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Background: Evidence of lymphopoiesis, exhaustion, and premature aging in Chinese patients with human immunodeficiency virus (HIV) is very limited., Objective: To assess biological aging and immune senescence in Chinese healthy controls (HC) and ART-naïve HIV-infected men who have sex with men (MSM)., Methods: This case-control study was conducted in Beijing Ditan Hospital from March 2018 to June 2019. The percentages of naïve (TN), central memory (TCM), effector memory (TEM), and terminally differentiated memory (TemRA) subsets of CD4 and CD8 T cells were studied, along with markers of senescence (CD28-CD57+) and activation (HLA-DR+). Telomere length of naïve (CD45RA+) and memory (CD45RO+) CD8 T cells were quantified by real-time PCR., Results: A total of 26 HIV-infected and 20 age-matched HC MSM were included. Compared to the HC group, the CD4/CD8 ratio of the HIV-infected group was significantly reduced (0.30 vs. 1.70, P<0.001); significant differences emerged among all CD8 but not CD4 T cell subsets (all P<0.05). In the HIV-infected group, the percentages of senescent cells (CD28-CD57+) in TN, TCM, TEM, and TemRA subsets of CD8 T cells were higher (all P<0.05); while a significant difference was only found in naïve CD4 T cells (P<0.05). HLA-DR expression was increased significantly in all CD4 and CD8 T cell subsets. Both naïve (CD45RA+) and memory (CD45RO+) CD8 T cells in this population had significantly shorter telomere lengths (P<0.01) compared to the HC group., Conclusion: HIV-infected MSM exhibit signs of accelerated immune senescence and biological aging, which particularly affects the CD8 T-cell subsets., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Two series of flavonoid hybrids, totaling 42 compounds, were designed, synthesized and evaluated to develop antiviral compounds effective against hepatitis A virus (HAV). A recombinant viral screening system revealed that most of the synthesized derivatives exhibited significant anti-HAV activity, and compounds B2, B3, B5 and B27 were identified as potential inhibitors of HAV. Post-treatment of cells with B2, B3, B5 and B27 after HAV infection strongly suppressed HAV infection, whereas pretreatment or simultaneous treatment were ineffective. Furthermore, these four compounds significantly inhibited HAV (HM175/18f strain) production in a dose-dependent manner. Analyses using HAV subgenomic replicon systems indicated that these compounds specifically inhibit HAV RNA replication. More importantly, the most potent compounds B2 and B27 also showed clear inhibitory effects on two other HAV strains, KRM031 and TKM005, which also isolated from clinical patients. Our study is the first to report these newly designed flavonoid hybrids as lead compounds for the development of novel anti-HAV drugs., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Ten compounds ( 1 - 10 ) including four new compounds ( 1 - 4 ) and six known compounds ( 5 - 10 ) were isolated from Solanum nigrum . Their structures were elucidated on the basis of spectroscopic data, gauge-including atomic orbital (GIAO) calculation of NMR data, DP4+ probability analysis and comparison of their experimental and calculated electronic circular dichroism (ECD) spectral data. All the isolated compounds were tested for their neuroprotective activities against H 2 O 2 -induced damage in SH-SY5Y cells. Among them, compounds 1 , 5 and 7 displayed moderate neuroprotective effects.

The first week after birth is a critical time for the establishment of microbial communities for infants. Preterm infants face unique environmental impacts on their newly acquired microbiomes, including increased incidence of cesarean section delivery and exposure to antibiotics as well as delayed enteral feeding and reduced human interaction during their intensive care unit stay. Using contextualized paired metabolomics and 16S sequencing data, the development of the gut, skin, and oral microbiomes of infants is profiled daily for the first week after birth, and it is found that the skin microbiome appears robust to early life perturbation, while direct exposure of infants to antibiotics, rather than presumed maternal transmission, delays microbiome development and prevents the early differentiation based on body site regardless of delivery mode. Metabolomic analyses identify the development of all gut metabolomes of preterm infants toward full-term infant profiles, but a significant increase of primary bile acid metabolism only in the non-antibiotic treated vaginally birthed late preterm infants. This study provides a framework for future multi-omic, multibody site analyses on these high-risk preterm infant populations and suggests opportunities for monitoring and intervention, with infant antibiotic exposure as the primary driver of delays in microbiome development., (© 2022 Wiley-VCH GmbH.)

Background: Although medial open-wedge high tibial osteotomy (MOWHTO) is the treatment of choice for patients with mild to moderate osteoarthritis with varus malalignment, concerns about inferior outcomes in patients with preoperative radiological kissing lesion (RKL) remain., Purpose: To compare the mid- to long-term clinical and radiological results and survivorship after MOWHTO in patients with versus without preoperative RKL., Study Design: Cohort study; Level of evidence, 3., Methods: Included were 122 knees in patients who underwent MOWHTO with a medial locked plate and had minimum 5-year follow-up data. The mean age at surgery was 55.9 years (range, 38-65 years), and the mean follow-up was 7.5 years (range, 5-12.8 years). All patients had undergone second-look arthroscopy around 2 years after MOWHTO. The knees were divided into an RKL group (n = 17) and no-RKL group (n = 105) based on preoperative standing radiographs. The authors compared postoperative American Knee Society (AKS) knee and function scores, range of motion, and improvements in AKS scores between groups, as well as hip-knee-ankle angle, medial proximal tibial angle, and joint-line convergence angle from preoperatively to postoperatively. Also compared were the degree of cartilage regeneration between first- and second-look arthroscopy and the survival rate after index surgery., Results: Preoperative AKS scores were significantly lower in the RKL group versus the no-RKL group (AKS knee, 79.6 ± 7.5 vs 83.8 ± 3.9, P = .037; AKS function, 68.8 ± 9.3 vs 76.0 ± 5.1, P = .006). Likewise, postoperative AKS scores were significantly lower in the RKL group versus the no-RKL group (AKS knee: 91.3 ± 4.2 vs 94.4 ± 1.6, respectively, P = .008; AKS function: 90.0 ± 10.0 vs 97.6 ± 4.5, respectively, P = .007). However, all patients had excellent postoperative AKS knee and function scores (>80). Moreover, there were no between-group differences in pre- to postoperative improvement in AKS scores, postoperative radiological changes, or grade of cartilage regeneration. The survival rates in the RKL and no-RKL groups were 100% and 97.1%, respectively ( P ≥ .999)., Conclusion: Although the latest clinical scores were lower in the RKL group than in the no-RKL group, comparable results in postoperative clinical improvement, cartilage regeneration, and survivorship were observed in patients with RKL at mid- to long-term follow-up., Competing Interests: The authors declared that they have no conflicts of interest in the authorship and publication of this contribution. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2022.)

Objectives: Ziyin Huatan Recipe (ZYHT), a traditional Chinese medicine comprised of Lilii Bulbus, Pinelliae Rhizoma, and Hedyotis Diffusa, has shown promise in treating gastric cancer (GC). However, its potential mechanism has not yet been clearly addressed. This study aimed to predict targets and molecular mechanisms of ZYHT in treating GC by network pharmacology analysis and to explore the role of ZYHT in GC both in vitro and in vivo., Methods: Targets and molecular mechanisms of ZYHT were predicted via network pharmacology analysis. The effects of ZYHT on the expression of metastasis-associated targets were further validated by Western blot and quantitative real-time polymerase chain reaction. To explore the specific molecular mechanisms of the effects of ZYHT on migration and invasion, the runt-related transcription factor 3 (RUNX3) gene was knocked out by clustered regularly interspaced short palindromic repeats/Cas9, and lentiviral vectors were transfected into SGC-7901 cells. Then lung metastasis model of GC in nude mice was established to explore the anti-metastasis effect of ZYHT. Western blot and immunohistochemistry were used to explore the impact of ZYHT on the expression of metastasis-related proteins with or without RUNX3 gene., Results: The network pharmacology analysis showed that ZYHT might inhibit focal adhesion, migration, invasion and metastasis of GC. ZYHT inhibited the proliferation, migration and invasion of GC cells in vitro via regulating the expression of metastasis-associated targets. Knocking out RUNX3 almost completely reversed the cell phenotypes (migration and invasion) and protein expression levels elicited by ZYHT. In vivo studies showed that ZYHT inhibited the metastasis of GC cells to the lung and prolonged the survival time of the nude mice. Knocking out RUNX3 partly reversed the metastasis of GC cells to the lung and the protein expression levels elicited by ZYHT., Conclusion: ZYHT can effectively inhibit the invasion and migration of GC in vitro and in vivo, and its molecular mechanism may relate to the upregulation of RUNX3 expression., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022 Shanghai Yueyang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine. Published by Elsevier B.V. All rights reserved.)

Seven lignans (1a/1b-2a/2b and 3-5), including six new compounds (1b, 2a/2b, 3-5), were isolated from the fruits of Crataegus pinnatifida. Their structures were elucidated by comprehensive spectroscopic analyses. Compounds 1b/1b-2a/2b were two pairs of enantiomers and the absolute configurations were determined by comparison of their experimental and calculated ECD spectra. Moreover, bioinformatics analysis suggested that more than a third of diseases were related to the nervous system. Therefore, all compounds were evaluated for neuroprotective effects toward human neuroblastoma SH-SY5Y cells injury induced by H 2 O 2 . Among them, compound 1a exhibited moderate protective effect., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background/aims: Obesity is a well-known risk factor for diabetes, but its association with diabetic retinopathy (DR) is inconclusive, in particular in Asians. We aimed to assess whether body mass index (BMI) is associated with the presence and severity of DR in Asian populations with diabetes., Methods: Pooled analysis of individual-level cross-sectional data from 10 010 adults with diabetes who participated in 12 population-based studies conducted in China, India, Japan, Russia (Asian), Singapore and South Korea that were part of the Asian Eye Epidemiology Consortium (AEEC). BMI was calculated as weight in kilograms divided by height in square metres and categorised into normal (<25 kg/m 2 , reference), overweight (25-29.9 kg/m 2 ) and obese (≥30 kg/m 2 ). Any-DR (n=1669) and vision-threatening DR (VTDR, n=489) were assessed from digital retinal photographs and graded according to standard protocols. Each study was analysed separately using multivariable logistic regression models adjusted for age, sex, haemoglobin A1c%, systolic blood pressure and diabetes duration, and the estimated odds ratios (ORs) and 95% confidence interval (CIs) from all studies were then combined using random-effects models., Results: In multivariable models, obesity showed a significant inverse association with any-DR (pooled OR (95% CI) =0.74 (0.59 to 0.91)) and VTDR (0.75 (0.60 to 0.93)). Similarly, in continuous analysis, BMI showed a significant inverse association with both any-DR (0.93 (0.87 to 0.99)) and VTDR (0.79 (0.68 to 0.92) per SD increase). Overweight did not show a significant association with any-DR., Conclusions: Among Asian adults with diabetes, both BMI and obesity showed an inverse association with DR. These findings warrant confirmation in further longitudinal studies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: The study aims to analyze long-term clinical and radiographic results, and survival of re-revision total knee arthroplasty (TKA) using fully cemented stems performed on femurs with diaphyseal deformation., Methods: Thirty-seven re-revision TKAs using fully cemented stems performed in femoral diaphyseal deformations, characterized as diaphyseal canal enlargement and cortex deformation due to aseptic loosening of previously implanted stems, between 2003 and 2015 were retrospectively reviewed. The mean follow-up period was 10.0 years. Clinically, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and range of motion (ROM) were evaluated. Radiographically, mechanical axis (MA) and component positions were measured. Complications and survival rates were also analyzed., Results: Clinically, the WOMAC significantly improved at final follow-up (61.2 vs 47.2, p < 0.001), but not the ROM (95.5 vs 102.5, p = 0.206). Radiographically, the MA and component positions were appropriate, with no changes in component positions from immediately post-operative to final follow-up, but with MA change from varus 2.9° to 3.7° (p = 0.020). Two cases (5.4%) with history of previous infections developed periprosthetic joint infection (PJI). Debridement with polyethylene insert exchange following antibiotic suppression were performed in those cases because of concern for difficult implant-cement removal. The five and ten year survival rates were 100% and 93.2%, respectively., Conclusion: Fully cemented stems are viable in providing long-term satisfactory survival after re-revision TKA in patients with femoral diaphyseal deformation. However, it should be used carefully for those with previous infections., (© 2022. The Author(s) under exclusive licence to SICOT aisbl.)

Microbiome data have several specific characteristics (sparsity and compositionality) that introduce challenges in data analysis. The integration of prior information regarding the data structure, such as phylogenetic structure and repeated-measure study designs, into analysis, is an effective approach for revealing robust patterns in microbiome data. Past methods have addressed some but not all of these challenges and features: for example, robust principal-component analysis (RPCA) addresses sparsity and compositionality; compositional tensor factorization (CTF) addresses sparsity, compositionality, and repeated measure study designs; and UniFrac incorporates phylogenetic information. Here we introduce a strategy of incorporating phylogenetic information into RPCA and CTF. The resulting methods, phylo-RPCA, and phylo-CTF, provide substantial improvements over state-of-the-art methods in terms of discriminatory power of underlying clustering ranging from the mode of delivery to adult human lifestyle. We demonstrate quantitatively that the addition of phylogenetic information improves effect size and classification accuracy in both data-driven simulated data and real microbiome data. IMPORTANCE Microbiome data analysis can be difficult because of particular data features, some unavoidable and some due to technical limitations of DNA sequencing instruments. The first step in many analyses that ultimately reveals patterns of similarities and differences among sets of samples (e.g., separating samples from sick and healthy people or samples from seawater versus soil) is calculating the difference between each pair of samples. We introduce two new methods to calculate these differences that combine features of past methods, specifically being able to take into account the principles that most types of microbes are not in most samples (sparsity), that abundances are relative rather than absolute (compositionality), and that all microbes have a shared evolutionary history (phylogeny). We show using simulated and real data that our new methods provide improved classification accuracy of ordinal sample clusters and increased effect size between sample groups on beta-diversity distances.

Intra-articular injection of adipose-derived mesenchymal stem cell (ADMSC) after medial open-wedge high tibial osteotomy (MOWHTO) would be a promising disease-modifying treatment by correcting biomechanical and biochemical environment for arthritic knee with varus malalignment. However, there is a paucity of clinical evidence of the treatment. This randomized controlled trial (RCT) was aimed to assess regeneration of cartilage defect, functional improvement, and safety of intra-articular injection of ADMSCs after MOWHTO compared with MOWHTO alone for osteoarthritic knee with varus malalignment. This RCT allocated 26 patients into the MOWHTO with ADMSC-injection group (n = 13) and control (MOWHTO-alone) group (n = 13). The primary outcome was the serial changes of cartilage defect on periodic magnetic resonance imaging (MRI) evaluation using valid measurements until postoperative 24 months. Secondary outcomes were the 2-stage arthroscopic evaluation for macroscopic cartilage status and the postoperative functional improvements of patient-reported outcome measures until the latest follow-up. Furthermore, safety profiles after the treatment were evaluated. Cartilage regeneration on serial MRIs showed significantly better in the ADMSC group than in the control group. The arthroscopic assessment revealed that total cartilage regeneration was significantly better in the ADMSC group. Although it was not significant, functional improvements after the treatment showed a tendency to be greater in the ADMSC group than in the control group from 18 months after the treatment. No treatment-related adverse events, serious adverse events, and postoperative complications occurred in all cases. Concomitant intra-articular injection of ADMSCs with MOWHTO had advantages over MOWHTO alone in terms of cartilage regeneration with safety at 2-year follow-up, suggesting potential disease-modifying treatment for knee OA with varus malalignment., (© The Author(s) 2022. Published by Oxford University Press.)

Scabertopin (SCP), an abundant germacrane-type sesquiterpene lactone (SLC) isolated from Elephantopus scaber, was selected as a reference compound for modification and evaluation as anticancer agents for non-small cell lung cancer (NSCLC) treatment. All derivatives (SCP-1-SCP-13) except for SCP-3 showed potential inhibitory effect (IC 50 5.2-9.7 μM) against A549 cells. The most promising compound SCP-7 also showed good cytotoxic activity against another two NSCLC cell lines (H1299 and H460), with IC 50 value of 4.4 and 8.9 μM, respectively. Furthermore, SCP-7 could induce apoptotic cell death that was associated with the increased reactive oxygen species (ROS) generation, the loss of mitochondrial membrane potential, Bcl-2 family proteins modulation, caspases-3 and PARP cleavage. In addition, SCP-7 also inhibited cell growth by increasing Bax expression and reducing the Ki-67 positive cells in vivo, but there were no obvious toxic and side effects on internal organs. Mechanistically, PharmMapper, molecular docking and Western blot analysis revealed that SCP-7 might interact with the epidermal growth factor receptor (EGFR) and inhibit its expression in lung cancer cells. Together, above results suggest further effective application of SCP-7 as a potential anti-tumor agent in the treatment of NSCLC., (Copyright © 2022. Published by Elsevier B.V.)

Assisted by an MS/MS-based molecular networking guided strategy, six undescribed germacrane-type sesquiterpene lactones, namely scaberxones A-F, along with a known analog were obtained and characterized from Elephantopus scaber L. Their structures were unequivocally assigned by detailed spectroscopic analyses, NMR and ECD spectral calculations, and computer-assisted structure elucidation (CASE), complemented with single-crystal X-ray diffraction. All compounds were measured for their production of nitric oxide (NO) levels in lipopolysaccharide (LPS)-induced BV-2 microglial cells to assess their anti-neuroinflammatory activity. Scaberxone F showed the most potent inhibition of NO production at a concentration of 10 μM., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

A molecular networking-guided study on the Daphne genkwa Sieb. et Zucc led to the isolation of twelve daphnane-type diterpenoids including four undescribed compounds, yuanhuakines A-D. Their structures were elucidated by spectroscopic analyses, ECD calculations, and single-crystal X-ray diffraction analysis. All isolates were evaluated for their inhibitory activity against the A549, Hep3B, and MCF-7 cell lines. The majority of compounds inhibited A549 cells with IC 50 values ranging from 7.77 to 20.56 μM, and their structure-activity relationship is preliminarily discussed. Five of these compounds were selected for further experiments, and they appear to inhibit A549 cell lines by inducing apoptosis., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: To compare unilateral versus bilateral antegrade cerebral perfusion (ACP) techniques on cerebral protection during acute type A aortic dissection repair., Methods: Using an institutional database, we retrospectively reviewed patients who underwent acute type A aortic dissection repair with selective ACP techniques from October 2008 to December 2019. Primary end point was the detection of neurologic dysfunctions. The secondary end point was mortality. For baseline adjustment, the propensity score matching method was used. Multivariable logistic regression analysis was performed to determine the predictor of neurologic events., Results: Among 522 patients (aged 62.0 ± 14.9 years; 45.7% women), unilateral and bilateral ACP techniques were used in 357 (64.7%) and 165 (35.3%) patients, respectively. Transient (19.6% vs 21.2%; P  = .65) and permanent (7.0% vs 10.3%; P  = .70) neurologic dysfunction rates were not significantly different in patients with unilateral versus bilateral ACP, respectively. Observed mortality rate was higher in the patients with bilateral ACP (hazard ratio, 2.05; 95% CI, 1.33-3.14; P  = .001). Propensity-score matching yielded 94 pairs of patients. In matched analysis, bilateral ACP did not significantly lower the risks for transient (odds ratio, 0.87; 95% CI, 0.42-1.81; P  = .71) and permanent (odds ratio, 1.42; 95% CI, 0.55-3.85; P  = .47) neurologic dysfunction or death (hazard ratio, 1.65; 95% CI, 0.87-3.15; P  = .13). In the multivariable analysis, the ACP technique was not significantly associated with perioperative neurologic deficit., Conclusions: Despite additional supply, the patients undergoing bilateral ACP during acute type A aortic dissection repair did not have superior outcomes in neurologic and death events compared with the patients undergoing unilateral ACP., (© 2022 The Author(s).)

Plants have long been considered a cost-effective platform for recombinant production. A recently recognized additional advantage includes the low risk of contamination of human pathogens, such as viruses and bacterial endotoxins. Indeed, a great advance has been made in developing plants as a "factory" to produce recombinant proteins to use for biopharmaceutical purposes. However, there is still a need to develop new tools for recombinant protein production in plants. In this study, we provide data showing that the B1 domain of Streptococcal protein G (GB1) can be a multi-functional domain of recombinant proteins in plants. N-terminal fusion of the GB1 domain increased the expression level of various target proteins ranging from 1.3- to 3.1-fold at the protein level depending on the target proteins. GB1 fusion led to the stabilization of the fusion proteins. Furthermore, the direct detection of GB1-fusion proteins by the secondary anti-IgG antibody eliminated the use of the primary antibody for western blot analysis. Based on these data, we propose that the small GB1 domain can be used as a versatile tag for recombinant protein production in plants., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Song, Diao, Moon, Yun and Hwang.)

Preterm infants are at a greater risk for the development of asthma and atopic disease, which can lead to lifelong negative health consequences. This may be due, in part, to alterations that occur in the gut microbiome and metabolome during their stay in the Neonatal Intensive Care Unit (NICU). To explore the differential roles of family history (i.e., predisposition due to maternal asthma diagnosis) and hospital-related environmental and clinical factors that alter microbial exposures early in life, we considered a unique cohort of preterm infants born ≤ 34 weeks gestational age from two local level III NICUs, as part of the MAP (Microbiome, Atopic disease, and Prematurity) Study. From MAP participants, we chose a sub-cohort of infants whose mothers had a history of asthma and matched gestational age and sex to infants of mothers without a history of asthma diagnosis (control). We performed a prospective, paired metagenomic and metabolomic analysis of stool and milk feed samples collected at birth, 2 weeks, and 6 weeks postnatal age. Although there were clinical factors associated with shifts in the diversity and composition of stool-associated bacterial communities, maternal asthma diagnosis did not play an observable role in shaping the infant gut microbiome during the study period. There were significant differences, however, in the metabolite profile between the maternal asthma and control groups at 6 weeks postnatal age. The most notable changes occurred in the linoleic acid spectral network, which plays a role in inflammatory and immune pathways, suggesting early metabolomic changes in the gut of preterm infants born to mothers with a history of asthma. Our pilot study suggests that a history of maternal asthma alters a preterm infants' metabolomic pathways in the gut, as early as the first 6 weeks of life., (© 2022. The Author(s).)

Background: Although total knee arthroplasty (TKA) in hemophilic arthropathy (HA) or rheumatoid arthritis (RA) can improve functional ability, the postoperative range of motion (ROM) and prosthesis durability are reduced compared with those in osteoarthritic patients., Aim: We aimed to compare (1) the pre- and postoperative flexion contracture after TKA in HA and RA, (2) the threshold of preoperative flexion contracture as a predictor of residual contracture > 15° after TKA, and (3) the survival rate., Methods: Data from a consecutive cohort comprising 48 TKAs in HA and 92 TKAs in RA were retrospectively reviewed. The degree of flexion contracture was analyzed. Through receiver operating characteristics analysis, we aimed to determine the cutoff value of preoperative flexion contracture that increases the risk of residual contracture > 15° after TKA and compare the cutoff value in HA and RA. The survival rate was evaluated based on life table analysis and the Kaplan-Meier method., Results: The degree of preoperative flexion contracture was not significantly different. The degree of postoperative residual flexion contracture was 5.6° in the HA group and 1.4° in the RA group, respectively (p < 0.001). The cutoff value of preoperative flexion contracture for residual contracture of > 15° at last-follow up was 25.0° in the HA group and 32.5° in the RA group. The 5- and 12-year survival rates were 96% and 87% in the HA and 99% and 95% in the RA group, respectively (n.s.)., Conclusions: The postoperative residual flexion contracture was greater and the cutoff value of preoperative flexion contracture for residual contracture was smaller in the HA group than the RA group. Appropriate intra- and postoperative care to avoid postoperative residual contracture is required in HA patients., Level of Evidence: III., (© 2022. The Author(s).)

Background and Objective: Age-related macular degeneration (AMD) is one of the most common diseases that can lead to blindness worldwide. Recently, various fundus image analyzing studies are done using deep learning methods to classify fundus images to aid diagnosis and monitor AMD disease progression. But until now, to the best of our knowledge, no attempt was made to generate future synthesized fundus images that can predict AMD progression. In this paper, we developed a deep learning model using fundus images for AMD patients with different time elapses to generate synthetic future fundus images., Method: We exploit generative adversarial networks (GANs) with additional drusen masks to maintain the pathological information. The dataset included 8196 fundus images from 1263 AMD patients. A proposed GAN-based model, called Multi-Modal GAN (MuMo-GAN), was trained to generate synthetic predicted-future fundus images., Results: The proposed deep learning model indicates that the additional drusen masks can help to learn the AMD progression. Our model can generate future fundus images with appropriate pathological features. The drusen development over time is depicted well. Both qualitative and quantitative experiments show that our model is more efficient to monitor the AMD disease as compared to other studies., Conclusion: This study could help individualized risk prediction for AMD patients. Compared to existing methods, the experimental results show a significant improvement in terms of tracking the AMD stage in both image-level and pixel-level., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2022. Published by Elsevier B.V.)

Four undescribed sesquiterpenes (1-4) and 20 known sesquiterpenes (5-24) were obtained from the fruits of Litsea lancilimba Merr. by Small Molecule Accurate Recognition Technology (SMART). The gross structures and the relative configurations of the new compounds were deduced by spectroscopic data analysis. The absolute configurations were defined by comparison of their experimental and calculated electronic circular dichroism (ECD) spectra data. All compounds were screened for their neuroprotective effects against H 2 O 2 -induced SH-SY5Y cells injury. Compounds 2, 3, 7, 8 and 13 exhibited comparable neuroprotective activity to the positive trolox at 50 μM., (Copyright © 2022. Published by Elsevier B.V.)

Although oxaliplatin-based chemotherapy is the current standard adjuvant therapy for colorectal cancer (CRC), the molecular mechanisms underlying oxaliplatin resistance remain unclear. Here, we examined the molecular mechanisms underlying SLC22A18-associated oxaliplatin resistance and strategies for overcoming oxaliplatin resistance. We evaluated the association between SLC22A18 and prognosis in 337 patients with CRC and its functional significance and studied the mechanisms through which SLC22A18 affects oxaliplatin resistance development in CRC cells, using CRC cell lines and patient-derived cells (PDCs). SLC22A18 downregulation was positively correlated with worse survival in patients with CRC. Low SLC22A18-expressing cells showed relatively lower sensitivity to oxaliplatin than high SLC22A18-expressing cells. In addition, ERK activation was found to be involved in the mechanisms underlying SLC22A18-related oxaliplatin resistance. To confirm ERK pathway dependence, we used an ERK inhibitor and found that combined treatment with oxaliplatin and the ERK inhibitor overcame oxaliplatin resistance in the low SLC22A18-expressing cells. Ex vivo approaches using PDC confirmed the correlation between SLC22A18 expression and oxaliplatin resistance. Results of the in vivo study showed that SLC22A18 expression regulated oxaliplatin efficacy, and that combined treatment with an ERK inhibitor could be a useful therapeutic strategy when SLC22A18 is downregulated. Together, our findings indicate that SLC22A18 could serve as a biomarker for the prediction of oxaliplatin resistance. In cases of oxaliplatin resistance due to low SLC22A18 expression, resistance can be overcome by combined treatment with an ERK inhibitor., Competing Interests: None., (AJCR Copyright © 2022.)

Background: The treatment approach for proximal humeral fractures is determined by various factors, including patient age, sex, dominant arm, fracture pattern, presence of osteoporosis, preexisting arthritis, rotator cuff status, and medical comorbidities. However, there is a lack of consensus in the literature regarding the optimal treatment for displaced proximal humeral fractures. This study aimed to assess and quantify the decision-making process for either conservative or surgical treatment and the choice of surgical method among shoulder surgeons when treating proximal humeral fractures., Methods: Forty sets of true anteroposterior view, scapular Y projection view, and three-dimensional computed tomography of proximal humeral fractures were provided to 12 shoulder surgeons along with clinical information. Surveys regarding Neer classification, decisions between conservative and surgical treatments, and chosen methods were conducted twice with an interval of 2 months. The factors affecting the treatment plans were also assessed., Results: The inter-rater agreement was fair for Neer classification (kappa=0.395), moderate for the decision between conservative and surgical treatments (kappa=0.528), and substantial for the chosen method of surgical treatment (kappa=0.740). The percentage of agreement was 71.1% for Neer classification, 84.6% for the decision between conservative and surgical treatment, and 96.4% for the chosen method of surgical treatment. The fracture pattern was the most crucial factor in deciding between conservative and surgical treatments, followed by age and physical activity., Conclusions: The decision between conservative and surgical treatment for proximal humeral fractures showed good agreement, while the chosen method between osteosynthesis and arthroplasty showed substantial agreement among shoulder surgeons.

Recent literature has implicated a thick cobalt chromium baseplate as a potential source of stress shielding and medial tibial bone resorption after total knee arthroplasty (TKA) in a Western population. The purpose was to calculate the incidence of various types and severity of medial tibial bone resorption utilizing a novel classification system after TKA with a thick cobalt chromium baseplate in Asian patients. Five hundred TKAs using Attune prostheses with mean follow-up of 3.4 years were evaluated, using the prospective radiographic data. The mean age was 71.3 years. The preoperative mechanical axis was varus, 11.2 degrees. The type and severity of medial tibial bone resorption were categorized as type U (resorption under the tibial baseplate up to 50% [U1] or beyond 50% [U2] of medial tibial tray width), C (resorption around the penetrated cement under the baseplate), and M (resorption on the medial tibial cortex without extension to the baseplate). Bone resorption of medial proximal tibia was observed in 96 knees (19.2%). Types U1 and U2 were seen in 46 and 28 knees, respectively. Type C was observed in 12 knees and type M in 10 knees. The type U resorption group had significantly more preoperative varus deformity (varus 12.9 vs. 10.9 degrees, p  = 0.017). Medial tibial bone resorption after TKAs using a thick cobalt chromium baseplate is not uncommon and has various locations, types, and severities. The medial tibial bone resorption might be related to various causes, including stress shielding, thermal necrosis from cement in the bony hole, and bony devascularization. The type-U resorption has to be closely observed in patients with preoperative severe varus deformity. This is a Level IV study., Competing Interests: None declared., (Thieme. All rights reserved.)

Cumulative evidence indicates that mitochondria dysfunction plays an important role in tumour treatment. Given the limited efficacy and toxicity of current mitochondria-targeted drugs, research into effective mitochondria-targeted anticancer agents remains an irresistible general trend. In this study, it was found that dehydrocrenatidine (DEC), a β-carbolin alkaloid isolated from Picrasma quassiodes, displays a promising growth inhibitory effect in vitro and in vivo by inducing apoptosis of hepatocellular carcinoma (HCC) cells. Mechanistically, we provided that the possible target of DEC against HCC cells was determined by isobaric labels for relative and absolute quantification assay and validated them using further experiments. The results suggested that DEC can target and regulate the function of mitochondrial complexes I, III and IV, affecting oxidative phosphorylation and ultimately leading to mitochondrial dysfunction to exert its anti-HCC effects. In addition, the combination of DEC and sorafenib showed a synergistic effect and was also associated with mitochondrial dysfunction. Importantly, DEC did not show significant toxicity in mice. This study provided a new insight into underlying mechanisms in DEC-treated HCC cells, suggesting that DEC might be a mitochondrial targeting lead compound., (© 2022 John Wiley & Sons Ltd.)

Purpose: To compare long-term clinical and radiographic results and survival rates between hybrid and cemented total knee arthroplasties (TKAs) performed on paired knees., Methods: Seventy-two patients with hybrid and cemented TKAs performed on paired knees with NexGen® cruciate-retaining prostheses were retrospectively reviewed after a minimum 15 years of follow-up. Mean follow-up period was 17.5 years. Preoperative alignment deformity and range of motion (ROM) were not different between groups. The Knee Society score, Western Ontario and McMaster Universities Osteoarthritis Index, and ROM were evaluated. Radiographically, change in joint space width, component loosening, and osteolysis were evaluated. Implant survival rate was analyzed., Results: There were no significant differences in clinical results between hybrid and cemented TKAs performed on paired knees of 72 patients at the last follow-up. No significant difference was observed in the change in joint space width between the two groups at the last follow-up (medial = 0.3 mm vs. 0.4 mm; lateral = 0.1 mm vs. 0.2 mm). One hybrid TKA showed tibial component loosening, for which revision was performed. There was femoral osteolysis in one hybrid and one cemented TKA, and tibial osteolysis in eight hybrid TKAs and seven cemented TKAs (n.s., respectively). The 20-year survival rate was 97.7% for hybrid TKAs and 100% for cemented TKAs (n.s.)., Conclusion: The long-term outcomes were similar between hybrid and cemented TKAs performed on paired knees at a minimum 15 years of follow-up. The method of femoral component fixation did not have a significant effect on long-term TKA success., Level of Evidence: III., (© 2021. European Society of Sports Traumatology, Knee Surgery, Arthroscopy (ESSKA).)

Two series of germacrane-type sesquiterpene lactones were produced by semisynthetic modulation of scaberol C, which was prepared by a standard chemical transformation from an Elephantopus scaber extract. Their inhibition activities against non-small-cell lung cancer cells were screened, and preliminary structure-activity relationships were also established. Among them, monomeric analog 1u and dimeric analog 3d exhibited superior anti-non-small-cell lung cancer cytotoxic potencies with IC 50 values of 4.3 and 0.7 μM against A549 cells, respectively, and were more active than cisplatin and the standard sesquiterpene lactones, parthenolide and scabertopin. Further studies revealed that compounds 1u and 3d cause G2/M phase arrest and induce apoptosis through the activation of mitochondrial pathways in A549 cells. Collectively, the results obtained suggest that compounds 1u and 3d are promising anti-non-small-cell lung cancer lead compounds.

The CLP (containment liner plate) of a nuclear power plant protects the internal system from the external environment and sudden changes in internal pressure or temperature, and it is a structure that blocks and protects radioactive materials leaking inside and outside in the event of a nuclear accident and is composed of a liner plate, reinforcing bars, tendons, and concrete. Recently, corrosion on the rear side of the liner plate and concrete voids has emerged as a severe defect in nuclear power plants across South Korea. Therefore, in this study, we proposed a new inspection method that a line-type inspection method applied phased array ultrasonic testing and the area inspection method applied acoustic resonance method using developed moveable tapper. The acoustic signals were signal-processed and reproduced to a mapping image following the inspection area, and with the image, it was possible to determine the type of defect. Furthermore, an automated inspection system for within the CLP was proposed.

Background: Individual diet components and specific dietary regimens have been shown to impact the gut microbiome., Objectives: Here, we explored the contribution of long-term diet by searching for dietary patterns that would best associate with the gut microbiome in a population-based cohort., Methods: Using a priori and a posteriori approaches, we constructed dietary patterns from an FFQ completed by 1800 adults in the American Gut Project. Dietary patterns were defined as groups of participants or combinations of food variables (factors) driven by criteria ranging from individual nutrients to overall diet. We associated these patterns with 16S ribosomal RNA-based gut microbiome data for a subset of 744 participants., Results: Compared to individual features (e.g., fiber and protein), or to factors representing a reduced number of dietary features, 5 a posteriori dietary patterns based on food groups were best associated with gut microbiome beta diversity (P ≤ 0.0002). Two patterns followed Prudent-like diets-Plant-Based and Flexitarian-and exhibited the highest Healthy Eating Index 2010 (HEI-2010) scores. Two other patterns presented Western-like diets with a gradient in HEI-2010 scores. A fifth pattern consisted mostly of participants following an Exclusion diet (e.g., low carbohydrate). Notably, gut microbiome alpha diversity was significantly lower in the most Western pattern compared to the Flexitarian pattern (P ≤ 0.009), and the Exclusion diet pattern was associated with low relative abundance of Bifidobacterium (P ≤ 1.2 × 10-7), which was better explained by diet than health status., Conclusions: We demonstrated that global-diet a posteriori patterns were more associated with gut microbiome variations than individual dietary features among adults in the United States. These results confirm that evaluating diet as a whole is important when studying the gut microbiome. It will also facilitate the design of more personalized dietary strategies in general populations., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Hepatocellular carcinoma (HCC), the most prevalent liver cancer, is considered one of the most lethal malignancies with a dismal outcome. There is an urgent need to find novel therapeutic approaches to treat HCC. At present, natural products have served as a valuable source for drug discovery. Here, we obtained five known biflavones from the root of Stellera chamaejasme and evaluated their activities against HCC Hep3B cells in vitro. Chamaejasmenin E (CE) exhibited the strongest inhibitory effect among these biflavones. Furthermore, we found that CE could suppress the cell proliferation and colony formation, as well as the migration ability of HCC cells, but there was no significant toxicity on normal liver cells. Additionally, CE induced mitochondrial dysfunction and oxidative stress, eventually leading to cellular apoptosis. Mechanistically, the potential target of CE was predicted by database screening, showing that the compound might exert an inhibitory effect by targeting at c-Met. Next, this result was confirmed by molecular docking, cellular thermal shift assay (CETSA), as well as RT-PCR and Western blot analysis. Meanwhile, CE also reduced the downstream proteins of c-Met in HCC cells. In concordance with above results, CE is efficacious and non-toxic in tumor xenograft model. Taken together, our findings revealed an underlying tumor-suppressive mechanism of CE, which provided a foundation for identifying the target of biflavones., (Copyright © 2021. Published by Elsevier Inc.)

Demyelination is a critical neurological disease, and there is still a lack of effective treatment methods. In the past two decades, stem cells have emerged as a novel therapeutic effector for neural regeneration. However, owing to the existence of the blood-brain barrier (BBB) and the complex microenvironment, targeted therapy still faces multiple challenges. Targeted exosome carriers for drug delivery may be considered a promising therapeutic method. Exosomes were isolated from mice neural stem cells. To develop targeting exosomes, we generated a lentivirus armed PDGFR α ligand that could anchor the membrane. Exosome targeting tests were carried out in vitro and in vivo. The modified exosomes showed an apparent ability to target OPCs in the lesion area. Next, the exosomes were loaded with Bryostatin-1 (Bryo), and the cuprizone-fed mice were administered with the targeting exosomes. The data show that Bryo exhibits a powerful therapeutic effect compared with Bryo alone after exosome encapsulation. Specifically, this novel exosome-based targeting delivery of Bryo significantly improves the protection ability of the myelin sheath and promotes remyelination. Moreover, it blocks astrogliosis and axon damage, and also has an inhibitory effect on pro-inflammatory microglia. The results of this investigation provide a straightforward strategy to produce targeting exosomes and indicate a potential therapeutic approach for demyelinating disease.

UV-guided fractionation led to the isolation of thirteen new polyacetylenes (1-13) from the roots of Bupleurum scorzonerifolium Willd. All polyacetylenes were analyzed as racemates since the lack of optical activity and Cotton effects in the ECD spectra. The sequent chiral-phase HPLC resolution successfully gave twelve pairs of enantiomers 1a/1b and 3a/3b-13a/13b. Their structures were elucidated based on the HRESIMS and NMR data analyses. The absolute configurations were determined by the combination of Snatzke's method, electronic circular dichroism calculations, and single-crystal X-ray diffraction. Using Griess methods and MTT assays, polyacetylenes 1a, 3a, 4a/4b-12a/12b, and 13a displayed inhibitory activities against LPS-induced NO release in BV-2 microglial cells., (Copyright © 2021. Published by Elsevier Inc.)

The aristolochic acids (AAs), derived from Aristolochia and Asarum species used widely in herbal medicines, are closely associated with liver cancer. The major AA derivatives are aristolochic acid I (AAI) and II (AAII), which can bind DNA covalently to form AA-DNA adducts after metabolic activation in vivo. Among all these AA-DNA adducts, 7-(deoxyadenosine-N 6 -yl) aristolactam I (dA-AL-I) is the most abundant and persistent DNA lesion in patients. However, the direct evidence indicating AA exposure in human liver cancer is still missing. Here, we analyzed dA-AL-I adduct, the direct biomarker of AAI exposure, by ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometry (UPLC-TQ/MS) in 209 liver cancer patients. Also, DNA samples from mice treated with/without AAI were used as positive and negative controls. dA-AL-I adduct was present in 110 of 209 (52.6%) patients, indicating that these patients were exposed to AAI prior to their clinical investigations and also had a worse prognosis. The relative high AA exposure rate and worse prognosis in our cohort of patients emphasize the significance to increase public awareness to avoid the use of herbal medicine containing AAs or their derivatives., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

We report synthesis, crystal structure, and physical properties of Sr2Cr2AsO3. The new compound crystallizes in a Sr2GaO3CuS-type structure with two distinct Cr sites, Cr(1) in the perovskite-like block layers of "Sr3Cr2O6" and Cr(2) in the ThCr2Si2-type layers of "SrCr2As2". An inter-block-layer charge transfer is explicitly evidenced, which dopes electrons in the CrO2 planes and simultaneously dopes holes into the CrAs layers. Measurements of electrical resistivity, magnetization, and specific heat, in combination with density-functional theoretical calculations, indicate that the title material is an antiferromagnetic metal. The Cr(2) magnetic moments in the CrAs layers order at 420 K, while the Cr(1) spins in the CrO2 planes show quasi-two-dimensional magnetism with long-range ordering below 80 K. Both Néel temperatures are significantly reduced, compared with those of the cousin material Sr2Cr3As2O2, probably due to the intrinsic charge-carrier doping. Complex re-entrant magnetic transitions with a huge magnetic hysteresis were observed at low temperatures., Competing Interests: The authors declare no conflicts of interest.

Objective: To evaluate the concentration of cytokines in the aqueous humor of neovascular glaucoma (NVG) patients at the angle-closure stage in different treatment periods and its relationship with recurrence. Methods: A prospective case-control study. Angle-closure stage NVG patients who came to Peking University Third Hospital from September 2018 to September 2019 were enrolled and followed-up for at least 12 months. Patients received triple sequential therapy, including anti-vascular endothelium growth factor (VEGF) injection, trabeculectomy, and panretinal photocoagulation. The aqueous humor before anti-VEGF treatment, before trabeculectomy, and during recurrence was collected. Multiplex bead immunoassay was applied to measure the concentration of 45 cytokines including VEGF, interleukin (IL), and chemokine. The relevant data were compared with the values of 25 proliferative diabetic retinopathy (PDR) patients and 24 age-related cataract patients undergoing phacoemulsification as controls. The concentration of cytokines was presented as M ( Q 1 , Q 3 ). The nonparametric Kruskal-Wallis H test was applied to compare the cytokine concentration between the NVG group and controls. The difference between the recurrence and non-recurrence groups was compared with the Mann-Whitney U test. Results: The average age of NVG patients was (60±11) years, and there were 22 males and 10 females. No significant differences were found in age and gender between the NVG group and the two control groups (both P >0.05). The median concentrations of VEGF in the NVG group before anti-VEGF treatment, before trabeculectomy, and after recurrence were 2 151.3 (1 433.1, 4 280.0) ng/L, 655.4 (287.3, 836.3) ng/L and 2 003.4 (1 603.1, 2 468.9) ng/L respectively. The concentrations of VEGF before anti-VEGF treatment and after recurrence in the NVG group were significantly higher than the PDR group [453.8 (189.9, 595.8) ng/L] and the cataract group [143.5 (112.7, 269.8) ng/L] (all P <0.05). The median concentration of programmed cell death protein ligand 1 (PD-L1) was 38.9 (22.4, 50.6) ng/L before anti-VEGF treatment, higher than that in the PDR group [12.0 (6.3, 20.1) ng/L] and the cataract group [14.6 (11.4, 19.3) ng/L]. The median concentration of fractalkine was 242.7 (189.0, 306.7) ng/L, higher than that in the PDR group [131.1 (119.1, 157.6) ng/L] and the cataract group [116.7 (10.2, 135.9) ng/L]. The median concentration of IL-7 was 18.0 (12.0, 32.7) ng/L, higher than that in the PDR group [7.7 (2.0, 10.8) ng/L] and the cataract group [3.3 (1.9, 6.8) ng/L]. The median concentration of eotaxin was 84.0 (52.4, 122.7) ng/L, higher than that in the PDR group [26.6 (17.1, 72.3) ng/L] and the cataract group [7.1 (5.6, 14.8) ng/L]. The median concentration of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was 3.6 (2.8, 6.4) ng/L, higher than that in the cataract group [1.1 (0.3, 2.3) ng/L]. All the differences were statistically significant (all P <0.05). There were no significant differences between the NVG and control groups in other cytokines or other treatment periods (all P >0.05). Six NVG patients suffered recurrence during the follow-up. The baseline concentration of IL-7 of these patients [10.5 (8.4, 16.0) ng/L] was significantly lower than that in patients who did not have recurred disease [22.7 (15.7, 34.1) ng/L] ( Z =-2.74, P <0.01). Conclusions: In the angle-closure stage of NVG patients, the concentrations of VEGF, PD-L1, fractalkine, IL-7, eotaxin, and TRAIL in the aqueous humor significantly increase during the onset of disease. Lower IL-7 may indicate a recurring tendency.

Self-assembled peptide nanostructures recently have gained much attention as drug delivery systems. As biomolecules, peptides have enhanced biocompatibility and biodegradability compared to polymer-based carriers. We introduce a peptide nanoparticle system containing arginine, histidine, and an enzyme-responsive core of repeating GLFG oligopeptides. GLFG oligopeptides exhibit specific sensitivity towards the enzyme cathepsin B that helps effective controlled release of cargo molecules in the cytoplasm. Arginine can induce cell penetration, and histidine facilitates lysosomal escape by its buffering capacity. Herein, we propose an enzyme-responsive amphiphilic peptide delivery system (Arg-His-(Gly-Phe-Lue-Gly) 3 , RH-(GFLG) 3 ). The self-assembled RH-(GFLG) 3 globular nanoparticle structure exhibited a positive charge and formulation stability for 35 days. Nile Red-tagged RH-(GFLG) 3 nanoparticles showed good cellular uptake compared to the non-enzyme-responsive control groups with d-form peptides (LD ( L RH- D (GFLG) 3 ), DL ( D RH-L(GFLG) 3 ), and DD ( D RH- D (GFLG) 3 ). The RH-(GFLG) 3 nanoparticles showed negligible cytotoxicity in HeLa cells and human RBCs. To determine the drug delivery efficacy, we introduced the anticancer drug doxorubicin (Dox) in the RH-(GFLG) 3 nanoparticle system. LL-Dox exhibited formulation stability, maintaining the physical properties of the nanostructure, as well as a robust anticancer effect in HeLa cells compared to DD-Dox. These results indicate that the enzyme-sensitive RH-(GFLG) 3 peptide nanoparticles are promising candidates as drug delivery carriers for biomedical applications.

Viral diseases are extremely widespread infections that change constantly through mutations. To produce vaccines against viral diseases, transient expression systems are employed, and Nicotiana benthamiana (tobacco) plants are a rapidly expanding platform. In this study, we developed a recombinant protein vaccine targeting the major capsid protein (MCP) of iridovirus fused with the lysine motif (LysM) and coiled-coil domain of coronin 1 (ccCor1) for surface display using Lactococcus lactis . The protein was abundantly produced in N. benthamiana in its N -glycosylated form. Total soluble proteins isolated from infiltrated N. benthamiana leaves were treated sequentially with increasing ammonium sulfate solution, and recombinant MCP mainly precipitated at 40-60%. Additionally, affinity chromatography using Ni-NTA resin was applied for further purification. Native structure analysis using size exclusion chromatography showed that recombinant MCP existed in a large oligomeric form. A minimum OD 600 value of 0.4 trichloroacetic acid (TCA)-treated L. lactis was required for efficient recombinant MCP display. Immunogenicity of recombinant MCP was assessed in a mouse model through enzyme-linked immunosorbent assay (ELISA) with serum-injected recombinant MCP-displaying L. lactis . In summary, we developed a plant-based recombinant vaccine production system combined with surface display on L. lactis ., Competing Interests: Conflict of interestThe authors have no competing interests to declare., (© Korean Society of Plant Biologist 2021.)

Alveolar ridge preservation (ARP) is indicated to attenuate anatomic and physiologic changes following tooth extraction. A properly contoured ovate pontic placed immediately into an extraction socket may be adequate to maintain alveolar ridge architecture for improved esthetic results. This prospective clinical study evaluated the ability of immediately placed ovate pontics in conjunction with ARP to attenuate postextraction tissue dimensional changes in the esthetic zone and maintain alveolar ridge contour. Ten patients (11 sites) completed the study. All subjects received a combination of socket grafting with allogeneic particulate graft material and socket sealing with an ovate pontic provisional restoration. A set of clinical linear and volumetric outcomes were assessed after a 6-month healing period. At 6 months postoperative, the linear measurements for the mean ridge dimensional loss were 0.9 ± 0.6 mm (range: 0.2 to 1.8 mm) in height and 1.4 ± 0.6 mm (range: 0.1 to 2.4 mm) in width. The mean volumetric tissue loss observed was 24.4 ± 15.4 mm 3 (range: 2.6 to 50.1 mm 3 ) at 3 months postoperative and 32.2 ± 14.2 mm 3 (range: 3.8 to 50.5 mm 3 ) at 6 months postoperative. Resorption pattern assessment showed the overall cervical area to have less resorption than the apical areas at 6 months postoperative, with the least amount of resorption in the midbuccal cervical section. When compared to the data of a previous pilot study, no statistically significant difference was seen between the dimensional losses when using ovate pontics with and without ARP. This may be evidence that the use of an ovate pontic provisional restoration immediately after extraction effectively attenuates postextraction dimensional changes.

Particulate matter (PM) is an environmental hazard that is associated with various human health risks. The olfactory system is directly exposed to PM; therefore, the influence of PM exposure on olfactory function must be investigated. In this study, we propose a zebrafish olfactory model to evaluate the effects of exposure to diesel particulate matter (DPM), which was labeled Korean diesel particulate matter (KDP20). KDP20 comprises heavy metals and polycyclic aromatic hydrocarbons (PAHs). KDP20 exposed olfactory organs exhibited reduced cilia and damaged epithelium. Olfactory dysfunction was confirmed using an odor-mediated behavior test. Furthermore, the olfactory damage was analyzed using Alcian blue and anti-calretinin staining. KDP20 exposed olfactory organs exhibited histological damages, such as increased goblet cells, decreased cell density, and calretinin level. Quantitative real-time polymerase chain reaction (qRT-PCR) revealed that PAHs exposure related genes ( AHR2 and CYP1A ) were upregulated. Reactive oxidation stress (ROS) ( CAT ) and inflammation ( IL-1B ) related genes were upregulated. Furthermore, olfactory sensory neuron (OSN) related genes ( OMP and S100 ) were downregulated. In conclusion, KDP20 exposure induced dysfunction of the olfactory system. Additionally, the zebrafish olfactory system exhibited a regenerative capacity with recovery conditions. Thus, this model may be used in future investigating PM-related diseases.

Accelerated glycolysis is the main metabolic change observed in cancer, but the underlying molecular mechanisms and their role in cancer progression remain poorly understood. Here, we show that the deletion of the long noncoding RNA (lncRNA) Neat1 in MMTV-PyVT mice profoundly impairs tumor initiation, growth, and metastasis, specifically switching off the penultimate step of glycolysis. Mechanistically, NEAT1 directly binds and forms a scaffold bridge for the assembly of PGK1/PGAM1/ENO1 complexes and thereby promotes substrate channeling for high and efficient glycolysis. Notably, NEAT1 is upregulated in cancer patients and correlates with high levels of these complexes, and genetic and pharmacological blockade of penultimate glycolysis ablates NEAT1-dependent tumorigenesis. Finally, we demonstrate that Pinin mediates glucose-stimulated nuclear export of NEAT1, through which it exerts isoform-specific and paraspeckle-independent functions. These findings establish a direct role for NEAT1 in regulating tumor metabolism, provide new insights into the Warburg effect, and identify potential targets for therapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: Most vulvar squamous cell carcinomas are human papillomavirus (HPV)-associated or TP53-mutant. A third category of HPV-independent TP53-wild-type lesions is uncommon and not fully understood. Differentiated exophytic vulvar intraepithelial lesion (DEVIL) has been characterised as a precursor of this latter category. The reproducibility of the diagnosis of DEVIL and its distinction from lesions with overlapping morphology has not been studied. Our aim was to establish the interobserver agreement in the diagnosis of DEVIL and its distinction from neoplastic and reactive conditions of the vulva on haematoxylin and eosin evaluation., Methods and Results: A set of 35 slides was evaluated by eight reviewers (two trainees and six practising gynaecological pathologists). The set included DEVIL, condyloma, established vulvar precursors [high-grade squamous intraepithelial lesion (HSIL) and differentiated vulvar intraepithelial neoplasia (dVIN)] with superimposed acanthosis or verruciform growth, lichen simplex chronicus (LSC), and psoriasis. Kappa (κ) values were calculated. Overall, interobserver agreement was moderate (κ = 0.56), improving to substantial (κ = 0.7) when evaluation was performed by practising pathologists. Agreement was strong for the diagnosis of HSIL (κ = 0.88), and substantial for the diagnosis of DEVIL (κ = 0.61), condyloma (κ = 0.79), and LSC (κ = 0.72). Agreement was moderate for the diagnosis of dVIN (κ = 0.59) and psoriasis (κ = 0.53). Perfect agreement (6/6) among practising pathologists was observed in 43% of cases, and majority agreement (5/6 or 4/6) was observed in 48% of cases., Conclusions: Reproducibility in the diagnosis of verruciform vulvar lesions, including the novel DEVIL, is acceptable overall. Reproducibility is higher for well-known lesions such as HSIL and condyloma than for more challenging diagnoses such as DEVIL, dVIN, and psoriasis. Agreement is higher among practising gynaecological pathologists, suggesting that training and experience improve reproducibility. Our findings support the inclusion of DEVIL as a diagnostic entity in the classification of vulvar squamous lesions., (© 2021 John Wiley & Sons Ltd.)

Background: Many surgeons have determined the surgical transepicondylar axis (sTEA) after distal femur resection in total knee arthroplasty (TKA). However, in most navigation systems, the registration of the sTEA precedes the distal femur resection. This sequential difference can influence the accuracy of intraoperative determination for sTEA when considering the proximal location of the anatomical references for sTEA and the arthritic environment. We compared the accuracy and precision in determinations of the sTEA between before and after distal femur resection during navigation-assisted TKA., Methods: Ninety TKAs with Attune posterior-stabilized prostheses were performed under imageless navigation. The sTEA was registered before distal femur resection, then reassessed and adjusted after distal resection. The femoral component was implanted finally according to the sTEA determined after distal femur resection. Computed tomography (CT) was performed postoperatively to analyze the true sTEA (the line connecting the tip of the lateral femoral epicondyle to the lowest point of the medial femoral epicondylar sulcus on axial CT images) and femoral component rotation (FCR) axis. The FCR angle after distal femur resection (FCRA-aR) was defined as the angle between the FCR axis and true sTEA on CT images. The FCR angle before distal resection (FCRA-bR) could be presumed to be the value of FCRA-aR minus the difference between the intraoperatively determined sTEAs before and after distal resection as indicated by the navigation system. It was considered that the FCRA-bR or FCRA-aR represented the differences between the sTEA determined before or after distal femur resection and the true sTEA, respectively., Results: The FCRA-bR was -1.3 ± 2.4° and FCRA-aR was 0.3 ± 1.7° (p < 0.001). The range of FCRA-bR was from -6.6° to 4.1° and that of FCRA-aR was from -2.7° to 3.3°. The proportion of appropriate FCRA (≤ ±3°) was significantly higher after distal femur resection than that before resection (91.1% versus 70%; p < 0.001)., Conclusions: The FCR was more appropriate when the sTEA was determined after distal femur resection than before resection in navigation-assisted TKA. The reassessment and adjusted registration of sTEA after distal femur resection could improve the rotational alignment of the femoral component in navigation-assisted TKA., Level of Evidence: IV., (© 2021. The Author(s).)

Daphnenoids A-C ( 1 - 3 ), three unusual sesquiterpenes with distinctive ring skeletons, together with a biogenetically related daphnenoid D ( 4 ) were obtained from the herb of Daphne penicillata by molecular networking strategies. Daphnenoid A ( 1 ) possesses a unique caged tetracyclo [5.3.2.0 1 , 6 .0 4 , 11 ] dodecane scaffold by unexpected cyclizations of C-1/C-11 and C-2/C-14. Daphnenoids B and C ( 2 and 3 ) were the first discovered natural sesquiterpenes with unique 5/5 spirocyclic systems in nature. Their structures were determined by NMR spectroscopic analysis, computer-assisted structure elucidation methods, quantum chemical calculations, and X-ray diffraction. A hypothetical biogenetic pathway begins with typical guaiane sesquiterpene ( a ), including a key intermediate ( 4 ) was proposed. Daphnenoids B and C ( 2 and 3 ) exhibited potential inhibitory activities on the production of NO against LPS-induced BV2 microglial cells.

Background: There is an unprecedented surge of forcibly displaced people globally, with a crisis of unaccompanied minors seeking haven across the US border., Aims: This paper aims to provide an understanding of the intersection between mental health and immigration policies., Method: Examples of contemporary policies that focus on the deterrence, detention and deportation of unaccompanied minors in the USA, will be discussed, as well as the mental health effects of such 'iron triangle' immigration policies., Results: In the ideal circumstances, systems and policies for migrant children would uphold international humanitarian law, hasten the shift from enforcement to protection, adhere to a 'do no (further) harm' model that uses a trauma-informed, culturally responsive approach to engaging with migrant children, engage the community as stakeholders to end detention and advocate to share the burden of responsibility., Conclusions: Building a humanitarian response that protects both country and migrant interest is possible through commitment and policy change that addresses mental, physical and legal protection needs.

Prenylated flavonoids, a unique class of flavonoids which combine a flavonoid skeleton and a lipophilic prenyl side-chain, possess great potential biological activities including cytotoxicity, anti-inflammation, anti-Alzheimer, anti-microbial, anti-oxidant, anti-diabetes, estrogenic, vasorelaxant and enzyme inhibition. Recently, prenylated flavonoids have become an indispensable anchor for the development of new therapeutic agents, and have received increasing from medicinal chemists. The prenylated flavonoids have been outstanding developed through isolation, semi or fully synthesis in a very short period of time, which proves the great value in medicinal chemistry researches. In this review, research progress of prenylated flavonoids including natural prenylated flavonoids, structural modification, synthetic methodologies and pharmacological activities was summarized comprehensively. Furthermore, the structure-activity relationships (SARs) of prenylated flavonoids were summarized which provided a basis for the selective design and optimization of multifunctional prenylated flavonoid derivatives for the treatment of multi-factorial diseases in clinic., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: This double-blind, randomized, Phase III clinical trial was conducted to assess the efficacy and safety of the novel divinyl sulfone cross-linked hyaluronate (YYD302) compared with the 1,4-butanediol diglycidyl ether cross-linked hyaluronate (Synovian) in patients with knee osteoarthritis., Methods: A total of 184 patients with osteoarthritis (Kellgren-Lawrence grade I-III) were randomized to 1 of 2 study groups (YYD302 group, n = 95; Synovian group, n = 89). A single injection of YYD302 or Synovian was given to both groups, and 182 participants completed the study (YYD302 group, n = 95; Synovian group, n = 87). The primary end point was the change in weight-bearing pain (WBP) at 12 weeks after the primary single injection. Secondary end points included the Knee Injury and Osteoarthritis Outcome Score; the Western Ontario and McMaster Universities Osteoarthritis Index score; the Patient Global Assessment and Investigator Global Assessment; the range of motion, swelling, and tenderness of the target knee; OMERACT-OARSI responder rate; WBP responder rate (the proportion of patients achieving at least 20 mm or 40% decrease in WBP); and rate of rescue medicine use and its total consumption at weeks 2, 4, and 12. Based on the efficacy results at week 12, the responders were administered an additional single injection of the same study drug at week 24, and safety and efficacy were additionally assessed at week 36., Findings: Mean changes of WBP at 12 weeks after the primary injection were -31.76 mm with YYD302 and -29.74 mm with Synovian, proving noninferiority of the YYD302 group to the Synovian group as the lower bound of the 95% CI (-4.3 to 8.3) was well above the predefined margin (-10 mm). At week 2, the Knee Injury and Osteoarthritis Outcome Score (total, pain, activities of daily living, and sports/recreation) and Western Ontario and McMaster Universities Osteoarthritis Index scores (total, stiffness) were significantly better in the YYD302 group than in the Synovian group. There were no significant differences between the groups in all other end points. Local overall adverse events (pain, heat, erythema, or swelling) at the injection site were observed in 48.4% of the YYD302 group and in 47.7% of the Synovian group. No serious reactions were reported. There was no statistically significant difference between the 2 groups regarding re-injected patients (YYD302 group, n = 54; Synovian group, n = 46) in any of the efficacy outcomes at week 36., Implications: The results of this study support that YYD302 is comparable to Synovian in terms of the efficacy and safety of the intra-articular injection treatment for osteoarthritis of the knee joint. Furthermore, YYD302 provided faster improvements in some efficacy assessments compared with Synovian. ClinicalTrials.gov identifier: NCT03561779., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Chemical investigations of the 75% EtOH extract from the fruits of Crataegus pinnatifida led to the isolation of three undescribed naturally occurring sesquineolignans with two 8- O -4'-type neolignan moieties, cratapinnatifidas A-C ( 1 - 3 ). Their chemical structures were elucidated by the comprehensive spectroscopic analyses (HRESIMS, 1D and 2D-NMR). In the bioactivity assay, their cytotoxic activities against two human hepatoma cell lines (HepG2 and Hep3B) were evaluated and no significant activity was seen with IC 50 values ranging from 12.5 to 50.0 μM.