PRL2 phosphatase enhances oncogenic FLT3 signaling via dephosphorylation of the E3 ubiquitin ligase CBL at tyrosine 371.

Acute myeloid leukemia (AML) is an aggressive blood cancer with poor prognosis. FMS-like tyrosine kinase receptor-3 (FLT3) is one of the major oncogenic receptor tyrosine kinases aberrantly activated in AML. Although protein tyrosine phosphatase PRL2 is highly expressed in some subtypes of AML compared with normal human hematopoietic stem and progenitor cells, the mechanisms by which PRL2 promotes leukemogenesis are largely unknown. We discovered that genetic and pharmacological inhibition of PRL2 significantly reduce the burden of FLT3-internal tandem duplications-driven leukemia and extend the survival of leukemic mice. Furthermore, we found that PRL2 enhances oncogenic FLT3 signaling in leukemia cells, promoting their proliferation and survival. Mechanistically, PRL2 dephosphorylates the E3 ubiquitin ligase CBL at tyrosine 371 and attenuates CBL-mediated ubiquitination and degradation of FLT3, leading to enhanced FLT3 signaling in leukemia cells. Thus, our study reveals that PRL2 enhances oncogenic FLT3 signaling in leukemia cells through dephosphorylation of CBL and will likely establish PRL2 as a novel druggable target for AML.

New Evolutionary Insights into RpoA: A Novel Quorum Sensing Reprograming Factor in Pseudomonas aeruginosa.

Quorum-sensing (QS) coordinates the expression of virulence factors in Pseudomonas aeruginosa, an opportunistic pathogen known for causing severe infections in immunocompromised patients. QS has a master regulator, the lasR gene, but in clinical settings, P. aeruginosa isolates have been found that are QS-active but LasR-null. In this study, we developed an experimental evolutionary approach to identify additional QS-reprogramming determinants. We began the study with a LasR-null mutant with an extra copy of mexT, a transcriptional regulator gene that is known to be able to reprogram QS in laboratory LasR-null strains. In this strain, spontaneous single mexT mutations are expected to have no or little phenotypic consequences. Using this novel method, which we have named "targeted gene duplication followed by mutant screening", we identified QS-active revertants with mutations in genes other than mexT. One QS-active revertant had a point mutation in rpoA, a gene encoding the α-subunit of RNA polymerase. QS activation in this mutant was found to be associated with the downregulated expression of mexEF-oprN efflux pump genes. Our study therefore uncovers a new functional role for RpoA in regulating QS activity. Our results indicate that a RpoA-dependent regulatory circuit controlling the expression of the mexEF-oprN operon is critical for QS-reprogramming. In conclusion, our study reports on the identification of non-MexT proteins associated with QS-reprogramming in a laboratory strain, shedding light on possible QS activation mechanisms in clinical P. aeruginosa isolates.

Novel antibiotic susceptibility of an RNA polymerase α-subunit mutant in Pseudomonas aeruginosa.

BACKGROUND: RNA polymerase (RNAP) is highly conserved and essential for prokaryotic housekeeping activities, making it an important target for the development of new antibiotics. The rpoB gene, encoding a ß-subunit of bacterial RNAP, has a well-known association with rifampicin resistance. However, the roles of other RNAP component genes such as rpoA, encoding an α-subunit of RNAP, in antibiotic resistance remain unexplored. OBJECTIVES: To characterize the antibiotic resistance-related role of RpoA. METHODS: We measured the expression of the MexEF-OprN efflux pump in an RpoA mutant using a transcriptional reporter. The MICs of various antibiotics for this RpoA mutant were determined. RESULTS: We uncover a novel role of antibiotic susceptibility for an RpoA mutant in Pseudomonas aeruginosa. We found that a single amino acid substitution in RpoA resulted in reduced activity of the MexEF-OprN efflux pump, which is responsible for the exportation of various antibiotics, including ciprofloxacin, chloramphenicol, ofloxacin and norfloxacin. This attenuated efflux pump activity, caused by the RpoA mutation, conferred the bacteria further susceptibility to antibiotics regulated by MexEF-OprN. Our work further revealed that certain clinical P. aeruginosa isolates also contained the same RpoA mutation, providing clinical relevance to our findings. Our results elucidate why this new antibiotic-susceptible function of RpoA mutants would have remained undetected in conventional screens for mutants involving antibiotic resistance. CONCLUSIONS: The discovery of antibiotic susceptibility in an RpoA mutant implicates a new therapeutic approach for treating clinical isolates of P. aeruginosa with RpoA mutations, using specific antibiotics regulated by MexEF-OprN. More generally, our work suggests that RpoA could serve as a promising candidate target for anti-pathogen therapeutic purposes.

Pharmacological treatment of neuropsychiatric symptoms of dementia: a network meta-analysis.

BACKGROUND: Pharmacological treatments are very common to be used for alleviating neuropsychiatric symptoms (NPS) in dementia. However, decision on drug selection is still a matter of controversy. AIMS: To summarise the comparative efficacy and acceptability of currently available monotherapy drug regimens for reducing NPS in dementia. METHOD: We searched PubMed, MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials between inception and 26 December 2022 without language restrictions; and reference lists scanned from selected studies and systematic reviews. Double-blind randomised controlled trials were identified from electronic databases for reporting NPS outcomes in people with dementia. Primary outcomes were efficacy and acceptability. Confidence in the evidence was assessed using Confidence in Network Meta-Analysis (CINeMA). RESULTS: We included 59 trials (15,781 participants; mean age, 76.6 years) and 15 different drugs in quantitative syntheses. Risperidone (standardised mean difference [SMD] -0.20, 95% credible interval [CrI] -0.40 to -0.10) and galantamine (-0.20, -0.39 to -0.02) were more effective than placebo in short-term treatment (median duration: 12 weeks). Galantamine (odds ratio [OR] 1.95, 95% CrI 1.38-2.94) and rivastigmine (1.87, 1.24-2.99) were associated with more dropouts than placebo, and some active drugs. Most of the results were rated as low or very low according to CINeMA. CONCLUSIONS: Despite the scarcity of high-quality evidence, risperidone is probably the best pharmacological option to consider for alleviating NPS in people with dementia in short-term treatment when considering the risk-benefit profile of drugs.

Rehmannia glutinosa polysaccharides attenuates colitis via reshaping gut microbiota and short-chain fatty acid production.

BACKGROUND: Ulcerative colitis is a gastrointestinal disease closely related to intestinal epithelial barrier damage and intestinal microbiome imbalance; however, effective treatment methods are currently limited. Rehmannia glutinosa polysaccharide (RGP) is an important active ingredient with a wide range of pharmacological activities, although its protective effect on colitis remains to be explored. In the present study, we verified the in vitro anti-inflammatory effect of RGP, and observed the ameliorating effect of RGP on dextran sulfate sodium-induced colitis in mice. RESULTS: The results showed that (i) RGP attenuates lipopolysaccharide-induced overexpression of inflammatory factors in RAW264.7 cells; (ii) RGP improves the pathological damage caused by DSS, including weight loss, increased disease activity index and intestinal tissue ulcers; (iii) RGP improves tight junction proteins to protects the tightness of the intestinal epithelium; (iv) RGP inhibits the expression of inflammatory factors through the nuclear factor-kappa B pathway, and improved the of intestinal tissues inflammation; and (v) RGP can maintain the species diversity of intestinal microbes, increase the content of short-chain fatty acids and then restore the imbalance of intestinal microecology. CONCLUSION: RGP can improve the intestinal microbiota to strengthen the intestinal epithelial barrier and protect against DSS-induced colitis. © 2022 Society of Chemical Industry.

Role of p53 in regulation of hematopoiesis in health and disease.

PURPOSE OF REVIEW: Human aging is associated with an exponential increase in the occurrence of clonal hematopoiesis of indeterminate potential (CHIP). CHIP is associated with increased risks of de novo and therapy-related hematologic neoplasms and serves as a reservoir for leukemic relapse. Somatic mutations in the TP53 gene, which encodes the tumor suppressor protein p53, rank in the top five among genes that were mutated in CHIP. TP53 mutations in CHIP are associated with an increased incidence of myeloid neoplasms such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). This review focuses on mechanisms by which mutant p53 promotes CHIP progression and drives the pathogenesis of MDS and AML. We will also discuss potential therapeutic approaches that can target mutant p53 and improve treatment outcomes of MDS and AML. RECENT FINDINGS: TP53 was frequently mutated in individuals with CHIP as well as in patients with MDS and AML. While clinical studies suggest that p53 mutant hematopoietic stem and progenitor cell expansion may predispose the elderly to hematologic neoplasms, the underlying mechanisms are not fully understood. Recent findings suggest that mutant p53 may utilize both cell autonomous and noncell autonomous mechanisms to promote CHIP development. Furthermore, we and others have demonstrated that several gain-of-function mutant p53 proteins have enhanced oncogenic potential beyond dominant-negative and loss-of-function effects. Notably, TP53 allelic state has important implications for genome stability, clinical presentation, and outcomes in MDS. Some small molecules reactivating wild-type p53 tumor suppressor activity show promising effects on some human MDS and AML cells with TP53 mutations in preclinical and early phases of clinical studies. SUMMARY: TP53 mutations in MDS and AML are correlated with advanced disease, poor prognosis, reduced overall survival, and dismal outcomes. Deep understanding of the functions of mutant p53 proteins is essential to devise effective therapies for patients with myeloid neoplasms and other human cancers with TP53 mutations. Targeting mutant p53 directly or pathways regulated by mutant p53 holds great potential in preventing CHIP progression and treating MDS and AML patients with TP53 mutations.

Improved Adaptive Augmentation Control for a Flexible Launch Vehicle with Elastic Vibration.

The continuous development of spacecraft with large flexible structures has resulted in an increase in the mass and aspect ratio of launch vehicles, while the wide application of lightweight materials in the aerospace field has increased the flexible modes of launch vehicles. In order to solve the problem of deviation from the nominal control or even destabilization of the system caused by uncertainties such as unknown or unmodelled dynamics, frequency perturbation of the flexible mode, changes in its own parameters, and external environmental disturbances during the flight of such large-scale flexible launch vehicles with simultaneous structural deformation, rigid-elastic coupling and multimodal vibrations, an improved adaptive augmentation control method based on model reference adaption, and spectral damping is proposed in this paper, including a basic PD controller, a reference model, and an adaptive gain adjustment based on spectral damping. The baseline PD controller was used for flight attitude control in the nominal state. In the non-nominal state, the spectral dampers in the adaptive gain adjustment law extracted and processed the high-frequency signal from the tracking error and control-command error between the reference model and the actual system to generate the adaptive gain. The adjustment gain was multiplied by the baseline controller gain to increase/decrease the overall gain of the system to improve the system's performance and robust stability, so that the system had the ability to return to the nominal state when it was affected by various uncertainties and deviated from the nominal state, or even destabilized.

Materials Engineering of Violin Soundboards by Stradivari and Guarneri.

We investigated the material properties of Cremonese soundboards using a wide range of spectroscopic, microscopic, and chemical techniques. We found similar types of spruce in Cremonese soundboards as in modern instruments, but Cremonese spruces exhibit unnatural elemental compositions and oxidation patterns that suggest artificial manipulation. Combining analytical data and historical information, we may deduce the minerals being added and their potential functions-borax and metal sulfates for fungal suppression, table salt for moisture control, alum for molecular crosslinking, and potash or quicklime for alkaline treatment. The overall purpose may have been wood preservation or acoustic tuning. Hemicellulose fragmentation and altered cellulose nanostructures are observed in heavily treated Stradivari specimens, which show diminished second-harmonic generation signals. Guarneri's practice of crosslinking wood fibers via aluminum coordination may also affect mechanical and acoustic properties. Our data suggest that old masters undertook materials engineering experiments to produce soundboards with unique properties.

Differential expression of microRNAs in the human fetal left and right cerebral cortex.

Human brain is anatomically and functionally asymmetric. How brain asymmetry is initiated and established during fetal development is poorly understood. Accumulating evidence has shown that microRNAs (miRNAs) play crucial roles in brain development and function. In this study, we investigate miRNA expression profiles in left and right hemispheres of human fetal brains at 12 weeks post conception (PC), and identify 42 miRNAs showing differential expression between two hemispheres using Affymetrix microarray analyses. Target genes for left- and right-biased miRNAs are largely involved in developmental and functional regulations in the cortex such as axon guidance, GABAergic synapse and dopaminergic synapse pathways. Moreover, we find that predicted targets associated with canonical and non-canonical WNT signaling pathway show variations and differential expression between two hemispheres in response to left- and right-biased miRNAs. Our results highlight a potential role of miRNAs in regulating asymmetric development of human fetal brains.

Hepatic Sirt3 expression declines postpartum in dairy goats.

The experiments reported in this research communication aimed to plot the expression pattern of Sirt3, a master regulator of energy metabolism and antioxidation defence, in the liver of dairy goats during perinatal period. Ten healthy dairy goats in late pregnancy were chosen, and needle biopsy was applied to collect liver samples at 1-week intervals. Protein levels of hepatic Sirt3 were analysed by western-blotting. Serum enzyme activities of manganese superoxide dismutase (Mn-SOD) and non-esterified fatty acids (NEFA) levels were measured, and their correlation with Sirt3 mRNA levels was also estimated. Compared with >3-week before parturition (BP), Sirt3 proteins were significantly reduced at 1-week after parturition (AP) and 2-week AP (P < 0·05), but increased on the day of parturition (P < 0·01). Correlation analysis revealed a positive association between hepatic Sirt3 mRNA levels and serum enzyme activity of Mn-SOD (r = 0·46), but a negative association between that and serum NEFA levels (r = -0·41). These data indicate that the decreased hepatic expression of Sirt3 might be one of the reasons that dairy goats undergo oxidative stress after parturition.

[The Molecular Switches and Atomic Biological Mechanisms Underlying the Physiological and Pathophysio-logical Effects of Hydrogen Sulfide to Regulate Its "Receptors"].

Hydrogen sulfide (H2S)has emerged as pivotal signaling molecules since it is recognized as the third gasotransmitter together with nitric oxide and carbon monoxide. The development of detecting technologies contributed to the research in H2S biology.H2S plays significant roles in human body systems, such as the cardiovascular system, nervous system, respiratory system etc.. Alterations of H2S concentrations have been connected with many diseases. Hypertension, atherosclerosis, neurodegenerative disorder, asthma and many other diseases are found to be related with abnormal H2S metabolism. It has become a potential drug for therapeutic purposes. Understanding the mechanism of H2S biology, including a molecular switch contained in its "receptor", has deepened the research on how small molecules regulate big molecules, as well as providing new strategy for the therapeutic approaches for varies of diseases.

The mitochondrion interfering compound NPC-26 exerts potent anti-pancreatic cancer cell activity in vitro and in vivo.

The development of novel anti-pancreatic cancer agents is extremely important. Here, we investigated the anti-pancreatic cancer activity by NPC-26, a novel mitochondrion interfering compound. We showed that NPC-26 was anti-proliferative and cytotoxic to human pancreatic cancer cells, possibly via inducing caspase-9-dependent cell apoptosis. Pharmacological inhibition or shRNA-mediated silence of caspase-9 attenuated NPC-26-induced pancreatic cancer cell death and apoptosis. Further, NPC-26 treatment led to mitochondrial permeability transition pore (mPTP) opening in the cancer cells, which was evidenced by mitochondrial depolarization, ANT-1(adenine nucleotide translocator-1)-Cyp-D (cyclophilin-D) association and oxidative phosphorylation disturbance. mPTP blockers (cyclosporin and sanglifehrin A) or shRNA-mediated knockdown of key mPTP components (Cyp-D and ANT-1) dramatically attenuated NPC-26-induced pancreatic cancer cell apoptosis. Importantly, we showed that NPC-26, at a low concentration, potentiated gemcitabine-induced mPTP opening and subsequent pancreatic cancer cell apoptosis. In vivo, NPC-26 intraperitoneal injection significantly suppressed the growth of PANC-1 xenograft tumors in nude mice. Meanwhile, NPC-26 sensitized gemcitabine-mediated anti-pancreatic cancer activity in vivo. In summary, the results of this study suggest that NPC-26, alone or together with gemcitabine, potently inhibits pancreatic cancer cells possibly via disrupting mitochondrion.

H2S Is a Promoter of Angiogenesis: Identification of H2S "Receptors" and Its Molecular Switches in Vascular Endothelial Cells.

Angiogenesis is a physiological process in organ development and also a compensatory response in ischemia. When ischemia occurs, oxygen sensors in vascular endothelial cells sense the decrease in oxygen, thus activating downstream signaling pathways to promote the proliferation, migration, and tube formation of the endothelial cells. The new vasculatures are formed by sprouting from preexisting vessels, in order to maintain oxygen homeostasis in ischemic tissues (Folkman and Shing 1992). Collateral circulation is sometimes established under chronic ischemic conditions such as chronic myocardial ischemia (Banai et al. 1994). However, naturally occurring angiogenesis is usually not sufficient to compensate for ischemia in ischemic tissues. Proangiogenic drugs may be useful to promote angiogenesis in these diseases.

[Intrahepatic hepatitis B virus covalently closed circular DNA correlation with serum HBV DNA, serum HBsAg, alanine aminotransferase and age].

OBJECTIVE: To investigate the correlation between intrahepatic eovalently closed circular (ccc)DNA of hepatitis B virus (HBV) and pathogen-and patient-related parameters. METHODS: Ultrasound-guided liver biopsies were obtained from 60 patients with chronic HBV infection. Levels of intrahepatic HBV cccDNA and serum HBV DNA were measured by quantitative fluorescence PCR. Level of serum hepatitis B surface antigen (HBsAg) was measured by chemiluminescence immunoassay. Clinical parameters, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (AKP), albumin, globulin (GLO), white blood cell, platelet, prothrombin-international normalized ratio, were measured by standard assay. Demographic information was recorded.The correlation between intrahepatic HBV cccDNA and pathogen-and patient-related parameters was assessed. RESULTS: Intrahepatic HBV cccDNA level was negatively correlated with age, GLO, ALT and grade of necroinflammation. Patients with age of 30 years or more showed significantly higher level of HBV cccDNA level than patients under 30 years-old (7.44±0.58 and 5.66±1.35; t=7.157, P less than 0.001). Intrahepatic HBV cccDNA level was positively correlated with serum HBV DNA level (r=0.916, P less than 0.001) and serum HBsAg level (r=0.727, P less than 0.001). The median ratio of HBV cccDNA to HBV DNA was 1.18, and of HBV cccDNA to HBsAg was 1.67. CONCLUSION: Intrahepatic HBV cccDNA levels decrease with age, level of ALT, level of GLO and grade of liver necroinflammation, but increase with level of serum HBV DNA and level of serum HBsAg. To a certain extent, serum HBV DNA and serum HBsAg levels may be a sufficient marker of intrahepatic HBV cccDNA levels.

Effects of Lifestyle Interventions on Health and Life Quality of Colorectal Cancer Survivors: A Systematic Review and Meta-analysis.

BACKGROUND: The results of previous studies on the effects of lifestyle interventions on the quality of life (QoL) in colorectal cancer (CRC) survivors remain controversial, and there have been several new publications in this area in recent years. OBJECTIVES: To assess whether lifestyle interventions can lead to favorable health outcomes and improved QoL in CRC survivors, we performed a meta-analysis. METHODS: PubMed, EMBASE, Web of Science, and Cochrane Library were systematically searched to obtain relevant literature published from January 1, 1990, to November 1, 2021. The required data were extracted and summarized to compare the physical activity levels, QoL, mental health assessment, and anthropometric data between lifestyle interventions and routine nursing. RESULTS: Twelve studies were included. Compared with the control group, lifestyle interventions could significantly increase the physical activity time (weighted mean difference [WMD], 9.84; 95% confidence interval [CI], 1.20-18.48; P = .026), metabolic equivalent task levels (WMD, 10.40; 95% CI, 5.30-15.49; P < .001), and Functional Assessment of Cancer Therapy Scale-Colorectal scores (WMD, 3.12; 95% CI, 0.24-5.99; P = .034). However, lifestyle interventions were not noticeably able to improve the fatigue, depression levels, anxiety levels, waist circumference, or body mass index in CRC survivors. CONCLUSION: Lifestyle interventions could generate an increase in physical activity time, metabolic equivalent task levels, and QoL in CRC survivors. IMPLICATIONS FOR PRACTICE: Lifestyle interventions in the future that include physical activity, diet, or comprehensive programs are needed to increase physical activity levels and improve QoL in CRC survivors.

A lightweight deep learning approach for detecting electrocardiographic lead misplacement.

Objective. Electrocardiographic (ECG) lead misplacement can result in distorted waveforms and amplitudes, significantly impacting accurate interpretation. Although lead misplacement is a relatively low-probability event, with an incidence ranging from 0.4% to 4%, the large number of ECG records in clinical practice necessitates the development of an effective detection method. This paper aimed to address this gap by presenting a novel lead misplacement detection method based on deep learning models.Approach. We developed two novel lightweight deep learning model for limb and chest lead misplacement detection, respectively. For limb lead misplacement detection, two limb leads and V6 were used as inputs, while for chest lead misplacement detection, six chest leads were used as inputs. Our models were trained and validated using the Chapman database, with an 8:2 train-validation split, and evaluated on the PTB-XL, PTB, and LUDB databases. Additionally, we examined the model interpretability on the LUDB databases. Limb lead misplacement simulations were performed using mathematical transformations, while chest lead misplacement scenarios were simulated by interchanging pairs of leads. The detection performance was assessed using metrics such as accuracy, precision, sensitivity, specificity, and Macro F1-score.Main results. Our experiments simulated three scenarios of limb lead misplacement and nine scenarios of chest lead misplacement. The proposed two models achieved Macro F1-scores ranging from 93.42% to 99.61% on two heterogeneous test sets, demonstrating their effectiveness in accurately detecting lead misplacement across various arrhythmias.Significance. The significance of this study lies in providing a reliable open-source algorithm for lead misplacement detection in ECG recordings. The source code is available athttps://github.com/wjcai/ECG_lead_check.

Multi-branch myocardial infarction detection and localization framework based on multi-instance learning and domain knowledge.

Objective. Myocardial infarction (MI) is a serious cardiovascular disease that can cause irreversible damage to the heart, making early identification and treatment crucial. However, automatic MI detection and localization from an electrocardiogram (ECG) remain challenging. In this study, we propose two models, MFB-SENET and MFB-DMIL, for MI detection and localization, respectively.Approach. The MFB-SENET model is designed to detect MI, while the MFB-DMIL model is designed to localize MI. The MI localization model employs a specialized attention mechanism to integrate multi-instance learning with domain knowledge. This approach incorporates handcrafted features and introduces a new loss function called lead-loss, to improve MI localization. Grad-CAM is employed to visualize the decision-making process.Main Results.The proposed method was evaluated on the PTB and PTB-XL databases. Under the inter-patient scheme, the accuracy of MI detection and localization on the PTB database reached 93.88% and 67.17%, respectively. The accuracy of MI detection and localization on the PTB-XL database were 94.89% and 85.83%, respectively.Significance. Our method achieved comparable or better performance than other state-of-the-art algorithms. The proposed method combined deep learning and medical domain knowledge, demonstrates effectiveness and reliability, holding promise as an efficient MI diagnostic tool to assist physicians in formulating accurate diagnoses.

Gut microbial dysbiosis is associated with metabolism and immune factors in liver fibrosis mice.

Gut microbial dysbiosis has always served as a potential factor in the occurrence and development of liver fibrosis. Liver and gut microflora can regulate each other through the gut-liver axis. In this study, the 16S rRNA and RNA-seq were chosen to sequence gut microbiota alteration and liver differentially expressed genes (DEGs) in carbon tetrachloride (CCl4) included-liver fibrosis mice, and analyze the correlations between gut microbiota constituents and DEGs. Results indicated that, CCl4 significantly increased the abundance of Desulfobactera in the phylum level, destroyed gut microbiota balance in the genus levels, especially Enterorhabdus and Desulfovibrio. Through analysis, 1416 genes were found differentially expressed in mice liver tissue in the CCl4 Group, compared with the Control Group; and the DEGs were mainly involved in the lipid metabolic process and immune system process. The correlation analysis revealed that the relative abundance of microbiota phylum (Desulfobactera) and genus (Enterorhabdus and Desulfovibrio) was negatively correlated with the metabolism related genes, while positively correlated with immune-related genes and the genes enriched in PI3K-Akt signaling pathway. To sum up, CCl4 can partially regulate gene expression in metabolism, immune response and the PI3K/Akt pathway, and further maintain the stability of the gut environment in liver fibrosis mice.

Deciphering Oligodendrocyte Lineages in the Human Fetal Central Nervous System Using Single-Cell RNA Sequencing.

Oligodendrocytes form myelin sheaths and wrap axons of neurons to facilitate various crucial neurological functions. Oligodendrocyte progenitor cells (OPCs) persist in the embryonic, postnatal, and adult central nervous system (CNS). OPCs and mature oligodendrocytes are involved in a variety of biological processes such as memory, learning, and diseases. How oligodendrocytes are specified in different regions in the CNS, in particular in humans, remains obscure. We here explored oligodendrocyte development in three CNS regions, subpallium, brainstem, and spinal cord, in human fetuses from gestational week 8 (GW8) to GW12 using single-cell RNA sequencing. We detected multiple lineages of OPCs and illustrated distinct developmental trajectories of oligodendrocyte differentiation in three CNS regions. We also identified major genes, particularly transcription factors, which maintain status of OPC proliferation and promote generation of mature oligodendrocytes. Moreover, we discovered new marker genes that might be crucial for oligodendrocyte specification in humans, and detected common and distinct genes expressed in oligodendrocyte lineages in three CNS regions. Our study has demonstrated molecular heterogeneity of oligodendrocyte lineages in different CNS regions and provided references for further investigation of roles of important genes in oligodendrocyte development in humans.

Oleanolic acid improved intestinal immune function by activating and potentiating bile acids receptor signaling in E. coli-challenged piglets.

BACKGROUND: Infection with pathogenic bacteria during nonantibiotic breeding is one of the main causes of animal intestinal diseases. Oleanolic acid (OA) is a pentacyclic triterpene that is ubiquitous in plants. Our previous work demonstrated the protective effect of OA on intestinal health, but the underlying molecular mechanisms remain unclear. This study investigated whether dietary supplementation with OA can prevent diarrhea and intestinal immune dysregulation caused by enterotoxigenic Escherichia coli (ETEC) in piglets. The key molecular role of bile acid receptor signaling in this process has also been explored. RESULTS: Our results demonstrated that OA supplementation alleviated the disturbance of bile acid metabolism in ETEC-infected piglets (P < 0.05). OA supplementation stabilized the composition of the bile acid pool in piglets by regulating the enterohepatic circulation of bile acids and significantly increased the contents of UDCA and CDCA in the ileum and cecum (P < 0.05). This may also explain why OA can maintain the stability of the intestinal microbiota structure in ETEC-challenged piglets. In addition, as a natural ligand of bile acid receptors, OA can reduce the severity of intestinal inflammation and enhance the strength of intestinal epithelial cell antimicrobial programs through the bile acid receptors TGR5 and FXR (P < 0.05). Specifically, OA inhibited NF-κB-mediated intestinal inflammation by directly activating TGR5 and its downstream cAMP-PKA-CREB signaling pathway (P < 0.05). Furthermore, OA enhanced CDCA-mediated MEK-ERK signaling in intestinal epithelial cells by upregulating the expression of FXR (P < 0.05), thereby upregulating the expression of endogenous defense molecules in intestinal epithelial cells. CONCLUSIONS: In conclusion, our findings suggest that OA-mediated regulation of bile acid metabolism plays an important role in the innate immune response, which provides a new diet-based intervention for intestinal diseases caused by pathogenic bacterial infections in piglets.