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"Luo, Yan"
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Integrated analysis of single-cell and bulk RNA sequencing data reveals a pan-cancer stemness signature predicting immunotherapy response
Background
Although immune checkpoint inhibitor (ICI) is regarded as a breakthrough in cancer therapy, only a limited fraction of patients benefit from it. Cancer stemness can be the potential culprit in ICI resistance, but direct clinical evidence is lacking.
Methods
Publicly available scRNA-Seq datasets derived from ICI-treated patients were collected and analyzed to elucidate the association between cancer stemness and ICI response. A novel stemness signature (Stem.Sig) was developed and validated using large-scale pan-cancer data, including 34 scRNA-Seq datasets, The Cancer Genome Atlas (TCGA) pan-cancer cohort, and 10 ICI transcriptomic cohorts. The therapeutic value of Stem.Sig genes was further explored using 17 CRISPR datasets that screened potential immunotherapy targets.
Results
Cancer stemness, as evaluated by CytoTRACE, was found to be significantly associated with ICI resistance in melanoma and basal cell carcinoma (both
P
< 0.001). Significantly negative association was found between Stem.Sig and anti-tumor immunity, while positive correlations were detected between Stem.Sig and intra-tumoral heterogenicity (ITH) / total mutational burden (TMB). Based on this signature, machine learning model predicted ICI response with an AUC of 0.71 in both validation and testing set. Remarkably, compared with previous well-established signatures, Stem.Sig achieved better predictive performance across multiple cancers. Moreover, we generated a gene list ranked by the average effect of each gene to enhance tumor immune response after genetic knockout across different CRISPR datasets. Then we matched Stem.Sig to this gene list and found Stem.Sig significantly enriched 3% top-ranked genes from the list (
P
= 0.03), including EMC3, BECN1, VPS35, PCBP2, VPS29, PSMF1, GCLC, KXD1, SPRR1B, PTMA, YBX1, CYP27B1, NACA, PPP1CA, TCEB2, PIGC, NR0B2, PEX13, SERF2, and ZBTB43, which were potential therapeutic targets.
Conclusions
We revealed a robust link between cancer stemness and immunotherapy resistance and developed a promising signature, Stem.Sig, which showed increased performance in comparison to other signatures regarding ICI response prediction. This signature could serve as a competitive tool for patient selection of immunotherapy. Meanwhile, our study potentially paves the way for overcoming immune resistance by targeting stemness-associated genes.
Journal Article
Slow-wave sleep is controlled by a subset of nucleus accumbens core neurons in mice
Sleep control is ascribed to a two-process model, a widely accepted concept that posits homoeostatic drive and a circadian process as the major sleep-regulating factors. Cognitive and emotional factors also influence sleep–wake behaviour; however, the precise circuit mechanisms underlying their effects on sleep control are unknown. Previous studies suggest that adenosine has a role affecting behavioural arousal in the nucleus accumbens (NAc), a brain area critical for reinforcement and reward. Here, we show that chemogenetic or optogenetic activation of excitatory adenosine A2A receptor-expressing indirect pathway neurons in the core region of the NAc strongly induces slow-wave sleep. Chemogenetic inhibition of the NAc indirect pathway neurons prevents the sleep induction, but does not affect the homoeostatic sleep rebound. In addition, motivational stimuli inhibit the activity of ventral pallidum-projecting NAc indirect pathway neurons and suppress sleep. Our findings reveal a prominent contribution of this indirect pathway to sleep control associated with motivation.
Journal Article
Genome-wide identification of pyrabactin resistance 1-like (PYL) gene family under phytohormones and drought stresses in alfalfa (Medicago sativa)
Background
The Pyrabactin resistance 1-like proteins (PYR/PYL/RCAR) protein plays a critical regulatory role in the ABA signal transduction pathway as a direct receptor of abscisic acid (ABA). Although PYL genes have been identified in a variety of plants, the evolution and structural characteristics of these genes in alfalfa (
Medicago sativa
) are largely unknown. Therefore, a comprehensive bioinformatics analysis of the PYL gene family was performed in this research.
Results
The results indicated that 41
MsPYL
genes were unevenly distributed across 24 chromosomes. According to gene structure, conservative features, and phylogenetic relationships, MsPYL proteins can be divided into 6 groups, all of which have PYR/PYL/RCAR domains, and MsPYL proteins are relatively small (molecular weight 19.59 kDa to 25.31 kDa).
MsPYL
genes contains cis-acting elements that has functions in plant growth and development, hormone regulation, and stress response. Furthermore, transcriptome data showed that drought stress affected the
MsPYL
genes’ expression levels in alfalfa. Tissue specificity analysis revealed that all
MsPYL
genes exhibited varying responses to drought, abscisic acid (ABA), salicylic acid (SA), and indole-3-acetic acid (IAA). Additionally, all
MsPYL
genes were expressed to different extents in both the aboveground and underground tissues following stimulation. They were induced by IAA, ABA, and SA from 6 h to 12 h, and ABA induced
MsPYL4
most significantly at the 12 h mark.
MsPYL4
,
MsPYL8
,
MsPYL11
, and
MsPYL19
were expressed only after hormone treatment.
Conclusions
The results of this study indicate that the
MsPYL
genes are closely related to stress response and provide new candidate genes for further exploration of
MsPYL
genes function and improvement and innovation of drought-resistant alfalfa germplasm.
Journal Article
Ligands with 1,10-phenanthroline scaffold for highly regioselective iron-catalyzed alkene hydrosilylation
Transition-metal-catalyzed alkene hydrosilylation is one of the most important homogeneous catalytic reactions, and the development of methods that use base metals, especially iron, as catalysts for this transformation is a growing area of research. However, the limited number of ligand scaffolds applicable for base-metal-catalyzed alkene hydrosilylation has seriously hindered advances in this area. Herein, we report the use of 1,10-phenanthroline ligands in base-metal catalysts for alkene hydrosilylation. In particular, iron catalysts with 2,9-diaryl-1,10-phenanthroline ligands exhibit unexpected reactivity and selectivity for hydrosilylation of alkenes, including unique benzylic selectivity with internal alkenes, Markovnikov selectivity with terminal styrenes and 1,3-dienes, and excellent activity toward aliphatic terminal alkenes. According to the mechanistic studies, the unusual benzylic selectivity of this hydrosilylation initiates from
π
–
π
interaction between the phenyl of the alkene and the phenanthroline of the ligand. This ligand scaffold and its unique catalytic model will open possibilities for base-metal-catalyzed hydrosilylation reactions.
Hydrosilylation of alkenes poses substantial challenges in terms of regioselectivity. Here, the authors report iron complexes with 1,10-phenantroline ligand scaffolds which display benzylic selectivity in the hydrosilylation of internal alkenes and Markovnikov selectivity with terminal styrenes and 1,3-dienes.
Journal Article
Physical activity, screen exposure and sleep among students during the pandemic of COVID-19
This study aimed to determine the levels of health-related behaviours (physical activity, screen exposure and sleep status) among Chinese students from primary, secondary and high schools during the pandemic of COVID-19, as well as their changes compared with their status before the pandemic. A cross-sectional online survey of 10,933 students was conducted among 10 schools in Guangzhou, China, between 8th and 15th March, 2020. After getting the informed consent from student’s caregivers, an online questionnaire was designed and used to obtain time spending on health-related behaviours during the pandemic of COVID-19, as well as the changes compared with 3 months before the pandemic, which was completed by students themselves or their caregivers. Students were stratified by regions (urban, suburban, exurban), gender (boys and girls), and grades (lower grades of primary school, higher grades of primary schools, secondary schools and high schools). Data were expressed as number and percentages and Chi-square test was used to analyse difference between groups. Overall, the response rate of questionnaire was 95.3% (10,416/10,933). The median age of included students was 13.0 (10.0, 16.0) years and 50.1% (n = 5,219) were boys. 41.4%, 53.6% and 53.7% of total students reported less than 15 min per day in light, moderate and vigorous activities and 58.7% (n = 6,113) reported decreased participation in physical activity compared with the time before pandemic. Over 5 h of screen time spending on online study was reported by 44.6% (n = 4,649) of respondents, particular among high school students (81.0%). 76.9% of students reported increased screen time compared with the time before pandemic. Inadequate sleep was identified among 38.5% of students and the proportion was highest in high school students (56.9%). Our study indicated that, during the COVID-19 pandemic, the school closure exerted tremendous negative effects on school-aged children’s health habits, including less physical activity, longer screen exposure and irregular sleeping pattern.
Journal Article
Neferine inhibits LPS-ATP-induced endothelial cell pyroptosis via regulation of ROS/NLRP3/Caspase-1 signaling pathway
BackgroundOxidative stress-induced endothelial dysfunction and pyroptosis play an important role during chronic kidney disease (CKD) progression. Neferine, which is an alkaloid ingredient from the lotus seed embryo, has many biological actions such as anti-inflammatory, anticancer and antioxidant. However, the role of neferine in endothelial cell pyroptosis and the involved mechanism remain obscure. The aim is to probe the protective effects of neferine on cell pyroptosis and the involved underlying mechanism.MethodsAfter the HUVECs were primed with neferine treatment for 2 h prior to LPS and ATP exposure for 24 h, the cell proliferation was determined by BrdU; the cell LDH release was detected by LDH kits; the levels of intracellular ROS, MDA and SOD were tested by detection kits; Caspase-1 activity kit was used to determine caspase-1 activity; the contents of NLRP3, ASC, caspase-1, IL-1β, IL-18 and GSDMD were tested by RT-PCR and western blot.ResultsWe found that neferine could inhibit LPS-ATP-induced oxidative stress and the activation of NLRP3 inflammasome signaling, and increased the endothelial cell viability and SOD production. siRNA which mediated the knockdown of NLRP3 promoted the neferine-induced inhibition effects of cell pyroptosis. Furthermore, these neferine-induced effects were reversed by the over-expression of NLRP3.ConclusionsOur findings indicated neferine may reduce ROS by anti-oxidation and inhibit LPS-ATP-induced endothelial cell pyroptosis via blocking ROS/NLRP3/Caspase-1 signaling pathway, which provides the evidence for therapeutic effect in CKD.
Journal Article
Nucleus accumbens controls wakefulness by a subpopulation of neurons expressing dopamine D1 receptors
Nucleus accumbens (NAc) is involved in behaviors that depend on heightened wakefulness, but its impact on arousal remains unclear. Here, we demonstrate that NAc dopamine D
1
receptor (D
1
R)-expressing neurons are essential for behavioral arousal. Using in vivo fiber photometry in mice, we find arousal-dependent increases in population activity of NAc D
1
R neurons. Optogenetic activation of NAc D
1
R neurons induces immediate transitions from non-rapid eye movement sleep to wakefulness, and chemogenetic stimulation prolongs arousal, with decreased food intake. Patch-clamp, tracing, immunohistochemistry, and electron microscopy reveal that NAc D
1
R neurons project to the midbrain and lateral hypothalamus, and might disinhibit midbrain dopamine neurons and lateral hypothalamus orexin neurons. Photoactivation of terminals in the midbrain and lateral hypothalamus is sufficient to induce wakefulness. Silencing of NAc D
1
R neurons suppresses arousal, with increased nest-building behaviors. Collectively, our data indicate that NAc D
1
R neuron circuits are essential for the induction and maintenance of wakefulness.
The nucleus accumbens regulates many behaviours that depend on arousal. Here the authors show that dopamine D
1
receptor neurons in the nucleus accumbens can directly regulate wakefulness.
Journal Article
A unified formula for the half-life of the α and β decay
This article explores a novel idea by proposing a unified semi-empirical formula for both alpha and beta decay in unstable nuclei. A key feature of this formula is its simplicity and ability to provide highly accurate decay information based solely on the fundamental properties of the parent nucleus. Another remarkable aspect is the large number of isotopes used to fit the formula, exceeding 2200. This extensive data set has significantly enhanced the formula’s reliability. Additionally, we have included thorough comparisons between our results and those of other studies, which clearly demonstrate the higher performance of our formula. Even while our suggested formula is applicable to beta decay, the other formulae were particularly created for alpha decay.
Journal Article
Hypothalamic modulation of adult hippocampal neurogenesis in mice confers activity-dependent regulation of memory and anxiety-like behavior
Adult hippocampal neurogenesis plays a critical role in memory and emotion processing, and this process is dynamically regulated by neural circuit activity. However, it remains unknown whether manipulation of neural circuit activity can achieve sufficient neurogenic effects to modulate behavior. Here we report that chronic patterned optogenetic stimulation of supramammillary nucleus (SuM) neurons in the mouse hypothalamus robustly promotes neurogenesis at multiple stages, leading to increased production of neural stem cells and behaviorally relevant adult-born neurons (ABNs) with enhanced maturity. Functionally, selective manipulation of the activity of these SuM-promoted ABNs modulates memory retrieval and anxiety-like behaviors. Furthermore, we show that SuM neurons are highly responsive to environmental novelty (EN) and are required for EN-induced enhancement of neurogenesis. Moreover, SuM is required for ABN activity-dependent behavioral modulation under a novel environment. Our study identifies a key hypothalamic circuit that couples novelty signals to the production and maturation of ABNs, and highlights the activity-dependent contribution of circuit-modified ABNs in behavioral regulation.Li et al. report a key brain region in the hypothalamus that effectively modulates the production and properties of new neurons generated in adulthood. These hypothalamic modified new neurons are critical for memory and anxiety-like behavior.
Journal Article