Glioblastoma evolution and heterogeneity from a 3D whole-tumor perspective.

Treatment failure for the lethal brain tumor glioblastoma (GBM) is attributed to intratumoral heterogeneity and tumor evolution. We utilized 3D neuronavigation during surgical resection to acquire samples representing the whole tumor mapped by 3D spatial coordinates. Integrative tissue and single-cell analysis revealed sources of genomic, epigenomic, and microenvironmental intratumoral heterogeneity and their spatial patterning. By distinguishing tumor-wide molecular features from those with regional specificity, we inferred GBM evolutionary trajectories from neurodevelopmental lineage origins and initiating events such as chromothripsis to emergence of genetic subclones and spatially restricted activation of differential tumor and microenvironmental programs in the core, periphery, and contrast-enhancing regions. Our work depicts GBM evolution and heterogeneity from a 3D whole-tumor perspective, highlights potential therapeutic targets that might circumvent heterogeneity-related failures, and establishes an interactive platform enabling 360° visualization and analysis of 3D spatial patterns for user-selected genes, programs, and other features across whole GBM tumors.

YTHDC1 delays cellular senescence and pulmonary fibrosis by activating ATR in an m6A-independent manner.

Accumulation of DNA damage in the lung induces cellular senescence and promotes age-related diseases such as idiopathic pulmonary fibrosis (IPF). Hence, understanding the mechanistic regulation of DNA damage repair is important for anti-aging therapies and disease control. Here, we identified an m6A-independent role of the RNA-binding protein YTHDC1 in counteracting stress-induced pulmonary senescence and fibrosis. YTHDC1 is primarily expressed in pulmonary alveolar epithelial type 2 (AECII) cells and its AECII expression is significantly decreased in AECIIs during fibrosis. Exogenous overexpression of YTHDC1 alleviates pulmonary senescence and fibrosis independent of its m6A-binding ability, while YTHDC1 deletion enhances disease progression in mice. Mechanistically, YTHDC1 promotes the interaction between TopBP1 and MRE11, thereby activating ATR and facilitating DNA damage repair. These findings reveal a noncanonical function of YTHDC1 in delaying cellular senescence, and suggest that enhancing YTHDC1 expression in the lung could be an effective treatment strategy for pulmonary fibrosis.

TOR-mediated Ypt1 phosphorylation regulates autophagy initiation complex assembly.

The regulation of autophagy initiation is a key step in autophagosome biogenesis. However, our understanding of the molecular mechanisms underlying the stepwise assembly of ATG proteins during this process remains incomplete. The Rab GTPase Ypt1/Rab1 is recognized as an essential autophagy regulator. Here, we identify Atg23 and Atg17 as binding partners of Ypt1, with their direct interaction proving crucial for the stepwise assembly of autophagy initiation complexes. Disruption of Ypt1-Atg23 binding results in significantly reduced Atg9 interactions with Atg11, Atg13, and Atg17, thus preventing the recruitment of Atg9 vesicles to the phagophore assembly site (PAS). Likewise, Ypt1-Atg17 binding contributes to the PAS recruitment of Ypt1 and Atg1. Importantly, we found that Ypt1 is phosphorylated by TOR at the Ser174 residue. Converting this residue to alanine blocks Ypt1 phosphorylation by TOR and enhances autophagy. Conversely, the Ypt1S174D phosphorylation mimic impairs both PAS recruitment and activation of Atg1, thus inhibiting subsequent autophagy. Thus, we propose TOR-mediated Ypt1 as a multifunctional assembly factor that controls autophagy initiation via its regulation of the stepwise assembly of ATG proteins.

The OsEIL1-OsWOX11 transcription factor module controls rice crown root development in response to soil compaction.

Optimizing the root architecture of crops is an effective strategy for improving crop yields. Soil compaction is a serious global problem that limits crop productivity by restricting root growth, but the underlying molecular mechanisms are largely unclear. Here, we show that ethylene stimulates rice (Oryza sativa) crown root development in response to soil compaction. First, we demonstrate that compacted soil promotes ethylene production and the accumulation of ETHYLENE INSENSITIVE 3-LIKE 1 (OsEIL1) in rice roots, stimulating crown root primordia initiation and development, thereby increasing crown root number in lower stem nodes. Through transcriptome profiling and molecular analyses, we reveal that OsEIL1 directly activates the expression of WUSCHEL-RELATED HOMEOBOX 11 (OsWOX11), an activator of crown root emergence and growth, and that OsWOX11 mutations delay crown root development, thus impairing the plant's response to ethylene and soil compaction. Genetic analysis demonstrates that OsWOX11 functions downstream of OsEIL1. In summary, our results demonstrate that the OsEIL1-OsWOX11 module regulates ethylene action during crown root development in response to soil compaction, providing a strategy for the genetic modification of crop root architecture and grain agronomic traits.

Null and missense mutations of ERI1 cause a recessive phenotypic dichotomy in humans.

ERI1 is a 3'-to-5' exoribonuclease involved in RNA metabolic pathways including 5.8S rRNA processing and turnover of histone mRNAs. Its biological and medical significance remain unclear. Here, we uncover a phenotypic dichotomy associated with bi-allelic ERI1 variants by reporting eight affected individuals from seven unrelated families. A severe spondyloepimetaphyseal dysplasia (SEMD) was identified in five affected individuals with missense variants but not in those with bi-allelic null variants, who showed mild intellectual disability and digital anomalies. The ERI1 missense variants cause a loss of the exoribonuclease activity, leading to defective trimming of the 5.8S rRNA 3' end and a decreased degradation of replication-dependent histone mRNAs. Affected-individual-derived induced pluripotent stem cells (iPSCs) showed impaired in vitro chondrogenesis with downregulation of genes regulating skeletal patterning. Our study establishes an entity previously unreported in OMIM and provides a model showing a more severe effect of missense alleles than null alleles within recessive genotypes, suggesting a key role of ERI1-mediated RNA metabolism in human skeletal patterning and chondrogenesis.

Eltrombopag plus diacerein vs. eltrombopag in patients with ITP: a multicenter, randomized, open-label, phase 2 trial.

This study aimed to compare the efficacy and safety of eltrombopag plus diacerein vs. eltrombopag alone in patients with primary immune thrombocytopenia (ITP) who were previously unresponsive to 14 days of eltrombopag treatment at the full dose. Recruited patients were randomly assigned 1:1 to receive either eltrombopag plus diacerein (n=50) or eltrombopag monotherapy (n=52). Overall response rate, defined as a platelet count at or above 30×109/L, at least doubling of the baseline platelet count, and no bleeding, was reached in 44% of patients in the eltrombopag plus diacerein group compared with 13% in the eltrombopag group at day 15 (P = .0009), and reached in 42% of patients in the combination group compared with 12% in the monotherapy group at day 28 (P = .0006). The addition of diacerein to eltrombopag also led to a longer duration of response (P = .0004). The two most common treatment-emergent adverse events were respiratory infection and gastrointestinal reactions in the combination group, and fatigue and respiratory infection in the eltrombopag group. In conclusion, eltrombopag plus diacerein was well tolerated, and induced higher overall response rates and longer duration of response than eltrombopag alone, offering a rejuvenating salvage therapy for ITP patients unresponsive to 14 days of full dosage eltrombopag. Our work has the potential to enhance the care of patients treated with thrombopoietin receptor agonists, reducing the need for rapid transitions to less-preferable therapies. This study is registered at ClinicalTrials.gov as NCT04917679.

Anisotropic cell growth at the leaf base promotes age-related changes in leaf shape in Arabidopsis thaliana.

Plants undergo extended morphogenesis. The shoot apical meristem (SAM) allows for reiterative development and the formation of new structures throughout the life of the plant. Intriguingly, the SAM produces morphologically different leaves in an age-dependent manner, a phenomenon known as heteroblasty. In Arabidopsis thaliana, the SAM produces small orbicular leaves in the juvenile phase, but gives rise to large elliptical leaves in the adult phase. Previous studies have established that a developmental decline of microRNA156 (miR156) is necessary and sufficient to trigger this leaf shape switch, although the underlying mechanism is poorly understood. Here we show that the gradual increase in miR156-targeted SQUAMOSA PROMOTER BINDING PROTEIN-LIKE transcription factors with age promotes cell growth anisotropy in the abaxial epidermis at the base of the leaf blade, evident by the formation of elongated giant cells. Time-lapse imaging and developmental genetics further revealed that the establishment of adult leaf shape is tightly associated with the longitudinal cell expansion of giant cells, accompanied by a prolonged cell proliferation phase in their vicinity. Our results thus provide a plausible cellular mechanism for heteroblasty in Arabidopsis, and contribute to our understanding of anisotropic growth in plants.

A map of cis-regulatory elements and 3D genome structures in zebrafish.

The zebrafish (Danio rerio) has been widely used in the study of human disease and development, and about 70% of the protein-coding genes are conserved between the two species1. However, studies in zebrafish remain constrained by the sparse annotation of functional control elements in the zebrafish genome. Here we performed RNA sequencing, assay for transposase-accessible chromatin using sequencing (ATAC-seq), chromatin immunoprecipitation with sequencing, whole-genome bisulfite sequencing, and chromosome conformation capture (Hi-C) experiments in up to eleven adult and two embryonic tissues to generate a comprehensive map of transcriptomes, cis-regulatory elements, heterochromatin, methylomes and 3D genome organization in the zebrafish Tübingen reference strain. A comparison of zebrafish, human and mouse regulatory elements enabled the identification of both evolutionarily conserved and species-specific regulatory sequences and networks. We observed enrichment of evolutionary breakpoints at topologically associating domain boundaries, which were correlated with strong histone H3 lysine 4 trimethylation (H3K4me3) and CCCTC-binding factor (CTCF) signals. We performed single-cell ATAC-seq in zebrafish brain, which delineated 25 different clusters of cell types. By combining long-read DNA sequencing and Hi-C, we assembled the sex-determining chromosome 4 de novo. Overall, our work provides an additional epigenomic anchor for the functional annotation of vertebrate genomes and the study of evolutionarily conserved elements of 3D genome organization.

Atomic coordination environment engineering of bimetallic alloy nanostructures for efficient ammonia electrosynthesis from nitrate.

Electrochemical nitrate reduction reaction (NO3RR) to ammonia has been regarded as a promising strategy to balance the global nitrogen cycle. However, it still suffers from poor Faradaic efficiency (FE) and limited yield rate for ammonia production on heterogeneous electrocatalysts, especially in neutral solutions. Herein, we report one-pot synthesis of ultrathin nanosheet-assembled RuFe nanoflowers with low-coordinated Ru sites to enhance NO3RR performances in neutral electrolyte. Significantly, RuFe nanoflowers exhibit outstanding ammonia FE of 92.9% and yield rate of 38.68 mg h-1 mgcat-1 (64.47 mg h-1 mgRu-1) at -0.30 and -0.65 V (vs. reversible hydrogen electrode), respectively. Experimental studies and theoretical calculations reveal that RuFe nanoflowers with low-coordinated Ru sites are highly electroactive with an increased d-band center to guarantee efficient electron transfer, leading to low energy barriers of nitrate reduction. The demonstration of rechargeable zinc-nitrate batteries with large-specific capacity using RuFe nanoflowers indicates their great potential in next-generation electrochemical energy systems.

Reprogramming and multi-lineage transdifferentiation attenuate the tumorigenicity of colorectal cancer cells.

Significant advances have been made in reprogramming various somatic cells into induced pluripotent stem cells (iPSCs) and in multi-lineage differentiation (transdifferentiation) into different tissues. These manipulable transdifferentiating techniques may be applied in cancer therapy. Limited works have been reported that cancer cell malignancy can be switched to benign phenotypes through reprogramming techniques. Here, we reported that two colorectal cancer (CRC) cell lines (DLD1, HT29) could be reprogrammed into iPSCs (D-iPSCs, H-iPSCs). D- and H-iPSCs showed reduced tumorigenesis. Furthermore, we successfully induced D- and H-iPSCs differentiation into terminally differentiated cell types such as cardiomyocyte, neuron, and adipocyte-like cells. Impressively, the differentiated cells exhibited further attenuated tumorigenesis in vitro and in vivo. RNA-Seq further indicated that epigenetic changes occurred after reprogramming and transdifferentiation that caused reduced tumorigenicity. Overall, our study indicated that CRC cells can be reprogrammed and further differentiated into terminally differentiated lineages with attenuation of their malignancy in vitro and in vivo. The current work sheds light on a potential multi-lineage differentiation therapeutic strategy for colorectal cancer.

miR-107 reverses the multidrug resistance of gastric cancer by targeting the CGA/EGFR/GATA2 positive feedback circuit.

Chemotherapy is still the main therapeutic strategy for gastric cancer (GC). However, most patients eventually acquire multidrug resistance (MDR). Hyperactivation of the EGFR signaling pathway contributes to MDR by promoting cancer cell proliferation and inhibiting apoptosis. We previously identified the secreted protein CGA as a novel ligand of EGFR and revealed a CGA/EGFR/GATA2 positive feedback circuit that confers MDR in GC. Herein, we outline a microRNA-based treatment approach for MDR reversal that targets both CGA and GATA2. We observed increased expression of CGA and GATA2 and increased activation of EGFR in GC samples. Bioinformatic analysis revealed that miR-107 could simultaneously target CGA and GATA2, and the low expression of miR-107 was correlated with poor prognosis in GC patients. The direct interactions between miR-107 and CGA or GATA2 were validated by luciferase reporter assays and western blot analysis. Overexpression of miR-107 in MDR GC cells increased their susceptibility to chemotherapeutic agents, including fluorouracil, adriamycin and vincristine, in vitro. Notably, intratumor injection of the miR-107 prodrug enhanced MDR xenograft sensitivity to chemotherapies in vivo. Molecularly, targeting CGA and GATA2 with miR-107 inhibited EGFR downstream signaling, as evidenced by the reduced phosphorylation of ERK and AKT. These results suggest that miR-107 may contribute to the development of a promising therapeutic approach for the treatment of MDR in GC.

SlPP2C2 interacts with FZY/SAUR and regulates tomato development via signaling crosstalk of ABA and auxin.

Abscisic acid (ABA) signaling interacts frequently with auxin signaling when it regulates plant development, affecting multiple physiological processes; however, to the best of our knowledge, their interaction during tomato development has not yet been reported. Here, we found that type 2C protein phosphatase (SlPP2C2) interacts with both flavin monooxygenase FZY, an indole-3-acetic acid (IAA) biosynthetic enzyme, and small auxin upregulated RNA (SAUR) of an IAA signaling protein and regulates their activity, thereby affecting the expression of IAA-responsive genes. The expression level of SlPP2C2 was increased by exogenous ABA, IAA, NaCl, or dehydration treatment of fruits, leaves, and seeds, and it decreased in imbibed seeds. Manipulating SlPP2C2 with overexpression, RNA interference, and CRISPR/Cas9-mediated genome editing resulted in pleiotropic changes, such as morphological changes in leaves, stem trichomes, floral organs and fruits, accompanied by alterations in IAA and ABA levels. Furthermore, the RNA-seq analysis indicated that SlPP2C2 regulates the expression of auxin-/IAA-responsive genes in different tissues of tomato. The results demonstrate that SlPP2C2-mediated ABA signaling regulates the development of both vegetative and reproductive organs via interaction with FZY/SAUR, which integrates the cross-talk of ABA and auxin signals during development and affects the expressions of development-related genes in tomato.

TFIIB-related factor 1 is a nucleolar protein that promotes RNA polymerase I-directed transcription and tumour cell growth.

Eukaryotic RNA polymerase I (Pol I) products play fundamental roles in ribosomal assembly, protein synthesis, metabolism and cell growth. Abnormal expression of both Pol I transcription-related factors and Pol I products causes a range of diseases, including ribosomopathies and cancers. However, the factors and mechanisms governing Pol I-dependent transcription remain to be elucidated. Here, we report that transcription factor IIB-related factor 1 (BRF1), a subunit of transcription factor IIIB required for RNA polymerase III (Pol III)-mediated transcription, is a nucleolar protein and modulates Pol I-mediated transcription. We showed that BRF1 can be localized to the nucleolus in several human cell types. BRF1 expression correlates positively with Pol I product levels and tumour cell growth in vitro and in vivo. Pol III transcription inhibition assays confirmed that BRF1 modulates Pol I-directed transcription in an independent manner rather than through a Pol III product-to-45S pre-rRNA feedback mode. Mechanistically, BRF1 binds to the Pol I transcription machinery components and can be recruited to the rDNA promoter along with them. Additionally, alteration of BRF1 expression affects the recruitment of Pol I transcription machinery components to the rDNA promoter and the expression of TBP and TAF1A. These findings indicate that BRF1 modulates Pol I-directed transcription by controlling the expression of selective factor 1 subunits. In summary, we identified a novel role of BRF1 in Pol I-directed transcription, suggesting that BRF1 can independently regulate both Pol I- and Pol III-mediated transcription and act as a key coordinator of Pol I and Pol III.

Rabl2 GTP hydrolysis licenses BBSome-mediated export to fine-tune ciliary signaling.

Cilia of higher animals sense various environmental stimuli. Proper ciliary signaling requires appropriate extent of BBSome-mediated export of membrane receptors across ciliary barrier transition zone (TZ) through retrograde intraflagellar transport (IFT) machinery. How the barrier passage is controlled, however, remains unknown. Here, we show that small GTPase Rabl2 functions as a molecular switch for the outward TZ passage. Rabl2-GTP enters cilia by binding to IFT-B complex. Its GTP hydrolysis enables the outward TZ passage of the BBSome and its cargos with retrograde IFT machinery, whereas its persistent association leads to their shedding from IFT-B during the passing process and consequently ciliary retention. Rabl2 deficiency or expression of a GTP-locked mutant impairs the ciliary hedgehog signaling without interfering with ciliation and respectively results in different spectrums of mouse developmental disorders. We propose that the switch role of Rabl2 ensures proper turnover of the BBSome and ciliary membrane receptors to fine-tune cilia-dependent signaling for normal embryonic development and organismic homeostasis.

ARF6 plays a general role in targeting palmitoylated proteins from the Golgi to the plasma membrane.

Protein palmitoylation is a post-translational lipid modification of proteins. Accumulating evidence reveals that palmitoylation functions as a sorting signal to direct proteins to destinations; however, the sorting mechanism remains largely unknown. Here, we show that ARF6 plays a general role in targeting palmitoylated proteins from the Golgi to the plasma membrane (PM). Through shRNA screening, we identified ARF6 as the key small GTPase in targeting CD36, a palmitoylated protein, from the Golgi to the PM. We found that the N-terminal myristoylation of ARF6 is required for its binding with palmitoylated CD36, and the GTP-bound form of ARF6 facilitates the delivery of CD36 to the PM. Analysis of stable isotope labeling by amino acids in cell culture revealed that ARF6 might facilitate the sorting of 359 of the 531 palmitoylated PM proteins, indicating a general role of ARF6. Our study has thus identified a sorting mechanism for targeting palmitoylated proteins from the Golgi to the PM.

5-Hydroxytryptamine 4 Receptor Agonist Attenuates Diabetic Enteric Neuropathy through Inhibition of the Receptor-Interacting Protein Kinase 3 Pathway.

Necroptosis, considered as a form of programmed cell death, contributes to neural loss. The 5-hydroxytryptamine 4 receptor (5-HT4R) is involved in neurogenesis in the enteric nervous system. However, whether the activation of 5-HT4R can alleviate diabetic enteric neuropathy by inhibiting receptor-interacting protein kinase 3 (RIPK3)-mediated necroptosis is unclear. This study aimed to explore the beneficial effects of 5-HT4R agonist on enteric neuropathy in a mouse model of diabetes and the mechanisms underlying these effects. Diabetes developed neural loss in the colon of mice. 5-HT4Rs localized in submucosal and myenteric plexuses were confirmed. Administration of 5-HT4R agonist attenuated diabetes-induced colonic hypomotility and neural loss of the colon in mice. Remarkably, RIPK3, phosphorylated RIPK3, and its downstream target mixed lineage kinase domain-like protein (MLKL), two key proteins regulating necroptosis, were significantly up-regulated in the colon of diabetic mice. Treatment with 5-HT4R agonist appeared to inhibit diabetes-induced elevation of RIPK3, phosphorylated RIPK3, and MLKL in the colon of mice. Diabetes-induced up-regulation of MLKL in both the mucosa and the muscularis of the colon was prevented by Ripk3 deletion. Moreover, diabetes-evoked neural loss and delayed colonic transit were significantly inhibited by Ripk3 removal. These findings suggest that activation of 5-HT4Rs could potentially provide a protective effect against diabetic enteric neuropathy by suppressing RIPK3-mediated necroptosis.

Regulatory loops between rice transcription factors OsNAC25 and OsNAC20/26 balance starch synthesis.

Several starch synthesis regulators have been identified, but these regulators are situated in the terminus of the regulatory network. Their upstream regulators and the complex regulatory network formed between these regulators remain largely unknown. A previous study demonstrated that NAM, ATAF, and CUC (NAC) transcription factors, OsNAC20 and OsNAC26 (OsNAC20/26), redundantly and positively regulate the accumulation of storage material in rice (Oryza sativa) endosperm. In this study, we detected OsNAC25 as an upstream regulator and interacting protein of OsNAC20/26. Both OsNAC25 mutation and OE resulted in a chalky seed phenotype, decreased starch content, and reduced expression of starch synthesis-related genes, but the mechanisms were different. In the osnac25 mutant, decreased expression of OsNAC20/26 resulted in reduced starch synthesis; however, in OsNAC25-overexpressing plants, the OsNAC25-OsNAC20/26 complex inhibited OsNAC20/26 binding to the promoter of starch synthesis-related genes. In addition, OsNAC20/26 positively regulated OsNAC25. Therefore, the mutual regulation between OsNAC25 and OsNAC20/26 forms a positive regulatory loop to stimulate the expression of starch synthesis-related genes and meet the great demand for starch accumulation in the grain filling stage. Simultaneously, a negative regulatory loop forms among the 3 proteins to avoid the excessive expression of starch synthesis-related genes. Collectively, our findings demonstrate that both promotion and inhibition mechanisms between OsNAC25 and OsNAC20/26 are essential for maintaining stable expression of starch synthesis-related genes and normal starch accumulation.

Orchestration of ethylene and gibberellin signals determines primary root elongation in rice.

Primary root growth in cereal crops is fundamental for early establishment of the seedling and grain yield. In young rice (Oryza sativa) seedlings, the primary root grows rapidly for 7-10 days after germination and then stops; however, the underlying mechanism determining primary root growth is unclear. Here, we report that the interplay of ethylene and gibberellin (GA) controls the orchestrated development of the primary root in young rice seedlings. Our analyses advance the knowledge that primary root growth is maintained by higher ethylene production, which lowers bioactive GA contents. Further investigations unraveled that ethylene signaling transcription factor ETHYLENE INSENSITIVE3-LIKE 1 (OsEIL1) activates the expression of the GA metabolism genes GIBBERELLIN 2-OXIDASE 1 (OsGA2ox1), OsGA2ox2, OsGA2ox3, and OsGA2ox5, thereby deactivating GA activity, inhibiting cell proliferation in the root meristem, and ultimately gradually inhibiting primary root growth. Mutation in OsGA2ox3 weakened ethylene-induced GA inactivation and reduced the ethylene sensitivity of the root. Genetic analysis revealed that OsGA2ox3 functions downstream of OsEIL1. Taken together, we identify a molecular pathway impacted by ethylene during primary root elongation in rice and provide insight into the coordination of ethylene and GA signals during root development and seedling establishment.

Proximal tubular MBD2 promotes autophagy to drive the progression of AKI caused by vancomycin via regulation of miR-597-5p/S1PR1 axis.

Our recent investigation has indicated that the global deletion of MBD2 can mitigate the progression of AKI induced by VAN. Nevertheless, the role and regulatory mechanisms of proximal tubular MBD2 in this pathophysiological process have yet to be elucidated. Our preceding investigation revealed that autophagy played a crucial role in advancing AKI induced by VAN. Consequently, we postulated that MBD2 present in the proximal tubule could upregulate the autophagic process to expedite the onset of AKI. In the present study, we found for the first time that MBD2 mediated the autophagy production induced by VAN. Through the utilization of miRNA chip analysis, we have mechanistically demonstrated that MBD2 initiates the activation of miR-597-5p through promoter demethylation. This process leads to the suppression of S1PR1, which results in the induction of autophagy and apoptosis in renal tubular cells. Besides, PT-MBD2-KO reduced autophagy to attenuate VAN-induced AKI via regulation of the miR-597-5p/S1PR1 axis, which was reversed by rapamycin. Finally, the overexpression of MBD2 aggravated the diminished VAN-induced AKI in autophagy-deficient mice (PT-Atg7-KO). These data demonstrate that proximal tubular MBD2 facilitated the process of autophagy via the miR-597-5p/S1PR1 axis and subsequently instigated VAN-induced AKI through the induction of apoptosis. The potentiality of MBD2 being a target for AKI was established.

Descending dopaminergic pathway facilitates itch signal processing via activating spinal GRPR+ neurons.

A11 dopaminergic neurons regulate somatosensory transduction by projecting from the diencephalon to the spinal cord, but the function of this descending projection in itch remained elusive. Here, we report that dopaminergic projection neurons from the A11 nucleus to the spinal dorsal horn (dopaminergicA11-SDH ) are activated by pruritogens. Inhibition of these neurons alleviates itch-induced scratching behaviors. Furthermore, chemogenetic inhibition of spinal dopamine receptor D1-expressing (DRD1+ ) neurons decreases acute or chronic itch-induced scratching. Mechanistically, spinal DRD1+ neurons are excitatory and mostly co-localize with gastrin-releasing peptide (GRP), an endogenous neuropeptide for itch. In addition, DRD1+ neurons form synapses with GRP receptor-expressing (GRPR+ ) neurons and activate these neurons via AMPA receptor (AMPAR). Finally, spontaneous itch and enhanced acute itch induced by activating spinal DRD1+ neurons are relieved by antagonists against AMPAR and GRPR. Thus, the descending dopaminergic pathway facilitates spinal itch transmission via activating DRD1+ neurons and releasing glutamate and GRP, which directly augments GRPR signaling. Interruption of this descending pathway may be used to treat chronic itch.