CT-based delta-radiomics nomogram to predict pathological complete response after neoadjuvant chemoradiotherapy in esophageal squamous cell carcinoma patients.

BACKGROUND: This study developed a nomogram model using CT-based delta-radiomics features and clinical factors to predict pathological complete response (pCR) in esophageal squamous cell carcinoma (ESCC) patients receiving neoadjuvant chemoradiotherapy (nCRT). METHODS: The study retrospectively analyzed 232 ESCC patients who underwent pretreatment and post-treatment CT scans. Patients were divided into training (n = 186) and validation (n = 46) sets through fivefold cross-validation. 837 radiomics features were extracted from regions of interest (ROIs) delineations on CT images before and after nCRT to calculate delta values. The LASSO algorithm selected delta-radiomics features (DRF) based on classification performance. Logistic regression constructed a nomogram incorporating DRFs and clinical factors. Receiver operating characteristic (ROC) and area under the curve (AUC) analyses evaluated nomogram performance for predicting pCR. RESULTS: No significant differences existed between the training and validation datasets. The 4-feature delta-radiomics signature (DRS) demonstrated good predictive accuracy for pCR, with α-binormal-based and empirical AUCs of 0.871 and 0.869. T-stage (p = 0.001) and differentiation degree (p = 0.018) were independent predictors of pCR. The nomogram combined the DRS and clinical factors improved the classification performance in the training dataset (AUCαbin = 0.933 and AUCemp = 0.941). The validation set showed similar performance with AUCs of 0.958 and 0.962. CONCLUSIONS: The CT-based delta-radiomics nomogram model with clinical factors provided high predictive accuracy for pCR in ESCC patients after nCRT.

An inactivated PDCoV vaccine induces robust neutralizing antibodies and immune protection in pigs lasting for three months.

Porcine deltacoronavirus (PDCoV), a novel enteropathogenic coronavirus, causes diarrhea mainly in suckling piglets and has the potential to infect humans. Whereas, there is no commercially available vaccine which can effectively prevent this disease. In this study, to ascertain the duration of immune protection of inactivated PDCoV vaccine, suckling piglets were injected subcutaneously with inactivated PDCoV vaccine using a prime/boost strategy at 3 and 17-day-old. Neutralizing antibody assay showed that the level of the inactivated PDCoV group was still ≥1:64 at three months after prime vaccination. The three-month-old pigs were orally challenged with PDCoV strain CZ2020. Two pigs in challenge control group showed mild to severe diarrhea at 10-11 day-post-challenge (DPC), while the inactivated PDCoV group had no diarrhea. High levels of viral shedding, substantial intestinal villus atrophy, and positive straining of viral antigens in ileum were detected in challenge control group, while the pigs in inactivated PDCoV group exhibited significantly reduced viral load, minor intestinal villi damage and negative straining of viral antigens. These results demonstrated that PDCoV was pathogenic against three-month-old pigs and inactivated PDCoV vaccine can provide effective protection in pigs lasting for three months.

Integrating single-nucleus sequence profiling to reveal the transcriptional dynamics of Alzheimer's disease, Parkinson's disease, and multiple sclerosis.

BACKGROUND: Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS) are three nervous system diseases that partially overlap clinically and genetically. However, bulk RNA-sequencing did not accurately detect the core pathogenic molecules in them. The availability of high-quality single cell RNA-sequencing data of post-mortem brain collections permits the generation of a large-scale gene expression in different cells in human brain, focusing on the molecular features and relationships between diseases and genes. We integrated single-nucleus RNA-sequencing (snRNA-seq) datasets of human brains with AD, PD, and MS to identify transcriptomic commonalities and distinctions among them. METHODS: The snRNA-seq datasets were downloaded from Gene Expression Omnibus (GEO) database. The Seurat package was used for snRNA-seq data processing. The uniform manifold approximation and projection (UMAP) were utilized for cluster identification. The FindMarker function in Seurat was used to identify the differently expressed genes. Functional enrichment analysis was carried out using the Gene Set Enrichment Analysis (GSEA) and Gene ontology (GO). The protein-protein interaction (PPI) analysis of differentially expressed genes (DEGs) was analyzed using STRING database ( http://string-db.org ). SCENIC analysis was performed using utilizing pySCENIC (v0.10.0) based on the hg19-tss-centered-10 kb-10species databases. The analysis of potential therapeutic drugs was analyzed on Connectivity Map ( https://clue.io ). RESULTS: The gene regulatory network analysis identified several hub genes regulated in AD, PD, and MS, in which HSPB1 and HSPA1A were key molecules. These upregulated HSP family genes interact with ribosome genes in AD and MS, and with immunomodulatory genes in PD. We further identified several transcriptional regulators (SPI1, CEBPA, TFE3, GRHPR, and TP53) of the hub genes, which has important implications for uncovering the molecular crosstalk among AD, PD, and MS. Arctigenin was identified as a potential therapeutic drug for AD, PD, and MS. CONCLUSIONS: Together, the integrated snRNA-seq data and findings have significant implications for unraveling the shared and unique molecular crosstalk among AD, PD, and MS. HSPB1 and HSPA1A as promising targets involved in the pathological mechanisms of neurodegenerative diseases. Additionally, the identification of arctigenin as a potential therapeutic drug for AD, PD, and MS further highlights its potential in treating these neurological disorders. These discoveries lay the groundwork for future research and interventions to enhance our understanding and treatment of AD, PD, and MS.

GIPC1 CGG Repeat Expansion Is Associated with Movement Disorders.

OBJECTIVE: CGG/GGC repeat expansion in FMR1 and NOTCH2NLC is reportedly associated with movement disorders; therefore, we hypothesized that the CGG repeat expansion in LRP12, NUTM2B-AS1, and GIPC1, which was previously identified in myopathy, might also be associated with movement-disorder phenotypes. Here, we investigated whether CGG repeat expansion in LRP12, NUTM2B-AS1, and GIPC1 presents in a cohort of patients with movement disorders. METHODS: We screened for the CGG repeat expansion in LRP12, NUTM2B-AS1, and GIPC1 in 1,346 movement-disorder patients and 1,451 matched healthy controls. RESULTS: No patients or controls harbored expanded CGG repeats in LRP12 or NUTM2B-AS1, whereas 16 patients harbored >40 CGG repeats in GIPC1, with 11 of these patients harboring >60 CGG repeats. One control individual harbored an expanded GIPC1 allele (83 CGG units), suggesting that approximately 1% of patients affected by movement disorders in our population might harbor GIPC1 CGG repeat expansion, with this likely extremely rare in healthy controls (<0.001). The clinical phenotypes of the GIPC1 CGG repeat-positive patients strongly resembled those in patients displaying NOTCH2NLC GGC repeat-positive movement disorders. Additionally, the GIPC1 CGG repeat-positive patients presented white-matter hyperintensities but without typical NOTCH2NLC-related high-intensity signals in the corticomedullary junction. Furthermore, 44% of the GIPC1 CGG repeat-positive patients showed a cognitive deficit, and skin biopsies in 2 patients revealed deposition of intranuclear inclusions. INTERPRETATION: The CGG repeat expansion in GIPC1 might be associated with movement-disorder phenotypes and lead to diseases related to intranuclear inclusions. ANN NEUROL 2022;91:704-715.

Spinocerebellar Ataxia Type 10 with Atypical Clinical Manifestation in Han Chinese.

Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant cerebellar ataxia accompanied by extracerebellar signs and other neurological disorders. It is caused by an expansion of the ATTCT pentanucleotide repeat in intron 9 of ATXN10. Cases of SCA10, formerly confined to America, have been reported in Europe and Asia. In the present study, we aim to report an atypical SCA10 family in China and provide a reference for the diagnosis of SCA10 in Asia by comparing their clinical and genetic features with former SCA10 pedigrees. Genomic DNA was extracted from patients and subjected to RP-PCR (repeat-primed PCR), Southern blotting, and haplotype analysis to determine the genetic pathogenesis. Patients with SCA10 in this pedigree demonstrated atypical SCA10 manifestations, including the absence of seizures and ocular abnormalities. Magnetic resonance imaging (MRI) showed cerebellar atrophy in five patients with available data. RP-PCR and Southern blotting revealed abnormal expansion. Analysis of single nucleotide polymorphisms (SNPs) surrounding the SCA10 locus in the proband and other affected family members revealed the "C-expansion-G-G-C" haplotype, consistent with former studies. These findings imply that the SCA10 mutation may have occurred before the Amerindian migration from East Asia to North America. It also suggested that SCA10 should be taken into account during differential diagnosis in patients of Asian ancestry, even if they do not present with typical features such as epilepsy.

Lycium barbarum polysaccharide-glycoprotein promotes osteogenesis in hPDLSCs via ERK activation.

OBJECTIVE: A lack of relevant research on Lycium barbarum polysaccharide-glycoprotein (LBP) application in oral diseases. Here, we focused on the effect of LBP on osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) and periodontitis bone loss. METHODS: Human periodontal ligament stem cells (hPDLSCs) were isolated and identified by flow cytometry. Alkaline phosphatase (ALP) activity, Alizarin Red staining, and combined qPCR and Western blot analyses were performed to elucidate the effects of LBP on the osteogenic potential of hPDLSCs. In vivo experiments were performed with the treatment of LBP in rat periodontal model. MicroCT scanning and histological analysis were conducted to evaluate osteogenesis in situ. RESULTS: Human periodontal ligament stem cells (hPDLSCs) were successfully isolated and identified with CD90, CD29, and CD45. LBP enhanced hPDLSCs proliferation and migration and promoted RUNX2, ALP, Collagen I, and Osteocalcin expression through activating the ERK1/2 signaling pathway in vitro. The inflammatory factors, including interleukin 6 (IL-6) and interleukin 8 (IL-8) were reduced after LBP treatment. Alveolar bone resorption was significantly decreased in the LBP-treated groups in vivo, and osteoclast was markedly decreased by LBP application. CONCLUSION: LBP promoted hPDLSC osteogenesis by targeting the ERK1/2 signaling pathway and reverse bone loss by reducing inflammation. These findings provided latent hope for LBP application in periodontal therapy.

Bone marrow mesenchymal stem cell-derived exosomes loaded with miR-26a through the novel immunomodulatory peptide DP7-C can promote osteogenesis.

PURPOSE: As small bioactive molecules, exosomes can deliver osteogenesis-related miRNAs to target cells and promote osteogenesis. This study aimed to investigate miR-26a as a therapeutic cargo to be loaded into bone marrow stromal cell exosomes through a novel immunomodulatory peptide (DP7-C). METHODS: After transfecting BMSCs with DP7-C as a transfection agent, exosomes were extracted by ultracentrifugation from the culture supernatant of miR-26a-modified BMSCs. We then characterized and identified the engineered exosomes. The effect of the engineered exosomes on osteogenesis was then evaluated in vitro and in vivo, including transwell, wound healing, modified alizarin red staining, western blot, real-time quantitative PCR, and experimental periodontitis assays. Bioinformatics and data analyses were conducted to investigate the role of miR-26a in bone regeneration. RESULTS: The DP7-C/miR-26a complex successfully transfected miR-26a into BMSCs and stimulated them to release more than 300 times the amount of exosomes overexpressing miR-26a compared with the ExoNC group. Furthermore, exosomes loaded with miR-26a could enhance proliferation, migration, and osteogenic differentiation of BMSCs in vitro compared with the ExoNC and blank groups. In vivo, the ExomiR-26a group inhibited the destruction of periodontitis compared with the ExoNC and blank groups, as revealed by HE staining. Micro-CT indicated that treatment of ExomiR-26a increased the percent bone volume and the bone mineral density compared with those of the ExoNC (P < 0.05) and blank groups (P < 0.001). Target gene analysis indicated that the osteogenic effect of miR-26a is related to the mTOR pathway. CONCLUSION: miR-26a can be encapsulated into exosomes through DP7-C. Exosomes loaded with miR-26a can promote osteogenesis and inhibit bone loss in experimental periodontitis and serve as the foundation for a novel treatment strategy.

NOTCH2NLC Intermediate-Length Repeat Expansions Are Associated with Parkinson Disease.

NOTCH2NLC GGC repeat expansions were recently identified in neuronal intranuclear inclusion disease (NIID); however, it remains unclear whether they occur in other neurodegenerative disorders. This study aimed to investigate the role of intermediate-length NOTCH2NLC GGC repeat expansions in Parkinson disease (PD). We screened for GGC repeat expansions in a cohort of 1,011 PD patients and identified 11 patients with intermediate-length repeat expansions ranging from 41 to 52 repeats, with no repeat expansions in 1,134 controls. Skin biopsy revealed phospho-alpha-synuclein deposition, confirming the PD diagnosis in 2 patients harboring intermediate-length repeat expansions instead of NIID or essential tremor. Fibroblasts from PD patients harboring intermediate-length repeat expansions revealed NOTCH2NLC upregulation and autophagic dysfunction. Our results suggest that intermediate-length repeat expansions in NOTCH2NLC are potentially associated with PD. ANN NEUROL 2021;89:182-187.

Correction to: Circular RNA profiling and its potential for esophageal squamous cell cancer diagnosis and prognosis.

An amendment to this paper has been published and can be accessed via the original article.

Correction to: Circular RNA profiling and its potential for esophageal squamous cell cancer diagnosis and prognosis.

After publication of the article [1], the author reported that this article contained error. In Funding section, the funding number provided 2016YFC0105100 should have been 2016YFC0105106.

Circular RNA profiling and its potential for esophageal squamous cell cancer diagnosis and prognosis.

Esophageal squamous cell cancer (ESCC) is a high incidence and mortality disease worldwide. However, specificity and sensitivity of its diagnostic and prognostic biomarkers are still unsatisfactory. Recently, circular RNAs (circRNAs) as biomarkers have been studied extensively while the expression profile and clinical significance of circRNAs in ESCC have rarely been studied. We performed circular RNA microarray in 3 pairs of ESCC frozen tumor and non-tumor tissues to identify ESCC-related circRNAs and found 1045 up-regulated and 1032 down-regulated circRNAs among which 6 circRNAs (hsa_circ_0062459, hsa_circ_0076535, hsa_circ_0072215, hsa_circ_0042261, hsa_circ_0001946, and hsa_circ_0043603) displayed consistency with microarray results by qRT-PCR. 3 circRNAs (hsa_circ_0062459, hsa_circ_0001946, and hsa_circ_0043603) were also detected in plasma and 2 of them except hsa_circ_0062459 could be used as diagnostic biomarkers and found in exosome of cell-conditioned culture conditioned media. The AUC, sensitivity and specificity of hsa_circ_0001946 were 0.894, 92, 80%, of hsa_circ_0043603 were 0.836, 64, 92% while a signature combining them were 0.928, 84 and 98%. Hsa_circ_0001946 was confirmed to predict the recurrence, overall survival (OS) and disease-free survival (DFS) in frozen and FFPE tissues, while its overexpression decreased cell proliferation, migration, and invasion.

Phosphorylation of G3BP1 is involved in the regulation of PDCoV-induced inflammatory response.

Stress granules (SGs), the main component is GTPase-activating protein-binding protein 1 (G3BP1), which are assembled during viral infection and function to sequester host and viral mRNAs and proteins, are part of the antiviral responses. In this study, we found that porcine deltacoronavirus (PDCoV) infection induced stable formation of robust SGs in cells through a PERK (protein kinase R-like endoplasmic reticulum kinase)-dependent mechanism. Overexpression of SGs marker proteins G3BP1 significantly reduced PDCoV replication in vitro, while inhibition of endogenous G3BP1 enhanced PDCoV replication. Moreover, PDCoV infected LLC-PK1 cells raise the phosphorylation level of G3BP1. By overexpression of the G3BP1 phosphorylated protein or the G3BP1 dephosphorylated protein, we found that phosphorylation of G3BP1 is involved in the regulation of PDCoV-induced inflammatory response. Taken together, our study presents a vital aspect of the host innate response to invading pathogens and reveals attractive host targets for antiviral target.

A novel virus-like particles vaccine induces broad immune protective against deltacoronavirus in piglets.

Coronaviruses (CoVs) comprise a group of important human and animal pathogens that threaten public health because of their interspecies transmission potential to humans. However, virus-like particles (VLPs) constitute versatile tools in CoVs vaccine development due to their favorable immunological characteristics. Here, we engineered the VLPs composed of the spike (S), membrane (M), and envelope (E) structural proteins of the Porcine deltacoronavirus (PDCoV) and examined their immune responses in mice. Neutralization assays and flow Cytometry demonstrated that PDCoV VLPs induced highly robust neutralizing antibodies (NAbs) and elicited cellular immunity. To assess the protective efficacy of VLPs in newborn piglets, pregnant sows received vaccinations with either a PDCoV-inactivated vaccine or VLPs at 40 and 20 days before delivery. Five days post-farrowing, piglets were orally challenged with the PDCoV strain. Severe diarrhea, high viral RNA copies, and substantial intestinal villus atrophy were detected in piglets born to unimmunized sows. However, piglets from sows immunized with VLPs exhibited high NAbs titers and markedly reduced microscopic damage to the intestinal tissues, with no piglet showing diarrhea. Hence, the results indicate that the VLPs are a potential clinical candidate for PDCoV vaccination, while the strategy may serve as a platform for developing other coronavirus vaccines.

Nonstructural protein 14 of PDCoV promotes complement C3 expression via the activation of p38-MAPK-C/EBP pathway.

Porcine deltacoronavirus (PDCoV) is an emergent enteric coronavirus, primarily inducing diarrhea in swine, particularly in nursing piglets, with the additional potential for zoonotic transmission to humans. Despite the significant impact of PDCoV on swine populations, its pathogenic mechanisms remain incompletely understood. Complement component 3 (C3) plays a pivotal role in the prevention of viral infections, however, there are no reports concerning the influence of C3 on the proliferation of PDCoV. In this study, we initially demonstrated that PDCoV is capable of activating the C3 and eliciting inflammatory responses. The overexpression of C3 significantly suppressed PDCoV replication, while inhibition of C3 expression facilitated PDCoV replication. We discovered that nonstructural proteins Nsp7, Nsp14, and M, considerably stimulated C3 expression, particularly Nsp14, through activation of the p38-MAPK-C/EBP-ß pathway. The N7-MTase constitutes a significant functional domain of the non-structural protein Nsp14, which is more obvious to upregulate C3. Furthermore, functional mutants of the N7-MTase domain suggested that the D44 and T135 of N7-Mtase constituted a pivotal amino acid site to promote C3 expression. This provides fresh insights into comprehending how the virus manipulates the host immune response and suggests potential antiviral strategies against PDCoV.

A method for synthesis of homoallylic bromide.

Cyclopropyl Grignard reagents react with carbonyl compounds in the presence of diethyl phosphite to give homoallylic bromides. The reaction is effectively carried out under mild conditions in a one-pot fashion with moderate to good yields.

Interfacial Polymerization of Highly Active Thiolated Cyclodextrin for the Fabrication of a Loose Nanofiltration Membrane with a Chlorine-Resistant Poly(thioester) Linkage.

Cyclodextrins have been frequently used to fabricate membranes via interfacial polymerization (IP). However, the relatively low reactivity of pristine cyclodextrins often induces a lower cross-linking density and unsatisfactory separation performance. In this work, to introduce a highly active thiolated ß-cyclodextrin (CD-SH) monomer into IP progress, we constructed a dense and porous poly(thioester) linkage on a commercial membrane surface with loose nanofiltration by IP of CD-SH and trimesoyl trichloride (TMC) as the monomer in an aqueous phase and organic phase separately for the first time. Furthermore, the reactivity of CD-SH has been fully demonstrated by the two-phase IP aiming at unmodified ß-CD, a CD-SH/TMC freestanding membrane with a thicker interfacial layer and a smoother surface, and a PAN/CD-SH membrane with a narrow porous distribution. The composite membrane possessed superior separation performance for a high rejection (83.1-99.6%) of different anionic dyes and a low rejection (<20%) of salts, as well as a high-efficiency sieving ability of dye/dye and dye/salt mixtures. The membrane with a poly(thioester) selective layer could steadily operate in a long-term filtration test and exhibit great stability, chloride-resistance performance, and recyclability.

Ni dispersed ultrathin carbon nanosheets as bi-functional oxygen electrocatalyst induced from graphite-like porous supramolecule.

Excellent porosity and accessibility are key requirements during carbon-based materials design for energy conversion applications. Herein, a Ni-based porous supramolecular framework with graphite-like morphology (Ni-SOF) was rationally designed as a carbon precursor. Ultrathin carbon nanosheets dispersed with Ni nanoparticles and Ni-Nx sites (Ni@NiNx-N-C) were obtained via in-situ exfoliation during pyrolysis. Due to the hetero-porous structure succeeding from Ni-SOF, the Ni@NiNx-N-C catalyst showed outstanding bifunctional oxygen electrocatalytic activity with a narrow gap of 0.69 V between potential to deliver 10 mA cm-2 oxygen evolution and half-wave potential of oxygen reduction reaction, which even surpassed the Pt/C + IrO2 pair. Therefore, the corresponding zinc-air battery exhibited excellent power output and stability. The multiple Ni-based active sites, the unique 2D structure with a high graphitization degree and large specific surface area synergistically contributed to the excellent bifunctional electrocatalytic activity of Ni@NiNx-N-C. This work provided a novel viewpoint for the development of carbon-based electrocatalyst.

Soft-template derived Ni/Mo2C hetero-sheet arrays for large current density hydrogen evolution reaction.

Practical structural design and electronic regulation are significant for synthesising efficient electrocatalysts. Therefore, a facile soft-template approach has been applied to successfully grow Ni/Mo2C heterojunction nanosheet arrays on nickel foam (NF) skeleton (NS-Ni/Mo2C@NF) using polyvinylpyrrolidone (PVP) as a soft template. The density functional theory (DFT) calculations reveal that abundant Ni/Mo2C heterojunction in NS-Ni/Mo2C@NF can provide many active sites with a moderate hydrogen adsorption free energy (ΔGH*, 0.037 eV). Benefiting from this nanosheet array structure and abundant Ni/Mo2C heterojunctions, the NS-Ni/Mo2C@NF catalyst can efficiently catalyze HER, especially at large current densities. As a result, only 151 and 271 mV overpotentials are needed to deliver 100 and 1000 mA/cm2 HER, respectively. More importantly, the hydrogen production testing with NS-Ni/Mo2C@NF as the working electrode can run stably for 500 h without activity decay under the current density of 500 mA/cm2 commonly used in industrial water electrolyzers, indicating that NS-Ni/Mo2C@NF has broad application prospects.

Shared metabolic shifts in endothelial cells in stroke and Alzheimer's disease revealed by integrated analysis.

Since metabolic dysregulation is a hallmark of both stroke and Alzheimer's disease (AD), mining shared metabolic patterns in these diseases will help to identify their possible pathogenic mechanisms and potential intervention targets. However, a systematic integration analysis of the metabolic networks of the these diseases is still lacking. In this study, we integrated single-cell RNA sequencing datasets of ischemic stroke (IS), hemorrhagic stroke (HS) and AD models to construct metabolic flux profiles at the single-cell level. We discovered that the three disorders cause shared metabolic shifts in endothelial cells. These altered metabolic modules were mainly enriched in the transporter-related pathways and were predicted to potentially lead to a decrease in metabolites such as pyruvate and fumarate. We further found that Lef1, Elk3 and Fosl1 may be upstream transcriptional regulators causing metabolic shifts and may be possible targets for interventions that halt the course of neurodegeneration.

Single-nucleus transcriptional profiling uncovers the reprogrammed metabolism of astrocytes in Alzheimer's disease.

Astrocytes play an important role in the pathogenesis of Alzheimer's disease (AD). It is widely involved in energy metabolism in the brain by providing nutritional and metabolic support to neurons; however, the alteration in the metabolism of astrocytes in AD remains unknown. Through integrative analysis of single-nucleus sequencing datasets, we revealed metabolic changes in various cell types in the prefrontal cortex of patients with AD. We found the depletion of some important metabolites (acetyl-coenzyme A, aspartate, pyruvate, 2-oxoglutarate, glutamine, and others), as well as the inhibition of some metabolic fluxes (glycolysis and tricarbocylic acid cycle, glutamate metabolism) in astrocytes of AD. The abnormality of glutamate metabolism in astrocytes is unique and important. Downregulation of GLUL (GS) and GLUD1 (GDH) may be the cause of glutamate alterations in astrocytes in AD. These results provide a basis for understanding the characteristic changes in astrocytes in AD and provide ideas for the study of AD pathogenesis.