Single-cell multi-omics map of human fetal blood in Down syndrome.

Down syndrome predisposes individuals to haematological abnormalities, such as increased number of erythrocytes and leukaemia in a process that is initiated before birth and is not entirely understood1-3. Here, to understand dysregulated haematopoiesis in Down syndrome, we integrated single-cell transcriptomics of over 1.1 million cells with chromatin accessibility and spatial transcriptomics datasets using human fetal liver and bone marrow samples from 3 fetuses with disomy and 15 fetuses with trisomy. We found that differences in gene expression in Down syndrome were dependent on both cell type and environment. Furthermore, we found multiple lines of evidence that haematopoietic stem cells (HSCs) in Down syndrome are 'primed' to differentiate. We subsequently established a Down syndrome-specific map linking non-coding elements to genes in disomic and trisomic HSCs using 10X multiome data. By integrating this map with genetic variants associated with blood cell counts, we discovered that trisomy restructured regulatory interactions to dysregulate enhancer activity and gene expression critical to erythroid lineage differentiation. Furthermore, as mutations in Down syndrome display a signature of oxidative stress4,5, we validated both increased mitochondrial mass and oxidative stress in Down syndrome, and observed that these mutations preferentially fell into regulatory regions of expressed genes in HSCs. Together, our single-cell, multi-omic resource provides a high-resolution molecular map of fetal haematopoiesis in Down syndrome and indicates significant regulatory restructuring giving rise to co-occurring haematological conditions.

Application of eye organoids in the study of eye diseases.

The eyes are one of the most important sensory organs in the human body. Currently, diseases such as limbal stem cell deficiency, cataract, retinitis pigmentosa and dry eye seriously threaten the quality of people's lives, and the treatment of advanced blinding eye disease and dry eye is ineffective and costly. Thus, new treatment modalities are urgently needed to improve patients' symptoms and suffering. In recent years, stem cell-derived three-dimensional structural organoids have been shown to mimic specific structures and functions similar to those of organs in the human body. Currently, 3D culture systems are used to construct organoids for different ocular growth and development models and ocular disease models to explore their physiological and pathological mechanisms. Eye organoids can also be used as a platform for drug screening. This paper reviews the latest research progress in regard to eye organoids (the cornea, lens, retina, lacrimal gland, and conjunctiva).

Role of microglia in diabetic neuropathic pain.

Approximately one-third of the patients with diabetes worldwide suffer from neuropathic pain, mainly categorized by spontaneous and stimulus-induced pain. Microglia are a class of immune effector cells residing in the central nervous system and play a pivotal role in diabetic neuropathic pain (DNP). Microglia specifically respond to hyperglycemia along with inflammatory cytokines and adenosine triphosphate produced during hyperglycemic damage to nerve fibers. Because of the presence of multiple receptors on the microglial surface, microglia are dynamically and highly responsive to their immediate environment. Following peripheral sensitization caused by hyperglycemia, microglia are affected by the cascade of inflammatory factors and other substances and respond accordingly, resulting in a change in their functional state for DNP pathogenesis. Inhibition of receptors such as P2X reporters, reducing cytokine expression levels in the microglial reactivity mechanisms, and inhibiting their intracellular signaling pathways can effectively alleviate DNP. A variety of drugs attenuate DNP by inhibiting the aforementioned processes induced by microglial reactivity. In this review, we summarize the pathological mechanisms by which microglia promote and maintain DNP, the drugs and therapeutic techniques available, and the latest advances in this field.

Application of novel magnetic lignin hydrogels: Activated persulfate degrades pesticide contaminants.

Lignin hydrogels have garnered significant attention due to their distinctive three-dimensional structures and potent swelling ability. In this work, a novel magnetic nanocomposite lignin hydrogel (MNLH) was fabricated through organic synthesis and solution immersion reduction. The obtained MNLH was used to activate persulfate(PDS) for pesticide degradation. Scanning electron microscopy (SEM), X-ray diffractometry (XRD), Brunauer-Emmett-Teller (BET), X-ray photoelectron spectroscopy (XPS), and Fourier transform infrared spectroscopy (FTIR) were used to characterize the structure and morphology of MNLH. The influence of factors such as the lignin hydrogel to nano-zero-valent iron (nZVI) and copper oxide (CuO) mass ratio, MNLH dosage, initial pH on the MNLH/PDS/imidacloprid (IMI) system. Remarkably, the MNLH/PDS/IMI system has a removal rate of up to 100%. Quenching and electron paramagnetic resonance (EPR) studies disclosed that the MNLH/PDS system degraded IMI through a combination of free radical and non-free radical pathways, with the latter being dominant. More importantly, in this study, the toxicity and hydrolysis sites of IMI were analyzed using ECOSAR and Gaussian09, respectively, confirming the feasibility of activating persulfate with MNLH. These findings underscore the potential of MNLH as a function material suitable for facilitating the persulfate-activated degradation of organic pollutants.

A Discussion of Building a Smart SHM Platform for Long-Span Bridge Monitoring.

This paper explores the development of a smart Structural Health Monitoring (SHM) platform tailored for long-span bridge monitoring, using the Forth Road Bridge (FRB) as a case study. It discusses the selection of smart sensors available for real-time monitoring, the formulation of an effective data strategy encompassing the collection, processing, management, analysis, and visualization of monitoring data sets to support decision-making, and the establishment of a cost-effective and intelligent sensor network aligned with the objectives set through comprehensive communication with asset owners. Due to the high data rates and dense sensor installations, conventional processing techniques are inadequate for fulfilling monitoring functionalities and ensuring security. Cloud-computing emerges as a widely adopted solution for processing and storing vast monitoring data sets. Drawing from the authors' experience in implementing long-span bridge monitoring systems in the UK and China, this paper compares the advantages and limitations of employing cloud- computing for long-span bridge monitoring. Furthermore, it explores strategies for developing a robust data strategy and leveraging artificial intelligence (AI) and digital twin (DT) technologies to extract relevant information or patterns regarding asset health conditions. This information is then visualized through the interaction between physical and virtual worlds, facilitating timely and informed decision-making in managing critical road transport infrastructure.

LINK-A: unveiling its functional role and clinical significance in human tumors.

LINK-A, also recognized as LINC01139, has emerged as a key oncological lncRNA in cancer. LINK-A is upregulated in solid and liquid tumor samples, including breast cancer, ovarian cancer, glioma, non-small-cell lung cancer, and mantle cell lymphoma. Notably, LINK-A is involved in regulating critical cancer-related pathways, such as AKT and HIF1α signaling, and is implicated in a range of oncogenic activities, including cell proliferation, apoptosis, epithelial-mesenchymal transition (EMT), cell invasion and migration, and glycolysis reprogramming. LINK-A's differential expression and its correlation with clinical features enable it to be a promising biomarker for cancer diagnosis, prognosis, and the stratification of tumor progression. Additionally, LINK-A's contribution to the development of resistance to cancer therapies, including AKT inhibitors and immunotherapy, underscores its potential as a therapeutic target. This review provides a comprehensive overview of the available data on LINK-A, focusing on its molecular regulatory pathways and clinical significance. By exploring the multifaceted nature of LINK-A in cancer, the review aims to offer a valuable resource for future research directions, potentially guiding the development of novel therapeutic strategies targeting this lncRNA in cancer treatment.

Ramelteon alleviates myocardial ischemia/reperfusion injury (MIRI) through Sirt3--dependent regulation of cardiomyocyte apoptosis.

Reperfusion stands as a pivotal intervention for ischemic heart disease. However, the restoration of blood flow to ischemic tissue always lead to further damage, which is known as myocardial ischemia/reperfusion injury (MIRI). Ramelteon is an orally administered drug used to improve sleep quality, which is famous for its high bioadaptability and absence of notable addictive characteristics. However, the specific mechanism by which it improves MIRI is still unclear. Sirtuin-3 (Sirt3), primarily located in mitochondria, is crucial in mitigating many cardiac diseases, including MIRI. Based on the structure of Sirt3, we simulated molecular docking and identified several potential amino acid binding sites between it and ramelteon. Therefore, we propose a hypothesis that ramelteon may exert cardioprotective effects by activating the Sirt3 signaling pathway. Our results showed that the activation levels and expression level of Sirt3 were significantly decreased in MIRI tissue and H2O2 stimulated H9C2 cells, while ramelteon treatment upregulated Sirt3 activity and expression. After treat with 3-TYP, a classic Sirt3 activity inhibitor, we constructed myocardial ischemia/reperfusion surgery in vivo and induced H9C2 cells with H2O2 in vitro. The results showed that the myocardial protection and anti-apoptotic effects of ramelteon were antagonized by 3-TYP, indicating that the activation of Sirt3 is a key mechanism for ramelteon to exert myocardial protection. In summary, our results confirm a novel mechanism by which ramelteon improves MIRI by activating Sirt3 signaling pathway, providing strong evidence for the treatment of MIRI with ramelteon.

NRF1 promotes primordial germ cell development, proliferation and survival.

Primordial germ cells (PGCs) are the germline precursors that give rise to oocytes and sperm, ensuring the continuation of life. While the PGC specification is extensively studied, it remains elusive how the PGC population is sustained and expanded after they migrate to embryonic gonads before birth. This study demonstrates that NRF1, a known regulator for mitochondrial metabolism, plays critical roles in post-migrating PGC development. We show that NRF1 protein level gradually increases in post-migrating PGCs during embryonic development. Conditional Nrf1 knockout from embryonic germ cells leads to impaired PGC proliferation and survival. In addition, NRF1 may also actively drive PGC derivation from pluripotent stem cells. Using whole genome transcriptome profiling and ChIP-seq analyses, we further reveal that NRF1 directly regulates key signalling molecules in PGC formation, transcription factors in proliferation and cell cycle and enzymes in mitochondrial metabolism. Overall, our findings highlight an essential requirement of NRF1 in regulating a broad transcriptional network to support post-migrating PGC development both in vitro and in vivo.

Berberine inhibits NLRP3 inflammasome activation by regulating mTOR/mtROS axis to alleviate diabetic cardiomyopathy.

Diabetes cardiomyopathy (DCM) refers to myocardial dysfunction and disorganization resulting from diabetes. In this study, we investigated the effects of berberine on cardiac function in male db/db mice with metformin as a positive control. After treatment for 8 weeks, significant improvements in cardiac function and a reduction in collagen deposition were observed in db/db mice. Furthermore, inflammation and pyroptosis were seen to decrease in these mice, as evidenced by decreased expressions of p-mTOR, NOD-like receptor thermal protein domain associated protein 3 (NLRP3), IL-1ß, IL-18, caspase-1, and gasdermin D (GSDMD). In vitro experiments on H9C2 cells showed that glucose exposure at 33 mmol/L induced pyroptosis, whereas berberine treatment reduced the expression of p-mTOR and NLRP3 inflammasome components. Moreover, berberine treatment was seen to inhibit the generation of mitochondrial reactive oxygen species (mtROS) and effectively improve cell damage in high glucose-induced H9C2 cells. The mTOR inhibitor, Torin-1, showed a therapeutic effect similar to that of berberine, by reducing the expression of NLRP3 inflammasome components and inhibiting mtROS generation. However, the activation of mTOR by MHY1485 partially nullified berberine's protective effects during high glucose stress. Collectively, our study reveals the mechanism that berberine regulates the mTOR/mtROS axis to inhibit pyroptosis induced by NLRP3 inflammasome activation, thereby alleviating DCM.

Detection of mesenchymal chondrosarcoma in pleural effusion with immunocytochemistry and determination of HEY1::NCOA2 fusion by next-generation sequencing on cell block.

Mesenchymal chondrosarcoma (MC) is a rare but extremely aggressive type of chondrosarcoma distinguished by the presence of both primitive mesenchymal cells and fully developed chondroid tissue. The identification of a biphasic morphology in pleural effusion, along with detection of the HEY1::NCOA2 fusion using next-generation sequencing, serve as vital indicators for an accurate diagnosis.

Case report metastatic SMARCB1 (INI1)-deficient gastric undifferentiated carcinoma in pleural effusion: A case report and literature review.

INI1-deficient gastric undifferentiated carcinoma is a rare tumour that may present as high-grade epithelioid morphology without apparent rhabdoid tumour cells. Syncytial tumour cells may be a crucial clue in such cases, especially in cytological specimens. Cell block and immunocytochemical staining can be valuable tools in achieving an accurate diagnosis.

LHP1-mediated epigenetic buffering of subgenome diversity and defense responses confers genome plasticity and adaptability in allopolyploid wheat.

Polyploidization is a major driver of genome diversification and environmental adaptation. However, the merger of different genomes may result in genomic conflicts, raising a major question regarding how genetic diversity is interpreted and regulated to enable environmental plasticity. By analyzing the genome-wide binding of 191 trans-factors in allopolyploid wheat, we identified like heterochromatin protein 1 (LHP1) as a master regulator of subgenome-diversified genes. Transcriptomic and epigenomic analyses of LHP1 mutants reveal its role in buffering the expression of subgenome-diversified defense genes by controlling H3K27me3 homeostasis. Stripe rust infection releases latent subgenomic variations by eliminating H3K27me3-related repression. The simultaneous inactivation of LHP1 homoeologs by CRISPR-Cas9 confers robust stripe rust resistance in wheat seedlings. The conditional repression of subgenome-diversified defenses ensures developmental plasticity to external changes, while also promoting neutral-to-non-neutral selection transitions and adaptive evolution. These findings establish an LHP1-mediated buffering system at the intersection of genotypes, environments, and phenotypes in polyploid wheat. Manipulating the epigenetic buffering capacity offers a tool to harness cryptic subgenomic variations for crop improvement.

Transposable element-initiated enhancer-like elements generate the subgenome-biased spike specificity of polyploid wheat.

Transposable elements (TEs) comprise ~85% of the common wheat genome, which are highly diverse among subgenomes, possibly contribute to polyploid plasticity, but the causality is only assumed. Here, by integrating data from gene expression cap analysis and epigenome profiling via hidden Markov model in common wheat, we detect a large proportion of enhancer-like elements (ELEs) derived from TEs producing nascent noncoding transcripts, namely ELE-RNAs, which are well indicative of the regulatory activity of ELEs. Quantifying ELE-RNA transcriptome across typical developmental stages reveals that TE-initiated ELE-RNAs are mainly from RLG_famc7.3 specifically expanded in subgenome A. Acquisition of spike-specific transcription factor binding likely confers spike-specific expression of RLG_famc7.3-initiated ELE-RNAs. Knockdown of RLG_famc7.3-initiated ELE-RNAs resulted in global downregulation of spike-specific genes and abnormal spike development. These findings link TE expansion to regulatory specificity and polyploid developmental plasticity, highlighting the functional impact of TE-driven regulatory innovation on polyploid evolution.

Preventive effects of Ramelteon on bleomycin-induced pulmonary fibrosis in mice.

Pulmonary fibrosis (PF) is a devastating lung disease that leads to impaired lung function and ultimately death. Several studies have suggested that melatonin, a hormone involved in regulating sleep-wake cycles, may be effective in improving PF. Ramelteon, an FDA-approved melatonin receptor agonist, has shown promise in exerting an anti-PF effect similar to melatonin. However, further investigations are required for illuminating the extent on its therapeutic benefits and the underlying molecular mechanisms. In this work, a mouse lung fibrosis model was built through intratracheal administration of bleomycin (BLM). Subsequently, the mice were administrated Ramelteon for a duration of 3 weeks to explore its efficacy and mechanism of action. Additionally, we utilized a TGF-ß1-induced MRC-5 cell model to further investigate the molecular mechanism underlying ramelteon's effects. Functionally, Ramelteon partially abrogated TGF-ß1-induced pulmonary fibrosis and reduced fibroblast proliferation, extracellular matrix deposition, and differentiation into myofibroblasts. In vivo experiments, ramelteon attenuated BLM-induced pulmonary fibrosis and collagen deposition. Mechanistically, ramelteon exerts its beneficial effect by alleviating translocation and expression of YAP1, a core component of Hippo pathway, from cytoplasm to nucleus; however, overexpression of YAP1 reversed this effect. In conclusion, our findings indicate that ramelteon can improve PF by regulating Hippo pathway and may become a potential candidate as a therapy to PF.

Virus-Bionic Mesoporous Silica Nanoplatform for Malignant Tumor Inhibition via Effective Cellular Uptake and Precise Drug Delivery.

Over the past few decades, sophisticated nanomaterials have been used as carries for the targeted delivery of therapeutics to solid tumors. However, the low efficiency of intracellular internalization of nanocarriers in current use restricts their biomedical application. In this work, we demonstrate that novel virus-bionic mesoporous-silica-based nanocarriers can be successfully prepared for programmed precise drug delivery. These unique viral mimic nanovesicles not only present virus bionic counterparts and nanostructures, but also have infectious virus-like properties toward tumor cells and tumor tissues. Encouragingly, their large surface area (322.1 m2 /g) endows them with high loading capacity for therapeutic agents, especially, they have more effective gene transfection properties than the commercially available LipoGeneTM transfection reagent. Thanks to their virus-inspired morphology, they exhibit outstanding cellular uptake efficiency with living tumor cells and the ability to invade cells in large quantities with incubation times as short as 5 min, which is much faster than traditional mesoporous silica nanoparticles (mSN) with smooth appearance. Importantly, after doxorubicin (DOX) loading and surface modification of tumor recognition motifs, RGD (Arg-Gly-Asp, vMN@DOX-RGD), the bionic drug-loaded viral mimics elicit potent tumor cell elimination both in vitro and in vivo, greatly exceeding the mSN-based group. Our work paves the way toward virus bionic nanocarrier design for malignant tumor suppression in the clinic.

Identification and validation of DNA methylation-driven gene PCDHB4 as a novel tumor suppressor for glioblastoma diagnosis and prognosis.

Aberrant DNA methylation is a critical regulator of gene expression in the development and progression of glioblastoma (GBM). However, the impact of methylation-driven gene PCDHB4 changes on GBM occurrence and progression remains unclear. Therefore, this study aimed to identify the PCDHB4 gene for early diagnosis and prognostic evaluation and clarify its functional role in GBM. Methylation-driven gene PCDHB4 was selected for GBM using the multi-omics integration method based on publicly available data sets. The diagnostic capabilities of PCDHB4 methylation and 5-hydroxymethylcytosines were validated in tissue and blood cell-free DNA (cfDNA) samples, respectively. Combined survival analysis of PCDHB4 methylation and immune infiltration cells evaluated the prognostic predictive performance of GBM patients. We identified that the PCDHB4 gene achieved high discriminative capabilities for GBM and normal tissues with an area under the curve value of 0.941. PCDHB4 hypermethylation was observed in cfDNA blood samples from GBM patients. Compared with GBM patients with PCDHB4 hypermethylation level, patients with PCDHB4 hypomethylation level had significantly poorer overall survival (p = 0.035). In addition, GBM patients with PCDHB4 hypermethylation and high infiltration of CD4+ T cell activation level had a favorable survival (p = 0.026). Moreover, we demonstrated that mRNA expression of PCDHB4 was downregulated in GBM tissues and upregulated in GBM cell lines with PCDHB4 demethylation, and PCDHB4 overexpression inhibited GBM cell proliferation and migration. In summary, we discovered a novel methylation-driven gene PCDHB4 for the diagnosis and prognosis of GBM and demonstrated that PCDHB4 is a tumor suppressor in vitro experiments.

STUB1-mediated ubiquitination regulates the stability of GLUD1 in lung adenocarcinoma.

The dysregulation of glutamine metabolism provides survival advantages for tumors by supplementing tricarboxylic acid cycle. Glutamate dehydrogenase 1 (GLUD1) is one of the key enzymes in glutamine catabolism. Here, we found that enhanced protein stability was the key factor for the upregulation of GLUD1 in lung adenocarcinoma. We discovered that GLUD1 showed a high protein expression in lung adenocarcinoma cells or tissues. We elucidated that STIP1 homology and U-box-containing protein 1 (STUB1) was the key E3 ligase responsible for ubiquitin-mediated proteasomal degradation of GLUD1. We further showed that lysine 503 (K503) was the main ubiquitination site of GLUD1, inhibiting the ubiquitination at this site promoted the proliferation and tumor growth of lung adenocarcinoma cells. Taken together, this study clarifies the molecular mechanism of GLUD1 in maintaining protein homeostasis in lung adenocarcinoma, which provides a theoretical basis for the development of anti-cancer drugs targeting GLUD1.

Heat shock cognate 70 protein like-2 protein in camphor pollen is one of the major culprits of asthma.

AIMS: In recent decades, Cinnamomum camphora have gradually become the main street trees in Shanghai. This study aims to investigate the allergenicity of camphor pollen. MAIN METHODS: A total of 194 serum samples from patients with respiratory allergy were collected and analyzed. Through protein profile identification and bioinformatics analysis, we hypothesized that heat shock cognate protein 2-like protein (HSC70L2) is the major potential allergenic protein in camphor pollen. Recombinant HSC70L2 (rHSC70L2) was expressed and purified, and a mouse model of camphor pollen allergy was established by subcutaneous injection of total camphor pollen protein extract (CPPE) and rHSC70L2. KEY FINDINGS: Specific IgE was found in the serum of 5 patients in response to camphor pollen and three positive bands were identified by Western blotting. Enzyme-linked immunosorbent assay (ELISA), Immune dot blot and Western blot experiments confirmed that CPPE and rHSC70L2 can cause allergies in mice. Moreover, rHSC70L2 induces polarization of peripheral blood CD4+ T cells to Th2 cells in patients with respiratory allergies and mice with camphor pollen allergy. Finally, we predicted the T cell epitope of the HSC70L2 protein, and through the mouse spleen T cell stimulation experiment, we found that the 295EGIDFYSTITRARFE309 peptide induced T cells differentiation to Th2 and macrophages differentiation to the alternatively activated (M2) state. Moreover, 295EGIDFYSTITRARFE309 peptide increased the serum IgE levels in mice. SIGNIFICANCE: The identification of HSC70L2 protein can provide novel diagnostic and therapeutic targets for allergies caused by camphor pollen.