Noncritical birefringence phase-matched second harmonic generation in a lithium-niobate-on-insulator micro-waveguide for green light emission.

Lithium niobate on insulator (LNOI) holds great potential for frequency conversion, where a variety of high-performance nonlinear devices based on different structures has been demonstrated. Here, we report on second harmonic generation (SHG) in MgO-doped LNOI ridge micro-waveguides for efficient green light emission, via an exact type-I noncritical birefringence phase matching (BPM). The LNOI micro-waveguide has a cross section of ∼3×4 µm2, featuring low coupling loss with lens fiber. The normalized conversion efficiency from a continuous-wave (cw) pump to its second harmonic is measured to be 37%/Wcm2 in a single-pass configuration. The device shows both relatively high efficiency and a void of periodic poling, offering a potential solution for efficient and scalable green light sources and frequency converters.

Broadband second-harmonic generation in an angle-cut lithium niobate-on-insulator waveguide by a temperature gradient.

Frequency conversion via nonlinear wave mixing is an important technology to broaden the spectral range of lasers, propelling their applications in optical communication, spectroscopy, signal processing, and quantum information. Many applications require not only a high conversion efficiency but also a broad phase matching bandwidth. Here, we demonstrate broadband birefringence phase matching (BPM) second-harmonic generation (SHG) in angle-cut lithium niobate-on-insulator (LNOI) ridge waveguides based on a temperature gradient scheme. The bandwidth and shift of the phase matching spectrum can be effectively tuned by controlling the temperature gradient of the waveguide. Broadband SHG of a telecom C-band femtosecond laser is also demonstrated. The approach may open a new avenue for tunable broadband nonlinear frequency conversion in various integrated photonics platforms.

Highly tunable birefringent phase-matched second-harmonic generation in an angle-cut lithium niobate-on-insulator ridge waveguide.

Phase-matched nonlinear wave mixing, e.g., second-harmonic generation (SHG), is crucial for frequency conversion for integrated photonics and applications, where phase matching wavelength tunability in a wide manner is important. Here, we propose and demonstrate a novel design of angle-cut ridge waveguides for SHG on the lithium niobate-on-insulator (LNOI) platform via type-I birefringent phase matching (BPM). The unique strong birefringence of LN is used to achieve flexible temperature tuning. We experimentally demonstrate a normalized BPM conversion efficiency of 2.7%W-1cm-2 in an angle-cut LN ridge waveguide with a thermo tuning slope of 1.06 nm/K at the telecommunication C band. The approach effectively overcomes the spatial walk-off effect and avoids the need for periodic domain engineering. Furthermore, the angle-cut ridge waveguide scheme can be universally extended to other on-chip birefringent platforms where domain engineering is difficult or immature. The approach may open up an avenue for tunable nonlinear frequency conversion on integrated photonics for broad applications.

Potent inhibition of TGF-ß signaling pathway regulator Abl: potential therapeutics for hepatic fibrosis.

Hepatic fibrosis is overly exuberant wound healing in which excessive connective tissue builds up in the liver. The treatment of hepatic fibrosis is still difficult and remains a challenge to the clinician. In recent years, the TGF-ß signaling pathway regulator tyrosine kinase Abl has been raised as a new and promising target of hepatic fibrosis therapy. Here, considering that there are numerous drugs and drug-like compounds being approved or under clinical development and experimental investigation, it is expected that some of the existing drugs can be re-exploited as new agents to target Abl with the capability of suppressing hepatic fibrosis. To achieve this, a synthetic protocol that integrated molecular docking, affinity scoring dynamics simulation and free energy analysis was described to systematically profile the inhibitory potency of various drugs and drug-like compounds against the kinase domain of Abl. Consequently, 4 out of 13 tested drug candidates were successfully identified to have high-Abl inhibitory activities. By visually examining the dynamics behavior, structural basis and energetic property of few typical Abl-drug complex cases, a significantly different pattern of non-bonded interactions between the binding of active and inactive drug ligands to Abl receptor was revealed; the former is defined by strong, specific chemical forces, while the latter can only form non-specific hydrophobic contacts with slight atomic collisions.

[Hepatitis B e antigen perturbs the LPS-stimulated production of inflammatory cytokines by mononuclear-derived dendritic cells].

OBJECTIVE: To investigate whether hepatitis B e antigen (HBeAg) can modulate the ability of dendritic cells (DCs) to produce inflammatory cytokines (IL-12/IL-6) upon stimulation in vitro. METHODS: Purified adherent mononuclear cells isolated by Ficoll-hypaque density gradient centrifugation were cultured in complete medium containing granulocyte macrophage colony-stimulating factor plus interleukin (IL)-4 to generate immature (i)DCs. Microscopic analysis and flow cytometry were performed to define the phenotypic characteristics of the iDCs. Then, different concentrations (1, 2 and 5 mug/ml) of HBeAg were added to the culture medium and for 24 hrs of incubation. To induce iDCs' maturation, the various groups of cells were incubated for 24 hrs in differentiation culture with lipopolysaccharide (LPS). Effects on secreted inflammatory cytokines were determined by enzyme-linked immunosorbent assay of the cells' supernatants. RESULTS: All concentrations of HBeAg led to significant reductions in IL-6 (all P less than 0.05). Similar significant reduction trends were seen for IL-12 at the HBeAg concentrations of 2 and 5 mug/ml (both P less than 0.05), but not at the 1 mug/ml concentration. CONCLUSION: HBeAg may suppress the production of cytokines from DCs; this mechanism may contribute to the immune escape of HBV that supports persistent infection.

Salvigenin Suppresses Hepatocellular Carcinoma Glycolysis and Chemoresistance Through Inactivating the PI3K/AKT/GSK-3ß Pathway.

Salvigenin is a Trimethoxylated Flavone enriched in Scutellariae Barbatae Herba and Scutellariae Radix and is demonstrated to have anti-tumor properties in colon cancer. Notwithstanding, the function and mechanism of Salvigenin in hepatocellular carcinoma (HCC) are less well studied. Different doses of Salvigenin were taken to treat HCC cells. Cell viability, colony formation ability, cell migration, invasion, apoptosis, glucose uptake, and lactate production levels were detected. As shown by the data, Salvigenin concentration dependently dampened HCC cell proliferation, migration, and invasion, weakened glycolysis by abating glucose uptake and lactate generation, and suppressed the profiles of glycolytic enzymes. Moreover, Salvigenin strengthened HCC cells' sensitivity to 5-fluorouracil (5-FU) and attenuated HCC 5-FU-resistant cells' resistance to 5-FU. Through network pharmacological analysis, we found Salvigenin potentially regulates PI3K/AKT pathway. As shown by the data, Salvigenin repressed the phosphorylated levels of PI3K, AKT, and GSK-3ß. The PI3K activator 740Y-P induced PI3K/AKT/GSK-3ß pathway activation and promotive effects in HCC cells. However, Salvigenin substantially weakened 740Y-P-mediated effects. In-vivo assay revealed that Salvigenin hampered the growth and promoted apoptosis of HCC cells in nude mice. Collectively, Salvigenin impedes the aerobic glycolysis and 5-FU chemoresistance of HCC cells by dampening the PI3K/AKT/GSK-3ß pathway.

Effect of portal vein thrombosis on the prognosis of patients with cirrhosis without a liver transplant: A systematic review and meta-analysis.

BACKGROUND: Portal vein thrombosis (PVT) is a relatively common complication of cirrhosis. However, the effect of PVT on the prognosis might not be unequivocal. A systematic review and meta-analysis were performed to investigate the effect of PVT on the prognosis of patients with cirrhosis who have not received a liver transplant. METHODS: Three databases, including PubMed, EMBASE, and Cochrane Library, were searched for studies published up to March 2020. The survival or mortality rate of patients with PVT served as the main index to evaluate the prognosis of these patients. Hepatic decompensation served as the index of disease progression. Meta-analyses were conducted using Review Manager software 5.2. RESULTS: Sixteen clinical studies were included and analyzed. PVT was associated with an increased risk of mortality in patients with decompensated cirrhosis. According to the meta-analysis, patients with cirrhosis presenting with PVT had a lower 1-year survival rate than patients without PVT (odds ratio (OR), 0.32; 95% confidence interval (CI), 0.14-0.75; P = .008). The cumulative survival rates were similar between the 2 groups at 3 years (OR, 1.04; 95% CI, 1.00-1.08; P = .06), 5 years (OR, 1.33; 95% CI, 0.71-2.48; P = .38) and 10 years (OR, 1.24; 95% CI, 0.79-1.93; P = .35). PVT was associated with a higher mortality rate in patients with Child-Pugh class B and C disease. A significantly increased risk of death was observed in patients with complete PVT. Patients with both PVT and cirrhosis had a higher rate of decompensation than patients without PVT. CONCLUSIONS: The presence of PVT might exert a slight effect on the overall prognosis of patients with cirrhosis. PVT might mainly affect the short-term prognosis by increasing hepatic decompensation events in patients with cirrhosis. However, PVT might not influence the long-term prognosis of patients with cirrhosis.

Integration of virtual screening and susceptibility test to discover active-site subpocket-specific biogenic inhibitors of Helicobacter pylori shikimate dehydrogenase.

Shikimate dehydrogenase (HpSDH) (EC 1.1.1.25) is a key enzyme in the shikimate pathway of Helicobacter pylori (H. pylori), which catalyzes the NADPH-dependent reversible reduction of 3-dehydroshikimate to shikimate. Targeting HpSDH has been recognized as an attractive therapeutic strategy against H. pylori infection. Here, the catalytic active site in the crystal structure of HpSDH in complex with its substrate NADPH and product shikimate was examined in detail; the site can be divided into three spatially separated subpockets that separately correspond to the binding regions of shikimate, NADPH dihydronicotinamide moiety, and NADPH adenine moiety. Subsequently, a cascading protocol that integrated virtual screening and antibacterial test was performed against a biogenic compound library to identify biologically active, subpocket-specific inhibitors. Consequently, five, eight, and six promising compounds for, respectively, subpockets 1, 2, and 3 were selected from the top-100 docking-ranked hits, from which 11 compounds were determined to have high or moderate antibacterial potencies against two reference H. pylori strains, with MIC range between 8 and 93 µg/mL. It is found that the HpSDH active site prefers to accommodate amphipathic and polar inhibitors that consist of an aromatic core as well as a number of oxygen-rich polar/charged substituents such as hydroxyl, carbonyl, and carboxyl groups. Subpockets 1- and 2-specific inhibitors exhibit a generally higher activity than subpocket 3-specific inhibitors. Molecular dynamics simulations revealed an intense nonbonded network of hydrogen bonds, π-π stacking, and van der Waals contacts at the tightly packed complex interfaces of active-site subpockets with their cognate inhibitors, conferring strong stability and specificity to these complex systems. Binding energetic analysis demonstrated that the identified potent inhibitors can target their cognate subpockets with an effective selectivity over noncognate ones.

Discovery of a Potential Plasma Protein Biomarker Panel for Acute-on-Chronic Liver Failure Induced by Hepatitis B Virus.

Hepatitis B virus (HBV)-associated acute-on-chronic liver failure (HBV-ACLF), characterized by an acute deterioration of liver function in the patients with chronic hepatitis B (CHB), is lack of predicting biomarkers for prognosis. Plasma is an ideal sample for biomarker discovery due to inexpensive and minimally invasive sampling and good reproducibility. In this study, immuno-depletion of high-abundance plasma proteins followed by iTRAQ-based quantitative proteomic approach was employed to analyze plasma samples from 20 healthy control people, 20 CHB patients and 20 HBV-ACLF patients, respectively. As a result, a total of 427 proteins were identified from these samples, and 42 proteins were differentially expressed in HBV-ACLF patients as compared to both CHB patients and healthy controls. According to bioinformatics analysis results, 6 proteins related to immune response (MMR), inflammatory response (OPN, HPX), blood coagulation (ATIII) and lipid metabolism (APO-CII, GP73) were selected as biomarker candidates. Further ELISA analysis confirmed the significant up-regulation of GP73, MMR, OPN and down-regulation of ATIII, HPX, APO-CII in HBV-ACLF plasma samples (p < 0.01). Moreover, receiver operating characteristic (ROC) curve analysis revealed high diagnostic value of these candidates in assessing HBV-ACLF. In conclusion, present quantitative proteomic study identified 6 novel HBV-ACLF biomarker candidates and might provide fundamental information for development of HBV-ACLF biomarker.

Repair of critical size bone defects with porous poly(D,L-lactide)/nacre nanocomposite hollow scaffold.

OBJECTIVE: To generate a novel porous poly(D,L-lactide)/nacre nanocomposite hollow scaffold. METHODS: This study was performed in the Department of Spine Surgery, Southern Medical University, Guangzhou, China from September 2010 to September 2011. Nacre nanoparticles were prepared using a physical process and identified by x-ray diffraction and transmission electron microscopy, to generate a novel scaffold though the salt leaching processing technique. The morphology and structure properties of this scaffold were further investigated under scanning electron microscope and mechanical property testing. Additionally, the biological characteristics were evaluated by cell culture experiments in vitro. Thirty-six rabbits were randomly divided into 3 groups. The defects were implanted with/without poly(D,L-lactide)/nacre scaffold or poly(D,L-lactide) scaffold. The results were assessed by radiographs and bone mineral density to monitor bone repairing. RESULTS: The nacre nanoparticles were spherical in shape, with a diameter range from 45-95 nm. The scaffolds possessed an interconnected porous structure with an average pore size of 322.5+/-50.8 µm, and exhibited a high porosity (82.5 +/-0.8%), as well as good compressive strength of 4.5+/-0.25 Mpa. Primary biocompatibility experiments in vitro showed that cells adhered and proliferated well on the scaffolds. The animal study further demonstrated that the scaffolds could repair the critical size segmental bone defects in 12 weeks. CONCLUSION: Newly established scaffolds may serve as a promising biomaterial for bone tissue engineering.

[Effect and mechanism of leptin on osteoblastic differentiation of hBMSCs].

OBJECTIVE: To investigate the effect and mechanism of leptin (LEP) on the osteoblastic differentiation of hBMSCs in vitro. METHODS: Whole bone marrow culture method was applied to culture hMBSCs and hBMSCs at passage 3 were divided into groups A, B, C, D, E and F, and when cell attachment was evident, 400, 200, 100 and 50 ng/mL LEP, 100 ng/mL BMP and common nutrient medium were added into each group, respectively. ALP staining and mineralized nodules staining were conducted at 7 and 21 days after culture, respectively. And inverted phase contrast microscope observation was performed. ALP activity and osteocalcin (OCN) level of hBMSCs in each group was detected at 7, 14 and 21 days after culture to select the best induced concentration of LEP on osteoblastic differentiation. For groups of B, E and F at 7 days after culture, RT-PCR was adopted to detect the expression of such osteogenesis-related genes as core-binding factor alpha 1 (Cbf alpha 1), ALP, Col I and OCN mRNA. RESULTS: At 7 days after induced culture, the ALP staining result showed that the endochylema in groups A, B, C, D and E were stained blue and the endochylema in the group F was slightly positive. At 21 days after induced culture, the mineralized nodules staining showed that cells in groups A, B, C, D and E were stained positively and cells in group F were negative. At 7, 14 and 21 days after culture, ALP and OCN activities in group B were less than that of group E (P < 0.05), but significant higher than that of groups A, C, D and F (P < 0.05), the optimal concentration of LEP was 200 ng/mL. At 7 days after culture, group F witnessed no expression of Cbf alpha 1, ALP, Col I and OCN mRNA, while groups B and E witnessed expressions of all those indexes, but the expressions in group B were less than those of group E. CONCLUSION: LEP can stimulate osteoblastic differentiation of hBMSCs in vitro, and the possible mechanism is its role of promoting the expression of osteoblastic related genes.

Leptin expression by heterotopic ossification-isolated tissue in rats with Achilles' tenotomy.

OBJECTIVE: To set up heterotopic ossification (HO) models according to McClure and determine whether leptin messenger ribonucleic acid (mRNA) and protein are expressed in HO-isolated tissue. METHODS: This study was performed in the Department of Spine and Orthopedics, Southern Medical University, Guangzhou, China from November 2007 to June 2008. Thirty-six male rats were randomly divided into sham, partial achilles' tenotomy (PAT), and achilles' tenotomy (AT) groups, with 12 rats in each group. X-ray and histological examination were carried out to ensure the formation of HO at 5 and 10 weeks after operation. Specimens from achilles tendons and surrounding tissue were taken and processed. Meanwhile, the expression of leptin mRNA (5 and 10 weeks) and protein (10 weeks) in achilles tendons and the surrounding tissue were examined respectively using reverse transcription-polymerase chain reaction assay and immunohistochemical methods. RESULTS: There were no leptin mRNA and protein expression in the sham and a weak expression in the PAT of Achilles tendons and surrounding tissue, whereas there was strong expression in the AT group. CONCLUSION: Leptin is involved in the formation of HO, its mechanisms is related to induction of bone formation and maturation through a series of cellular events, including: proliferation/differentiation of many kinds of cells, collagen synthesis, mineralization, and vascularization of the extracellular matrix.

[Preparation of nano-nacre artificial bone].

OBJECTIVE: To assess the improvements in the properties of nano-nacre artificial bone prepared on the basis of nacre/polylactide acid composite artificial bone and its potential for clinical use. METHODS: The compound of nano-scale nacre powder and poly-D, L-lactide acid (PDLLA) was used to prepare the cylindrical hollow artificial bone, whose properties including raw material powder scale, pore size, porosity and biomechanical characteristics were compared with another artificial bone made of micron-scale nacre powder and PDLLA. RESULTS: Scanning electron microscope showed that the average particle size of the nano-nacre powder was 50.4-/+12.4 nm, and the average pore size of the artificial bone prepared using nano-nacre powder was 215.7-/+77.5 microm, as compared with the particle size of the micron-scale nacre powder of 5.0-/+3.0 microm and the pore size of the resultant artificial bone of 205.1-/+72.0 microm. The porosities of nano-nacre artificial bone and the micron-nacre artificial bone were (65.4-/+2.9)% and (53.4-/+2.2)%, respectively, and the two artificial bones had comparable compressive strength and Young's modulus, but the flexural strength of the nano-nacre artificial bone was lower than that of the micro-nacre artificial bone. CONCLUSIONS: The nano-nacre artificial bone allows better biodegradability and possesses appropriate pore size, porosity and biomechanical properties for use as a promising material in bone tissue engineering.