[Mechanism of astragaloside â £ in regulating autophagy of PC12 cells under oxygen-glucose deprivation by medicating Akt/mTOR/HIF-1α pathway].

This study explored the protective effect of astragaloside Ⅳ(AS-Ⅳ) on oxygen-glucose deprivation(OGD)-induced autophagic injury in PC12 cells and its underlying mechanism. An OGD-induced autophagic injury model in vitro was established in PC12 cells. The cells were divided into a normal group, an OGD group, low-, medium-, and high-dose AS-Ⅳ groups, and a positive drug dexmedetomidine(DEX) group. Cell viability was measured using the MTT assay. Transmission electron microscopy was used to observe autophagosomes and autolysosomes, and the MDC staining method was used to assess the fluorescence intensity of autophagosomes. Western blot was conducted to determine the relative expression levels of functional proteins LC3-Ⅱ/LC3-Ⅰ, Beclin1, p-Akt/Akt, p-mTOR/mTOR, and HIF-1α. Compared with the normal group, the OGD group exhibited a significant decrease in cell viability(P<0.01), an increase in autophagosomes(P<0.01), enhanced fluorescence intensity of autophagosomes(P<0.01), up-regulated Beclin1, LC3-Ⅱ/LC3-Ⅰ, and HIF-1α(P<0.05 or P<0.01), and down-regulated p-Akt/Akt and p-mTOR/mTOR(P<0.05 or P<0.01). Compared with the OGD group, the low-and medium-dose AS-Ⅳ groups and the DEX group showed a significant increase in cell viability(P<0.01), decreased autophagosomes(P<0.01), weakened fluorescence intensity of autophagosomes(P<0.01), down-regulated Beclin1, LC3-Ⅱ/LC3-Ⅰ, and HIF-1α(P<0.05 or P<0.01), and up-regulated p-Akt/Akt and p-mTOR/mTOR(P<0.01). AS-Ⅳ at low and medium doses exerted a protective effect against OGD-induced autophagic injury in PC12 cells by activating the Akt/mTOR pathway, subsequently influencing HIF-1α. The high-dose AS-Ⅳ group did not show a statistically significant difference compared with the OGD group. This study provides a certain target reference for the prevention and treatment of OGD-induced cellular autophagic injury by AS-Ⅳ and accumulates laboratory data for the secondary development of Astragali Radix and AS-Ⅳ.

cTULIP: application of a human-based RNA-seq primary tumor classification tool for cross-species primary tumor classification in canine.

Introduction: The domestic dog, Canis familiaris, is quickly gaining traction as an advantageous model for use in the study of cancer, one of the leading causes of death worldwide. Naturally occurring canine cancers share clinical, histological, and molecular characteristics with the corresponding human diseases. Methods: In this study, we take a deep-learning approach to test how similar the gene expression profile of canine glioma and bladder cancer (BLCA) tumors are to the corresponding human tumors. We likewise develop a tool for identifying misclassified or outlier samples in large canine oncological datasets, analogous to that which was developed for human datasets. Results: We test a number of machine learning algorithms and found that a convolutional neural network outperformed logistic regression and random forest approaches. We use a recently developed RNA-seq-based convolutional neural network, TULIP, to test the robustness of a human-data-trained primary tumor classification tool on cross-species primary tumor prediction. Our study ultimately highlights the molecular similarities between canine and human BLCA and glioma tumors, showing that protein-coding one-to-one homologs shared between humans and canines, are sufficient to distinguish between BLCA and gliomas. Discussion: The results of this study indicate that using protein-coding one-to-one homologs as the features in the input layer of TULIP performs good primary tumor prediction in both humans and canines. Furthermore, our analysis shows that our selected features also contain the majority of features with known clinical relevance in BLCA and gliomas. Our success in using a human-data-trained model for cross-species primary tumor prediction also sheds light on the conservation of oncological pathways in humans and canines, further underscoring the importance of the canine model system in the study of human disease.

Identifying prognostic biomarker related to immune infiltration in acute myeloid leukemia.

The immune cells of tumor microenvironment (TME) constitute a vital element of the tumor tissue. There is increasing evidence for their clinical significance in predicting prognosis and therapeutic outcomes. However, the TME immune cell infiltrating pattern of the bone marrow in acute myeloid leukemia (AML) patients remains unclear. Here, RNA-sequencing results of AML patients from TCGA database were used to quantify the abundance of 28 types of immune cells in the TME using the single-sample gene set enrichment analysis algorithm. We comprehensively evaluated the immune infiltration status in the TCGA-LAML cohort and defined two immunophenotypes: the immune hot and immune cold subtypes. Additionally, we constructed a TME score reflecting the immune infiltrating pattern of the patients using Cox regression algorithm. Subtypes with high TME score were characterized by over-activation of immune inflammation-related pathways, release of inflammatory factors, T-cell dysfunction, and poor prognosis. Subtypes with a low TME score were characterized by relatively low immune infiltration and immune exclusion. Our analysis indicated that patients in the low TME score group were more sensitive to chemotherapeutic drugs, and those in high TME score were more likely to respond to immunotherapy. Our study provides a new direction to evaluate anti-tumor therapy from immune infiltration of the TME, and the individualized scoring system in this study has important clinical significance in identifying patients who respond to immunotherapy.

The role of NLRP3 inflammasome-mediated pyroptosis in ischemic stroke and the intervention of traditional Chinese medicine.

Ischemic stroke (IS) is the second leading cause of death and disability in the world. Pyroptosis, a form of programmed cell death initiated by caspases, participates in the occurrence and development of IS. Because it can increase cell membrane permeability, mediate the release of inflammatory factors, and aggravate inflammation, inhibiting this process can significantly reduce the pathological injury of IS. The nucleotide binding oligomerization domain-like receptor family pyrin domain protein 3 (NLRP3) is a multiprotein complex whose activation is the core link of pyroptosis. In recent years, studies have reported that traditional Chinese medicine (TCM) could regulate pyroptosis mediated by NLRP3 inflammasome through multi-channel and multi-target networks and thus exert the effect against IS. This article reviews 107 papers published in recent years in PubMed, Chinese National Knowledge Infrastructure (CNKI), and WanFang Data in recent years. It has found that the activation factors of NLRP3 inflammasome include ROS, mitochondrial dysfunction, K+, Ca2+, lysosome rupture, and trans-Golgi breakdown. TLR4/NF-κB/NLRP3, ROS/TXNIP/NLRP3, AMPK/Nrf2/NLRP3, DRP1/NLRP3, TAK1/JNK/NLRP3 signaling pathways regulate the initiation and assembly of the NLRP3 inflammasome, subsequently induce pyroptosis, affecting the occurrence and development of IS. TCM can affect the above signaling pathways and regulate the pyroptosis mediated by NLRP3 inflammasome, so as to play a protective role against IS, which provides a new entry point for discussing the pathological mechanism of IS and a theoretical basis for developing TCM treasure house.

Contribution of the histone variant H2A.Z to expression of responsive genes in plants.

The histone variant H2A.Z plays a critical role in chromatin-based processes such as transcription, replication, and repair in eukaryotes. Although many H2A.Z-associated processes and features are conserved in plants and animals, a distinguishing feature of plant chromatin is the enrichment of H2A.Z in the bodies of genes that exhibit dynamic expression, particularly in response to differentiation and the environment. Recent work sheds new light on the plant machinery that enables dynamic changes in H2A.Z enrichment and identifies additional chromatin-based pathways that contribute to transcriptional properties of H2A.Z-enriched chromatin. In particular, analysis of a variety of responsive loci reveals a repressive role for H2A.Z in expression of responsive genes and identifies roles for SWR1 and INO80 chromatin remodelers in enabling dynamic regulation of H2A.Z levels and transcription. These studies lay the groundwork for understanding how this ancient histone variant is harnessed by plants to enable responsive and dynamic gene expression (Graphical Abstract).

Gut microbiota in ischemic stroke: Where we stand and challenges ahead.

Gut microbiota is increasingly recognized to affect host health and disease, including ischemic stroke (IS). Here, we systematically review the current understanding linking gut microbiota as well as the associated metabolites to the pathogenesis of IS (e.g., oxidative stress, apoptosis, and neuroinflammation). Of relevance, we highlight that the implications of gut microbiota-dependent intervention could be harnessed in orchestrating IS.

Single-cell RNA sequencing to explore composition of peripheral blood NK cells in patients with chronic myeloid leukemia in treatment-free remission.

This study was to explore the role of NK cell subsets and gene expression in maintaining TFR status. We identified six types of NK cells in the PBMCs over both groups (healthy controls and patients with TFR). Gene Oncology analysis showed that up regulated genes were enriched in the categories of "immune response," "reaction to tumor cells," and "cytolysis." In addition, we found that the three NK cell subsets, mature and terminal NK cells, CD56 bright NK cells, and transitional NK cells, contained many significantly up regulated genes in both groups, and that CD56 bright NK cells and transitional NK cells in patients with CML-TFR were in a proliferating and activated state. Through single-cell RNA sequencing analysis, we confirmed that the mature and terminal, CD56 bright, and transitional subsets of NK cells play an indispensable role in maintaining TFR in patients with CML.

Sentential position of VN combination modulates the rhythmic pattern effect during Chinese sentence reading: Evidence from eye movements.

Though previous research has examined how implicit meter can facilitate the processing of stress-timed languages, syllable-timed languages, such as Chinese, remain under studied. Past research has shown that among verb-noun combinations in Chinese, the processing of [2 + 2] (two disyllabic words) combination rhythmic pattern is easier than that of [2 + 1] (a disyllabic word and a monosyllabic word) pattern, though it is unclear whether this effect is modulated by the sentential position of the verb-noun combination. The present study uses eye-tracking to examine the influence of position on rhythmic pattern during silent reading. In Experiment 1, participants read sentences with [2 + 1] versus [2 + 2] VN phrases embedded in different sentential positions. Results show that the fixation duration of [2 + 1] VN phrases is significantly longer than that of [2 + 2] and that the fixation duration of VN phrases is shorter at the sentence-middle position than it is at the sentence-final position, suggesting that the rhythmic pattern effect at the sentence-middle position exhibits a reduced magnitude compared to the sentence-final position. In Experiment 2, participants read sentences with either mono- or disyllabic words after the VN phrases to further explore whether the reduction of the rhythmic pattern effect is related to the number of succeeding syllables. Results show that while the fixation duration of the [2 + 1] VN pattern is significantly longer than that of the [2 + 2] pattern, there is no significant difference between the monosyllabic versus the disyllabic conditions, nor is there a significant interaction between rhythmic pattern and syllable length post VN phrases, thus ruling out the rhythmic effect from succeeding context. Together, these patterns suggest that the reduction of the rhythmic pattern effect is caused by position rather than number of syllables after phrases.

CHD Chromatin Remodeling Protein Diversification Yields Novel Clades and Domains Absent in Classic Model Organisms.

Chromatin remodelers play a fundamental role in the assembly of chromatin, regulation of transcription, and DNA repair. Biochemical and functional characterizations of the CHD family of chromatin remodelers from a variety of model organisms have shown that these remodelers participate in a wide range of activities. However, because the evolutionary history of CHD homologs is unclear, it is difficult to predict which of these activities are broadly conserved and which have evolved more recently in individual eukaryotic lineages. Here, we performed a comprehensive phylogenetic analysis of 8,042 CHD homologs from 1,894 species to create a model for the evolution of this family across eukaryotes with a particular focus on the timing of duplications that gave rise to the diverse copies observed in plants, animals, and fungi. Our analysis confirms that the three major subfamilies of CHD remodelers originated in the eukaryotic last common ancestor, and subsequent losses occurred independently in different lineages. Improved taxon sampling identified several subfamilies of CHD remodelers in plants that were absent or highly divergent in the model plant Arabidopsis thaliana. Whereas the timing of CHD subfamily expansions in vertebrates corresponds to whole genome duplication events, the mechanisms underlying CHD diversification in land plants appear more complicated. Analysis of protein domains reveals that CHD remodeler diversification has been accompanied by distinct transitions in domain architecture, contributing to the functional differences observed between these remodelers. This study demonstrates the importance of proper taxon sampling when studying ancient evolutionary events to prevent misinterpretation of subsequent lineage-specific changes and provides an evolutionary framework for functional and comparative analysis of this critical chromatin remodeler family across eukaryotes.