferentiated state of ES cells. Whereas Oct3/4 is expressed in totipotent and pluripotent cells in the mouse life cycle, Rex1 expression is restricted to the ICM, and is downregulated in pluripotent cell populations in the later stages, i.e. the epiblast and primitive ectoderm (PrE). To address whether ES cells comprise a homogeneous population equivalent to a certain developmental stage of pluripotent cells or a heterogeneous population composed of cells corresponding to various stages of differentiation, we established knock-in ES cell lines in which genes for fluorescent proteins were inserted into the Rex1 and Oct3/4 gene loci to visualize the expression of these genes. We found that undifferentiated ES cells included at least two different populations, Rex1(+)/Oct3/4(+) cells and Rex1(-)/Oct3/4(+) cells. The Rex1(-)/Oct3/4(+) and Rex1(+)/Oct3/4(+) populations could convert into each other in the presence of LIF. In accordance with our assumption that Rex1(+)/Oct3/4(+) cells and Rex1(-)/Oct3/4(+) cells have characteristics similar to those of ICM and early-PrE cells, Rex1(+)/Oct3/4(+) cells predominantly differentiated into primitive ectoderm and contributed to chimera formation, whereas Rex1(-)/Oct3/4(+) cells differentiated into cells of the somatic lineage more efficiently than non-fractionated ES cells in vitro and showed poor ability to contribute to chimera formation. These results confirmed that undifferentiated ES cell culture contains subpopulations corresponding to ICM, epiblast and PrE.

MXenes are a set of two-dimensional transition metal carbides and nitrides that offer many potential applications in energy storage and electronic devices. As an important parameter to design new electronic devices, we investigate the work functions of bare MXenes and their functionalized ones with F, OH, and O chemical groups using first-principles calculations. From our calculations, it turns out that the OH-terminated MXenes attain ultralow work functions between 1.6 and 2.8 eV. Moreover, depending on the type of the transition metal, the F or O functionalization affects increasing or decreasing the work functions. We show that the changes in the work functions upon functionalizations are linearly correlated with the changes in the surface dipole moments. It is shown that the work functions of the F- or O-terminated MXenes are controlled by two factors: the induced dipole moments by the charge transfers between F/O and the substrate, and the changes in the total surface dipole moments caused by surface relaxation upon the functionalization. However, in the cases of the OH-terminated MXenes, in addition to these two factors, the intrinsic dipole moments of the OH groups play an important role in determining the total dipole moments and consequently justify their ultralow work functions.

In the past decade, the cell-type specific connectivity and activity of local cortical networks have been characterized experimentally to some detail. In parallel, modeling has been established as a tool to relate network structure to activity dynamics. While available comprehensive connectivity maps ( Thomson, West, et al. 2002; Binzegger et al. 2004) have been used in various computational studies, prominent features of the simulated activity such as the spontaneous firing rates do not match the experimental findings. Here, we analyze the properties of these maps to compile an integrated connectivity map, which additionally incorporates insights on the specific selection of target types. Based on this integrated map, we build a full-scale spiking network model of the local cortical microcircuit. The simulated spontaneous activity is asynchronous irregular and cell-type specific firing rates are in agreement with in vivo recordings in awake animals, including the low rate of layer 2/3 excitatory cells. The interplay of excitation and inhibition captures the flow of activity through cortical layers after transient thalamic stimulation. In conclusion, the integration of a large body of the available connectivity data enables us to expose the dynamical consequences of the cortical microcircuitry.

Development of a highly reproducible and sensitive single-cell RNA sequencing (RNA-seq) method would facilitate the understanding of the biological roles and underlying mechanisms of non-genetic cellular heterogeneity. In this study, we report a novel single-cell RNA-seq method called Quartz-Seq that has a simpler protocol and higher reproducibility and sensitivity than existing methods. We show that single-cell Quartz-Seq can quantitatively detect various kinds of non-genetic cellular heterogeneity, and can detect different cell types and different cell-cycle phases of a single cell type. Moreover, this method can comprehensively reveal gene-expression heterogeneity between single cells of the same cell type in the same cell-cycle phase.

We previously reported that primordial germ cells (PGCs) in mice erase genome-wide DNA methylation and histone H3 lysine9 dimethylation (H3K9me2), and instead acquire high levels of tri-methylation of H3K27 (H3K27me3) during their migration, a process that might be crucial for the re-establishment of potential totipotency in the germline. We here explored a cellular dynamics associated with this epigenetic reprogramming. We found that PGCs undergo erasure of H3K9me2 and upregulation of H3K27me3 in a progressive, cell-by-cell manner, presumably depending on their developmental maturation. Before or concomitant with the onset of H3K9 demethylation, PGCs entered the G2 arrest of the cell cycle, which apparently persisted until they acquired high H3K27me3 levels. Interestingly, PGCs exhibited repression of RNA polymerase II-dependent transcription, which began after the onset of H3K9me2 reduction in the G2 phase and tapered off after the acquisition of high-level H3K27me3. The epigenetic reprogramming and transcriptional quiescence were independent from the function of Nanos3. We found that before H3K9 demethylation, PGCs exclusively repress an essential histone methyltransferase, GLP, without specifically upregulating histone demethylases. We suggest the possibility that active repression of an essential enzyme and subsequent unique cellular dynamics ensures successful implementation of genome-wide epigenetic reprogramming in migrating PGCs.

Bipotent mesendoderm that can give rise to both endoderm and mesoderm is an established entity from C. elegans to zebrafish. Although previous studies in mouse embryo indicated the presence of bi-potent mesendoderm cells in the organizer region, characterization of mesendoderm and its differentiation processes are still unclear. As bi-potent mesendoderm is implicated as the major precursor of definitive endoderm, its identification is also essential for exploring the differentiation of definitive endoderm. In this study, we have established embryonic stem (ES) cell lines that carry GFP gene in the goosecoid (Gsc) gene locus and have investigated the differentiation course of mesendodermal cells using Gsc expression as a marker. Our results show that mesendoderm is represented as a Gsc-GFP+ E-cadherin(ECD)+ PDGFRalpha(alphaR)+ population and is selectively induced from ES cells under defined conditions containing either activin or nodal. Subsequently, it diverges to Gsc+ ECD+ alphaR- and Gsc+ ECD- alphaR+ intermediates that eventually differentiate into definitive endoderm and mesodermal lineages, respectively. The presence of mesendodermal cells in nascent Gsc+ ECD+ alphaR+ population was also confirmed by single cell analysis. Finally, we show that the defined culture condition and surface markers developed in this study are applicable for obtaining pure mesendodermal cells and their immediate progenies from genetically unmanipulated ES cells.

Radial glia cells function as neural stem cells in the developing brain and generate self-renewing and differentiating daughter cells by asymmetric cell divisions. During these divisions, the apical process or basal process of the elongated epithelial structure is asymmetrically partitioned into daughter cells, depending on developmental contexts. However, in mammalian neurogenesis, the relationship between these subcellular structures and self-renewability is largely unknown. We induced oblique cleavages of radial glia cells to split the apical and basal processes into two daughters, and investigated the fate and morphology of the daughters in slice cultures. We observed that the more basal daughter cell that inherits the basal process self-renews outside of the ventricular zone (VZ), while the more apical daughter cell differentiates. These self-renewing progenitors, termed "outer VZ progenitors," retain the basal but not the apical process, as recently reported for the outer subventricular zone (OSVZ) progenitors in primates (Fietz et al., 2010; Hansen et al., 2010); to self-renew, they require clonal Notch signaling between sibling cells. We also found a small endogenous population of outer VZ progenitors in the mouse embryonic neocortex, consistent with a low frequency of oblique radial glia divisions. Our results describe the general role of the basal process in the self-renewal of neural progenitors and implicate the loss of the apical junctions during oblique divisions as a possible mechanism for generating OSVZ progenitors. We propose that mouse outer VZ progenitors, induced by oblique cleavages, provide a model to study both progenitor self-renewal and OSVZ progenitors.

OBJECTIVE: Soluble oligomers of amyloid beta (Abeta), rather than amyloid fibrils, have been proposed to initiate synaptic and cognitive dysfunction in Alzheimer's disease (AD). However, there is no direct evidence in humans that this mechanism can cause AD. Here, we report a novel amyloid precursor protein (APP) mutation that may provide evidence to address this question. METHODS: A Japanese pedigree showing Alzheimer's-type dementia was examined for mutations in APP, PSEN1, and PSEN2. In addition, 5,310 Japanese people, including 2,121 patients with AD, were screened for the novel APP mutation. The pathogenic effects of this mutation on Abeta production, degradation, aggregation, and synaptotoxicity were also investigated. RESULTS: We identified a novel APP mutation (E693Delta) producing variant Abeta lacking gulutamate-22 (E22Delta) in Japanese pedigrees showing Alzheimer's-type dementia and AD. Although the secretion of total Abeta was markedly reduced by this mutation, the variant Abeta was more resistant to proteolytic degradation. The mutant peptides showed the unique aggregation property of enhanced oligomerization but no fibrillization, and inhibited hippocampal long-term potentiation more potently than wild-type peptide in rats in vivo. Consistent with the nonfibrillogenic property of the variant Abeta, a very low amyloid signal was observed in the patient's brain on positron emission tomography using Pittsburgh compound-B. INTERPRETATION: The E693Delta mutation has been suggested as a cause of dementia because of enhanced formation of synaptotoxic Abeta oligomers. Our findings may provide genetic validation in humans for the emerging hypothesis that the synaptic and cognitive impairment in AD is primarily caused by soluble Abeta oligomers.

This article reviews the development of a global non-hydrostatic model, focusing on the pioneering research of the Non-hydrostatic Icosahedral Atmospheric Model (NICAM). Very high resolution global atmospheric circulation simulations with horizontal mesh spacing of approximately O (km) were conducted using recently developed supercomputers. These types of simulations were conducted with a specifically designed atmospheric global model based on a quasi-uniform grid mesh structure and a non-hydrostatic equation system. This review describes the development of each dynamical and physical component of NICAM, the assimilation strategy and its related models, and provides a scientific overview of NICAM studies conducted to date.

Tardigrades, also known as water bears, are small aquatic animals. Some tardigrade species tolerate almost complete dehydration and exhibit extraordinary tolerance to various physical extremes in the dehydrated state. Here we determine a high-quality genome sequence of Ramazzottius varieornatus, one of the most stress-tolerant tardigrade species. Precise gene repertoire analyses reveal the presence of a small proportion (1.2% or less) of putative foreign genes, loss of gene pathways that promote stress damage, expansion of gene families related to ameliorating damage, and evolution and high expression of novel tardigrade-unique proteins. Minor changes in the gene expression profiles during dehydration and rehydration suggest constitutive expression of tolerance-related genes. Using human cultured cells, we demonstrate that a tardigrade-unique DNA-associating protein suppresses X-ray-induced DNA damage by ∼40% and improves radiotolerance. These findings indicate the relevance of tardigrade-unique proteins to tolerability and tardigrades could be a bountiful source of new protection genes and mechanisms.