Immunogenicity and Safety of a 3-Dose Regimen of a SARS-CoV-2 Inactivated Vaccine in Adults: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial.

BACKGROUND: Control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic needs effective vaccines. METHODS: In a phase 2 randomized, double-blind, placebo-controlled trial, 500 adults aged 18-59 years or ≥60 years were randomized in 2:2:1 ratio to receive 3 doses of 5 µg or 10 µg of a SARS-CoV-2 inactivated vaccine, or placebo separated by 28 days. Adverse events (AEs) were recorded through day 28 after each dosing. Live virus or pseudovirus neutralizing antibodies, and receptor binding domain immunoglobulin G (RBD-IgG) antibody were tested after the second and third doses. RESULTS: Two doses of the vaccine elicited geometric mean titers (GMTs) of 102-119, 170-176, and 1449-1617 for the 3 antibodies in younger adults. Pseudovirus neutralizing and RBD-IgG GMTs were similar between older and younger adults. The third dose slightly (<1.5 fold) increased GMTs. Seroconversion percentages were 94% or more after 2 doses, which were generally similar after 3 doses. The predominant AEs were injection-site pain. All the AEs were grade 1 or 2 in intensity. No serious AE was deemed related to study vaccination. CONCLUSIONS: Two doses of this vaccine induced robust immune response and had good safety profile. A third dose given 28 days after the second dose elicited limited boosting antibody response.

Divergent Total Syntheses of (+)-Vulgarisins†A-E.

The asymmetric total syntheses of (+)-vulgarisins A-E, which share a rare and highly oxygenated [5-6-4-5] tetracyclic core structure that were isolated from P. vulgaris Linn., have been described for the first time in a divergent manner. Key transformations include: 1) a catalytic asymmetric intramolecular cyclopropanation to forge the A ring bearing desired stereochemistry at C14; 2) a one-pot borylation/conjugate addition process for creation of the C1-C11 bond; 3) a Wolff ring contraction to assemble the bicyclo[3.2.0]heptane subunit (CD rings); and 4) a stereocontrolled pinacol cyclization for construction of the central B ring of the natural products.

Divergent Total Syntheses of (-)-Crinipellins Facilitated by a HAT-Initiated Dowd-Beckwith Rearrangement.

A hydrogen atom transfer (HAT)-initiated Dowd-Beckwith rearrangement reaction was developed, which enables the efficient assembly of diversely functionalized polyquinane frameworks. By incorporation of an iridium-catalyzed regio- and enantioselective hydrogenation and a diastereocontrolled ODI-[5+2] cycloaddition/pinacol rearrangement cascade reaction, the asymmetric total syntheses of eight tetraquinane natural products, including (-)-crinipellins A-F and (-)-dihydrocrinipellins A and B, have been achieved in a concise and divergent manner.

Tetracyclic Diterpenoid Synthesis Facilitated by ODI-Cascade Approaches to Bicyclo[3.2.1]octane Skeletons.

Tetracyclic diterpenoids (C20) mainly refer to the plant terpenoids bearing biogenetically related carbon skeletons derived from copalyl diphosphates (ent-CPP and syn-CPP). This large family contains over 1600 known members that can be categorized into 11 major structural types. Among them, more than three-quarters share a bridged bicyclo[3.2.1]octane subunit, which is also an important branching point in biosynthesis en route to the other types of bicyclic scaffolds, such as bicyclo[2.2.2]-, bicyclo[3.3.0]-, and tricyclo[3.2.1.0]octanes. Combined with the significance of its stereochemical importance in biological activity, the assembly of the bicyclo[3.2.1]octane skeletons is critical to the success of the whole synthesis blueprint toward tetracyclic diterpenoids. Although a number of inspiring methodologies have been disclosed, general approaches by the incorporation of innovative cascade reactions permitting access to diverse structural types of tetracyclic diterpenoids remain limited and in urgent demand.Because of the long-standing interest in the synthesis of bridged diterpenoids, we have recently developed two complementary types of oxidative dearomatization induced (ODI) cascade approaches to the rapid and efficient construction of bicyclo[3.2.1]octane skeletons. In this Account, we summarize our original synthesis design, methodology development, and the application of these two strategies in tetracyclic diterpenoid synthesis during the past few years in our laboratory.First, we detail our preliminary investigation of the ODI-[5 + 2] cycloaddition/pinacol rearrangement cascade reaction, which showed a wide scope of vinylphenol substrates and led to cyclopentane and cyclohexane-fused bicyclo[3.2.1]octanes in good yields with excellent dr values. Next, we describe the utilization of this ODI-[5 + 2] cascade reaction which resulted in the asymmetric total syntheses of four highly oxygenated ent-kauranoids. The strategy concerning accurate stereochemical control in the ODI-[5 + 2] cycloaddition was then successfully transplanted to the total syntheses of three stemaranoids, thus providing a straightforward and diastereoselective route to C9-ethano-bridged tetracyclic diterpenoids. To access more complex diterpenoid rhodomollanol A, we exploited two additional biomimetic rearrangements, namely, the retro-Dieckmann fragmentation/vinylogous Dieckmann cyclization cascade and the photo-Nazarov cyclization/intramolecular cycloetherification cascade. Taken together with the ODI-[5 + 2] cascade, the asymmetric total synthesis of the target molecule was realized, which shed light on the biogenetic pathway of the unprecedented rhodomollane-type carbon framework. Finally, we describe an ODI-Diels-Alder/Beckwith-Dowd cascade approach as a valuable supplement to the ODI-[5 + 2] cascade for the fabrication of cycloheptane-fused bicyclo[3.2.1]octane skeletons. Its versatility was also demonstrated by the total syntheses of two challenging grayanane diterpenoids. In view of the high functional-group compatibility and scalability, we anticipate that the two novel cascade approaches will find further use in the field of complex natural product synthesis.

LncRNA ST3Gal6-AS1/ST3Gal6 axis mediates colorectal cancer progression by regulating α-2,3 sialylation via PI3K/Akt signaling.

Sialylation is associated with cancer progression. Long noncoding RNAs (lncRNAs) have important roles in diverse diseases including cancer. The lncRNA ST3Gal6 antisense 1 (ST3Gal6-AS1) derives from the promoter region of sialyltransferase ST3Gal6. However, the mechanisms by which ST3Gal6-AS1 modulates colorectal cancer (CRC) development through sialylation remain largely unknown. Here, we found that ST3Gal6-AS1 and ST3Gal6 levels were lower in tumor tissues than adjacent normal tissues of CRC patients. The correlation between ST3Gal6-AS1 and ST3Gal6 was further validated in several types of CRC cell lines. In addition, ST3Gal6 was dysregulated and positively correlated to ST3Gal6-AS1. ST3Gal6-AS1 recruited histone methyltransferase MLL1 to the promoter region of ST3Gal6, induced H3K4me3 modification and activated ST3Gal6 transcription. Furthermore, ST3Gal6-AS1/ST3Gal6 axis mediated α-2, 3 sialylation and inhibited the activation of PI3K/Akt signaling, thereby resulting in Foxo1 nuclear translocation in CRC cells. ST3Gal6-AS1 was a target of transcription factor Foxo1 and regulated by Foxo1. ST3Gal6-AS1 also inhibited CRC cell proliferation, metastasis, and promoted cell apoptosis in vitro. Overexpression of ST3Gal6-AS1 significantly decreased the tumorigenesis, lung and liver metastasis of SW620 cells in vivo. ST3Gal6-AS1 expression was negatively correlated with tumor size, lymphatic metastasis, distant metastasis and tumor stage in CRC patients. Collectively, these data indicated that ST3Gal6-AS1, ST3Gal6, PI3K/Akt, and Foxo1 formed a positive feedback loop, which might play a key role in CRC progression.

Total Synthesis of (-)-Pavidolide B: A Ring Contraction Strategy.

A ring contraction approach for the total synthesis of (-)-pavidolide B was developed, which assembles this polycyclic natural product within 13 steps from known chiral alcohol 11. The key features of the strategy include (a) a double Mukaiyama-Michael addition/elimination, (b) a ring-closing metathesis, (c) a Wolff rearrangement, and (d) a late-stage regioselective Schenck ene reaction.

Neonatal and juvenile exposure to perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS): Advance puberty onset and kisspeptin system disturbance in female rats.

Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) are widespread and persistent chemicals in the environment, and limited data about their effects on puberty development are available. In order to explore the effects of neonatal and juvenile PFOA/PFOS exposure on puberty maturation, female rats were injected with PFOA or PFOS at 0.1, 1 and 10 mg/kg/day during postnatal day (PND) 1-5 or 26-30. The day of vaginal opening (VO) and first estrus were significantly advanced in 10 mg/kg PFOA, 1 and 10 mg/kg PFOS groups after neonatal and juvenile exposure. Besides, neonatal PFOA/PFOS exposure increased body weight and anogenital distance (AGD) in a non-dose-dependent manner. Estradiol and luteinizing hormone levels were also increased with more frequent occurrences of irregular estrous cycles in 0.1 and 1 mg/kg PFOA/PFOS exposure groups. Although no altered ovarian morphology was observed, follicles numbers were reduced in neonatal groups. Kiss1, Kiss1r and ERα mRNA expressions were downregulated after two periods' exposure in the hypothalamic anteroventral periventricular (AVPV) and arcuate (ARC) nuclei. PFOA/PFOS exposure also suppressed kisspeptin fiber intensities, especially at the high dose. In conclusion, neonatal and juvenile are critical exposure periods, during which puberty maturation may be vulnerable to environmental exposure of PFOA/PFOS, and kisspeptin system plays a key role during these processes.

MiR-193a-3p and miR-224 mediate renal cell carcinoma progression by targeting alpha-2,3-sialyltransferase IV and the phosphatidylinositol 3 kinase/Akt pathway.

Tumor metastasis is a major cause of cancer-related death in renal cell carcinoma (RCC). MicroRNAs (miRNAs) have been widely known to modulate proliferation invasion, metastasis, and apoptosis of cancer cells. In this study, we aimed to investigate the function and novel target of miR-193a-3p and miR-224 in RCC. The levels of miR-193a-3p and miR-224 were significantly increased in RCC tissues and RCC cell lines. Alpha-2,3-Sialyltransferase IV (ST3GalIV) was highly expressed in adjacent nontumor tissues and human normal proximal tubular cell line HK-2 compared to RCC tissues and cell lines. ST3GalIV expression was negatively correlated with miR-193a-3p and miR-224. Further analysis indicated that miR-193a-3p and miR-224 directly targeted ST3GalIV. MiR-193a-3p and miR-224 increased cell proliferation and migration by directly inhibiting ST3GalIV, and this effect was reversed by co-transfection with ST3GalIV in vitro. Overexpression of miR-193a-3p and miR-224 increased RCC cell proliferation in vivo. Furthermore, the phosphatidylinositol 3 kinase (PI3K)/Akt pathway was mediated by miR-193a-3p and miR-224 in RCC cell lines. Collectively, these results suggested that miR-193a-3p and miR-224 played an important role in regulation of RCC by targeting ST3GalIV via PI3K/Akt pathway.

Total Syntheses of Highly Oxidized ent-Kaurenoids Pharicin A, Pharicinin B, 7-O-Acetylpseurata C, and Pseurata C: A [5+2] Cascade Approach.

The unprecedented oxidative dearomatization-induced [5+2] cycloaddition/pinacol-type 1,2-acyl migration cascade efficiently generates a quaternary carbon center and assembles the highly oxygenated bicyclo[3.2.1]octane framework of ent-kaurene diterpenoids. By incorporation of the subsequent retro-aldol/aldol process and singlet oxygen ene reaction, this concise and convergent approach has enabled the first asymmetric total syntheses of pharicin A, pharicinin B, 7-O-acetylpseurata C, and pseurata C.

miR-182 and miR-135b Mediate the Tumorigenesis and Invasiveness of Colorectal Cancer Cells via Targeting ST6GALNAC2 and PI3K/AKT Pathway.

BACKGROUND: Metastasis is a leading cause of cancer-related death including colorectal cancer (CRC). MicroRNAs are known to regulate cancer pathways and to be expressed aberrantly in cancer. Aberrant sialylation is closely associated with malignant phenotype of tumor cells, including invasiveness and metastasis. AIM: This study aimed to investigate the association of miR-182 and miR-135b with proliferation and invasion by targeting sialyltransferase ST6GALNAC2 in CRC cells and explore the potential molecular mechanism. METHODS: We measured the levels of miR-182, miR-135b, and ST6GALNAC2 in a series of CRC cell lines and tissues using real-time PCR. Bioinformatics analysis and luciferase reporter assay were performed to test the direct binding of miR-182 and miR-135b to the target gene ST6GALNAC2. We also analyzed the possible role of miR-182/-135b on colony formation, wound healing, invasion, and tube formation. RESULTS: The expression of miR-182 and miR-135b was higher in tumor tissues compared to adjacent noncancerous tissues of CRC patients, as well as up-regulated in SW620 cells than in SW480 cells with different metastatic potential. By applying bioinformatics analysis and luciferase reporter assay, we identified ST6GALNAC2 as the direct target of miR-182/-135b. Furthermore, miR-182/-135b inhibited significantly ST6GALNAC2 expression, and consistently, ST6GALNAC2 mediated migration, adhesion, invasion, proliferation, and tumor angiogenesis in CRC cell lines. Additionally, PI3K/AKT signaling pathway was regulated by miR-182/135b, which was partially blocked by altered level of ST6GALNAC2 in CRC. CONCLUSIONS: The miR-182/-135b/ST6GALNAC2/PI3K/AKT axis may serve as a predictive biomarker and a potential therapeutic target in CRC treatment.

Safety and immunogenicity of a novel recombinant adenovirus type-5 vector-based Ebola vaccine in healthy adults in China: preliminary report of a randomised, double-blind, placebo-controlled, phase 1 trial.

BACKGROUND: Up to now, all tested Ebola virus vaccines have been based on the virus strain from the Zaire outbreak in 1976. We aimed to assess the safety and immunogenicity of a novel recombinant adenovirus type-5 vector-based Ebola vaccine expressing the glycoprotein of the 2014 epidemic strain. METHODS: We did this randomised, double-blind, placebo-controlled, phase 1 clinical trial at one site in Taizhou County, Jiangsu Province, China. Healthy adults (aged 18-60 years) were sequentially enrolled and randomly assigned (2:1), by computer-generated block randomisation (block size of six), to receive placebo, low-dose adenovirus type-5 vector-based Ebola vaccine, or high-dose vaccine. Randomisation was pre-stratified by dose group. All participants, investigators, and laboratory staff were masked to treatment allocation. The primary safety endpoint was occurrence of solicited adverse reactions within 7 days of vaccination. The primary immunogenicity endpoints were glycoprotein-specific antibody titres and T-cell responses at day 28 after the vaccination. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT02326194. FINDINGS: Between Dec 28, 2014, and Jan 9, 2015, 120 participants were enrolled and randomly assigned to receive placebo (n=40), low-dose vaccine (n=40), or high-dose vaccine. Participants were followed up for 28 days. Overall, 82 (68%) participants reported at least one solicited adverse reaction within 7 days of vaccination (n=19 in the placebo group vs n=27 in the low-dose group vs n=36 in the high-dose group; p=0·0002). The most common reaction was mild pain at the injection site, which was reported in eight (20%) participants in the placebo group, 14 (35%) participants in the low-dose group, and 29 (73%) participants in the high-dose vaccine group (p<0·0001). We recorded no statistical differences in other adverse reactions and laboratory tests across groups. Glycoprotein-specific antibody titres were significantly increased in participants in the low-dose and high-dose vaccine groups at both day 14 (geometric mean titre 421·4 [95% CI 249·7-711·3] and 820·5 [598·9-1124·0], respectively; p<0·0001) and day 28 (682·7 [424·3-1098·5] and 1305·7 [970·1-1757·2], respectively; p<0·0001). T-cell responses peaked at day 14 at a median of 465·0 spot-forming cells (IQR 180·0-1202·5) in participants in the low-dose group and 765·0 cells (400·0-1460·0) in those in the high-dose group. 21 (18%) participants had mild fever (n=9 in the placebo group, n=6 in the low-dose group, and n=6 in the high-dose group). No serious adverse events were recorded. INTERPRETATION: Our findings show that the high-dose vaccine is safe and robustly immunogenic. One shot of the high-dose vaccine could mount glycoprotein-specific humoral and T-cell response against Ebola virus in 14 days. FUNDING: China National Science and Technology, Beijing Institute of Biotechnology, and Tianjin CanSino Biotechnology.

Enantioselective Total Synthesis of (+)-Steenkrotin†A and Determination of Its Absolute Configuration.

The first enantioselective total synthesis of (+)-steenkrotin A has been achieved in 18 steps and 4.2 % overall yield. The key features of the strategy entail a Rh-catalyzed O-H bond insertion followed by an intramolecular carbonyl-ene reaction, two sequential SmI2 -mediated Ueno-Stork and ketyl-olefin cyclizations, and a cascade intramolecular aldol condensation/vinylogous retro-aldol/aldol process with inversion of the relative configuration at the C7 position. The absolute configuration of (+)-steenkrotin A was determined based on the stepwise construction of the stereocenters during the total synthesis.

The in vitro estrogenic activities of triclosan and triclocarban.

Triclosan (TCS) and triclocarban (TCC), as broad spectrum antibacterial agents, are distributed widely in the environment and humans. Most studies have focused on their distribution and biodegradation, but the endocrine-disrupting effects of these chemicals, especially their estrogenic effects, are still unclear. In the present study, we investigated the estrogenic effects of TCS and TCC using a series of in vitro assays, including the ER reporter gene assay in the CV-1 cells, E-screen assay and evaluation of estrogen-responsive genes in the MCF-7 cells. The tested concentrations of TCS and TCC were both from 1 × 10(-9) to 1 × 10(-6) M. Results showed that TCS and TCC exerted estrogenic activities by inducing luciferase activities in an ER reporter gene assay, promoting the proliferation of the MCF-7 cells, up-regulating the expression of pS2 and down-regulating ERα expression at both the mRNA and protein levels in the MCF-7 cells. We further found that TCS and TCC could alter the expression of multiple microRNAs (mir-22, mir-206 and mir-193b) in the MCF-7 cells, which would help understand the mechanisms of their estrogenic effects on regulating the expression of ERα. In brief, our results demonstrated the potential estrogenic effects and profiled in vitro data for further risk assessment of TCS and TCC.

The circZEB1/miR-337-3p/OGT axis mediates angiogenesis and metastasis via O-GlcNAcylation and up-regulating YBX1 in breast cancer.

Background: A growing corpus of research has revealed that circular RNAs (circRNAs) have become increasingly important for the growth of malignancies in recent years. CircRNAs as ideal candidates for breast cancer (BC) therapeutic targets is still absent. Methods: In our study, the dysregulated circRNAs in BC progression were explored, we analysed the BC's circRNA expression profiles using publicly available datasets (GSE101124 and GSE101122). The expression of circZEB1 in BC and cell lines was investigated by qPCR. RNase and actinomycin D were used to examine the features of circZEB1. The function of circZEB1 was subsequently investigated through the utilisation of colony formation, tube formation, transwell assays, and xenograft animal models.RNA immunoprecipitation (RIP), luciferase reporter assays, immunoprecipitation (co-IP) test in conjunction with LC-MS, and ChIP-seq assay to investigate the molecular mechanism underlying the biological activity of circZEB1 in BC. Results: Among the circRNAs, we were particularly interested in hsa_circ_0000228, which is spliced from the oncogene ZEB1. In BC cell lines, CircZEB1 expression was upregulated. CircZEB1 knockdown prevented BC cells from migrating and invading, as well as HUVECs from forming tubes and developing. By sponging miR-337-3p, functional testing revealed that circZEB1 promoted O-GlcNAcylation, increased YBX1, and OGT expression. Moreover, circZEB1 overexpression is reversible, in contrast to YBX1 knockdown, which mostly results in the downregulation of multiple oncogenes. Conclusion: Our study indicate that circZEB1 had oncogenic function in BC by focusing on circZEB1/miR-337-3p/OGT and YBX1. It might be inferred that circZEB1 could be a promising new target for BC treatment.

Immunogenicity and safety of an ORF7-deficient skin-attenuated and neuro-attenuated live vaccine for varicella: a randomised, double-blind, controlled, phase 2a trial.

BACKGROUND: The Oka varicella vaccine strain remains neurovirulent and can establish lifelong latent infection, raising safety concerns about vaccine-related herpes zoster. In this study, we aimed to evaluate the immunogenicity and safety of a skin-attenuated and neuro-attenuated varicella vaccine candidate (v7D vaccine). METHODS: We did this randomised, double-blind, controlled, phase 2a clinical trial in Jiangsu, China. Healthy children aged 3-12 years with no history of varicella infection or vaccination were enrolled and randomly assigned (1:1:1:1) to receive a single subcutaneous injection of the v7D vaccine at 3·3 log10 plaque forming units (PFU; low-dose v7D group), 3·9 log10 PFU (medium-dose v7D group), and 4·2 log10 PFU (high-dose v7D group), or the positive control varicella vaccine (vOka vaccine group). All the participants, laboratory personnel, and investigators other than the vaccine preparation and management staff were masked to the vaccine allocation. The primary outcome was assessment of the geometric mean titres (GMTs) and seroconversion rates of anti-varicella zoster virus immunoglobulin G (IgG) induced by different dose groups of v7D vaccine at 0, 42, 60, and 90 days after vaccination in the per-protocol set for humoral immune response analysis. Safety was a secondary outcome, focusing on adverse events within 42 days post-vaccination, and serious adverse events within 6 months after vaccination. This study was registered on Chinese Clinical Trial Registry, ChiCTR2000034434. FINDINGS: On Aug 18-21, 2020, 842 eligible volunteers were enrolled and randomly assigned treatment. After three participants withdrew, 839 received a low dose (n=211), middle dose (n=210), or high dose (n=210) of v7D vaccine, or the vOka vaccine (n=208). In the per-protocol set for humoral immune response analysis, the anti-varicella zoster virus IgG antibody response was highest at day 90. At day 90, the seroconversion rates of the low-dose, medium-dose, and high-dose groups of v7D vaccine and the positive control vOka vaccine group were 100·0% (95% CI 95·8-100·0; 87 of 87 participants), 98·9% (93·8-100·0; 87 of 88 participants), 97·8% (92·4-99·7; 91 of 93 participants), and 96·4% (89·8-99·2; 80 of 83 participants), respectively; the GMTs corresponded to values of 30·8 (95% CI 26·2-36·0), 31·3 (26·7-36·6), 28·2 (23·9-33·2), and 38·5 (31·7-46·7). The v7D vaccine, at low dose and medium dose, elicited a humoral immune response similar to that of the vOka vaccine. However, the high-dose v7D vaccine induced a marginally lower GMT compared with the vOka vaccine at day 90 (p=0·027). In the per-protocol set, the three dose groups of the v7D vaccine induced a similar humoral immune response at each timepoint, with no statistically significant differences. The incidence of adverse reactions in the low-dose, medium-dose, and high-dose groups of v7D vaccine was significantly lower than that in the vOka vaccine group (17% [35 of 211 participants], 20% [41 of 210 participants], and 13% [27 of 210 participants] vs 24% [50 of 208 participants], respectively; p=0·025), especially local adverse reactions (10% [22 of 211 participants], 14% [30 of 210 participants] and 9% [18 of 210 participants] vs 18% [38 of 208 participants], respectively; p=0·016). None of the serious adverse events were vaccine related. INTERPRETATION: The three dose groups of the candidate v7D vaccine exhibit similar humoral immunogenicity to the vOka vaccine and are well tolerated. These findings encourage further investigations on two-dose vaccination schedules, efficacy, and the potential safety benefit of v7D vaccine in the future. FUNDING: The National Natural Science Foundation of China, CAMS Innovation Fund for Medical Sciences, the Fundamental Research Funds for the Central Universities, and Beijing Wantai. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Reprogramming of mouse and human somatic cells by high-performance engineered factors.

Reprogramming somatic cells to become induced pluripotent stem cells (iPSCs) by using defined factors represents an important breakthrough in biology and medicine, yet remains inefficient and poorly understood. We therefore devised synthetic factors by fusing the VP16 transactivation domain to OCT4 (also known as Pou5f1), NANOG and SOX2, respectively. These synthetic factors could reprogramme both mouse and human fibroblasts with enhanced efficiency and accelerated kinetics. Remarkably, Oct4-VP16 alone could efficiently reprogramme mouse embryonic fibroblasts (MEFs) into germline-competent iPSCs. Furthermore, episomally delivered synthetic factors could reproducibly generate integration-free iPSCs from MEFs with enhanced efficiency. Our results not only demonstrate the feasibility of engineering more potent reprogramming factors, but also suggest that transcriptional reactivation of OCT4 target genes might be a rate-limiting step in the conversion of somatic cells to pluripotent cells. Synthetic factor-based reprogramming might lead to a paradigm shift in reprogramming research.

Safety and immunogenicity of a modified Omicron-adapted inactivated vaccine in healthy adults: a randomized, double-blind, active-controlled Phase III clinical trial.

Background: Updated vaccine strategies are needed to protect against new SARS-CoV-2 variants with increased immune escape. Here, information on the safety and immunogenicity of an inactivated Omicron-adapted vaccine is presented, as compared with CoronaVac. Methods: A randomized, double-blind, active-controlled, phase III clinical trial was conducted to compare a modified Omicron-adapted vaccine (Omicron vaccine) with the authorized prototype vaccine (CoronaVac®) as a booster dose. Healthy adults aged ≥18 years, who have previously received 2 or 3 doses of CoronaVac (2C or 3C cohort) at least 6 months before, were enrolled to get a booster dose of Omicron vaccine or CoronaVac in a ratio of 2:1 (2C/3C+1O/1C). Back-up serums after two initial doses of CoronaVac (2C+0) for adults aged 26-45 years were collected from a previous study. Immunogenicity and safety data at 28 days after vaccination were collected and analyzed. One of the primary objectives was to evaluate the superiority of immunogenicity of Omicron vaccine booster against Omicron BA.1, compared with CoronaVac booster against BA.1. Another objective was to evaluate the non-inferiority of immunogenicity of Omicron vaccine booster against BA.1, compared with two initial doses of CoronaVac against ancestral strain. Results: Between June 1st and July 21st, 2022, a total of 1,500 healthy adults were enrolled. Results show that all pre-specified superiority criteria for BA.1 neutralizing antibody were met. Specifically, within the 3C cohort (3C+1O vs. 3C+1C), the geometric mean titers' (GMT) ratio and 95% confidence interval (CI) was 1.64 (1.42, 1.89), with the lower 95%CI ≥1; a GMT ratio of 1.84 (1.57, 2.16) was observed for 2C+1O versus 3C+1C. For seroconversion rate, the lower 95%CIs of differences between immuno-comparative groups (2/3C+1O vs. 3C+1C) were all above the superiority criterion 0%. However, the non-inferiority criterion of the lower 95%CI of GMT ratio ≥2/3 was unfulfilled for 2C/3C+1O against BA.1 versus 2C+0 against ancestral strain. Safety profiles were similar between groups, with no safety concerns identified. Conclusion: The Omicron-adapted vaccine was well-tolerated and could elicit superior immune responses as compared with CoronaVac against Omicron, while it appeared inferior to CoronaVac against ancestral strain. Clinical trial registration: https://classic.clinicaltrials.gov/ct2/show/NCT05381350?term=NCT05381350&draw=2&rank=1, identifier NCT05381350.

The N-terminus of histone H3 is required for de novo DNA methylation in chromatin.

DNA methylation and histone modification are two major epigenetic pathways that interplay to regulate transcriptional activity and other genome functions. Dnmt3L is a regulatory factor for the de novo DNA methyltransferases Dnmt3a and Dnmt3b. Although recent biochemical studies have revealed that Dnmt3L binds to the tail of histone H3 with unmethylated lysine 4 in vitro, the requirement of chromatin components for DNA methylation has not been examined, and functional evidence for the connection of histone tails to DNA methylation is still lacking. Here, we used the budding yeast Saccharomyces cerevisiae as a model system to investigate the chromatin determinants of DNA methylation through ectopic expression of murine Dnmt3a and Dnmt3L. We found that the N terminus of histone H3 tail is required for de novo methylation, while the central part encompassing lysines 9 and 27, as well as the H4 tail are dispensable. DNA methylation occurs predominantly in heterochromatin regions lacking H3K4 methylation. In mutant strains depleted of H3K4 methylation, the DNA methylation level increased 5-fold. The methylation activity of Dnmt3a largely depends on the Dnmt3L's PHD domain recognizing the histone H3 tail with unmethylated lysine 4. Functional analysis of Dnmt3L in mouse ES cells confirmed that the chromatin-recognition ability of Dnmt3L's PHD domain is indeed required for efficient methylation at the promoter of the endogenous Dnmt3L gene. These findings establish the N terminus of histone H3 tail with an unmethylated lysine 4 as a chromatin determinant for DNA methylation.

Sikokianin D, a new C-3/C-3"-biflavanone from the roots of Wikstroemia indica.

A new 3,3''-biflavanone, sikokianin D (1), was isolated from the roots of Wikstroemia indica, together with two known compounds. Their structures were elucidated by chemical evidence and spectral analyses, including HR-ESI-MS, and 1D- and 2D-NMR techniques.

Exosomal circPABPC1 promotes colorectal cancer liver metastases by regulating HMGA2 in the nucleus and BMP4/ADAM19 in the cytoplasm.

Liver metastasis is the leading cause of death in colorectal carcinoma (CRC). However, little is known about the mechanisms of transferring effector messages between the primary tumor and the site of metastasis. Exosomes provide a novel transfer message method, and exosomal circular RNAs (circRNAs) play critical regulatory roles in cancer biology. In this study, the results showed that the expression of circPABPC1 was aberrantly upregulated in CRC tissues and exosomes. Exosomal circPABPC1 was considered an oncogene by functional experimental analysis in vitro and in vivo. Mechanistically, circPABPC1 recruited KDM4C to the HMGA2 promoter, reduced its H3K9me3 modification and initiated the transcription process in the nucleus. Moreover, cytoplasmic circPABPC1 promoted CRC progression by protecting ADAM19 and BMP4 from miR-874-/miR-1292-mediated degradation. Our findings indicated that exosomal circPABPC1 is an essential regulator in CRC liver metastasis progression by promoting HMGA2 and BMP4/ADAM19 expression. CircPABPC1 is expected to be a novel biomarker and antimetastatic therapeutic target in CRC.