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Continuous emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants urges the development of new vaccines. We assessed the safety and immunogenicity of SYS6006.32, a bivalent vaccine (XBB.1.5/BQ.1), in healthy adults who had received SARS-CoV-2 primary vaccination. In a randomised, double-blinded, active-controlled trial, 200 participants were randomised to receive one dose of SYS6006.32 (N = 100) or a prototype-based, monovalent control vaccine SYS6006 (N = 100). Adverse events (AEs) were collected through the study. Immunogenicity was assessed by live-virus neutralising antibody (Nab) and pseudovirus Nab. 61 (61.0 %) and 60 (60.0 %) participants reported AE in the SYS6006.32 and SYS6006 groups, respectively. Most AEs were grade 1 or 2. Pain and fever were the most common injection-site and systemic AEs, respectively. No serious AEs were observed. SYS6006.32 heterologous boosting induced robust Nab responses against BA.5, XBB.1.5 and EG.5 with live-virus Nab geometric mean titres (GMTs) increased by 17.1-, 34.0-, and 48.0-fold, and pseudovirus Nab GMTs increased by 12.2-, 32.0-, and 35.1-fold, respectively, 14 days after vaccination. SYS6006.32 demonstrated a superior immunogenicity to SYS6006. SYS6006.32 also induced robust pseudovirus Nab responses against XBB.1.16, XBB.2.3, and BA.2.86, with GMTs 3- to 6-fold higher than those induced by SYS6006. In conclusion, SYS6006.32 showed good safety profile and superior immunogenicity to the monovalent vaccine SYS6006. [ABSTRACT FROM AUTHOR]

Abstract Faulty bony repair causes dysrepair of injured growth plate cartilage and bone growth defects in children; however, the underlying mechanisms are unclear. Recently, we observed the prominent induction of neurotrophin‑3 (NT-3) and its important roles as an osteogenic and angiogenic factor promoting the bony repair. The current study investigated its roles in regulating injury site remodelling. In a rat tibial growth plate drill-hole injury repair model, NT-3 was expressed prominently in osteoblasts at the injury site. Recombinant NT-3 (rhNT-3) systemic treatment enhanced, but NT-3 immunoneutralization attenuated, expression of cartilage-removal proteases (MMP-9 and MMP-13), presence of bone-resorbing osteoclasts and expression of osteoclast protease cathepsin K, and remodelling at the injury site. NT-3 was also highly induced in cultured mineralizing rat bone marrow stromal cells, and the conditioned medium augmented osteoclast formation and resorptive activity, an ability that was blocked by presence of anti-NT-3 antibody. Moreover, NT-3 and receptor TrkC were induced during osteoclastogenesis, and rhNT-3 treatment activated TrkC downstream kinase Erk1/2 in differentiating osteoclasts although rhNT-3 alone did not affect activation of osteoclastogenic transcription factors NF-κB or NFAT in RAW 264.7 osteoclast precursor cells. Furthermore, rhNT-3 treatment increased, but NT-3 neutralization reduced, expression of osteoclastogenic cytokines (RANKL, TNF-α, and IL-1) in mineralizing osteoblasts and in growth plate injury site, and rhNT-3 augmented the induction of these cytokines caused by RANKL treatment in RAW 264.7 cells. Thus, injury site osteoblast-derived NT-3 is important in promoting growth plate injury site remodelling, as it induces cartilage proteases for cartilage removal and augments osteoclastogenesis and resorption both directly (involving activing Erk1/2 and substantiating RANKL-induced increased expression of osteoclastogenic signals in differentiating osteoclasts) and indirectly (inducing osteoclastogenic signals in osteoblasts). Graphical abstract Unlabelled Image Highlights • Injury site osteoblast-derived NT-3 has both direct and indirect roles in promoting growth plate injury site remodeling. • NT-3 enhances expression of MMP-9 and MMP-13 and osteoclast recruitment and function at the growth plate injury site. • NT-3 was induced in mineralizing BMSCs, and the conditioned medium augmented osteoclastogenesis and resorptive activity. • NT-3 can induce osteoclastogenic cytokines and RANKL in osteoblasts. • NT-3 and TrkC were induced, and rhNT-3 treatment activated TrkC downstream kinase Erk1/2 in differentiating osteoclasts. [ABSTRACT FROM AUTHOR]

Background Although accumulating evidence suggests urinary calculi may be associated with an increased risk of cardiovascular disease (CVD), the number of longitudinal studies linking urolithiasis to CVD events is limited. We investigated the association between urinary calculi and the risk of development of myocardial infarction (MI) and/or stroke in a nationwide, population-based cohort database in Taiwan. Methods Our analyses were conducted using information from a random sample of 1 million people enrolled in the nationally representative Taiwan National Health Insurance Research Database. A total of 81,546 subjects aged 18 years or above, including 40,773 subjects diagnosed with urinary calculi during the study period and a propensity score-matched 40,773 subjects without urinary calculi were enrolled in our study. Results During a 10-year follow-up period, 501 MI events and 1295 stroke events were identified. By comparison, the urinary calculi group had a higher incidence rate of MI occurrence (11.79 vs 8.94 per 10,000 person-years) and stroke (31.41 vs 22.45 per 10,000 person-years). Cox proportional hazard regression model analysis showed that development of urinary calculi was independently associated with higher risk of developing future MI (HR, 1.31; 95% CI, 1.09–1.56, p = 0.003), stroke (HR, 1.39; 95% CI, 1.24–1.55, p < 0.001), and total cardiovascular events (HR, 1.38; 95% CI, 1.25–1.51, p < 0.001). Conclusions Urinary calculi were associated with an increased risk of future cardiovascular events in the Asian population, which was consistent with the recent epidemiologic evidence in Western countries. [ABSTRACT FROM AUTHOR]

Highlights: [•] Pleurotus tuber-regium (PTR) mycelia were obtained by submerged fermentation. [•] Cerevisterol and ergosta-4,6,8(14)-tetraen-3-one was first been isolated from PTR. [•] CE and EG inhibit LPS induced-NO, TNF-α, and PGE2 production in RAW 264.7. [•] CE and EG inhibit iNOS and COX2 protein expression. [•] CE and EG downregulate LPS-induced iNOS, COX2, TNF-α, and SOCS3 mRNA expression. [Copyright &y& Elsevier]

Abstract: This study examines the impact on inbound tourism caused by the presence of world heritage sites. The statistics are derived from panel data for 66 countries for the period 2006–2009. The results indicate that there exists a positive relationship between having such heritage sites and tourist numbers, and the relationship is stronger for natural rather than for cultural heritage sites. The evidence also indicates the presence of a U-shaped relationship between numbers of world heritage sites in a country and tourist numbers. These relationships are found to be robust even though differences in patterns are found in different regions. [Copyright &y& Elsevier]

Abstract: In July 2008, Taiwan passed a legislation allowing Chinese tourists to travel into Taiwan. We are interested in crowding-out effects which may have a negative impact on Taiwan''s tourism. However, lack of data compels us to employ monthly tourist arrivals from China to Japan as a reference for impacts of opening policies. We project that Chinese tourists into Taiwan due to the opening policy for individual tourists would increase substantially. We also analyze tourist arrivals from Japan, Hong Kong, and the United States to explore the crowding-out effect. Using seasonal ARIMA models with joint estimation of intervention and outlier effects, we find that Chinese tourists significantly crowd out Taiwan''s international tourists from Japan and the United States, but not those from Hong Kong, even with Taiwan''s increased tourism capacity. Therefore, our results indicate that Taiwan should either further enhance tourism capacity or decelerate its opening policy to avoid severe crowding-out effects. [Copyright &y& Elsevier]

Abstract: Many different kinds of fermented food are consumed daily in Taiwan, such as stinky tofu, suan-tsai, and fu-tsai. We have previously reported the diversity of lactic acid bacteria (LAB) at different stages of fermentation in the production of suan-tsai and fu-tsai. In this study, the anti-inflammatory and immunomodulatory activities of Lactobacillus plantarum K68 (K68) isolated from fu-tsai were evaluated. K68 significantly inhibited the production of tumor necrosis factor-α (TNF-α) and prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-induced murine macrophage RAW 264.7 cells and stimulated interferon-γ (IFN-γ) production in human peripheral blood mononuclear cells (hPBMCs). Additionally, orally administered K68 ameliorated dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in BALB/c mice. Both the disease activity index (DAI) and histological scores (HIS) showed that the severity of UC was significantly reduced by oral administration of K68. Furthermore, the production of pro inflammatory cytokines TNF-α, interleukin-1β (IL-1β), and interleukin-6 (IL-6) was significantly reduced in K68-administered group. Colonic mRNA expression levels of TNF-α, cyclooxygenase-2 (COX-2), forkhead box P3 (Foxp3), suppressors of cytokine signaling 3 (SOCS3), and toll like receptor 4 (TLR4), were also reduced in the K68-administered group. These results suggest that K68 exhibits anti-inflammatory and immunomodulatory activities that ameliorate DSS-induced experimental colitis. [Copyright &y& Elsevier]

Abstract: Angelica sinensis (AS), an herb used in traditional Chinese medicine, is thought to have anti-inflammatory activities. Ligustilide is its most abundant ingredient. This study sought to determine ligustilide''s effects on lipopolysaccharide (LPS)-induced inflammation in RAW 264.7 macrophages. Ligustilide significantly suppressed the production of nitric oxide (NO), prostaglandin E2 (PGE2) and tumor necrosis factor-α (TNF-α). The inhibition of NO was concomitant with a decrease in the protein and mRNA levels of LPS-induced nitric oxide synthase (iNOS). Furthermore, activation of activator protein-1 (AP-1) and nuclear factor κB (NF-κB) in the nucleus and the cytosolic degradation of IκBα were abrogated by ligustilide. Ligustilide also inhibited the phosphorylation of IκB kinase (IKK) and mitogen-activated protein kinases (MAPKs), including p38 MAPK, extracellular signal-regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK). The intracellular reactive oxygen species (iROS) level was also significantly decreased. These results suggest that ligustilide exhibits anti-inflammatory activities by blocking the activation of MAPKs/IKK and the downstream transcription factors AP-1 and NF-κB, which may result from ligustilide''s down-regulation of iROS production. [Copyright &y& Elsevier]

Strengthening the gut epithelial barrier is a potential strategy for management of gut microbiota-associated illnesses. Here, we demonstrate that dual-specificity phosphatase 6 (Dusp6) knockout enhances baseline colon barrier integrity and ameliorates dextran sulfate sodium (DSS)-induced colonic injury. DUSP6 mutation in Caco-2 cells enhances the epithelial feature and increases mitochondrial oxygen consumption, accompanied by altered glucose metabolism and decreased glycolysis. We find that Dusp6 -knockout mice are more resistant to DSS-induced dysbiosis, and the cohousing and fecal microbiota transplantation experiments show that the gut/fecal microbiota derived from Dusp6 -knockout mice also confers protection against colitis. Further culturomics and mono-colonialization experiments show that one gut microbiota member in the genus Duncaniella confers host protection from DSS-induced injury. We identify Dusp6 deficiency as beneficial for shaping the gut microbiota eubiosis necessary to protect against gut barrier-related diseases. [Display omitted] • Dusp6 deficiency protects against DSS-induced colitis in mice • Dusp6 knockout induces tight junction- and microvilli-associated gene expression • Dusp6 knockout results in elevation of mitochondrial oxygen consumption • A potential anti-colitis bacterium, NHRI-C1-K-H-1-87, is found in Dusp6 -knockout mice Chang et al. report that Dusp6 deficiency strengthens the junctions and extends the microvilli, thereby enhancing colonic barrier integrity. Dusp6 deficiency also promotes glucose-to-lipid metabolic switch and elevates mitochondrial oxygen consumption, thereby maintaining the anaerobic state for preserving obligatory bacteria. An anti-colitis anaerobe, NHRI-C1-K-H-1-87, is identified in Dusp6 -knockout mice. [ABSTRACT FROM AUTHOR]

Growth plate cartilage injuries often result in bony repair at the injury site and premature mineralisation at the uninjured region causing bone growth defects, for which underlying mechanisms are unclear. With the prior microarray study showing upregulated bone morphogenetic protein (BMP) signalling during the injury site bony repair and with the known roles of BMP signalling in bone healing and growth plate endochondral ossification, this study used a rat tibial growth plate drill-hole injury model with or without systemic infusion of BMP antagonist noggin to investigate roles of BMP signalling in injury repair responses within the injury site and in the adjacent "uninjured" cartilage. At days 8, 14 and 35 post-injury, increased expression of BMP members and receptors and enhanced BMP signalling (increased levels of phosphorylated (p)-Smad1/5/8) were found during injury site bony repair. After noggin treatment, injury site bony repair at days 8 and 14 was reduced as shown by micro-CT and histological analyses and lower mRNA expression of osteogenesis-related genes Runx2 and osteocalcin (by RT-PCR). At the adjacent uninjured cartilage, the injury caused increases in the hypertrophic zone/proliferative zone height ratio and in mRNA expression of hypertrophy marker collagen-10, but a decrease in chondrogenesis marker Sox9 at days 14 and/or 35, which were accompanied by increased BMP signalling (increased levels of pSmad1/5/8 protein and BMP7, BMPR1a and target gene Dlx5 mRNA). Noggin treatment reduced the hypertrophic zone/proliferative zone height ratio and collagen-10 mRNA expression, but increased collagen-2 mRNA levels at the adjacent growth plate. This study has identified critical roles of BMP signalling in the injury site bony repair and in the hypertrophic degeneration of the adjacent growth plate in a growth plate drill-hole repair model. Moreover, suppressing BMP signalling can potentially attenuate the undesirable bony repair at injury site and suppress the premature hypertrophy but potentially rescue chondrogenesis at the adjacent growth plate. • Trauma injury often leads to dysrepair at the injured growth plate cartilage, for which molecular mechanisms are unclear. • BMP signalling was shown upregulated in a prior microarray study, but its function in growth plate repair is unclear. • Systemic treatment with BMP inhibitor noggin suppressed the bony repair at the growth plate injury site in rats. • Systemic BMP inhibitor noggin treatment attenuated premature hypertrophy at the adjacent uninjured growth plate cartilage. • Enhanced BMP signalling promotes injury site bony repair and premature hypertrophy at the uninjured growth plate cartilage. [ABSTRACT FROM AUTHOR]

• PD-L1 expression (CPS ≥ 1) was found in 94.3% of R/M HNSCC patients. • PD-L1 expression rates do not differ in those with or without betel nut exposure. • Prior lines of systemic therapy did not influence PD-L1 expression rates. This study explored the relationship between betel-nut chewing and programmed death-ligand 1 (PD-L1) expression in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients in Taiwan. A total 280 R/M HNSCC patients, predominantly male, were evaluated; 75.4 % of whom chewed betel-nut. The prevalence of PD-L1 expression (combined positive score ≥1) was 94.3 % with similar PD-L1 expression rates between betel-nut-exposed and non-exposed groups. PD-L1 prevalence did not differ in those who received prior first-or second-line systemic therapy. In summary, betel-nut exposure did not notably affect PD-L1 expression rates in R/M HNSCC patients in Taiwan. [ABSTRACT FROM AUTHOR]