Serum neuronal pentraxin 2 is related to cognitive dysfunction and electroencephalogram slow wave/fast wave frequency ratio in epilepsy.

BACKGROUND: Cognitive dysfunction in epileptic patients is a high-incidence complication. Its mechanism is related to nervous system damage during seizures, but there is no effective diagnostic biomarker. Neuronal pentraxin 2 (NPTX2) is thought to play a vital role in neurotransmission and the maintenance of synaptic plasticity. This study explored how serum NPTX2 and electroencephalogram (EEG) slow wave/fast wave frequency ratio relate to cognitive dysfunction in patients with epilepsy. AIM: To determine if serum NPTX2 could serve as a potential biomarker for diagnosing cognitive impairment in epilepsy patients. METHODS: The participants of this study, conducted from January 2020 to December 2021, comprised 74 epilepsy patients with normal cognitive function (normal group), 37 epilepsy patients with cognitive dysfunction [epilepsy patients with cognitive dysfunction (ECD) group] and 30 healthy people (control group). The mini-mental state examination (MMSE) scale was used to evaluate cognitive function. We determined serum NPTX2 levels using an enzyme-linked immunosorbent kit and calculated the signal value of EEG regions according to the EEG recording. Pearson correlation coefficient was used to analyze the correlation between serum NPTX2 and the MMSE score. RESULTS: The serum NPTX2 level in the control group, normal group and ECD group were 240.00 ± 35.06 pg/mL, 235.80 ± 38.01 pg/mL and 193.80 ± 42.72 pg/mL, respectively. The MMSE score was lowest in the ECD group among the three, while no significant difference was observed between the control and normal groups. In epilepsy patients with cognitive dysfunction, NPTX2 level had a positive correlation with the MMSE score (r = 0.367, P = 0.0253) and a negative correlation with epilepsy duration (r = -0.443, P = 0.0061) and the EEG slow wave/fast wave frequency ratio value in the temporal region (r = -0.339, P = 0.039). CONCLUSION: Serum NPTX2 was found to be related to cognitive dysfunction and the EEG slow wave/fast wave frequency ratio in patients with epilepsy. It is thus a potential biomarker for the diagnosis of cognitive impairment in patients with epilepsy.

Prolonged generation of multi-lineage blood cells in wild-type animals from pluripotent stem cells.

Regenerating prolonged multi-lineage hematopoiesis from pluripotent stem cells (PSCs), an unlimited cell source, is a crucial aim of regenerative hematology. In this study, we used a gene-edited PSC line and revealed that simultaneous expression of three transcription factors, Runx1, Hoxa9, and Hoxa10, drove the robust emergence of induced hematopoietic progenitor cells (iHPCs). The iHPCs engrafted successfully in wild-type animals and repopulated abundant and complete myeloid-, B-, and T-lineage mature cells. The generative multi-lineage hematopoiesis distributed normally in multiple organs, persisted over 6 months, and eventually declined over time with no leukemogenesis. Transcriptome characterization of generative myeloid, B, and T cells at the single-cell resolution further projected their identities to natural cell counterparts. Thus, we provide evidence that co-expression of exogenous Runx1, Hoxa9, and Hoxa10 simultaneously leads to long-term reconstitution of myeloid, B, and T lineages using PSC-derived iHPCs as the cell source.

Short-term efficacy of repetitive transcranial magnetic stimulation in SCA3: A prospective, randomized, double-blind, sham-controlled study.

OBJECTIVE: Spinocerebellar ataxia type 3 (SCA3) is the most common autosomal dominant ataxia globally. No effective treatment is currently available for SCA3. Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive form of brain stimulation, demonstrated to improve symptoms in patients with neurodegenerative cerebellar ataxias. The present study investigated whether treatment with rTMS over the cerebellum for 15 consecutive days improved measures of ataxia in SCA3 patients. METHODS: A double-blind, prospective, randomized, sham-controlled trial was carried out on 44 SCA3 patients. Participants were randomly assigned to two groups: real or sham stimulation. Each participant underwent 30 minutes of 1Hz rTMS stimulation (a total of 900 pulses) for 15 consecutive days. The primary outcome measure was the score on the International Cooperative Ataxia Rating Scale (ICARS), and secondary outcomes were from the Scale for the Assessment and Rating of Ataxia (SARA) and the Berg Balance Scale (BBS). RESULTS: Nausea was the only adverse effect reported by 2 participants from the sham and real group. After 15 days of treatment, there was a significant improvement in all performance scores in both real and sham stimulation groups. However, compared to the sham group, the improvements were significantly larger in the real group for the ICARS (P = 0.002), SARA (P = 0.001), and BBS (P = 0.001). INTERPRETATION: A 15 days treatment with rTMS over the cerebellum improves the symptoms of ataxia in SCA3 patients. Our results suggest that rTMS is a promising tool for future rehabilitative approaches in SCA3.

Identification and characterization of innate lymphoid cells generated from pluripotent stem cells.

Innate lymphoid cells (ILCs) play important roles in regulating tissue homeostasis and innate immune responses. Generation of ILCs after engraftment of pluripotent stem cell (PSC)-derived hematopoietic progenitors (iHPCs) has not yet been reported. Here, we document that ILCs exist in Rag2-/-Il2rg-/- recipients engrafted with PSC-derived iHPCs guided by Runx1 and Hoxa9 expression. Upon transplantation, iHPCs immediately give rise to ILC-related progenitors containing common helper ILC progenitors in the bone marrow, followed by a more restricted population named ILC progenitors, which are able to further differentiate into mature ILCs in the primary and secondary immunodeficient recipients. The PSC-derived ILCs exhibit multiple tissue distributions and normal immunological functions. Single-cell transcriptomics illustrates the developmental trajectory of PSC-derived ILCs in vivo, which is consistent with that of natural ILCs. Our study provides insights into the generation of ILCs in animals transplanted with PSC-derived iHPCs as a cell source.

Lateral plate mesoderm cell-based organoid system for NK cell regeneration from human pluripotent stem cells.

Human pluripotent stem cell (hPSC)-induced NK (iNK) cells are a source of off-the-shelf cell products for universal immune therapy. Conventional methods for iNK cell regeneration from hPSCs include embryoid body (EB) formation and feeder-based expansion steps, which are time-consuming and cause instability and high costs of manufacturing. Here, we develop an EB-free, organoid aggregate method for NK cell regeneration from hPSCs. In a short time-window of 27-day induction, millions of hPSC input can output over billions of iNK cells without the necessity of NK cell expansion feeders. The iNK cells highly express classical toxic granule proteins, apoptosis-inducing ligands, as well as abundant activating and inhibitory receptors. Functionally, the iNK cells eradicate human tumor cells via mechanisms of direct cytotoxicity, apoptosis, and antibody-dependent cellular cytotoxicity. This study provides a reliable scale-up method for regenerating human NK cells from hPSCs, which promotes the universal availability of NK cell products for immune therapy.

ViRBase v3.0: a virus and host ncRNA-associated interaction repository with increased coverage and annotation.

As a means to aid in the investigation of viral infection mechanisms and identification of more effective antivirus targets, the availability of a source which continually collects and updates information on the virus and host ncRNA-associated interaction resources is essential. Here, we update the ViRBase database to version 3.0 (http://www.virbase.org/ or http://www.rna-society.org/virbase/). This update represents a major revision: (i) the total number of interaction entries is now greater than 820,000, an approximately 70-fold increment, involving 116 virus and 36 host organisms, (ii) it supplements and provides more details on RNA annotations (including RNA editing, RNA localization and RNA modification), ncRNA SNP and ncRNA-drug related information and (iii) it provides two additional tools for predicting binding sites (IntaRNA and PRIdictor), a visual plug-in to display interactions and a website which is optimized for more practical and user-friendly operation. Overall, ViRBase v3.0 provides a more comprehensive resource for virus and host ncRNA-associated interactions enabling researchers a more effective means for investigation of viral infections.

Regeneration of immunocompetent B lymphopoiesis from pluripotent stem cells guided by transcription factors.

Regeneration of functional B lymphopoiesis from pluripotent stem cells (PSCs) is challenging, and reliable methods have not been developed. Here, we unveiled the guiding role of three essential factors, Lhx2, Hoxa9, and Runx1, the simultaneous expression of which preferentially drives B lineage fate commitment and in vivo B lymphopoiesis using PSCs as a cell source. In the presence of Lhx2, Hoxa9, and Runx1 expression, PSC-derived induced hematopoietic progenitors (iHPCs) immediately gave rise to pro/pre-B cells in recipient bone marrow, which were able to further differentiate into entire B cell lineages, including innate B-1a, B-1b, and marginal zone B cells, as well as adaptive follicular B cells. In particular, the regenerative B cells produced adaptive humoral immune responses, sustained antigen-specific antibody production, and formed immune memory in response to antigen challenges. The regenerative B cells showed natural B cell development patterns of immunoglobulin chain switching and hypermutation via cross-talk with host T follicular helper cells, which eventually formed T cell-dependent humoral responses. This study exhibits de novo evidence that B lymphopoiesis can be regenerated from PSCs via an HSC-independent approach, which provides insights into treating B cell-related deficiencies using PSCs as an unlimited cell resource.

RNAInter in 2020: RNA interactome repository with increased coverage and annotation.

Research on RNA-associated interactions has exploded in recent years, and increasing numbers of studies are not limited to RNA-RNA and RNA-protein interactions but also include RNA-DNA/compound interactions. To facilitate the development of the interactome and promote understanding of the biological functions and molecular mechanisms of RNA, we updated RAID v2.0 to RNAInter (RNA Interactome Database), a repository for RNA-associated interactions that is freely accessible at http://www.rna-society.org/rnainter/ or http://www.rna-society.org/raid/. Compared to RAID v2.0, new features in RNAInter include (i) 8-fold more interaction data and 94 additional species; (ii) more definite annotations organized, including RNA editing/localization/modification/structure and homology interaction; (iii) advanced functions including fuzzy/batch search, interaction network and RNA dynamic expression and (iv) four embedded RNA interactome tools: RIscoper, IntaRNA, PRIdictor and DeepBind. Consequently, RNAInter contains >41 million RNA-associated interaction entries, involving more than 450 thousand unique molecules, including RNA, protein, DNA and compound. Overall, RNAInter provides a comprehensive RNA interactome resource for researchers and paves the way to investigate the regulatory landscape of cellular RNAs.

Exploration of invasive mechanisms via global ncRNA-associated virus-host crosstalk.

Viral infection is a complex pathogenesis and the underlying molecular mechanisms remain poorly understood. In this study, an integrated multiple resources analysis was performed and showed that the cellular ncRNAs and proteins targeted by viruses were primarily "hubs" and "bottlenecks" in the human ncRNA/protein-protein interaction. The common proteins targeted by both viral ncRNAs and proteins tended to skew toward higher degrees and betweenness compared with other proteins, showed significant enrichment in the cell death process. Specifically, >800 pairs of human cellular ncRNAs and viral ncRNAs that exhibited a high degree of functional homology were identified, representing potential ncRNA-mediated co-regulation patterns of viral invasion. Additionally, clustering analysis further revealed several distinct viral clusters with obvious functional divergence. Overall, this is the first attempt to systematically explore the invasive mechanism via global ncRNA-associated virus-host crosstalk. Our results provide useful information in comprehensively understanding the viral invasive mechanism.

Integrated Analysis of Brain Transcriptome Reveals Convergent Molecular Pathways in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a set of complex neurodevelopmental disorders with etiology that remains elusive. Although there is a mounting body of investigation in different brain regions related to ASD, our knowledge about the common and distinct perturb condition between them is at the threshold of accumulation. In this study, based on protein-protein interactions, post-mortem transcriptome analysis was performed with corpus callosum (CC) and prefrontal cortex (PFC) samples from ASD individuals and controls. Co-expression network analysis revealed that a total of seven (four for CC set, three for PFC set) core dysfunctional modules strongly enriched for known ASD-risk genes. Three quarters of them in CC set (M4, M6, M29) significantly enriched for genes annotated by genetically associated variants in our previous whole genome sequencing data. We further determined transcriptional and post-transcriptional regulation subnetwork for each ASD-correlated module, including 47 pivot transcription factors, 130 pivot miRNAs, and 7 pivot lncRNAs. Moreover, there were significantly more interactions between CC-M4, -M6, and PFC-M2, mainly involved in synaptic functions and neuronal development. Our integrated multifactor analysis of ASD brain transcriptome profile illustrated underlying common and distinct molecular mechanisms and the module crosstalk between CC and PFC, helping to shed light on the molecular neuropathological underlying ASD.

Dissecting dynamic expression of autophagy-related genes during human fetal digestive tract development via single-cell RNA sequencing.

Macroautophagy/autophagy has been demonstrated to play an essential role in embryonic development. However, the role of autophagy during human fetal digestive tract development has not been investigated. Here, by using over 5,000 human embryonic digestive tract cells ranging from 6 weeks to 25 weeks, we explored the dynamic expression of autophagy-related genes at single-cell resolution, and found that the transcriptional activity of autophagy-related genes boosted remarkably and specifically in the early (between 6 and 9 weeks) stages. Interestingly, the small intestine cells at 9 weeks showed the most significant enrichment of autophagy-related genes than any other stages. In summary, our results for the first time revealed that autophagy may play an essential role in the development of the digestive tract, especially for the small intestine, in early human embryos. Abbreviations: GI: gastrointestinal; S-Intes: small intestine; t-SNE: t-distributed stochastic neighbor embedding.

Individualized analysis reveals CpG sites with methylation aberrations in almost all lung adenocarcinoma tissues.

BACKGROUND: Due to the heterogeneity of cancer, identifying differentially methylated (DM) CpG sites between a set of cancer samples and a set of normal samples cannot tell us which patients have methylation aberrations in a particular DM CpG site. METHODS: We firstly showed that the relative methylation-level orderings (RMOs) of CpG sites within individual normal lung tissues are highly stable but widely disrupted in lung adenocarcinoma tissues. This finding provides the basis of using the RankComp algorithm, previously developed for differential gene expression analysis at the individual level, to identify DM CpG sites in each cancer tissue compared with its own normal state. Briefly, through comparing with the highly stable normal RMOs predetermined in a large collection of samples for normal lung tissues, the algorithm finds those CpG sites whose hyper- or hypo-methylations may lead to the disrupted RMOs of CpG site pairs within a disease sample based on Fisher's exact test. RESULTS: Evaluated in 59 lung adenocarcinoma tissues with paired adjacent normal tissues, RankComp reached an average precision of 94.26% for individual-level DM CpG sites. Then, after identifying DM CpG sites in each of the 539 lung adenocarcinoma samples from TCGA, we found five and 44 CpG sites hypermethylated and hypomethylated in above 90% of the disease samples, respectively. These findings were validated in 140 publicly available and eight additionally measured paired cancer-normal samples. Gene expression analysis revealed that four of the five genes, HOXA9, TAL1, ATP8A2, ENG and SPARCL1, each harboring one of the five frequently hypermethylated CpG sites within its promoters, were also frequently down-regulated in lung adenocarcinoma. CONCLUSIONS: The common DNA methylation aberrations in lung adenocarcinoma tissues may be important for lung adenocarcinoma diagnosis and therapy.

[A signature based on relative gene expression orderings for lung cancer diagnosis].

Traditional classifiers, such as support vector machine and Bayesian classifier, require data normalization for removing experimental batch effects, which limit their applications at the individual level. In this paper,we aim to build a classifier to distinguish lung cancer and non-cancer lung tissues(pneumonia and normal lung tissues).We identified gene pairs as signatures to build a classifier based on the within-sample relative expression orderings of gene pairs in a particular type of tissues(cancer or non-cancer). Using multiple independent datasets as the training data,including a total of 197 lung cancer cases and 189 non-cancer cases, we identified three gene pairs. Classifying a sample by the majority voting rule, the average accuracy reached 95.34% in the training data. Using multiple independent validation datasets, including a total of 251 lung cancer samples and 141 non-cancer samples without data normalization, the average accuracy was as high as 96.78%. The rank-based signature is robust against experimental batch effects and can be used to diagnose lung cancer using samples measured by different laboratories at the individual level.

Harnessing quinone methides: total synthesis of (±)-vaticanol†A.

Although quinone methides are often postulated as intermediates in the biosynthesis of many polyphenolic natural products, deploying their power in a laboratory setting to achieve similar bond constructions has sometimes proven challenging. Herein, a total synthesis of the resveratrol trimer vaticanol A has been achieved through three instances of quinone methide chemistry. These operations, one of which succeeded only under very specific conditions, expediently generated its [7,5]-carbocyclic core, afforded a unique sequence for dihydrobenzofuran formation, and concurrently generated, in addition to the target molecule, a series of diastereomers reflective of many other isolates.

Remediation of copper polluted red soils with clay materials.

Attapulgite and montmorillonite were utilized to remediate heavy metal polluted red soils in Guixi City, Jiangxi Province, China. The effects of clay minerals on availability, chemical distribution, and biotoxicity of Cu and Zn were evaluated. The results provided a reference for the rational application of clay materials to remediate heavy metal contaminated soils. From the sorption experiment, the maximum adsorbed Cu2+ by attapulgite and montmorillonite was 1501 and 3741 mg/kg, respectively. After polluted red soil was amended with attapulgite or montmorillonite and cultured at 30 and 60 days, soil pH increased significantly compared to the control. An 8% increase in the amount of montmorillonite in soil and 30 days incubation decreased acid exchangeable Cu by 24.7% compared to the control red soil. Acid exchangeable Cu decreased with increasing amounts of attapulgite and montmorillonite, with best remediation effect reached at a dose of 8%. Results also showed that the Cu poisoning effect on earthworms was reduced with the addition of attapulgite and montmorillonite. Montmorillonite showed the best effect, with the addition of a 2% dose the mortality of earthworms decreased from 60% to zero compared to the control. Our results indicated that the bioavailability of Cu in soils was reduced more effectively with the application of montmorillonite than attapulgite.

Total synthesis of diverse carbogenic complexity within the resveratrol class from a common building block.

Although biomimetic approaches have proven capable of converting resveratrol (1) concurrently into many of the more complex oligomers produced by plants throughout the world (such as 2-10), methods to access single members of the family have proven far more difficult to identify. Herein is described a strategy-level solution based on the use of a common building block, one distinct from Nature's starting material, that can participate in a variety of highly selective, reagent-controlled reaction cascades. These endeavors have led to the controlled synthesis of 25 natural products and analogues, molecules whose architectures encompass nearly all the carbogenic diversity of the resveratrol family.

[Study on the epidemiology and etiologic agent of Dengue fever outbreaks in Fuzhou in 2004].

OBJECTIVE: To study the epidemiology and etiologic characteristics of a Dengue fever outbreak in Fuzhou from the beginning of September to the end of October in 2004 in order to understand the source of infection. METHODS: Data on descriptive epidemiology was collected to study the characteristics and related factors to the epidemic. Dengue virus was isolated through the use of C6/36 cell line while viral serotypes were identified by indirect immunofluorecent assay with type-specific monoclonal antibody. The sources of infection were traced by nucleotide sequencing. RESULTS: During the epidemic, 93 cases occured consistently with the region entomoplily growth and decay. The viruses of 6 strains isolated from 10 patients' blood specimens were identified as dengue virus type 1. Phylogenetic evidence suggested that the viral isolate had high genetic relation with the isolates from Kampuchea (DENV-1/KHM/2001; GenBank Accession No. L0904278). CONCLUSION: The epidemic was caused by introduction of patients migrating into Fuzhou.