Developmental trajectory of pluripotent stem cell establishment in Arabidopsis callus guided by a quiescent center-related gene network.

In plant tissue culture, callus formation is induced by a high auxin concentration. Among the three cell layers (the outer, middle and inner cell layers) of the callus, pluripotency acquisition in the middle cell layer is required for the potential ability of the callus to regenerate organs. Here, we reveal the developmental trajectory of middle cell layer initiation and maintenance in callus tissue originating from Arabidopsis thaliana hypocotyls. The S phase of the cell cycle is essential for the expression of quiescent center-related SCARECROW (SCR), PLETHORA1 (PLT1) and WUSCHEL-RELATED HOMEOBOX5 (WOX5) genes during the division of callus founder cells to initiate the callus primordium. After callus initiation, SHOOT-ROOT (SHR) proteins move from the inner to the middle cell layer and act together with SCR to promote the expression of PLT1 and WOX5. WOX5 represses the expression of VASCULAR-RELATED NAC-DOMAIN (VND) genes, thereby preventing callus tissue from differentiating into xylem cells. PLT1 and PLT2 directly activate JACKDAW (JKD), which is necessary for pluripotency acquisition in the middle cell layer. We hypothesize that the middle cell layer could have pluripotent stem cell activity and its establishment requires the quiescent center-related SCR-SHR-WOX5-PLT1/2-JKD gene network.

Receptor-binding domain of SARS-CoV-2 is a functional αv-integrin agonist.

Among the novel mutations distinguishing SARS-CoV-2 from similar coronaviruses is a K403R substitution in the receptor-binding domain (RBD) of the viral spike (S) protein within its S1 region. This amino acid substitution occurs near the angiotensin-converting enzyme 2-binding interface and gives rise to a canonical RGD adhesion motif that is often found in native extracellular matrix proteins, including fibronectin. Here, the ability of recombinant S1-RBD to bind to cell surface integrins and trigger downstream signaling pathways was assessed and compared with RGD-containing, integrin-binding fragments of fibronectin. We determined that S1-RBD supported adhesion of fibronectin-null mouse embryonic fibroblasts as well as primary human small airway epithelial cells, while RBD-coated microparticles attached to epithelial monolayers in a cation-dependent manner. Cell adhesion to S1-RBD was RGD dependent and inhibited by blocking antibodies against αv and ß3 but not α5 or ß1 integrins. Similarly, we observed direct binding of S1-RBD to recombinant human αvß3 and αvß6 integrins, but not α5ß1 integrins, using surface plasmon resonance. S1-RBD adhesion initiated cell spreading, focal adhesion formation, and actin stress fiber organization to a similar extent as fibronectin. Moreover, S1-RBD stimulated tyrosine phosphorylation of the adhesion mediators FAK, Src, and paxillin; triggered Akt activation; and supported cell proliferation. Thus, the RGD sequence of S1-RBD can function as an αv-selective integrin agonist. This study provides evidence that cell surface αv-containing integrins can respond functionally to spike protein and raises the possibility that S1-mediated dysregulation of extracellular matrix dynamics may contribute to the pathogenesis and/or post-acute sequelae of SARS-CoV-2 infection.

Cancer immunometabolism: advent, challenges, and perspective.

For decades, great strides have been made in the field of immunometabolism. A plethora of evidence ranging from basic mechanisms to clinical transformation has gradually embarked on immunometabolism to the center stage of innate and adaptive immunomodulation. Given this, we focus on changes in immunometabolism, a converging series of biochemical events that alters immune cell function, propose the immune roles played by diversified metabolic derivatives and enzymes, emphasize the key metabolism-related checkpoints in distinct immune cell types, and discuss the ongoing and upcoming realities of clinical treatment. It is expected that future research will reduce the current limitations of immunotherapy and provide a positive hand in immune responses to exert a broader therapeutic role.

A lineage-specific requirement for YY1 Polycomb Group protein function in early T cell development.

Yin Yang 1 (YY1) is a ubiquitous transcription factor and mammalian Polycomb Group protein (PcG) with important functions for regulating lymphocyte development and stem cell self-renewal. YY1 mediates stable PcG-dependent transcriptional repression via recruitment of PcG proteins that result in histone modifications. Many questions remain unanswered regarding how cell- and tissue-specificity is achieved by PcG proteins. Here, we demonstrate that a conditional knockout of Yy1 in the hematopoietic system results in an early T cell developmental blockage at the double negative (DN) 1 stage with reduced Notch1 signaling. There is a lineage-specific requirement for YY1 PcG function. YY1 PcG domain is required for T and B cell development but not necessary for myeloid cells. YY1 functions in early T cell development are multicomponent and involve both PcG-dependent and -independent regulations. Although YY1 promotes early T cell survival through its PcG function, its function to promote the DN1-to-DN2 transition and Notch1 expression and signaling is independent of its PcG function. Our results reveal how a ubiquitously expressed PcG protein mediates lineage-specific and context-specific functions to control early T cell development.

The GPR40 novel agonist SZZ15-11 improves non-alcoholic fatty liver disease by activating the AMPK pathway and restores metabolic homeostasis in diet-induced obese mice.

AIM: Non-alcoholic fatty liver is the most common cause of chronic liver disease. GPR40 is a potential therapeutic target for energy metabolic disorders. GPR40 is a potential therapeutic target for energy metabolic disorders. SZZ15-11 is a newly synthesized GPR40 agonist. In this study, we estimate the potency of SZZ15-11 in fatty liver treatment. METHODS: In vivo, diet-induced obese (DIO) mice received SZZ15-11 (50 mg/kg) and TAK875 (50 mg/kg) for 6 weeks. Blood glucose and lipid, hepatocyte lipid and liver morphology were analysed. In vitro, HepG2 cells and GPR40-knockdown HepG2 cells induced with 0.3 mM oleic acid were treated with SZZ15-11. Triglyceride and total cholesterol of cells were measured. At the same time, the AMPK pathway regulating triglycerides and cholesterol esters synthesis was investigated via western blot and quantitative polymerase chain reaction in both liver tissue and HepG2 cells. RESULTS: SZZ15-11 was found to not only attenuate hyperglycaemia and hyperlipidaemia but also ameliorate fatty liver disease in DIO mice. At the same time, SZZ15-11 decreased triglyceride and total cholesterol content in HepG2 cells. Whether examined in the liver of DIO mice or in HepG2 cells, SZZ15-11 upregulated AMPKα phosphorylation and then downregulated the expression of the cholesterogenic key enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase and inhibited acetyl-CoA carboxylase activity. Furthermore, SZZ15-11 promotes AMPK activity via [cAMP]i accumulation. CONCLUSION: This study confirmed that SZZ15-11, a novel GPR40 agonist, improves hyperlipidaemia and fatty liver, partially via Gs signalling and the AMPK pathway in hepatocytes.

Investigation of the therapeutic effect of Hedan tablets on high-fat diet-induced obesity in rats by GC-MS technology and 16S ribosomal RNA gene sequencing.

Obesity is a persistent metabolic condition resulting from the excessive accumulation or abnormal distribution of body fat. This study aimed to establish an experimental rat model of obesity. The efficacy of treating obesity with Hedan tablets (HDT) was assessed by monitoring changes in weight, blood lipid levels, analyzing inflammatory factors, evaluating organ indices, and observing liver tissue pathology. Furthermore, we utilized 16S ribosomal RNA gene sequencing technology to explore changes in intestinal flora. In addition, GC-MS was used to measure fecal short-chain fatty acid (SCFA) content. The onset of obesity led to a significant decrease in the relative abundance of beneficial bacteria. Conversely, the administration of HDT demonstrated a substantial ability to increase the relative abundance of beneficial bacteria. Obesity resulted in a noteworthy reduction in total SCFAs, a trend significantly reversed in the HDT group. Through correlation analysis, it was determined that HDT mitigated the inflammatory response and improved blood lipid levels by augmenting the abundance of Lactobacillus, Limosilactobacillus, Ruminococcus, and Enterococcus. These particular intestinal flora were identified as regulators of SCFA metabolism, thereby ameliorating metabolic abnormalities associated with obesity. Moreover, HDT intervention elevated the overall fecal concentration of SCFAs, thereby improving metabolic disorders induced by obesity. The anti-obesity effects of HDT are likely attributable to their capacity to influence the composition of intestinal flora and boost SCFA levels in the intestine.

The role of LncRNAs in tumor immunotherapy.

Cancer immunotherapy is a major breakthrough in the history of tumor therapy in the last decade. Immune checkpoint inhibitors blocking CTLA-4/B7 or PD-1/PD-L1 pathways have greatly prolonged the survival of patients with different cancers. Long non-coding RNAs (lncRNAs) are abnormally expressed in tumors and play an important role in tumor immunotherapy through immune regulation and immunotherapy resistance. In this review, we summarized the mechanisms of lncRNAs in regulating gene expression and well-studied immune checkpoint pathways. The crucial regulatory function of immune-related lncRNAs in cancer immunotherapy was also described. Further understanding of the underlying mechanisms of these lncRNAs is of great importance to the development of taking lncRNAs as novel biomarkers and therapeutic targets for immunotherapy.

The Asymmetric Total Synthesis of (-)-Eurothiocin A and Its Enantiomer.

The first asymmetric total synthesis of (-)-eurothiocin A was achieved in 14 linear steps with 2% overall yield from the commercially available materials. A Sharpless asymmetric dihydroxylation reaction was utilized as the key step to construct the stereogenic center. Additionally, (+)- and (±)-eurothiocin A were also synthesized.

Asymmetric Total Synthesis of Griseofamine B and Its Three Stereoisomers.

The first total synthesis of griseofamine B is described starting from l-4-bromo tryptophan methyl ester hydrochloride via five steps and in 18% overall yield. Its three stereoisomers were also synthesized following the same procedure with the yields of 5%, 19%, and 5%, respectively. In vitro antibacterial activities were also evaluated. All four compounds exhibited less potent activity than griseofamine A.

Circular RNAs as a Diagnostic Biomarker in Oral Squamous Cell Carcinoma: A Meta-Analysis.

PURPOSE: Studies have found a positive correlation between various cancers and circular RNAs (circRNAs), which are newly discovered noncoding RNAs. However, limited scientific evidence is available to prove the clinical value of circRNAs in the presentation of oral squamous cell carcinoma (OSCC). This study aimed to explore comprehensively the potential of circRNAs as diagnostic indexes of OSCC. METHODS: Online databases were systematically searched to identify published literature on the discovery of circRNAs in OSCC. Data were acquired from each reviewed study and collated to create a 2 × 2 eventuality table. Hierarchical analysis of the literature was conducted for the type of cancer, year of publication, and the sample size of each study. The diagnostic accuracy was calculated using indexes such as the pooled sensitivity and specificity, and assessed critically using the Quality Assessment for Studies of Diagnostic Accuracy 2. RESULTS: This meta-analysis included findings of 6 studies on 335 patients diagnosed with OSCC. These 6 studies examined 7 circRNAs, 5 in tissues and 2 in the saliva of patients with OSCC. When used as a diagnostic tool for OSCC, circRNAs manifested a sensitivity level of 0.72 (95% confidence interval: 0.67 to 0.76) and a degree of specificity of 0.81 (95% confidence interval: 0.76 to 0.85), with a general projected probability rate of 3.82 (95% confidence interval: 2.98 to 4.91) being positive and 0.35 (95% confidence interval: 0.29 to 0.41) being negative. The combined probability rate was 11.07 (95% confidence interval: 7.64 to 16.04), comprising a total of 0.76 (95% confidence interval: 0.72 to 0.79) of the region under the curve. A higher diagnostic value was found for salivary circRNAs (diagnostic odds ratio = 17.52; 95% CI: 10.11 to 30.35) than for tissue circRNAs (diagnostic odds ratio = 8.47; 95% CI: 5.6 to 12.83). This indicated that circRNAs showed a good discrimination ability as biomarkers of OSCC. CONCLUSIONS: circRNAs showed high accuracy in the diagnosis of OSCC and could be used as prospective biomarkers to facilitate the diagnostic process.

Genome-Wide DNA Methylation Profile Indicates Potential Epigenetic Regulation of Aging in the Rhesus Macaque Thymus.

We analyzed whole-genome bisulfite sequencing (WGBS) and RNA sequencing data of two young (1 year old) and two adult (9 years old) rhesus macaques (Macaca mulatta) to characterize the genomic DNA methylation profile of the thymus and explore the molecular mechanism of age-related changes in the thymus. Combining the two-omics data, we identified correlations between DNA methylation and gene expression and found that DNA methylation played an essential role in the functional changes of the aging thymus, especially in immunity and coagulation. The hypomethylation levels of C3 and C5AR2 and the hypermethylation level of C7 may lead to the high expressions of these genes in adult rhesus macaque thymuses, thus activating the classical complement pathway and the alternative pathway and enhancing their innate immune function. Adult thymuses had an enhanced coagulation pathway, which may have resulted from the hypomethylation and upregulated expressions of seven coagulation-promoting factor genes (F13A1, CLEC4D, CLEC4E, FCN3, PDGFRA, FGF2 and FGF7) and the hypomethylation and low expression of CPB2 to inhibit the degradation of blood clots. Furthermore, the functional decline in differentiation, activation and maturation of T cells in adult thymuses was also closely related to the changes in methylation levels and gene expression levels of T cell development genes (CD3G, GAD2, ADAMDEC1 and LCK) and the thymogenic hormone gene TMPO. A comparison of the age-related methylated genes among four mammal species revealed that most of the epigenetic clocks were species-specific. Furthermore, based on the genomic landscape of allele-specific DNA methylation, we identified several age-related clustered sequence-dependent allele-specific DNA methylated (cS-ASM) genes. Overall, these DNA methylation patterns may also help to assist with understanding the mechanisms of the aging thymus with the epigenome.

The heterogeneous impacts of Sino-African trade relations on carbon intensity in Africa.

Studies on the environmental impacts of China-African trade relations are scarce. To fill the gap, this research examines the effects of Sino-African trade relations on carbon dioxide (CO2) emissions intensity in Africa, employing panel quantile regression for 39 African countries over the period of 1992-2015. The results indicate that imports have a negative and significant effect on CO2 emissions intensity across all quantile distributions, whereas exports have a positive and significant effect, except at the 25th and 35th quantiles. The findings also confirm the inverted U-shaped environmental Kuznets curve hypothesis, particularly for countries at higher emissions points. The study also demonstrates that urbanisation and energy intensity positively affect CO2 intensity, while the effect of foreign direct investment is negative and significant, confirming the pollution halo hypothesis. Finally, policy implications are presented based on the findings of the study.

ZmSPL10/14/26 are required for epidermal hair cell fate specification on maize leaf.

The epidermal hair and stomata are two types of specialized structures on the surface of plant leaves. On mature maize leaves, stomatal complexes and three types of hairs are distributed in a stereotyped pattern on the adaxial epidermis. However, the spatiotemporal relationship between epidermal hair and stomata development and the regulatory mechanisms governing their formation in maize remain largely unknown. Here, we report that three homologous ZmSPL transcription factors, ZmSPL10, ZmSPL14 and ZmSPL26, act in concert to promote epidermal hair fate on maize leaf. Cytological analyses revealed that Zmspl10/14/26 triple mutants are completely glabrous, but possess ectopic stomatal files. Strikingly, the precursor cells for prickle and bicellular hairs are transdifferentiated into ectopic stomatal complexes in the Zmspl10/14/26 mutants. Molecular analyses demonstrated that ZmSPL10/14/26 bind directly to the promoter of a WUSCHEL-related homeobox gene, ZmWOX3A, and upregulate its expression in the hair precursor cells. Moreover, several auxin-related genes are downregulated in the Zmspl10/14/26 triple mutants. Our results suggest that ZmSPL10/14/26 play a key role in promoting epidermal hair fate on maize leaves, possibly through regulating ZmWOX3A and auxin-related gene expression, and that the fates of epidermal hairs and stomata are switchable.

Assessment of tantalum nanoparticle-induced MC3T3-E1 proliferation and underlying mechanisms.

OBJECTIVE: In our previous study, tantalum nanoparticle (Ta-NPs) was demonstrated to promote osteoblast proliferation via autophagy induction, but the specific mechanism remains unclear. In the present study, we will explore the potential mechanism. METHODS: Ta-NPs was characterized by transmission electron microscopy, scanning electron microscopy, dynamic light scattering, and BET specific surface area test. MC3T3-E1 were treated with 0 or 20 µg/mL Ta-NPs with or without pretreatment with 10 µM LY294002, Triciribine, Rapamycin (PI3K/Akt/mTOR pathway inhibitors) for 1 h respectively. Western blotting was used to detect the expressions of pathway proteins and LC3B. CCK-8 assay was used to assess cell viability. Flow cytometry was used to detect apoptosis and cell cycle. RESULTS: After pretreatment with LY294002, Triciribine and Rapamycin, the p-Akt/Akt ratio of pathway protein in Triciribine and Rapamycin groups decreased (P < 0.05), while the autophagy protein LC3-II/LC3-I in the Rapamycin group was upregulated obviously (P < 0.001). In all pretreated groups, apoptosis was increased (LY294002 group was the most obvious), G1 phase cell cycle was arrested (Triciribine and Rapamycin groups were more obvious), and MC3T3-E1 cells were proliferated much more (P < 0.01, P < 0.001, P < 0.05). CONCLUSION: Pretreatment with Triciribine or Rapamycin has a greater effect on pathway protein Akt, cell cycle arrest, autophagy protein, and cell proliferation but with inconsistent magnitude, which may be inferred that the Akt/mTOR pathway, as well as its feedback loop, were more likely involved in these processes.

The differential inhibitive effects and fates of As(III) and As(V) mediated by Sulfobacillus thermosulfidooxidans grown on S0, Fe2+ and FeS2.

Arsenic often coexists with metal sulfide minerals and occurs in different speciation and different toxicity in responding to Fe/S biooxidation. The differential inhibitive effects and fates of As(III) and As(V) during biooxidations of elemental sulfur (S0), ferrous ions (Fe2+) and pyrite (FeS2) by Sulfobacillus thermosulfidooxidans were studied. The results revealed that the arsenic species hardly changed for the biooxidation of S0, but dramatically changed for the biooxidation of Fe2+ and FeS2. Different transformation degree between As(III) and As(V) occurred for biooxidation of FeS2 in the presence of arsenic, where about 72% of As(III) was transformed to As(V) for the group with As(III) added, and 16% of As(V) was transformed to As(III) for that with As(V) added. Both formation and dissolution of amorphous ferric arsenate occurred during biooxidation of FeS2 with the addition of As(III) or As(V) and for the group grown on Fe2+ with added As(V), which were controlled by the changes of Fe/As molar ratio and pH value in the solution. Jarosite was detected for the group grown on Fe2+ and could adsorb As(III) and As(V). The inhibitive effects of As(V) were higher than As(III) when the strain grew on FeS2, which was contrary to those when the strain grew on S0 and Fe2+. The above results signify that the fates and inhibitive effects of arsenic are much related to each other, and such a relationship is significantly affected by the utilization of Fe/S energy substrates by the sulfur- and ferrous-oxidizing microorganisms.

Aurora B kinase activity-dependent and -independent functions of the chromosomal passenger complex in regulating sister chromatid cohesion.

The chromosomal passenger complex (CPC) is a master regulator of mitosis. CPC consists of inner centromere protein (INCENP), Survivin, Borealin, and the kinase Aurora B and plays key roles in regulating kinetochore-microtubule attachments and spindle assembly checkpoint signaling. However, the role of CPC in sister chromatid cohesion, mediated by the cohesin complex, remains incompletely understood. Here, we show that Aurora B kinase activity contributes to centromeric cohesion protection partly through promoting kinetochore localization of the kinase Bub1. Interestingly, disrupting the interaction of INCENP with heterochromatin protein 1 (HP1) in HeLa cells selectively weakens cohesion at mitotic centromeres without detectably reducing the kinase activity of Aurora B. Thus, through this INCENP-HP1 interaction, the CPC also protects centromeric cohesion independently of Aurora B kinase activity. Moreover, the requirement for the INCENP-HP1 interaction in centromeric cohesion protection can be bypassed by tethering HP1 to centromeres or by depleting the cohesin release factor Wapl. We provide further evidence suggesting that the INCENP-HP1 interaction protects centromeric cohesion by promoting the centromere localization of Haspin, a protein kinase that antagonizes Wapl activity at centromeres. Taken together, this study identifies Aurora B kinase activity-dependent and -independent roles for the CPC in regulating centromeric cohesion during mitosis in human cells.

A positive feedback mechanism ensures proper assembly of the functional inner centromere during mitosis in human cells.

The inner centromere region of a mitotic chromosome critically regulates sister chromatid cohesion and kinetochore-microtubule attachments. However, the molecular mechanism underlying inner centromere assembly remains elusive. Here, using CRISPR/Cas9-based gene editing in HeLa cells, we disrupted the interaction of Shugoshin 1 (Sgo1) with histone H2A phosphorylated on Thr-120 (H2ApT120) to selectively release Sgo1 from mitotic centromeres. Interestingly, cells expressing the H2ApT120-binding defective mutant of Sgo1 have an elevated rate of chromosome missegregation accompanied by weakened centromeric cohesion and decreased centromere accumulation of the chromosomal passenger complex (CPC), an integral part of the inner centromere and a key player in the correction of erroneous kinetochore-microtubule attachments. When artificially tethered to centromeres, a Sgo1 mutant defective in binding protein phosphatase 2A (PP2A) is not able to support proper centromeric cohesion and CPC accumulation, indicating that the Sgo1-PP2A interaction is essential for the integrity of mitotic centromeres. We further provide evidence indicating that Sgo1 protects centromeric cohesin to create a binding site for the histone H3-associated protein kinase Haspin, which not only inhibits the cohesin release factor Wapl and thereby strengthens centromeric cohesion but also phosphorylates histone H3 at Thr-3 to position CPC at inner centromeres. Taken together, our findings reveal a positive feedback-based mechanism that ensures proper assembly of the functional inner centromere during mitosis. They further suggest a causal link between centromeric cohesion defects and chromosomal instability in cancer cells.

Stimuli-Enabled Artificial Synapses for Neuromorphic Perception: Progress and Perspectives.

Brain-inspired neuromorphic computing is intended to provide effective emulation of the functionality of the human brain via the integration of electronic components. Recent studies of synaptic plasticity, which represents one of the most significant neurochemical bases of learning and memory, have enhanced the general comprehension of how the brain functions and have thereby eased the development of artificial neuromorphic devices. An understanding of the synaptic plasticity induced by various types of stimuli is essential for neuromorphic system construction. The realization of multiple stimuli-enabled synapses will be important for future neuromorphic computing applications. In this Review, state-of-the-art synaptic devices with particular emphasis on their synaptic behaviors under excitation by a variety of external stimuli are summarized, including electric fields, light, magnetic fields, pressure, and temperature. The switching mechanisms of these synaptic devices are discussed in detail, including ion migration, electron/hole transfer, phase transition, redox-based resistive switching, and other mechanisms. This Review aims to provide a comprehensive understanding of the operating mechanisms of artificial synapses and thus provides the principles required for design of multifunctional neuromorphic systems with parallel processing capabilities.

Synthesis and cytotoxicity of (-)-homo-renieramycin G and its derivatives.

(-)-Homo-renieramycin G and its twenty derivatives were prepared from l-tyrosine methyl ester via a multi-step route. Their cytotoxicities were tested against four human cancer cell lines (A549, HeLa, KB and BGC-823). (-)-Renieramycin G and (-)-homo-renieramycin G showed comparable cytotoxicity against these four cancer cell lines, which indicated that the expansion of ring C from the six-membered 1,4-piperazinone to the seven-membered 1,4-diazepanone had no obvious impact on the cytotoxicity. Compound 42 with methyl side chain and compounds 38-41 with heterocyclic aromatic side chains at C-23 exhibited the most potent cytotoxicity with the IC50 values at the level of 10-6 M.

Design, synthesis and cytotoxicity of novel hexacyclic saframycin-ecteinascidin analogs.

Two series of novel hexacyclic skeletons and their thirty-four derivatives were prepared from l-tryptophan and l-DOPA. The cytotoxicities of these compounds were tested against four human cancer cell lines HCT-116, HepG2, BGC-823 and A2780. Compounds with the tetrahydro-ß-carboline moiety in the left-half of the hexacyclic skeleton showed more potent cytotoxicity with IC50 values in the range of 10-7-10-9 M. Compound 20 with the 4-methoxybenzamide side chain showed potent cytotoxicity towards HepG2 with an IC50 value of 1.32 nM. Compounds 29 and 30 with 2-pyridine amide and (2E)-3-(3-thifluoromethyl-phenyl)acrylic amide side chains showed selective cytotoxicity towards A2780 with IC50 values of 1.73 nM and 7 nM, respectively.