Neurulation of the cynomolgus monkey embryo achieved from 3D blastocyst culture.

Neural tube (NT) defects arise from abnormal neurulation and result in the most common birth defects worldwide. Yet, mechanisms of primate neurulation remain largely unknown due to prohibitions on human embryo research and limitations of available model systems. Here, we establish a three-dimensional (3D) prolonged in vitro culture (pIVC) system supporting cynomolgus monkey embryo development from 7 to 25 days post-fertilization. Through single-cell multi-omics analyses, we demonstrate that pIVC embryos form three germ layers, including primordial germ cells, and establish proper DNA methylation and chromatin accessibility through advanced gastrulation stages. In addition, pIVC embryo immunofluorescence confirms neural crest formation, NT closure, and neural progenitor regionalization. Finally, we demonstrate that the transcriptional profiles and morphogenetics of pIVC embryos resemble key features of similarly staged in vivo cynomolgus and human embryos. This work therefore describes a system to study non-human primate embryogenesis through advanced gastrulation and early neurulation.

Imaging surface structure and premelting of ice Ih with atomic resolution.

Ice surfaces are closely relevant to many physical and chemical properties, such as melting, freezing, friction, gas uptake and atmospheric reaction1-8. Despite extensive experimental and theoretical investigations9-17, the exact atomic structures of ice interfaces remain elusive owing to the vulnerable hydrogen-bonding network and the complicated premelting process. Here we realize atomic-resolution imaging of the basal (0001) surface structure of hexagonal water ice (ice Ih) by using qPlus-based cryogenic atomic force microscopy with a carbon monoxide-functionalized tip. We find that the crystalline ice-Ih surface consists of mixed Ih- and cubic (Ic)-stacking nanodomains, forming 19 × 19 periodic superstructures. Density functional theory reveals that this reconstructed surface is stabilized over the ideal ice surface mainly by minimizing the electrostatic repulsion between dangling OH bonds. Moreover, we observe that the ice surface gradually becomes disordered with increasing temperature (above 120 Kelvin), indicating the onset of the premelting process. The surface premelting occurs from the defective boundaries between the Ih and Ic domains and can be promoted by the formation of a planar local structure. These results put an end to the longstanding debate on ice surface structures and shed light on the molecular origin of ice premelting, which may lead to a paradigm shift in the understanding of ice physics and chemistry.

Distinct α-synuclein strains differentially promote tau inclusions in neurons.

Many neurodegenerative diseases are characterized by the accumulation of insoluble protein aggregates, including neurofibrillary tangles comprised of tau in Alzheimer's disease and Lewy bodies composed of α-synuclein in Parkinson's disease. Moreover, different pathological proteins frequently codeposit in disease brains. To test whether aggregated α-synuclein can directly cross-seed tau fibrillization, we administered preformed α-synuclein fibrils assembled from recombinant protein to primary neurons and transgenic mice. Remarkably, we discovered two distinct strains of synthetic α-synuclein fibrils that demonstrated striking differences in the efficiency of cross-seeding tau aggregation, both in neuron cultures and in vivo. Proteinase K digestion revealed conformational differences between the two synthetic α-synuclein strains and also between sarkosyl-insoluble α-synuclein extracted from two subgroups of Parkinson's disease brains. We speculate that distinct strains of pathological α-synuclein likely exist in neurodegenerative disease brains and may underlie the tremendous heterogeneity of synucleinopathies.

Primate gastrulation and early organogenesis at single-cell resolution.

Our understanding of human early development is severely hampered by limited access to embryonic tissues. Due to their close evolutionary relationship with humans, nonhuman primates are often used as surrogates to understand human development but currently suffer from a lack of in vivo datasets, especially from gastrulation to early organogenesis during which the major embryonic cell types are dynamically specified. To fill this gap, we collected six Carnegie stage 8-11 cynomolgus monkey (Macaca fascicularis) embryos and performed in-depth transcriptomic analyses of 56,636 single cells. Our analyses show transcriptomic features of major perigastrulation cell types, which help shed light on morphogenetic events including primitive streak development, somitogenesis, gut tube formation, neural tube patterning and neural crest differentiation in primates. In addition, comparative analyses with mouse embryos and human embryoids uncovered conserved and divergent features of perigastrulation development across species-for example, species-specific dependency on Hippo signalling during presomitic mesoderm differentiation-and provide an initial assessment of relevant stem cell models of human early organogenesis. This comprehensive single-cell transcriptome atlas not only fills the knowledge gap in the nonhuman primate research field but also serves as an invaluable resource for understanding human embryogenesis and developmental disorders.

The MdHSC70-MdWRKY75 module mediates basal apple thermotolerance by regulating the expression of heat shock factor genes.

Heat stress severely restricts the growth and fruit development of apple (Malus domestica). Little is known about the involvement of WRKY proteins in the heat tolerance mechanism in apple. In this study, we found that the apple transcription factor (TF) MdWRKY75 responds to heat and positively regulates basal thermotolerance. Apple plants that overexpressed MdWRKY75 were more tolerant to heat stress while silencing MdWRKY75 caused the opposite phenotype. RNA-seq and reverse transcription quantitative PCR showed that heat shock factor genes (MdHsfs) could be the potential targets of MdWRKY75. Electrophoretic mobility shift, yeast one-hybrid, ß-glucuronidase, and dual-luciferase assays showed that MdWRKY75 can bind to the promoters of MdHsf4, MdHsfB2a, and MdHsfA1d and activate their expression. Apple plants that overexpressed MdHsf4, MdHsfB2a, and MdHsfA1d exhibited heat tolerance and rescued the heat-sensitive phenotype of MdWRKY75-Ri3. In addition, apple heat shock cognate 70 (MdHSC70) interacts with MdWRKY75, as shown by yeast two-hybrid, split luciferase, bimolecular fluorescence complementation, and pull-down assays. MdHSC70 acts as a negative regulator of the heat stress response. Apple plants that overexpressed MdHSC70 were sensitive to heat, while virus-induced gene silencing of MdHSC70 enhanced heat tolerance. Additional research showed that MdHSC70 exhibits heat sensitivity by interacting with MdWRKY75 and inhibiting MdHsfs expression. In summary, we proposed a mechanism for the response of apple to heat that is mediated by the "MdHSC70/MdWRKY75-MdHsfs" molecular module, which enhances our understanding of apple thermotolerance regulated by WRKY TFs.

γδ T cell antigen receptor polyspecificity enables T cell responses to a broad range of immune challenges.

γδ T cells are essential for immune defense and modulating physiological processes. While they have the potential to recognize large numbers of antigens through somatic gene rearrangement, the antigens which trigger most γδ T cell response remain unidentified, and the role of antigen recognition in γδ T cell function is contentious. Here, we show that some γδ T cell receptors (TCRs) exhibit polyspecificity, recognizing multiple ligands of diverse molecular nature. These ligands include haptens, metabolites, neurotransmitters, posttranslational modifications, as well as peptides and proteins of microbial and host origin. Polyspecific γδ T cells are enriched among activated cells in naive mice and the responding population in infection. They express diverse TCR sequences, have different functional potentials, and include the innate-like γδ T cells, such as the major IL-17 responders in various pathological/physiological conditions. We demonstrate that encountering their antigenic microbiome metabolite maintains their homeostasis and functional response, indicating that their ability to recognize multiple ligands is essential for their function. Human γδ T cells with similar polyspecificity also respond to various immune challenges. This study demonstrates that polyspecificity is a prevalent feature of γδ T cell antigen recognition, which enables rapid and robust T cell responses to a wide range of challenges, highlighting a unique function of γδ T cells.

Atomic imaging of the edge structure and growth of a two-dimensional hexagonal ice.

The formation and growth of water-ice layers on surfaces and of low-dimensional ice under confinement are frequent occurrences1-4. This is exemplified by the extensive reporting of two-dimensional (2D) ice on metals5-11, insulating surfaces12-16, graphite and graphene17,18 and under strong confinement14,19-22. Although structured water adlayers and 2D ice have been imaged, capturing the metastable or intermediate edge structures involved in the 2D ice growth, which could reveal the underlying growth mechanisms, is extremely challenging, owing to the fragility and short lifetime of those edge structures. Here we show that noncontact atomic-force microscopy with a CO-terminated tip (used previously to image interfacial water with minimal perturbation)12, enables real-space imaging of the edge structures of 2D bilayer hexagonal ice grown on a Au(111) surface. We find that armchair-type edges coexist with the zigzag edges usually observed in 2D hexagonal crystals, and freeze these samples during growth to identify the intermediate edge structures. Combined with simulations, these experiments enable us to reconstruct the growth processes that, in the case of the zigzag edge, involve the addition of water molecules to the existing edge and a collective bridging mechanism. Armchair edge growth, by contrast, involves local seeding and edge reconstruction and thus contrasts with conventional views regarding the growth of bilayer hexagonal ices and 2D hexagonal matter in general.

Surface coordination layer passivates oxidation of copper.

Owing to its high thermal and electrical conductivities, its ductility and its overall non-toxicity1-3, copper is widely used in daily applications and in industry, particularly in anti-oxidation technologies. However, many widespread anti-oxidation techniques, such as alloying and electroplating1,2, often degrade some physical properties (for example, thermal and electrical conductivities and colour) and introduce harmful elements such as chromium and nickel. Although efforts have been made to develop surface passivation technologies using organic molecules, inorganic materials or carbon-based materials as oxidation inhibitors4-12, their large-scale application has had limited success. We have previously reported the solvothermal synthesis of highly air-stable copper nanosheets using formate as a reducing agent13. Here we report that a solvothermal treatment of copper in the presence of sodium formate leads to crystallographic reconstruction of the copper surface and formation of an ultrathin surface coordination layer. We reveal that the surface modification does not affect the electrical or thermal conductivities of the bulk copper, but introduces high oxidation resistance in air, salt spray and alkaline conditions. We also develop a rapid room-temperature electrochemical synthesis protocol, with the resulting materials demonstrating similarly strong passivation performance. We further improve the oxidation resistance of the copper surfaces by introducing alkanethiol ligands to coordinate with steps or defect sites that are not protected by the passivation layer. We demonstrate that the mild treatment conditions make this technology applicable to the preparation of air-stable copper materials in different forms, including foils, nanowires, nanoparticles and bulk pastes. We expect that the technology developed in this work will help to expand the industrial applications of copper.

High-quality genome assembly enables prediction of allele-specific gene expression in hybrid poplar.

Poplar (Populus) is a well-established model system for tree genomics and molecular breeding, and hybrid poplar is widely used in forest plantations. However, distinguishing its diploid homologous chromosomes is difficult, complicating advanced functional studies on specific alleles. In this study, we applied a trio-binning design and PacBio high-fidelity long-read sequencing to obtain haplotype-phased telomere-to-telomere genome assemblies for the 2 parents of the well-studied F1 hybrid "84K" (Populus alba × Populus tremula var. glandulosa). Almost all chromosomes, including the telomeres and centromeres, were completely assembled for each haplotype subgenome apart from 2 small gaps on one chromosome. By incorporating information from these haplotype assemblies and extensive RNA-seq data, we analyzed gene expression patterns between the 2 subgenomes and alleles. Transcription bias at the subgenome level was not uncovered, but extensive-expression differences were detected between alleles. We developed machine-learning (ML) models to predict allele-specific expression (ASE) with high accuracy and identified underlying genome features most highly influencing ASE. One of our models with 15 predictor variables achieved 77% accuracy on the training set and 74% accuracy on the testing set. ML models identified gene body CHG methylation, sequence divergence, and transposon occupancy both upstream and downstream of alleles as important factors for ASE. Our haplotype-phased genome assemblies and ML strategy highlight an avenue for functional studies in Populus and provide additional tools for studying ASE and heterosis in hybrids.

An investigation of the molecular characterization of the tripartite motif (TRIM) family and primary validation of TRIM31 in gastric cancer.

Most TRIM family members characterized by the E3-ubiquitin ligases, participate in ubiquitination and tumorigenesis. While there is a dearth of a comprehensive investigation for the entire family in gastric cancer (GC). By combining the TCGA and GEO databases, common TRIM family members (TRIMs) were obtained to investigate gene expression, gene mutations, and clinical prognosis. On the basis of TRIMs, a consensus clustering analysis was conducted, and a risk assessment system and prognostic model were developed. Particularly, TRIM31 with clinical prognostic and diagnostic value was chosen for single-gene bioinformatics analysis, in vitro experimental validation, and immunohistochemical analysis of clinical tissue microarrays. The combined dataset consisted of 66 TRIMs, of which 52 were differentially expressed and 43 were differentially prognostic. Significant survival differences existed between the gene clusters obtained by consensus clustering analysis. Using 4 differentially expressed genes identified by multivariate Cox regression and LASSO regression, a risk scoring system was developed. Higher risk scores were associated with a poorer prognosis, suppressive immune cell infiltration, and drug resistance. Transcriptomic data and clinical sample tissue microarrays confirmed that TRIM31 was highly expressed in GC and associated with a poor prognosis. Pathway enrichment analysis, cell migration and colony formation assay, EdU assay, reactive oxygen species (ROS) assay, and mitochondrial membrane potential assay revealed that TRIM31 may be implicated in cell cycle regulation and oxidative stress-related pathways, contribute to gastric carcinogenesis. This study investigated the whole functional and expression profile and a risk score system based on the TRIM family in GC. Further investigation centered around TRIM31 offers insight into the underlying mechanisms of action exhibited by other members of its family in the context of GC.

Genome-wide association study implicates lipid pathway dysfunction in antipsychotic-induced weight gain: multi-ancestry validation.

Antipsychotic-induced weight gain (AIWG) is a common side effect of antipsychotic medication and may contribute to diabetes and coronary heart disease. To expand the unclear genetic mechanism underlying AIWG, we conducted a two-stage genome-wide association study in Han Chinese patients with schizophrenia. The study included a discovery cohort of 1936 patients and a validation cohort of 534 patients, with an additional 630 multi-ancestry patients from the CATIE study for external validation. We applied Mendelian randomization (MR) analysis to investigate the relationship between AIWG and antipsychotic-induced lipid changes. Our results identified two novel genome-wide significant loci associated with AIWG: rs10422861 in PEPD (P = 1.373 × 10-9) and rs3824417 in PTPRD (P = 3.348 × 10-9) in Chinese Han samples. The association of rs10422861 was validated in the European samples. Fine-mapping and functional annotation revealed that PEPD and PTPRD are potentially causal genes for AIWG, with their proteins being prospective therapeutic targets. Colocalization analysis suggested that AIWG and type 2 diabetes (T2D) shared a causal variant in PEPD. Polygenic risk scores (PRSs) for AIWG and T2D significantly predicted AIWG in multi-ancestry samples. Furthermore, MR revealed a risky causal effect of genetically predicted changes in low-density lipoprotein cholesterol (P = 7.58 × 10-4) and triglycerides (P = 2.06 × 10-3) caused by acute-phase of antipsychotic treatment on AIWG, which had not been previously reported. Our model, incorporating antipsychotic-induced lipid changes, PRSs, and clinical predictors, significantly predicted BMI percentage change after 6-month antipsychotic treatment (AUC = 0.79, R2 = 0.332). Our results highlight that the mechanism of AIWG involves lipid pathway dysfunction and may share a genetic basis with T2D through PEPD. Overall, this study provides new insights into the pathogenesis of AIWG and contributes to personalized treatment of schizophrenia.

Identification of Hub Genes and Pathways of Middle Cerebral Artery Occlusion in Aged Rats Using the Gene Expression Omnibus Database.

Stroke remained the leading cause of disability in the world, and the most important non-modifiable risk factor was age. The treatment of stroke for elder patients faced multiple difficulties due to its complicated pathogenesis and mechanism. Therefore, we aimed to identify the potential differentially expressed genes (DEGs) and singnalling pathways for aged people of stroke. To compare the DEGs in the aged rats with or without middle cerebral artery occlusion (MCAO) and to analyse the important genes and the key signaling pathways involved in the development of cerebral ischaemia in aged rats. The Gene Expression Omnibus (GEO) analysis tool was used to analyse the DEGs in the GSE166162 dataset of aged MCAO rats compared with aged sham rats. Differential expression analysis was performed in aged MCAO rats and sham rats using limma. In addition, the 74 DEGs (such as Fam111a, Lcn2, Spp1, Lgals3 and Gpnmb were up-regulated; Egr2, Nr4a3, Arc, Klf4 and Nr4a1 were down-regulated) and potential compounds corresponding to the top 20 core genes in the Protein-Protein Interaction (PPI) network was constructed using the STRING database (version 12.0). Among these 30 compounds, resveratrol, cannabidiol, honokiol, fucoxanthin, oleandrin and tyrosol were significantly enriched. These DEGs were subjected to Gene Ontology (GO) function analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis to determine the most significantly enriched pathway in aged MCAO rats. Moreover, innate immune response, the complement and coagulation cascades signaling pathway, the IL-17 and other signaling pathways were significantly correlated with the aged MCAO rats. Our study indicates that multiple genes and pathological processes involved in the aged people of stroke. The immune response might be the key pathway in the intervention of cerebral infarction in aged people.

Genome-Wide CRISPR/Cas9 Screening Identifies That Mitochondrial Solute Carrier SLC25A23 Attenuates Type I IFN Antiviral Immunity via Interfering with MAVS Aggregation.

Activation of the mitochondrial antiviral signaling (MAVS) adaptor, also known as IPS-1, VISA, or Cardif, is crucial for antiviral immunity in retinoic acid-inducible gene I (RIG-I)-like receptor signaling. Upon interacting with RIG-I, MAVS undergoes K63-linked polyubiquitination by the E3 ligase Trim31, and subsequently aggregates to activate downstream signaling effectors. However, the molecular mechanisms that modulate MAVS activation are not yet fully understood. In this study, the mitochondrial solute carrier SLC25A23 was found to attenuate type I IFN antiviral immunity using genome-wide CRISPR/Cas9 screening. SLC25A23 interacts with Trim31, interfering with its binding of Trim31 to MAVS. Indeed, SLC25A23 downregulation was found to increase K63-linked polyubiquitination and subsequent aggregation of MAVS, which promoted type I IFN production upon RNA virus infection. Consistently, mice with SLC25A23 knockdown were more resistant to RNA virus infection in vivo. These findings establish SLC25A23 as a novel regulator of MAVS posttranslational modifications and of type I antiviral immunity.

A novel bispecific T-cell engager using the ligand-target csGRP78 against acute myeloid leukemia.

Current medical therapies for treating acute myeloid leukemia (AML) remain unmet, and AML patients may benefit from targeted immunotherapy approaches that focus on specific tumor antigens. GRP78, which is upregulated in various malignant tumors such as AML, is partially expressed as cell surface GRP78 (csGRP78) on the cell membrane, making it an ideal target for redirecting T cells, including T-cell engagers. However, considering the conventional approach of using two scFv segments to construct a bispecific T-cell engager (BiTE), we have undertaken the development of a novel BiTE that utilizes a cyclic peptide ligand to specifically target csGRP78, which we refer to as GRP78-CD3/BiTE. We studied the effects of GRP78-CD3/BiTE on treatments for AML in vitro and in vivo and assessed the pharmacokinetics of this engager. Our findings demonstrated that GRP78-CD3/BiTE could not only effectively mediate the cytotoxicity of T cells against csGRP78-expressing AML cells but also specifically eliminate primary AML tumor cells in vitro. Furthermore, GRP78-CD3/BiTE exhibited a longer half-life despite having a lower molecular weight than CD19-CD3/BiTE. In a xenograft mouse model of AML, treatment with GRP78-CD3/BiTE prolonged the survival time of the mice. Our findings demonstrate that GRP78-CD3/BiTE is effective and selective for eliminating csGRP78-expressing AML cells and suggest that this approach to targeted immunotherapy could lead to effective new treatments for AML.

Impairment of oocyte quality caused by gut microbiota dysbiosis in obesity.

Obesity poses risks to oocyte maturation and embryonic development in mice and humans, linked to gut microbiota dysbiosis and altered host metabolomes. However, it is unclear whether symbiotic gut microbes have a pivotal role in oocyte quality. In mouse models of fecal microbiota transplantation, we demonstrated aberrant meiotic apparatus and impaired maternal mRNA in oocytes, which is coincident with the poor developmental competence of embryos. Using metabolomics profiling, we discovered that the cytosine and cytidine metabolism was disturbed, which could account for the fertility defects observed in the high-fat diet (HFD) recipient mice. Additionally, cytosine and cytidine are closely related with gut microbiota dysbiosis, which is accompanied by a notable reduction of abundance of Christensenellaceae R-7 group in the HFD mice. In summary, our findings provided evidence that modifying the gut microbiota may be of value in the treatment of infertile female individuals with obesity.

On-Chip Topological Photonic Crystal Nanobeam Filters.

We present an on-chip filter with a broad tailorable working wavelength and a single-mode operation. This is realized through the application of topological photonic crystal nanobeam filters employing synthesis parameter dimensions. By introducing the translation of air holes as a new synthetic parameter dimension, we obtained nanobeams with tunable Zak phases. Leveraging the bulk-edge correspondence, we identify the existence of topological cavity modes and establish a correlation between the cavity's interface morphology and working wavelength. Through experiments, we demonstrate filters with adjustable filtering wavelengths ranging from 1301 to 1570 nm. Our work illustrates the use of the synthetic translation dimension in the design of on-chip filters, and it holds potential for applications in other devices such as microcavities.

HRD1 promotes non-small cell lung carcinoma metastasis by blocking autophagy-mediated MIEN1 degradation.

Dysregulation of autophagy has been implicated in the development of many diseases, including cancer. Here, we revealed a novel function of the E3 ubiquitin ligase HRD1 in non-small cell lung carcinoma (NSCLC) metastasis by regulating autophagy. Mechanistically, HRD1 inhibits autophagy by promoting ATG3 ubiquitination and degradation. Additionally, a pro-migratory and invasive factor, MIEN1 (migration and invasion enhancer 1), was found to be autophagically degraded upon HRD1 deficiency. Importantly, expression of both HRD1 and MIEN1 are upregulated and positively correlated in lung tumors. Based on these results, we proposed a novel mechanism of HRD1 function that the degradation of ATG3 protein by HRD1 leads to autophagy inhibition and MIEN1 release, thus promoting NSCLC metastasis. Therefore, our findings provided new insights into the role of HRD1 in NSCLC metastasis and new therapeutic targets for lung cancer treatment.

Periodontal ligament-associated protein-1 knockout mice regulate the differentiation of osteoclasts and osteoblasts through TGF-ß1/Smad signaling pathway.

It has been known that periodontal ligament-associated protein-1 (PLAP-1/Asporin) not only inhibits cartilage formation in osteoarthritis, but it also influences the healing of skull defect. However, the effect and mechanism of PLAP-1/Asporin on the mutual regulation of osteoclasts and osteoblasts in periodontitis are not clear. In this study, we utilized a PLAP-1/Asporin gene knockout (KO) mouse model to research this unknown issue. We cultured mouse bone marrow mesenchymal stem cells with Porphyromonas gingivalis lipopolysaccharide (P.g. LPS) for osteogenic induction in vitro. The molecular mechanism of PLAP-1/Asporin in the regulation of osteoblasts was detected by immunoprecipitation, immunofluorescence, and inhibitors of signaling pathways. The results showed that the KO of PLAP-1/Asporin promoted osteogenic differentiation through transforming growth factor beta 1 (TGF-ß1)/Smad3 in inflammatory environments. We further found the KO of PLAP-1/Asporin inhibited osteoclast differentiation and promoted osteogenic differentiation through the TGF-ß1/Smad signaling pathway in an inflammatory coculture system. The experimental periodontitis model was established by silk ligation and the alveolar bone formation in PLAP-1/Asporin KO mice was promoted through TGF-ß1/Smad3 signaling pathway. The subcutaneous osteogenesis model in nude mice also confirmed that the KO of PLAP-1/Asporin promoted bone formation by the histochemical staining. In conclusion, PLAP-1/Asporin regulated the differentiation of osteoclasts and osteoblasts through TGF-ß1/Smad signaling pathway. The results of this study lay a theoretical foundation for the further study of the pathological mechanism underlying alveolar bone resorption, and the prevention and treatment of periodontitis.

SIRT2 regulates high mobility group protein B1 nucleoplasmic shuttle and degradation via deacetylation in microglia.

High mobility group protein B1 (HMGB1) acts as a pathogenic inflammatory response to mediate ranges of conditions such as epilepsy, septic shock, ischemia, traumatic brain injury, Parkinson's disease, Alzheimer's disease and mass spectrometry. HMGB1 promotes inflammation during sterile and infectious damage and plays a crucial role in disease development. Mobilization from the nucleus to the cytoplasm is the first important step in the release of HMGB1 from activated immune cells. Here, we demonstrated that Sirtuin 2 (SIRT2) physically interacts with and deacetylates HMGB1 at 43 lysine residue at nuclear localization signal locations, strengthening its interaction with HMGB1 and causing HMGB1 to be localized in the cytoplasm. These discoveries are the first to shed light on the SIRT2 nucleoplasmic shuttle, which influences HMGB1 and its degradation, hence revealing novel therapeutic targets and avenues for neuroinflammation treatment.

Genome assembly of M. spongiola and comparative genomics of the genus Morchella provide initial insights into taxonomy and adaptive evolution.

Morchella spongiola is a highly prized mushroom for its delicious flavor and medical value and is one of the most flourishing, representative, and dominant macrofungi in the Qilian Mountains of the Qinghai-Tibet Plateau subkingdoms (QTPs). However, the understanding of M. spongiola remains largely unknown, and its taxonomy is ambiguous. In this study, we redescribed a unique species of M. spongiola, i.e., micromorphology, molecular data, genomics, and comparative genomics, and the historical biogeography of M. spongiola were estimated for 182 single-copy homologous genes. A high-quality chromosome-level reference genome of M. spongiola M12-10 was obtained by combining PacBio HiFi data and Illumina sequencing technologies; it was approximately 57.1 Mb (contig N50 of 18.14 Mb) and contained 9775 protein-coding genes. Comparative genome analysis revealed considerable conservation and unique characteristics between M. spongiola M12-10 and 32 other Morchella species. Molecular phylogenetic analysis indicated that M. spongiola M12-10 is similar to the M. prava/Mes-7 present in sandy soil near rivers, differentiating from black morels ~ 43.06 Mya (million years ago), and diverged from M. parva/Mes-7 at approximately 12.85 Mya (in the Miocene epoch), which is closely related to the geological activities in the QTPs (in the Neogene). Therefore, M. spongiola is a unique species rather than a synonym of M. vulgaris/Mes-5, which has a distinctive grey-brown sponge-like ascomata. This genome of M. spongiola M12-10 is the first published genome sequence of the species in the genus Morchella from the QTPs, which could aid future studies on functional gene identification, germplasm resource management, and molecular breeding efforts, as well as evolutionary studies on the Morchella taxon in the QTPs.