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Background/purpose Antimicrobial resistance in Taiwan has been on the rise for two decades. The implementation of pneumococcal conjugate vaccination (PCV13) and enhanced antimicrobial control (2013–2015) by the government may have changed the antibiotic resistance. Methods Four respiratory pathogens (Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus pyogenes, and Moraxella catarrhalis) isolated in a single medical center during 2008–2017 were studied. We defined three temporal stages: (a) the first era (2008–2012), prior to implementation of the national immunization program (PCV13 vaccination), (b) the second era (2013–2015), during which an enhanced antibiotic control strategy was implemented, and (c) the third era (2016–2017), after implementation. Antimicrobial drug sensitivities were collected from two other hospitals: one from east Taiwan, one from west-central Taiwan. Results S. pneumoniae was frequently isolated during the first era. It declined progressively during the second era of PCV13 vaccination. S. pyogenes and M. catarrhalis were not frequently isolated. The drug susceptibility of S. pneumoniae to ceftriaxone and vancomycin remained high. The antimicrobial susceptibility of H. influenzae to amoxillin/clavulante declined over the three temporal stages, from 91.9%-79.5%–58.5% (all p Conclusion Antimicrobial resistance of H. influenzae increased during the latter part of the study period. The PCV13 vaccination program reduced the invasive pneumococcal disease and reduced the stress on the emergent drug resistance. This enhanced antibiotic control strategy was effective in terms of nosocomial drug resistance but not for community-associated pathogens.

The regeneration of bone defects in patients with diabetes mellitus (DM) is remarkably impaired by hyperglycemia and over-expressed proinflammatory cytokines, proteinases (such as matrix metalloproteinases, MMPs), etc. In view of the fact that exosomes represent a promising nanomaterial, herein, we reported the excellent capacity of stem cells from apical papilla-derived exosomes (SCAP-Exo) to facilitate angiogenesis and osteogenesis whether in normal or diabetic conditions

Dissolved solids released from biochar (DSRB), including organic and inorganic compounds, may affect the role of biochar as a soil amendment. In this study, the effects of DSRB on soil microbe metabolism, especially CO

Background. The effect of circular RNA-RNA polymerase I and III subunit C (circPOLR1C) on esophageal cancer (EC) has not been reported. Herein, this study is designed to unveil the effect and the regulatory mechanism of circPOLR1C on EC. Methods. The expression of circPOLR1C in EC tissues and cells was detected by qRT-PCR. Circular structure, stability, and cell localization of circPOLR1C were confirmed by qRT-PCR, RNase R, actinomycin D, and fluorescence in situ hybridization (FISH) assay. Cell function experiments, nude mouse xenograft, lung transplant model, and HE staining were performed to evaluate the effects of CircPOLR1C on EC in vitro and in vivo. A regulatory relationship between miR-361-3p and circPOLR1C was confirmed by qRT-PCR, circRNA in vivo precipitation, RIP, FISH, CircInteractome database, dual-luciferase reporter assay, and immunohistochemistry. Rescue experiments were applied to assess the effects of miR-361-3p and circPOLR1C on EC cells and tissues. Apoptosis- and epithelial-mesenchymal transformation (EMT)-related gene expressions were quantified by qRT-PCR and Western blot. Results. Highly expressed circPOLR1C in EC was related to tumor differentiation and invasion. circPOLR1C, which mainly exists in the cytoplasm, is a stable circular RNA. circPOLR1C silencing inhibited circPOLR1C expression and EC cell malignant function, while circPOLR1C overexpression promoted the growth of transplanted tumors and lung metastasis. The enrichment of miR-361-3p was higher than that of other targeted miRNAs. circPOLR1C adsorbed miR-361-3p to regulate apoptosis- and EMT-related genes and partially reversed the tumor suppressive effect of miR-361-3p, which was lowly expressed in EC tissues. Silencing the target genes of miR-361-3p also inhibited the malignant development of EC cells. Conclusion. circPOLR1C adsorbs miR-361-3p and regulates apoptosis- and EMT-related gene expressions to promote the development of EC.

Achieving C3-selective pyridine functionalization is a longstanding challenge in organic chemistry. The existing methods, including electrophilic aromatic substitution and C-H activation, often require harsh reaction conditions and excess pyridine and generate multiple regioisomers. Herein, we report a method for borane-catalyzed tandem reactions that result in exclusively C3-selective alkylation of pyridines. These tandem reactions consist of pyridine hydroboration, nucleophilic addition of the resulting dihydropyridine to an imine, an aldehyde, or a ketone, and subsequent oxidative aromatization. Because the pyridine is the limiting reactant and the reaction conditions are mild, this method constitutes a practical tool for late-stage functionalization of structurally complex pharmaceuticals bearing a pyridine moiety.

We aimed to establish a long noncoding RNA (lncRNA)-based signature for accurately predicting prognosis and guiding the personalized clinical management of oral squamous cell carcinoma (OSCC).OSCC RNA sequencing profiles were acquired from The Cancer Genome Atlas and Gene Expression Omnibus. Univariate Cox regression, least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analyses were performed to construct a lncRNA-based prognostic signature. Kaplan-Meier survival analysis, receiver operating characteristic (ROC) curves and calibration curves were used to assess the effectiveness and accuracy of the signature. Additionally, we conducted single-sample gene-set enrichment analysis to infer the different degrees of immunocyte infiltration. Weighted correlation network analysis, enrichment analysis and Spearman's correlation analysis were implemented to screen immune-related genes that interact with the lncRNA signature.In total, 14 lncRNAs were defined as potential prognostic biomarkers. Based on these lncRNAs, patients were divided into low- and high-risk subgroups with different survival times (p 0.001). In addition, the reliability of the prognostic signature was verified by Kaplan-Meier analysis, ROC analysis and calibration curves. Patients in the low-risk group exhibited more significant immune cell infiltration. Simultaneously, a potential regulatory network consisting of eight lncRNAs and 159 protein-coding genes in the top 10 immune-related biological process terms was constructed.Our findings suggested that the 14-lncRNA signature has satisfactory performance in predicting the prognosis of OSCC, thereby providing new insights to the pathogenesis, clinical patient management and therapeutic intervention. The different immune cell infiltration statuses of OSCC patients may encourage immunotherapy.

We present detections of stellar flares of Wolf\,359, an M6.5 dwarf in the solar neighborhood (2.41~pc) known to be prone to flares due to surface magnetic activity. The observations were carried out from 2020 April 23 to 29 with a 1-m and a 0.5-m telescope separated by nearly 300~km in Xinjiang, China. In 27~hr of photometric monitoring, a total of 13 optical flares were detected, each with a total energy of $\gtrsim 5 \times 10^{29}$~erg. The measured event rate of about once every two hours is consistent with those reported previously in radio, X-ray and optical wavelengths for this star. One such flare, detected by both telescopes on 26 April, was an energetic event with a released energy of nearly $10^{33}$~erg. The two-telescope lightcurves of this major event sampled at different cadences and exposure timings enabled us to better estimate the intrinsic flare profile, which reached a peak of up to 1.6 times the stellar quiescent brightness, that otherwise would have been underestimated in the observed flare amplitudes of about $0.4$ and $0.8$, respectively, with single telescopes alone. The compromise between fast sampling so as to resolve a flare profile versus a longer integration time for higher photometric signal-to-noise provides a useful guidance in the experimental design of future flare observations., Comment: 16 pages, 10 figures, 3 tables

Proprotein convertase subtilisin/kexin type-9 (PCSK9), a member of the proprotein convertase family, is an important drug target because of its crucial role in lipid metabolism. Emerging evidence suggests a direct role of localized PCSK9 in the pathogenesis of vascular diseases. With this in our consideration, we reviewed PCSK9 physiology with respect to recent development and major studies (clinical and experimental) on PCSK9 functionality in vascular disease. PCSK9 upregulates low-density lipoprotein (LDL)-cholesterol levels by binding to the LDL-receptor (LDLR) and facilitating its lysosomal degradation. PCSK9 gain-of-function mutations have been confirmed as a novel genetic mechanism for familial hypercholesterolemia. Elevated serum PCSK9 levels in patients with vascular diseases may contribute to coronary artery disease, atherosclerosis, cerebrovascular diseases, vasculitis, aortic diseases, and arterial aging pathogenesis. Experimental models of atherosclerosis, arterial aneurysm, and coronary or carotid artery ligation also support PCSK9 contribution to inflammatory response and disease progression, through LDLR-dependent or -independent mechanisms. More recently, several clinical trials have confirmed that anti-PCSK9 monoclonal antibodies can reduce systemic LDL levels, total nonfatal cardiovascular events, and all-cause mortality. Interaction of PCSK9 with other receptor proteins (LDLR-related proteins, cluster of differentiation family members, epithelial Na+ channels, and sortilin) may underlie its roles in vascular disease. Improved understanding of PCSK9 roles and molecular mechanisms in various vascular diseases will facilitate advances in lipid-lowering therapy and disease prevention.

Oral infections are common among individuals of all ages and can activate local and systemic inflammation. The inflammatory response plays an important role in atherosclerosis. An increasing number of studies have reported an association between oral pathogen infection and atherosclerotic coronary heart disease. For instance, epidemiological studies support the positive correlation between oral infections and atherosclerosis. The presence of oral pathogens in human atherosclerotic plaques has been detected by multiple methods, and oral infections promote atherosclerosis in animal experiments. Various mechanisms are involved in oral infections, thereby promoting atherosclerosis. First, oral infections can trigger the local and systemic inflammatory response, causing vascular endothelial damage. Oral-derived pathogens that enter atherosclerotic plaque can activate macrophages and cause an intra-plaque inflammatory response. Second, oral infections can promote intra-plaque macrophage cholesterol accumulation and foam cell formation. Third, oral infections can regulate plasma lipid levels, thereby increasing atherogenic lipid low-density lipoprotein and triglyceride levels. Although atherosclerosis caused by oral infections is currently studied, the precise mechanism remains to be further explored. The rise of gut microbiota research also makes the relationship between oral microbiota and disease, especially the relationship with coronary heart disease, worthy of attention and in-depth research.

Three new diterpenoids (1–3) (two abietane type diterpenoids and a paralianone type diterpenoid), together with four known compounds (4–7) were isolated from the whole plants of Euphorbia peplus. T...

Non-small-cell lung cancer is one of the principal causes of cancer-related death around the world. Chemotherapy is commonly used to treat wild type of epidermal growth factor receptor non-small-cell lung cancer. (-)-Epigallocatechin-3-gallate is the most abundant and active catechin. However, (-)-epigallocatechin-3-gallate has limited clinical application due to its poor stability and absorption. Herein, we report that a glycosylated azide undergoes a click reaction with the terminal alkyne of (-)-epigallocatechin-3-gallate to yield a triazole-linked glucose-(-)-epigallocatechin-3-gallate derivative and have evaluated its in vitro anticancer activity against human non-small-cell lung cancer cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The product inhibits human non-small-cell lung cancer cell lines with wild type of epidermal growth factor receptor and in combination with cisplatin/paclitaxel results in more pronounced proliferation inhibition than when used alone. Stability investigations indicates that the conjugated glucose residue can improve the stability of the (-)-epigallocatechin-3-gallate scaffold. Our studies suggest that the combination of the glucose-(-)-epigallocatechin-3-gallate derivative and chemotherapeutic drugs may provide a novel strategy for the treatment of non-small-cell lung cancer.

Background. Posterior capsule opacification (PCO), a complication of extracapsular lens extraction surgery that causes visual impairment, is characterized by aberrant proliferation and epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs). Curcumin, exerting inhibitive effects on cell proliferation and EMT in cancer, serves as a possible antidote towards PCO. Methods. Cellular proliferation of LECs after treatment of curcumin was measured with MTT assay and flow cytometry. The transcriptional and expressional levels of proteins related to proliferation and EMT of LECs were quantified by western blotting and real-time PCR. Results. Curcumin was found to suppress the proliferation of LECs by inducing G2/M arrest via possible inhibition of cell cycle-related proteins including CDK1, cyclin B1, and CDC25C. It had also inactivated proliferation pathways involving ERK1/2 and Akt pathways in LECs. On the other hand, curcumin downregulated the EMT of LECs through blocking the TGF-β/Smad pathway and interfering Notch pathway which play important roles in PCO. Conclusions. This study shows that curcumin could suppress the proliferation and EMT in LECs, and it might be a potential therapeutic protection against visual loss induced by PCO.

Although xenografts are one of the most attractive strategies for overcoming the shortage of organ donors, cellular rejection by macrophages is a substantial impediment to this procedure. It is well known that macrophages mediate robust immune responses in xenografts. Macrophages also express various inhibitory receptors that regulate their immunological function. Recent studies have shown that the overexpression of inhibitory ligands on porcine target cells results in the phosphorylation of tyrosine residues on intracellular immunoreceptor tyrosine-based inhibitory motifs on macrophages, leading to the suppression of xenogenic rejection by macrophages. It has also been reported that myeloid-derived suppressor cells, a heterogeneous population of immature myeloid cells, suppress not only NK and cytotoxic T lymphocyte cytotoxicity but also macrophage-mediated cytotoxicity. This review is focused on the recent findings regarding strategies for inhibiting xenogenic rejection by macrophages.

Bismuth (Bi), as a topological semi-metallic material, has received widespread attention on account of its fascinating properties. Here, Bi films were successfully grown through a direct and facile...

B Cell-Specific Moloney Murine Leukemia Virus Integration Site 1 (Bmi-1, Bmi1), an epigenetic protein, is necessary for normal stem cell self-renewal in adult animals and for cancer stem cell (CSC) functions in adult animals. To elucidate the functions of Bmi-1 in the oral cavity we created a transgenic mouse line (KrTBmi-1) that expresses ectopic, Flag-tagged Bmi-1 in tongue basal epithelial stem cells only upon doxycycline (DOX) treatment. Genome wide transcriptomics and Ingenuity Pathway Analysis identified several pathways altered by exogenous Bmi-1 expression in the normal tongue epithelium, including EIF2 signaling (P value = 1.58 x 10(−49)), mTOR signaling (P value = 2.45 x 10(−12)), oxidative phosphorylation (P = 6.61 x 10(−3)) and glutathione redox reactions I (P = 1.74 x 10(−2)). Overall, our data indicate that ectopic Bmi-1 expression has an impact on normal tongue epithelial homeostasis. We then assessed the KrTBmi-1 mice in the 4-nitroquinoline 1-oxide (4-NQO) model of oral carcinogenesis. We found that 80% of mice expressing exogenous Bmi-1 (+DOX, +4-NQO KrTBmi-1; N = 10) developed tumors classified as grade 3 or higher, compared to 60% and 40% of mice expressing just endogenous Bmi-1 (+DOX, +4-NQO Kr and -DOX, +4-NQO KrTBmi-1 groups, respectively; N = 10/group; P value =

Atherosclerosis is a chronic inflammatory response that increases the risk of cardiovascular diseases. An in-depth study of the pathogenesis of atherosclerosis is critical for the treatment of atherosclerotic cardiovascular disease. The development of atherosclerosis involves many cells, such as endothelial cells, vascular smooth muscle cells, macrophages, and others. The considerable effects of macrophages in atherosclerosis are inextricably linked to macrophage polarization and the resulting phenotype. Moreover, the significant impact of macrophages on atherosclerosis depend not only on the function of the different macrophage phenotypes but also on the relative ratio of different phenotypes in the plaque. Research on atherosclerosis therapy indicates that the reduced plaque size and enhanced stability are partly due to modulating macrophage polarization. Therefore, regulating macrophage polarization and changing the proportion of macrophage phenotypes in plaques is a new therapeutic approach for atherosclerosis. This review provides a new perspective for atherosclerosis therapy by summarizing the relationship between macrophage polarization and atherosclerosis, as well as treatment targeting macrophage polarization.

In this paper, a Hessian matrix based multi-focus image fusion method is proposed. First, the integral map is introduced for fast compute the Hessian matrix of source images at different scales, and the multi-scale Hessian matrix of source image is obtained. Second, the multi-scale Hessian matrix is used to decompose each source image into two kinds of regions: the feature and background regions. In order to improve the fusion performance, two new focus measures based on the multi-scale Hessian matrix and two different fusion strategies for both feature and background regions are utilized to obtain the initial decision maps, respectively. Finally, the final decision map for image fusion is achieved by post-processing on the results of the previous step. The proposed method is a primary attempt to introduce image feature and background regions decomposition strategies in the field of multi-focus image fusion. The experimental results also show that our method outperforms the existing image fusion methods in both visual perception and objective evaluations.

Stem cells have been widely studied in cell biology and utilized in cell-based therapies, and fishing stem cells from marrow is highly challenging due to the ultralow content. Herein, a physically cross-linked DNA network-based cell fishing strategy is reported, achieving efficient capture, 3D envelop, and enzyme-triggered release of bone marrow mesenchymal stem cells (BMSCs). DNA network is constructed via a double rolling circle amplification method and through the intertwining and self-assembly of two strands of ultralong DNA chains. DNA-chain-1 containing aptamer sequences ensures specific anchor with BMSCs from marrow. Hybridization between DNA-chain-1 and DNA-chain-2 enables the cross-link of cell-anchored DNA chains to form a 3D network, thus realizing cell envelop and separation. DNA network creates a favorable microenvironment for 3D cell culture, and remarkably the physically cross-linked DNA network shows no damage to cells. DNA network is digested by nuclease, realizing the deconstruction from DNA network to fragments, and achieving enzyme-triggered cell release; after release, the activity of cells is well maintained. The strategy provides a powerful and effective method for fishing stem cells from tens of thousands of nontarget cells.

Polarized exocytosis is essential for plant development and defence. The exocyst, an octameric protein complex that tethers exocytotic vesicles to the plasma membrane, targets exocytosis. Upon pathogen attack, secreted materials form papillae to halt pathogen penetration. To determine if the exocyst is directly involved in targeting exocytosis to infection sites, information about its localization is instrumental. Here, we investigated exocyst subunit localization in the moss Physcomitrella patens upon pathogen attack and infection by Phytophthora capsici. Time-gated confocal microscopy was used to eliminate autofluorescence of deposited material around infection sites allowing the visualization of the subcellular localization of exocyst subunits and of v-SNARE Vamp72A1-labeled exocytotic vesicles during infection. This showed that exocyst subunits Sec3a, Sec5b, Sec5d and Sec6 accumulated at sites of attempted pathogen penetration. Upon pathogen invasion, the exocyst subunits accumulated on the membrane surrounding papilla-like structures and hyphal encasements. Vamp72A1-labeled vesicles were found to localize in the cytoplasm around infection sites. The re-localization of exocyst subunits to infection sites suggests that the exocyst is directly involved in facilitating polarized exocytosis during pathogenesis.

During land colonization, plants acquired a range of body plan adaptations, of which the\ud innovation of three-dimensional (3D) tissues increased organismal complexity and reproductivity.\ud In the moss, Physcomitrella patens, a 3D leafy gametophore originates from filamentous\ud cells that grow in a two-dimensional (2D) plane through a series of asymmetric cell\ud divisions. Asymmetric cell divisions that coincide with different cell division planes and growth\ud directions enable the developmental switch from 2D to 3D, but insights into the underlying\ud mechanisms coordinating this switch are still incomplete.\ud Using 2D and 3D imaging and image segmentation, we characterized two geometric cues,\ud the width of the initial cell and the angle of the transition division plane, which sufficiently distinguished\ud a gametophore initial cell from a branch initial cell. These identified cues were further\ud confirmed in gametophore formation mutants.\ud The identification of a fluorescent marker allowed us to successfully predict the gametophore\ud initial cell with > 90% accuracy before morphological changes, supporting our\ud hypothesis that, before the transition division, parental cells of the gametophore initials possess\ud different properties from those of the branch initials.\ud Our results suggest that the cell fate decision of the initial cell is determined in the parental\ud cell, before the transition division.

Objectives Different criteria for assessing the reduction quality of trochanteric fractures have been reported. The Baumgaertner reduction quality criteria (BRQC) are relatively common and the Chang reduction quality criteria (CRQC) are relatively new. The objectives of the current study were to compare the reliability of the BRQC and CRQC in predicting mechanical complications and to investigate the clinical implications of the CRQC. Methods A total of 168 patients were assessed in a retrospective observational study. Clinical information including age, sex, fracture side, American Society of Anesthesiologists (ASA) classification, tip-apex distance (TAD), fracture classification, reduction quality, blade position, BRQC, CRQC, bone quality, and the occurrence of mechanical complications were used in the statistical analysis. Results A total of 127 patients were included in the full analysis, and mechanical complications were observed in 26 patients. The TAD, blade position, BRQC and CRQC were significantly associated with mechanical complications in the univariate analysis. Only the TAD (p = 0.025) and the CRQC (p < 0.001) showed significant results in the multivariate analysis. In the comparison of the receiver operating characteristic curves, the CRQC also performed better than the BRQC. Conclusion The CRQC are reliable in predicting mechanical complications and are more reliable than the BRQC. Future studies could use the CRQC to assess fracture reduction quality. Intraoperatively, the surgeon should refer to the CRQC to achieve good reduction in trochanteric fractures. Cite this article: Bone Joint Res 2019;8:502–508. DOI: 10.1302/2046-3758.810.BJR-2019-0032.R1.

The construction and the operation of multi-reservoir has severely altered the downstream design flood. This paper quantified the flood frequency modifications caused by multi-reservoir regulation with recorded data and a numerical model composed of peaks-over-threshold (POT) samples and time-trend models. The whole research was carried out in Dongjiang River Basin, Southern China. Results showed that (1) Sampling with the POT method could eliminate fake changes in change detection and prevent the underestimation of the design floods with an exceeding probability over 90% and the overestimation of the design floods with an exceeding probability less than 80%; (2) Multi-reservoir regulation severely reduced design flood when the exceeding probability was greater than 1% and smaller than 95%. The 10-year floods were mitigated the most. However, when the exceeding probability was over 95%, the impact was insignificant; (3) Flood mitigation was positively correlated to the number of reservoirs, but negatively correlated to the distance between the affecting reservoir and the affected station. However, when multiple reservoirs took effect on the design flood in one station, the closest reservoir did not necessarily take the most effect. The results of this research will amplify the theoretical basis for flood protection and the planning of regulation.

Biodegradable aliphatic polyesters, especially polylactide (PLA), polyglycolide (PGA), and their copolymer poly(lactide-co-glycolide) (PLGA), are the most representative and widely used synthetic polymers in the field of tissue engineering and regenerative medicine. However, these polyesters often give rise to aseptic inflammation because of their acidic degradation products after implantation. Here, unidirectional shell-core structured fibers of chitosan/poly(lactide-co-glycolide) (i.e., CTS/PLGA) with acid-neutralizing capability were developed for addressing the noted issue by coating the PLGA fiber surfaces with a layer of the alkaline chitosan by coaxial electrospinning. Our results showed that during a period of 8-week degradation, the shell-layer of chitosan with its unique alkaline nature for acid-neutralization obviously hindered the pH decrease as a result of the degradation of PLGA-core. In a mocked acidic environment testing of the human dermal fibroblasts, chitosan-enabled acidity neutralization could significantly reduce in vitro the secretion of inflammatory factors and downregulate the expression of related inflammatory genes. Thereafter, biocompatibility assessment in vitro showed that the CTS/PLGA fibers had poorer cell adhesion capacity than the PLGA fibers but were cytocompatible and promoted cell migration and secretion of collagen. Moreover, subcutaneous embedding for two and four weeks in vivo revealed that the CTS/PLGA fibers significantly reduced the recruitment of inflammatory cells and the formation of foreign body giant cells (FBGCs). This study thereby demonstrated the evident acid-neutralizing effect of the chitosan-coating layer on alleviating the inflammatory responses caused by the acidic degradation products of the PLGA-core. Our highly aligned CTS/PLGA fibers, as a kind of quasi "pH-neutral fibers" with the acid-neutralizing capability, could be potentially applied for engineering those architecturally anisotropic tissues (e.g., tendon/ligament) toward improved efficacy of regeneration. STATEMENT OF SIGNIFICANCE: It is well known that acidic degradation products from representative aliphatic polyesters (e.g., PLA, PGA, and PLGA) give rise to the problem of aseptic inflammation. Various alkaline components acting as neutralizing agents have been used to address the noted issue. However, rather less attention has been paid to engineer these polyesters into a fibrous form with acid-neutralizing functionality. The present study proposes the concept of "pH-neutral fibers" and develops shell-core structured unidirectional fibers of chitosan/poly(lactide-co-glycolide) with acid-neutralizing capability for ameliorating inflammatory responses caused by the acidic degradation products of PLGA. It provides a comprehensive study encompassing fiber characterization and in vitro and in vivo evaluation, which would pave the way for developing sophisticated pH-neutral fibers for functional tissue regeneration.

Coronary angiography is an important diagnostic tool for coronary heart disease. While it can identify anatomical coronary stenosis, its ability to identify hemodynamic changes is limited. The Fractional Flow Reserve (FFR) technique, combined with coronary angiography, facilitates both the functional and anatomical assessment of heart disease. New studies have shown that FFR has unique advantages in guiding percutaneous coronary intervention (PCI), and it is currently being used in coronary artery bypass graft (CABG) as well as for assessing the prognosis of patients after surgery. It may also play a significant role in assessing the patency of a graft. However, some studies have shown that in considering the cardioprotective benefits of CABG, applying FFR guidelines to CABG may reduce or impair its "surgical collateralization" effect and increase the rate of incomplete revascularization. We compared the advantages and disadvantages of FFR to guide PCI and CABG, which will provide health practitioners with useful resources to determine the best diagnosis and treatment for patients.

The regeneration of diabetic bone defects remains challenging as the innate healing process is impaired by glucose fluctuation, reactive oxygen species (ROS), and overexpression of proteinases (such as matrix metalloproteinases, MMPs). A "diagnostic" and therapeutic dual-logic-based hydrogel for diabetic bone regeneration is therefore developed through the design of a double-network hydrogel consisting of phenylboronic-acid-crosslinked poly(vinyl alcohol) and gelatin colloids. It exhibits a "diagnostic" logic to interpret pathological cues (glucose fluctuation, ROS, MMPs) and determines when to release drug in a diabetic microenvironment and a therapeutic logic to program different cargo release to match immune-osteo cascade for better tissue regeneration. The hydrogel is also shown to be mechanically adaptable to the local complexity at the bone defect. Furthermore, the underlying therapeutic mechanism is elucidated, whereby the logic-based cargo release enables the regulation of macrophage polarization by remodeling the mitochondria-related antioxidative system, resulting in enhanced osteogenesis in diabetic bone defects. This study provides critical insight into the design and biological mechanism of dual-logic-based tissue-engineering strategies for diabetic bone regeneration.

Oxidative stress-induced degeneration and dysfunction of chondrocytes play a key role in the pathological progression of osteoarthritis (OA), a common degenerative joint disease in the elderly. Epigallocatechin-3-O-gallate (EGCG) increases Nrf2-mediated antioxidase expression levels. We aimed to determine the effects of EGCG on C28/I2 human chondrocytes subjected to interleukin-1β (IL-1β)-induced oxidative stress. EGCG suppressed IL-1β-induced oxidative stress, as indicated by decreased malondialdehyde (MDA) and reactive oxygen species (ROS) generation. Additionally, EGCG attenuated the IL-1β-induced reduction in cartilage matrix generated by chondrocytes by upregulating collagen II, aggrecan, sulfated proteoglycans, and SRY-box transcription factor 9 (SOX9). EGCG reversed the IL-1β-induced increased cyclooxygenase 2 (COX2), inducible nitric oxide synthase (iNOS), collagen X, and matrix metalloproteinases (MMPs). Furthermore, EGCG inhibited apoptosis and senescence of IL-1β-treated chondrocytes, as indicated by the decrease in mitochondrial membrane potential and senescence-associated β-galactosidase-positive cells, respectively. Mechanically, EGCG upregulated nuclear factor erythroid 2-related factor 2 (Nrf2), oxygenase-1 (HO-1), and NADPH quinone oxidoreductase1 (NQO1). The antioxidant and chondroprotective effects of EGCG were blocked by ML385, a Keap1/Nrf2/ARE signaling pathway inhibitor. Thus, EGCG ameliorated oxidative stress-induced chondrocyte dysfunction and exerted chondroprotective effects via Keap1/Nrf2/ARE signaling. This provides a novel perspective on the molecular mechanisms underlying the therapeutic effects of EGCG on OA.

Atrial fibrosis is the basis for the occurrence and development of atrial fibrillation (AF) and is closely related to the Warburg effect, endoplasmic reticulum stress (ERS) and mitochondrion dysfunctions-induced cardiomyocyte apoptosis. Hydrogen sulfide (H2S) is a gaseous signalling molecule with cardioprotective, anti-myocardial fibrosis and improved energy metabolism effects. Nevertheless, the specific mechanism by which H2S improves the progression of atrial fibrosis to AF remains unclear. A case-control study of patients with and without AF was designed to assess changes in H2S, the Warburg effect, and ERS in AF. The results showed that AF can significantly reduce cystathionine-γ-lyase (CSE) and 3-mercaptopyruvate thiotransferase (3-MST) expression and the H2S level, induce cystathionine-β-synthase (CBS) expression; increase the Warburg effect, ERS and atrial fibrosis; and promote left atrial dysfunction. In addition, AngII-treated SD rats had an increased Warburg effect and ERS levels and enhanced atrial fibrosis progression to AF compared to wild-type SD rats, and these conditions were reversed by sodium hydrosulfide (NaHS), dichloroacetic acid (DCA) or 4-phenylbutyric acid (4-PBA) supplementation. Finally, low CSE levels in AngII-induced HL-1 cells were concentration- and time-dependent and associated with mitochondrial dysfunction, apoptosis, the Warburg effect and ERS, and these effects were reversed by NaHS, DCA or 4-PBA supplementation. Our research indicates that H2S can regulate the AngII-induced Warburg effect and ERS and might be a potential therapeutic drug to inhibit atrial fibrosis progression to AF.

Introduction: Alcohol-induced thickening of the gut mucosal layer and increased expression of goblet cell gel-forming mucins, such as mucin-2 (MUC2) are associated with disruptions to the gut barrier in alcoholic liver disease (ALD). Interest in drugs that can target gut mucins in ALD has grown; however to date, no studies have examined the properties of drugs on expression of gut mucins in models of ALD. We previously demonstrated that at 10 mg/kg/day, the drug fenretinide (N-[4-hydroxyphenyl] retinamide [Fen]), a synthetic retinoid, mitigates alcohol-associated damage to the gut barrier and liver injury in a murine model of ALD. Methods: In this study, we specifically sought to examine the effects of Fen on gut goblet cells, and expression of mucins, including MUC2 using a 25-day Lieber-DeCarli model of chronic alcohol intake. Results: Our results show that chronic alcohol intake increased gut-mucosal thickening, goblet cell numbers, and mRNA and protein expression of MUC2 in both the ileum and colon. Alcohol intake was associated with marked decreases in ileal and colonic Notch signaling, levels of Notch ligands Dll1 and Dll4, and increases in the expression of Notch-associated genes indispensable for goblet cell specification, including Math1 and Spdef. Interestingly, ileal and colonic expression of KLF4, which is involved in terminal differentiation of goblet cells, was reduced in mice chronically fed alcohol. Coadministration of alcohol with Fen at 10 mg/kg/day significantly reduced alcohol-associated increases in ileal and colonic mucosal thickening, ileal Muc2, colonic Muc2, Muc5ac and Muc6 mRNAs, and goblet cell numbers. We also found that Fen strongly prevented alcohol-mediated suppression of the Notch ligand Dll1, Notch signaling, and alcohol-induced increases in expression of Notch-associated goblet cell specification genes in both the ileum and colon. In the absence of alcohol, Fen treatments alone at 10 mg/kg/day had no effects on any of the goblet cell-related endpoints. Conclusion: These data show for the first time that the drug Fen possesses mucosal layer-modulating properties in response to chronic alcohol abuse. These data warrant further preclinical examination of Fen given the need for anti-ALD drugs and emerging evidence of a role for intestinal goblet cell mucins in the progression of ALD.

Nematode species are well-known for their invariant cell lineage pattern during development. Combining knowledge about the fate specification induced by asymmetric division and the anti-correlation between cell cycle length and cell volume in Caenorhabditis elegans, we propose a minimal model to simulate lineage initiation by altering cell volume segregation ratio in each division, and quantify the derived pattern's performance in proliferation speed, fate diversity, and space robustness. The stereotypic pattern in C. elegans embryo is found to be one of the most optimal solutions taking minimum time to achieve the cell number before gastrulation, by programming asymmetric divisions as a strategy.

Background: Benign prostatic hyperplasia (BPH) is one of the most common urological disease and often associated with lower urinary tract symptoms (LUTS) in elderly men. Chinese acupuncturists found that deep acupuncture at Qugu point (CV2) can effectively relieve urination difficulties and improve quality of life of patients with troublesome BPH/LUTS. However, there are currently insufficient scientific evidence and well-designed trials to support its effect as well as safety in the treatment of BPH/LUTS. Therefore, this study protocol is designed to evaluate the effectiveness and safety of deep acupuncture at CV2 for men with BPH/LUTS.Methods: A single-center, randomized, subject-and assessor-blinded, placebo-controlled trial will be conducted in an outpatient acupuncture department in Beijing, China. A total of 120 subjects (50-80 yr) will be randomized to one of three balanced groups: deep acupuncture group 1 (deep acupuncture at CV2 with needle tip reaching the prostate capsule), deep acupuncture group 2 (deep acupuncture at CV2 with needle tip 10mm away from the prostate capsule), and sham acupuncture group (sham acupuncture with non-penetrating needle) in a ratio of 1:1:1. The study period for each subject will be 4 months, including 4 weeks baseline observation period, 4 weeks intervention period, and 8 weeks follow-up period. All subjects will receive 10 treatments during the intervention period. Subjects in deep acupuncture groups will be measured the needle depth and angle by computerized tomography (CT) in their first treatment. The primary outcome is the change in International Prostate Symptom Score. Secondary outcomes include quality of life, maximum urinary flow rate, and post-void residual.Discussion: The objectives of this study include: 1) to assess the efficacy of deep acupuncture at CV2 in the treatment of BPH; 2) to evaluate the safety of acupuncture at CV2 by measure the needle depth and angle under CT. This study will provide an evidence-based recommendation for acupuncture at CV2 in the treatment of BPH.Trial registration: Registered on 18 January 2020. Chinese Clinical Trials Register, ChiCTR2000029203.

In order to solve the problem of vigorous vibration of agricultural machinery frames, taking a vegetable precision seeder as an example, the concept of vibration reduction was proposed. The modal analysis of the frame was carried out, and the accuracy of the finite element model was verified by comparing the modal test of multipoint input and multipoint output (MIMO) and simulation results. Additionally, the main frequency of engine vibration was the main excitation source of frame resonance. According to the modal shapes, it was proposed to increase the fixed beam structure and to carry out simulation tests. The time-domain signal of the maximum deformation position in the first-order vibration mode was measured, and the vibration spectrum analysis maps before and after optimization were obtained by Fourier transform. A field experiment showed that the seeding quality of the whole machine was significantly improved after optimization. This study provides a reference for the analysis of vibration characteristics and the vibration reduction design of the agricultural machinery equipment.

Two new quassinoids (1 and 2) were isolated from the twigs of

Purpose. Leukocyte telomere length (LTL) is an important biomarker of aging. The oxidative balance score (OBS) is used to assess the oxidative stress-related exposures of diet and lifestyle. This study is aimed at exploring if the OBS was associated with LTL. Methods. 3220 adults were included in this study from the National Health and Nutrition Examination Survey (NHANES) 1999-2002. LTL was assayed from leukocyte DNA. Twenty dietary and lifestyle factors were selected to score the OBS. Survey-based multivariable linear regression was conducted to assess the association between the OBS and log-transformed LTL. Results. The association between the OBS and log-transformed LTL was positive in females but not males. For females, compared with the lowest OBS category as a reference, the multivariable-adjusted beta estimate (95% confidence interval, CI) for the highest OBS category was 0.0701 (0.0205–0.1197) ( p for trend < 0.01 ), and the multivariable-adjusted beta estimate (95% CI) of the continuous OBS was 0.0039 (0.0014–0.0065). There was also the gender difference in the correlations of the dietary OBS and the lifestyle OBS with log-transformed LTL. Conclusion. There was a positive association between the OBS and LTL in females. This result suggested that diet and lifestyle might affect LTL by regulating oxidative balance.

Zhiying Pang,&ast; Zengxin Jiang,&ast; Runwen Zhu, Chunfeng Song, Han Tang, Lu Cao, Changan Guo Department of Orthopedic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Changan Guo; Lu CaoDepartment of Orthopedic Surgery, Zhongshan Hospital, Fudan University, NO. 180 Feng Lin Road, Xuhui District, Shanghai, 200032, People’s Republic of ChinaTel +86 13681975321; +86 13482794964Email changanguo@hotmail.com; caolu922@126.comPurpose: Oxidative stress-induced chondrocyte apoptosis and extracellular matrix (ECM) degradation plays an important role in the progression of osteoarthritis (OA). Bardoxolone methyl (BM), a semisynthetic triterpenoid, exerts strong effect against oxidative stress. The purpose of the present study was to determine the effectiveness of bardoxolone-methyl (BM) in preventing oxidative stress-induced chondrocyte apoptosis and extracellular ECM degradation in vitro and the role of alleviating OA progression in vivo.Methods: Oxidative damage was induced by 25 mM tert-butyl hydroperoxide (TBHP) for 24 h in rat chondrocytes. 0.025 and 0.05 μM bardoxolone-methyl (BM) were used in vitro treatment. Ex-vivo cartilage explant model was established to evaluate the effect of BM on oxidative stress-induced ECM degradation. The mouse OA model was induced by surgical destabilization of the medial meniscus.Results: In vitro, 0.025 and 0.05 μM BM reduced TBHP-induced excessive ROS generation, improved cell viability, increased malondialdehyde level and decreased superoxide dismutase level. 0.025 and 0.05 μM BM prevented TBHP-induced mitochondrial damage and apoptosis in chondrocytes BM activated heme oxygenase-1 (HO-1)/NADPH quinone oxidoreductase 1 (NOQ1) signaling pathway through targeting nuclear factor erythroid derived-2-related factor 2 (Nrf2). Additionally, BM treatment enhanced the expression levels of aggrecan and collagen II and inhibited the expression levels of matrix metalloproteinase 9 (MMP 9), MMP 13, Bax and cleaved-caspase-3. BM increased proteoglycan staining area and IOD value in ex vivo cultured experiment cartilage explants and improved the OARSI score, stands, max contact mean intensity, print area and duty cycle in mouse OA model.Conclusion: BM prevented oxidative stress-induced chondrocyte apoptosis and ECM degradation in vitro and alleviated OA in vivo, suggesting that BM serves as an effective drug for treatment with OA.Keywords: osteoarthritis, chondrocyte apoptosis, extracellular matrix degradation, oxidative stress, bardoxolone-methyl

Significance: Artificial skin (AS) is widely used in dermatology, pharmacology, and toxicology, and has great potential in transplant medicine, burn wound care, and chronic wound treatment. There is a great demand for high-quality AS product and a non-invasive detection method is highly desirable. Aim: To quantify the constructure parameters (i.e., thickness and surface roughness) of AS samples in the culture cycle and explore the growth regularities using optical coherent tomography (OCT). Approach: An adaptive interface detection algorithm is developed to recognize surface points in each A-scan, offering a rapid method to calculate parameters without constructing OCT B-scan pictures and further achieving realizing real-time quantification of AS thickness and surface roughness. Experiments on standard roughness plates and H&E-staining microscopy were performed as a verification. Results: As applied on the whole cycle of AS culture, our method’s results show that during the air–liquid culture, the surface roughness of the skin first decreases and then exhibits an increase, which implies coincidence with the degree of keratinization under a microscope. And normal and typical abnormal samples can be differentiated by thickness and roughness parameters during the culture cycle. Conclusions: The adaptive interface detection algorithm is suitable for high-sensitivity, fast detection, and quantification of the interface with layered characteristic tissues, and can be used for non-destructive detection of the growth regularity of AS sample thickness and roughness during the culture cycle.

Diabetes mellitus (DM), a high incidence metabolic disease, is related to the impairment of male spermatogenic function. Spermidine (SPM), one of the biogenic amines, was identified from human seminal plasma and believed to have multiple pharmacological functions. However, there exists little evidence that reported SPM’s effects on moderating diabetic male spermatogenic function. Thus, the objective of this study was to investigate the SPM’s protective effects on testicular spermatogenic function in streptozotocin (STZ)-induced type 1 diabetic mice. Therefore, 40 mature male C57BL/6 J mice were divided into four main groups: the control group (n = 10), the diabetic group (n = 10), the 2.5 mg/kg SPM-treated diabetic group (n = 10) and the 5 mg/kg SPM-treated diabetic group (n = 10), which was given intraperitoneally for 8 weeks. The type 1 diabetic mice model was established by a single intraperitoneal injection of STZ 120 mg/kg. The results showed that, compare to the control group, the body and testis weight, as well the number of sperm were decreased, while the rate of sperm malformation was significantly increased in STZ-induced diabetic mice. Then the testicular morphology was observed, which showed that seminiferous tubule of testis were arranged in mess, the area and diameter of which was decreased, along with downregulated anti-apoptotic factor (Bcl-2) expression, and upregulated pro-apoptotic factor (Bax) expression in the testes. Furthermore, testicular genetic expression levels of Sertoli cells (SCs) markers (WT1, GATA4 and Vimentin) detected that the pathological changes aggravated observably, such as the severity of tubule degeneration increased. Compared to the saline-treated DM mice, SPM treatment markedly improved testicular function, with an increment in the body and testis weight as well as sperm count. Pro-apoptotic factor (Bax) was down-regulated expression with the up-regulated expression of Bcl-2 and suppression of apoptosis in the testes. What’s more, expression of WT1, GATA4, Vimentin and the expressions of glycolytic rate-limiting enzyme genes (HK2, PKM2, LDHA) in diabetic testes were also upregulated by SPM supplement. The evidence derived from this study indicated that the SMP’s positive effect on moderating spermatogenic disorder in T1DM mice’s testis. This positive effect is delivered via promoting spermatogenic cell proliferation and participating in the glycolytic pathway’s activation.