A Drosophila model to screen Alport syndrome COL4A5 variants for their functional pathogenicity.

Alport syndrome is a hereditary chronic kidney disease, attributed to rare pathogenic variants in either of three collagen genes (COL4A3/4/5) with most localized in COL4A5. Trimeric type IV Collagen α3α4α5 is essential for the glomerular basement membrane that forms the kidney filtration barrier. A means to functionally assess the many candidate variants and determine pathogenicity is urgently needed. We used Drosophila, an established model for kidney disease, and identify Col4a1 as the functional homolog of human COL4A5 in the fly nephrocyte (equivalent of human podocyte). Fly nephrocytes deficient for Col4a1 showed an irregular and thickened basement membrane and significantly reduced nephrocyte filtration function. This phenotype was restored by expressing human reference (wildtype) COL4A5, but not by COL4A5 carrying any of three established pathogenic patient-derived variants. We then screened seven additional patient COL4A5 variants; their ClinVar classification was either likely pathogenic or of uncertain significance. The findings support pathogenicity for four of these variants; the three others were found benign. Thus, demonstrating the effectiveness of this Drosophila in vivo kidney platform in providing the urgently needed variant-level functional validation.

Fat- and sugar-induced signals regulate sweet and fat taste perception in Drosophila.

In this study, we investigate the interplay between taste perception and macronutrients. While sugar's and protein's self-regulation of taste perception is known, the role of fat remains unclear. We reveal that in Drosophila, fat overconsumption reduces fatty acid taste in favor of sweet perception. Conversely, sugar intake increases fatty acid perception and suppresses sweet taste. Genetic investigations show that the sugar signal, gut-secreted Hedgehog, suppresses sugar taste and enhances fatty acid perception. Fat overconsumption induces unpaired 2 (Upd2) secretion from adipose tissue to the hemolymph. We reveal taste neurons take up Upd2, which triggers Domeless suppression of fatty acid perception. We further show that the downstream JAK/STAT signaling enhances sweet perception and, via Socs36E, fine-tunes Domeless activity and the fatty acid taste perception. Together, our results show that sugar regulates Hedgehog signaling and fat induces Upd2 signaling to balance nutrient intake and to regulate sweet and fat taste perception.

Cooperative role of AtRsmD and AtRimM proteins in modification and maturation of 16S rRNA in plastids.

Chloroplast pre-ribosomal RNA (rRNA) undergoes maturation, which is critical for ribosome assembly. While the central and auxiliary factors in rRNA maturation have been elucidated in bacteria, their mode of action remains largely unexplored in chloroplasts. We now reveal chloroplast-specific factors involved in 16S rRNA maturation, Arabidopsis thaliana orthologs of bacterial RsmD methyltransferase (AtRsmD) and ribosome maturation factor RimM (AtRimM). A forward genetic screen aimed to find suppressors of the Arabidopsis yellow variegated 2 (var2) mutant defective in photosystem II quality control found a causal nonsense mutation in AtRsmD. The substantially impaired 16S rRNA maturation and translation due to the mutation rescued the leaf variegation phenotype by lowering the levels of chloroplast-encoded proteins, including photosystem II core proteins, in var2. The subsequent co-immunoprecipitation coupled with mass spectrometry analyses and bimolecular fluorescence complementation assay found that AtRsmD interacts with AtRimM. Consistent with their interaction, loss of AtRimM also considerably impairs 16S rRNA maturation with decelerated m2 G915 modification in 16S rRNA catalyzed by AtRsmD. The atrimM mutation also rescued var2 mutant phenotypes, corroborating the functional interplay between AtRsmD and AtRimM towards modification and maturation of 16S rRNA and chloroplast proteostasis. The maturation and post-transcriptional modifications of rRNA are critical to assembling ribosomes responsible for protein translation. Here, we revealed that the cooperative regulation of 16S rRNA m2 G915 modifications by AtRsmD methyltransferase and ribosome assembly factor AtRimM contributes to 16S rRNA maturation, ribosome assembly, and proteostasis in chloroplasts.

Hedgehog-mediated gut-taste neuron axis controls sweet perception in Drosophila.

Dietary composition affects food preference in animals. High sugar intake suppresses sweet sensation from insects to humans, but the molecular basis of this suppression is largely unknown. Here, we reveal that sugar intake in Drosophila induces the gut to express and secrete Hedgehog (Hh) into the circulation. We show that the midgut secreted Hh localize to taste sensilla and suppresses sweet sensation, perception, and preference. We further find that the midgut Hh inhibits Hh signalling in the sweet taste neurons. Our electrophysiology studies demonstrate that the midgut Hh signal also suppresses bitter taste and some odour responses, affecting overall food perception and preference. We further show that the level of sugar intake during a critical window early in life, sets the adult gut Hh expression and sugar perception. Our results together reveal a bottom-up feedback mechanism involving a "gut-taste neuron axis" that regulates food sensation and preference.

Identification of a GABAergic neuroblast lineage modulating sweet and bitter taste sensitivity.

In Drosophila melanogaster, processing of gustatory information and controlling feeding behavior are executed by neural circuits located in the subesophageal zone (SEZ) of the brain.1 Gustatory receptor neurons (GRNs) project their axons in the primary gustatory center (PGC), which is located in the SEZ.1,2,3,4 To address the function of the PGC, we need detailed information about the different classes of gustatory interneurons that frame the PGC. In this work, we screened large collections of driver lines for SEZ interneuron-specific labeling and subsequently used candidate lines to access the SEZ neuroblast lineages. We converted 130 Gal4 lines to LexA drivers and carried out functional screening using calcium imaging. We found one neuroblast lineage, TRdm, whose neurons responded to both sweet and bitter tastants, and formed green fluorescent protein (GFP) reconstitution across synaptic partners (GRASP)-positive synapses with sweet sensory neurons. TRdm neurons express the inhibitory transmitter GABA, and silencing these neurons increases appetitive feeding behavior. These results demonstrate that TRdm generates a class of inhibitory local neurons that control taste sensitivity in Drosophila.

A Temporal PROTAC Cocktail-Mediated Sequential Degradation of AURKA Abrogates Acute Myeloid Leukemia Stem Cells.

AURKA is a potential kinase target in various malignancies. The kinase-independent oncogenic functions partially disclose the inadequate efficacy of the kinase inhibitor in a Phase III clinical trial. Simultaneously targeting the catalytic and noncatalytic functions of AURKA may be a feasible approach. Here, a set of AURKA proteolysis targeting chimeras (PROTACs) are developed. The CRBN-based dAurA383 preferentially degrades the highly abundant mitotic AURKA, while cIAP-based dAurA450 degrades the lowly abundant interphase AURKA in acute myeloid leukemia (AML) cells. The proteomic and transcriptomic analyses indicate that dAurA383 triggers the "mitotic cell cycle" and "stem cell" processes, while dAurA450 inhibits the "MYC/E2F targets" and "stem cell" processes. dAurA383 and dAurA450 are combined as a PROTAC cocktail. The cocktail effectively degrades AURKA, relieves the hook effect, and synergistically inhibits AML stem cells. Furthermore, the PROTAC cocktail induces AML regression in a xenograft mouse model and primary patient blasts. These findings establish the PROTAC cocktail as a promising spatial-temporal drug administration strategy to sequentially eliminate the multifaceted functions of oncoproteins, relieve the hook effect, and prevent cancer stem cell-mediated drug resistance.

Arabidopsis ETHYLENE INSENSITIVE 3 directly regulates the expression of PG1ß-like family genes in response to aluminum stress.

The genes in the subfamily PG1ß (beta subunit of poly-galacturonase isoenzyme 1) have a clear effect on the biosynthesis pathway of pectin, a main component of the cell wall. However, the detailed functions of the PG1ß-like gene members in Arabidopsis (AtPG1-3) have not yet been determined. In this study, we investigated their functional roles in response to aluminum (Al) stress. Our results indicate that the PG1ß-like gene members are indeed involved in the Al-stress response and they can modulate its accumulation in roots to achieve optimum root elongation and hence better seedling growth. We found that transcription factor EIN3 (ETHYLENE INSENSITIVE 3) alters pectin metabolism and the EIN3 gene responds to Al stress to affect the pectin content in the root cell walls, leading to exacerbation of the inhibition of root growth, as reflected by the phenotypes of overexpressing lines. We determined that EIN3 can directly bind to the promoter regions of PG1-3, which act downstream of EIN3. Thus, our results show that EIN3 responds to Al stress in Arabidopsis directly through regulating the expression of PG1-3. Hence, EIN3 mediates their functions by acting as a biomarker in their molecular biosynthesis pathways, and consequently orchestrates their biological network in response to Al stress.

Antagonistic modules regulate photosynthesis-associated nuclear genes via GOLDEN2-LIKE transcription factors.

GOLDEN2-LIKE (GLK) transcription factors drive the expression of photosynthesis-associated nuclear genes (PhANGs) indispensable for chloroplast biogenesis. Salicylic acid (SA)-induced SIGMA FACTOR-BINDING PROTEIN 1 (SIB1), a transcription coregulator and positive regulator of cell death, interacts with GLK1 and GLK2 to reinforce the expression of PhANGs, leading to photoinhibition of photosystem II and singlet oxygen (1O2) burst in chloroplasts. 1O2 then contributes to SA-induced cell death via EXECUTER 1 (EX1; 1O2 sensor protein)-mediated retrograde signaling upon reaching a critical level. This earlier finding has initiated research on the potential role of GLK1/2 and EX1 in SA signaling. Consistent with this view, we reveal that LESION-SIMULATING DISEASE 1 (LSD1), a transcription coregulator and negative regulator of SA-primed cell death, interacts with GLK1/2 to repress their activities in Arabidopsis (Arabidopsis thaliana). Overexpression of LSD1 repressed GLK target genes, including PhANGs, whereas loss of LSD1 enhanced their expression. Remarkably, LSD1 overexpression inhibited chloroplast biogenesis, resembling the characteristic glk1glk2 double mutant phenotype. Subsequent chromatin immunoprecipitation coupled with expression analyses further revealed that LSD1 inhibits the DNA-binding activity of GLK1 toward its target promoters. SA-induced nuclear-targeted SIB1 proteins appeared to interrupt the LSD1-GLK interaction, and the subsequent SIB1-GLK interaction activated EX1-mediated 1O2 signaling, elucidating antagonistic modules SIB1 and LSD1 in the regulation of GLK activity. Taken together, we provide a working model that SIB1 and LSD1, mutually exclusive SA-signaling components, antagonistically regulate GLK1/2 to fine-tune the expression of PhANGs, thereby modulating 1O2 homeostasis and related stress responses.

Halotrifluoromethylation of 1,3-Enynes: Access to Tetrasubstituted Allenes.

A highly regioselective copper-catalyzed 1,4-chloro- and bromotrifluoromethylation of 1,3-enynes has been presented for the first time, which affords an efficient transformation to access halo- and CF3-containing tetrasubstituted allene derivatives with good to excellent yield. This protocol is practical and convenient, in which a wide range of functional groups are compatible. Applications of this method for the gram-scale preparation and late-stage functionalization of biologically active molecules are also demonstrated.

Node Deployment of Marine Monitoring Networks: A Multiobjective Optimization Scheme.

The increasing demands for real-time marine monitoring call for the wide deployment of Marine Monitoring Networks (MMNs). The low-rate underwater communications over a long distance, long propagation delay of underwater acoustic channel, and high deployment costs of marine sensors in a large-scale three-dimensional space bring great challenges in the network deployment and management of MMN. In this paper, we first propose a multitier, hierarchical network architecture of MMN with the support of edge computing (HMMN-EC) to enable efficient monitoring services in a harsh marine environment, taking into consideration the salient features of marine communications. Specifically, HMMN-EC is composed of three subnetworks, i.e., underwater acoustic subnetwork, the sea-surface wireless subnetwork, and the air wireless subnetwork, with a diversity of network nodes with different capabilities. We then jointly investigate the deployment diverse network nodes with various constraints in different subnetworks of HMMN-EC. To this end, we formulate a Multiobjective Optimization (MO) problem to minimize the network deployment cost while achieving the maximal network lifetime, subject to the limited energy of different marine nodes and the complex deployment environment. To solve the formulated problem, we present an Ant-Colony-based Efficient Topology Optimization (AC-ETO) algorithm to find the optimal locations of nodes in different subnetworks of MMN in a large-scale deployment. The time complexity of the proposed algorithm is also analyzed. Finally, extensive simulations are carried out to validate the superior performance of the proposed algorithm compared with some existing solutions.

Bab2 Functions as an Ecdysone-Responsive Transcriptional Repressor during Drosophila Development.

Drosophila development is governed by distinct ecdysone steroid pulses that initiate spatially and temporally defined gene expression programs. The translation of these signals into tissue-specific responses is crucial for metamorphosis, but the mechanisms that confer specificity to systemic ecdysone pulses are far from understood. Here, we identify Bric-à-brac 2 (Bab2) as an ecdysone-responsive transcriptional repressor that controls temporal gene expression during larval to pupal transition. Bab2 is necessary to terminate Salivary gland secretion (Sgs) gene expression, while premature Bab2 expression blocks Sgs genes and causes precocious salivary gland histolysis. The timely expression of bab2 is controlled by the ecdysone-responsive transcription factor Broad, and manipulation of EcR/USP/Broad signaling induces inappropriate Bab2 expression and termination of Sgs gene expression. Bab2 directly binds to Sgs loci in vitro and represses all Sgs genes in vivo. Our work characterizes Bab2 as a temporal regulator of somatic gene expression in response to systemic ecdysone signaling.

Efficacy of cystectasia in the treatment of ketamine-induced bladder contracture.

BACKGROUND: The treatment of ketamine-induced bladder contractures remains poorly studied. We therefore evaluated the efficacy of cystectasia with a sodium hyaluronate balanced solution in this kind of bladder contracture. METHODS: Eighteen patients presenting with ketamine-induced bladder contracture between July 2010 and February 2018 were selected and analysed. Ketamine was discontinued in all patients, who were then treated with weekly cystectasia (0.09% sodium hyaluronate balanced solution) 3 times. The volume of the first perfusion was twice the preoperatively measured bladder capacity, and the volume of the subsequent two perfusions was increased by 100 mL each time. The Pelvic Pain and Urgency/Frequency (PUF) symptom score, O'Leary-Sant Interstitial Cystitis (IC) Symptom Index (ICSI), IC Problem Index (ICPI), Quality of Life (QOL) score, and bladder capacity were recorded before surgery and 3 and 12 months after the 3rd expansion. RESULTS: No significant complications were observed during the 3 expansions. Fourteen patients completed the full follow-up schedule. Preoperatively and at the 3- and 12-month follow-up evaluations performed after the 3rd expansion, the PUF symptom scores were 20.4±3.6, 11.5±3.1, and 13.2±3.3, respectively; the mean ICSI was 13.6±2.8, 7.7±2.3, and 8.2±2.5, respectively; the mean ICPI was 10.6±2.6, 7.3±2.1, and 7.7±2.5, respectively; and the mean QOL scores were 6.0±0, 2.1±0.5, and 2.7±0.8, respectively; and the mean bladder catheter volume was 83±27, 234±56, and 228±52 mL, respectively. There were significant differences between all preoperative and postoperative values. CONCLUSIONS: Cystectasia with a sodium hyaluronate balanced solution is an effective treatment modality for ketamine-induced bladder contracture.

PLANT NATRIURETIC PEPTIDE A and Its Putative Receptor PNP-R2 Antagonize Salicylic Acid-Mediated Signaling and Cell Death.

The plant stress hormone salicylic acid (SA) participates in local and systemic acquired resistance, which eventually leads to whole-plant resistance to bacterial pathogens. However, if SA-mediated signaling is not appropriately controlled, plants incur defense-associated fitness costs such as growth inhibition and cell death. Despite its importance, to date only a few components counteracting the SA-primed stress responses have been identified in Arabidopsis (Arabidopsis thaliana). These include other plant hormones such as jasmonic acid and abscisic acid, and proteins such as LESION SIMULATING DISEASE1, a transcription coregulator. Here, we describe PLANT NATRIURETIC PEPTIDE A (PNP-A), a functional analog to vertebrate atrial natriuretic peptides, that appears to antagonize the SA-mediated plant stress responses. While loss of PNP-A potentiates SA-mediated signaling, exogenous application of synthetic PNP-A or overexpression of PNP-A significantly compromises the SA-primed immune responses. Moreover, we identify a plasma membrane-localized receptor-like protein, PNP-R2, that interacts with PNP-A and is required to initiate the PNP-A-mediated intracellular signaling. In summary, our work identifies a peptide and its putative cognate receptor as counteracting both SA-mediated signaling and SA-primed cell death in Arabidopsis.

Ethylene insensitive3-like2 (OsEIL2) confers stress sensitivity by regulating OsBURP16, the ß subunit of polygalacturonase (PG1ß-like) subfamily gene in rice.

The transcription factors EIN3 (ETHYLENE-INSENSITIVE 3) and EILs (EIN3-Likes) play important roles in plant development and defense responses; however, their mechanism in these processes remain unclear. Here, we report that OsEIL2, an EIN3-like transcription factor from rice (Oryza sativa), plays important roles in abiotic stress and leaf senescence. OsEIL2 is a nuclear-localized protein with transactivation activity in the C-terminus (amino acids 344-583) and can be induced by NaCl, polyethylene glycol (PEG), dark, and abscisic acid (ABA) treatment. Transgenic plants of overexpressing OsEIL2 (OsEIL2-OX) show reduced tolerance to salt and drought stress compared with the controls. While the transgenic plants of overexpressing OsEIL2-RNA interference (OsEIL2-RNAi) exhibit enhanced tolerance to salt and drought stress compared with the controls. Moreover, seedlings of OsEIL2-overexpressing transgenic plants exhibit delayed leaf development and an accelerated dark-induced senescence phenotype, whereas OsEIL2-RNAi plants display the opposite phenotype. We further found that OsEIL2 functions upstream of OsBURP14 and OsBURP16. OsBURP14 and OsBURP16 are the members of the ß subunit of polygalacturonase subfamilies. OsBURP16 overexpression reduced pectin content and cell adhesion and increased abiotic stress sensitivity in rice. OsEIL2 binds directly to the promoter of OsBURP14 and OsBURP16 and activates their transcript levels. We also found that OsEIL2 overexpression decreased the pectin content by increasing polygalacturonase (PG) activity. Taken together, these results revealed a new mechanism of OsEIL2 in abiotic stress responses. These findings provide new insights into plant resistance to abiotic stress.

Impaired PSII Proteostasis Promotes Retrograde Signaling via Salicylic Acid.

Photodamage of the PSII reaction center (RC) is an inevitable process in an oxygen-rich environment. The damaged PSII RC proteins (Dam-PSII) undergo degradation via the thylakoid membrane-bound FtsH metalloprotease, followed by posttranslational assembly of PSII. While the effect of Dam-PSII on gene regulation is described for cyanobacteria, its role in land plants is largely unknown. In this study, we reveal an intriguing retrograde signaling pathway by using the Arabidopsis (Arabidopsis thaliana) yellow variegated2-9 mutant, which expresses a mutated FtsH2 (FtsH2G267D) metalloprotease, specifically impairing its substrate-unfolding activity. This lesion leads to the perturbation of PSII protein homeostasis (proteostasis) and the accumulation of Dam-PSII. Subsequently, this results in an up-regulation of salicylic acid (SA)-responsive genes, which is abrogated by inactivation of either an SA transporter in the chloroplast envelope membrane or extraplastidic SA signaling components as well as by removal of SA. These results suggest that the stress hormone SA, which is mainly synthesized via the chloroplast isochorismate pathway in response to the impaired PSII proteostasis, mediates the retrograde signaling. These findings reinforce the emerging view of chloroplast function toward plant stress responses and suggest SA as a potential plastid factor mediating retrograde signaling.

Impaired PSII proteostasis triggers a UPR-like response in the var2 mutant of Arabidopsis.

Cellular protein homeostasis (proteostasis) is maintained through the balance between de novo synthesis and proteolysis. The unfolded/misfolded protein response (UPR) that is triggered by stressed endoplasmic reticulum (ER) also plays an important role in proteostasis in both plants and animals. Although ER-triggered UPR has been extensively studied in plants, the molecular mechanisms underlying mitochondrial and chloroplastic UPRs are largely uncharacterized despite the fact that these organelles are sites of production of harmful reactive oxygen species (ROS), which damage proteins. In this study, we demonstrate that chloroplasts of the Arabidopsis yellow leaf variegation 2 (var2) mutant, which lacks the metalloprotease FtsH2, accumulate damaged chloroplast proteins and trigger a UPR-like response, namely the accumulation of a suite of chloroplast proteins involved in protein quality control (PQC). These PQC proteins include heat-shock proteins, chaperones, proteases, and ROS detoxifiers. Given that FtsH2 functions primarily in photosystem II proteostasis, the accumulation of PQC-related proteins may balance the FtsH2 deficiency. Moreover, the apparent up-regulation of the cognate transcripts indicates that the accumulation of PQC-related proteins in var2 is probably mediated by retrograde signaling, indicating the occurrence of a UPR-like response in var2.

FtsH2-Dependent Proteolysis of EXECUTER1 Is Essential in Mediating Singlet Oxygen-Triggered Retrograde Signaling in Arabidopsis thaliana.

Photosystem II reaction center (PSII RC) and light-harvesting complex inevitably generate highly reactive singlet oxygen (1O2) that can impose photo-oxidative damage, especially when the rate of generation exceeds the rate of detoxification. Besides being toxic, 1O2 has also been ascribed to trigger retrograde signaling, which leads to nuclear gene expression changes. Two distinctive molecular components appear to regulate 1O2 signaling: a volatile signaling molecule ß-cyclocitral (ß-CC) generated upon oxidation of ß-carotene by 1O2 in PSII RC assembled in grana core, and a thylakoid membrane-bound FtsH2 metalloprotease that promotes 1O2-triggered signaling through the proteolysis of EXECUTER1 (EX1) proteins associated with PSII in grana margin. The role of FtsH2 protease in 1O2 signaling was established recently in the conditional fluorescent (flu) mutant of Arabidopsis thaliana that generates 1O2 upon dark-to-light shift. The flu mutant lacking functional FtsH2 significantly impairs 1O2-triggered and EX1-mediated cell death. In the present study, the role of FtsH2 in the induction of 1O2 signaling was further clarified by analyzing the FtsH2-dependent nuclear gene expression changes in the flu mutant. Genome-wide transcriptome analysis showed that the inactivation of FtsH2 repressed the majority (85%) of the EX1-dependent 1O2-responsive genes (SORGs), providing direct connection between FtsH2-mediated EX1 degradation and 1O2-triggered gene expression changes. Furthermore, the overlap between ß-CC-induced genes and EX1-FtsH2-dependent genes was very limited, further supporting the coexistence of two distinctive 1O2 signaling pathways.

Bioinspired Ternary Artificial Nacre Nanocomposites Based on Reduced Graphene Oxide and Nanofibrillar Cellulose.

Inspired by the nacre, we demonstrated the integrated ternary artificial nacre nanocomposites through synergistic toughening of graphene oxide (GO) and nanofibrillar cellulose (NFC). In addition, the covalent bonding was introduced between adjacent GO nanosheets. The synergistic toughening effects from building blocks of one-dimensional NFC and two-dimensional GO, interface interactions of hydrogen and covalent bonding together result in the integrated mechanical properties including high tensile strength, toughness, and fatigue life as well as high electrical conductivity. These extraordinary properties of the ternary synthetic nacre nanocomposites allow the support for advances in diverse strategic fields including stretchable electronics, transportation, and energy. Such bioinspired strategy also provides a new insight in designing novel multifunctional nanocomposites.

Strained cyclooctyne as a molecular platform for construction of multimodal imaging probes.

Small-molecule-based multimodal and multifunctional imaging probes play prominent roles in biomedical research and have high clinical translation ability. A novel multimodal imaging platform using base-catalyzed double addition of thiols to a strained internal alkyne such as bicyclo[6.1.0]nonyne has been established in this study, thus allowing highly selective assembly of various functional units in a protecting-group-free manner. Using this molecular platform, novel dual-modality (PET and NIRF) uPAR-targeted imaging probe: (64)Cu-CHS1 was prepared and evaluated in U87MG cells and tumor-bearing mice models. The excellent PET/NIRF imaging characteristics such as good tumor uptake (3.69%ID/g at 2 h post-injection), high tumor contrast, and specificity were achieved in the small-animal models. These attractive imaging properties make (64)Cu-CHS1 a promising probe for clinical use.

Learning from nature: constructing integrated graphene-based artificial nacre.

Natural nacre supplies a number of properties that can be used in designing high-performance bioinspired materials. Likewise, due to the extraordinary properties of graphene, a series of bioinspired graphene-based materials have recently been demonstrated. Compared to other approaches for constructing graphene-based materials, bioinspired concepts result in high-loading graphene, and the resultant high-performance graphene-based artificial nacres demonstrate isotropic mechanical and electrical properties. In this Perspective, we describe how to construct integrated graphene-based artificial nacre through the synergistic relationship between interface interactions and building blocks. These integrated graphene-based artificial nacres show promising applications in many fields, such as aerospace, flexible supercapacitor electrodes, artificial muscle, and tissue engineering.