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In the present work a nonmonotonic dependence of standard rate constant (k0) on reorganization energy (λ) was discovered qualitatively from electron transfer (Marcus-Hush-Levich) theory for heterogeneous electron transfer processes on electrode surface. It was found that the nonmonotonic dependence of k0 on λ is another result, besides the disappearance of the famous Marcus inverted region, coming from the continuum of electronic states in electrode: with the increase of λ, the states for both Process I and Process II ET processes all vary from nonadiabatic to adiabatic state continuously, and the λ dependence of k0 for Process I is monotonic thoroughly, while for Process II on electrode surface the λ dependence of k0 could show a nonmonotonicity. [ABSTRACT FROM AUTHOR]

BACKGROUND: Foxtail millet (Setaria italica) is a whole millet grain that has been considered for improving the disorder of glucose and lipid metabolism. The purpose of the work is to explore the extraction and enrichment of polyphenols from foxtail millets which can regulate the disorder of glucose and lipid metabolism by increasing endogenous GLP‐1 (glucagon‐like peptide‐1). RESULTS: The optimum ultrasound‐assisted extraction (UAE) of foxtail millet polyphenols (FMPs) was as follows: 70 °C and 400 W and 70% ethanol concentration, further purification using macroporous resin. In vitro, the FMP eluent of 60% ethanol (FMP‐60) has the best effect in promoting GLP‐1 secretion from L cells among the different active components of FMP. Millet polyphenols (MPs) were obtained from finishing foxtail millet with the bran removed by the same extraction and purification method. Compared with MP‐60, FMP‐60 mainly included eight active phenolic constituents and contained more ferulic acid, p‐coumaric acid, 2‐hydroxycinnamic acid, and coniferaldehyde. After gavage treatment of diet‐induced obese (DIO) mice with FMP‐60, FMP‐60 promoted endogenous GLP‐1 secretion in mice and ameliorated disorders of glucolipid metabolism in DIO mice. CONCLUSION: FMP‐60 could improve glucose homeostasis and ameliorates metabolic disease by promoting the endogenous GLP‐1 level and preventing weight gain in DIO mice. © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Pyroptosis is a type of regulated cell death that relies on caspases, vesicles, and the cleavage of gasdermin proteins (which create pores in the cell membrane). The nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome, which is involved in this process, is the most widely studied inflammasome. Caspase-1 activates pro-inflammatory cytokines, such as IL-1ß and IL-18. Gasdermin D (GSDMD) is the most important executive protein. GSDMD, a substrate rather than an upstream protease, determines the occurrence of pyroptosis. Pyroptosis is essential for maintaining body homeostasis, but excessive or poorly regulated cell death can aggravate the inflammatory response. Undoubtedly, this will be an important direction for future research on Alzheimer's disease (AD). Here, we review recent research progress on the morphological characteristics, molecular mechanisms, and role of pyroptosis in the context of AD, thereby providing new directions for identifying potential disease biomarkers and treatment strategies for AD. [ABSTRACT FROM AUTHOR]

Gold-silver bimetallic nanoparticles with broad plasmon response were fabricated on soft substrates using a laser-induced transfer technique. The bimetallic nanostructures were fabricated with centimeter scale. By careful design, an approximately 200-nm broad plasmon response can be obtained by gold-silver alloy nanoparticles, which can be attributed to the electromagnetic interaction between gold and silver nanoparticles. This nanofabrication technique provides an annealing-free approach for the fabrication of flexible bimetallic nanostructures with a broad plasmon response with low cost. [ABSTRACT FROM AUTHOR]

The site preference, electronic structure and magnetic properties of Mn2RhAl have been studied by first-principles calculations. Both the Cu2MnAl-structure and the Hg2CuTi-type have been tested. For the compound Mn2RhAl, the Hg2CuTi structure is the more stable one with a lattice parameter of 5.80 Å. The Mn2RhAl alloy is predicted to be a half-metal with 100% spin polarization of the conduction electrons at the Fermi level (EF). The calculated total magnetic moment is 2.00 μB per unit cell, which is in line with the Slater-Pauling curve of Mt = Zt -- 24. The Mn(A) and Mn(B) atom-projected spin moments are --1.54 μB and 3.16 μB, respectively. The resulting moment is mainly determined by the antiparallel aligned Mn(A) and Mn(B) spin moment. Whereas, the small spin magnetic moment of Rh is small and only 0.38 μB and the Al atom is almost nonmagnetic. Such an alloy may be a promising material for future spintronics devices. [ABSTRACT FROM AUTHOR]

Pompe disease has resisted enzyme replacement therapy with acid ct-glucosidase (GAA), which has been attributed to inefficient cation-independent mannose-6-phosphate receptor (CI-MPR) mediated uptake. We evaluated 132-agonist drugs, which increased CI-MPR expression in GAA knockout (KO) mice. Clenbuterol along with a low-dose adeno-associated virus vector increased Rotarod latency by 75% at 4 wk, in comparison with vector alone (P<2x10-5). Glycogen content was lower in skeletal muscles, including soleus (P<0.01), extensor digitorum longus (EDL; P<0.001), and tibialis anterior (P<0.05) following combination therapy, in comparison with vector alone. Glycogen remained elevated in the muscles following clenbuterol alone, indicating an adjunctive effect with gene therapy. Elderly GAA-KO mice treated with combination therapy demonstrated 2-fold increased wire-hang latency, in comparison with vector or clenbuterol alone (P<0.001). The glycogen content of skeletal muscle decreased following combination therapy in elderly mice (P<0.05). Finally, CI-MPR-KO/GAA-KO mice did not respond to combination therapy, indicating that clenbuterol's effect depended on CI-MPR expression. In summary, adjunctive β2-agonist treatment increased CI-MPR expression and enhanced efficacy from gene therapy in Pompe disease, which has implications for other lysosomal storage disorders that involve primarily the brain. [ABSTRACT FROM AUTHOR]

Mangiferin has been shown to have the effect of improving dyslipidemia. Plasma free fatty acids (FFA) are closely associated with blood lipid metabolism as well as many diseases including metabolic syndrome. This study is to investigate whether mangiferin has effects on FFA metabolism in hyperlipidemic rats. Wistar rats were fed a high-fat diet and administered mangiferin simultaneously for 6 weeks. Mangiferin (50, 100, 150 mg/kg BW) decreased dose-dependently FFA and triglycerides (TG) levels in plasma, and their accumulations in liver, but increased the β-hydroxybutyrate levels in both plasma and liver of hyperlipidemic rats. HepG2 cells were treated with oleic acid (OA, 0.2 mmol/L) to simulate the condition of high level of plasma FFA in vitro, and were treated with different concentrations of mangiferin simultaneously for 24 h. We found that mangiferin significantly increased FFA uptake, significantly decreased intracellular FFA and TG accumulations in HepG2 cells. Mangiferin significantly increased AMP-activated protein kinase (AMPK) phosphorylation and its downstream proteins involved in fatty acid translocase (CD36) and carnitine palmitoyltransferase 1 (CPT1), but significantly decreased acyl-CoA: diacylgycerol acyltransferase 2 (DGAT2) expression and acetyl-CoA carboxylase (ACC) activity by increasing its phosphorylation level in both in vivo and in vitro studies. Furthermore, these effects were reversed by Compound C, an AMPK inhibitor in HepG2 cells. For upstream of AMPK, mangiferin increased AMP/ATP ratio, but had no effect on LKB1 phosphorylation. In conclusion, mangiferin decreased plasma FFA levels through promoting FFA uptake and oxidation, inhibiting FFA and TG accumulations by regulating the key enzymes expression in liver through AMPK pathway. Therefore, mangiferin is a possible beneficial natural compound for metabolic syndrome by improving FFA metabolism. [ABSTRACT FROM AUTHOR]

In the course of synthesizing 3-demethyltylophorine (1) by Lewis acid catalyzed intramolecular Friedel-Crafts reaction starting from N-(3-hydroxy-2,6,7-trimethoxyphenanthr- 9-ylmethyl)-2-chloromethylpyrrolidine, two chlorinated phenanthrene derivatives N-(4,10-dichloro-3-hydroxy-2,6,7-trimethoxyphenanthr-9-ylmethyl)-2-chloromethylpyrrolidine (4) and N-(4-chloro-3-hydroxy-2,6,7-trimethoxyphenanthr-9-ylmethyl)-2-chloromethylpyrrolidine (5) were obtained. The structures of these compounds were determined by spectroscopic analysis. [ABSTRACT FROM AUTHOR]

A series of phenanthrene-based tylophorine derivatives (PBTs) were synthesized and their cytotoxic activities against the H460 human large-cell lung carcinoma cell line were evaluated. Among these compounds, N-(3-hydroxy-2,6,7-trimethoxyphenanthr-9-ylmethyl)-L-prolinol (5a), and N-(3-hydroxy-2,6,7-trimethoxyphenanthr-9-ylmethyl)-L-valinol (9) exhibited good activities, with IC50 values of 11.6 and 6.1 μM, respectively. [ABSTRACT FROM AUTHOR]

In this study, we investigated the effect of bovine lactoferrin (BLf), lactoferrin hydrolysate, or iron-, zinc-saturated lactoferrin on hepatitis B virus (HBV)-infected HepG2 cells. Fluorescent quantitative polymerase chain reaction (FQ-PCR) was used to quantify HBV-DNA copies. BLf, iron- or zinc-saturated lactoferrin significantly inhibited the amplification of HBV-DNA in a dose-dependent manner in HBV-infected HepG2 cells. However, the inhibitive effect of lactoferrin hydrolysate on HBV-DNA copies was insignificant. These findings suggest that BLf inhibits the function of HBV by integrated structure. In conclusion, BLf, iron- or zinc-saturated BLf is one of the candidates for anti-HBV reagents in treatment of patients with hepatitis. [ABSTRACT FROM AUTHOR]

Plant viruses utilize the vascular system for systemic movement. The plant vascular network also transports water, photosynthates, and signaling molecules and is essential for plant growth. However, the molecular mechanisms governing vascular development and patterning are still largely unknown. From viral transport suppressor screening using virus-induced gene silencing, we identified a 26S proteasome subunit, RPN9, which is required for broad-spectrum viral systemic transport. Silencing of RPN9 in Nicotiana benthamiana inhibits systemic spread of two taxonomically distinct viruses, Tobacco mosaic virus and Turnip mosaic virus. The 26S proteasome is a highly conserved eukaryotic protease complex controlling many fundamental biochemical processes, but the functions of many 26S proteasome regulatory subunits, especially in plants, are still poorly understood. We demonstrate that the inhibition of viral systemic transport after RPN9 silencing is largely due to alterations in the vascular tissue. RPN9-silenced plants display extra leaf vein formation with increased xylem and decreased phloem. We further illustrate that RPN9 functions at least in part through regulation of auxin transport and brassinosteroid signaling, two processes that are crucial for vascular formation. We propose that RPN9 regulates vascular formation by targeting a subset of regulatory proteins for degradation. The brassinosteroid-signaling protein BZR1 is one of the targets. [ABSTRACT FROM AUTHOR]

Cs2SnI6 is a variant on tin-iodide solution-processable materials and may lead to a lead-free material for use in next-generation photovoltaic cells and other optoelectronics. So far, only a few studies have been conducted where shape and geometry control of Cs2SnI6 nanocrystals is demonstrated. Here we report a general approach to directly synthesize Cs2SnI6 of two-dimensional (2D) layered nanoplatelets as well as three-dimensional (3D) nanocrystals. The shape of Cs2SnI6 nanocrystals could be engineered into 3D nanoparticles and different 2D nanoplatelets with well-defined morphology by choosing different organic acid and amine ligands via a hot injection process. Moreover, the thickness of layered 2D nanoplatelets could be adjusted by changing the amount of Cs-oleate present during the synthesis. The photoluminescence emission peaks changed from 643 to 742 nm based on nanomaterial shape. Our method provides a facile and versatile route to rationally control the shape of the Cs2SnI6 nanocrystals, which will create opportunities for applications in lead-free optoelectronics. [ABSTRACT FROM AUTHOR]

One- and two-dimensional distributed feedback cavities were constructed on free-standing polymer membranes using spin-coating and lift-off techniques. Low threshold lasing was generated through feedback amplification when the 290-nm membrane device was optically pumped, which was attributed to the strong confinement mechanism provided by the active waveguide layer without a substrate. The free-standing membrane polymer laser is flexible and can be transplanted. Singleand dual-wavelength fiber lasers were achieved by directly attaching the membrane polymer laser on the optical fiber end face. This technique provides potential to fabricate polymer lasers on surfaces with arbitrary shapes. [ABSTRACT FROM AUTHOR]

Enzyme or gene replacement therapy with acid α-glucosidase (GAA) has achieved only partial efficacy in Pompe disease. We evaluated the effect of adjunctive clenbuterol treatment on cation-independent mannose-6-phosphate receptor (CI-MPR)-mediated uptake and intracellular trafficking of GAA during muscle-specific GAA expression with an adeno-associated virus (AAV) vector in GAA-knockout (KO) mice. Clenbuterol, which increases expression of CI-MPR in muscle, was administered with the AAV vector. This combination therapy increased latency during rotarod and wirehang testing at 12 wk, in comparison with vector alone. The mean urinary glucose tetrasaccharide (Glc4), a urinary biomarker, was lower in GAA-KO mice following combination therapy, compared with vector alone. Similarly, glycogen content was lower in cardiac and skeletal muscle following 12 wk of combination therapy in heart, quadriceps, diaphragm, and soleus, compared with vector alone. These data suggested that clenbuterol treatment enhanced trafficking of GAA to lysosomes, given that GAA was expressed within myofibers. The integral role of CI-MPR was demonstrated by the lack of effectiveness from clenbuterol in GAA-KO mice that lacked CI-MPR in muscle, where it failed to reverse the high glycogen content of the heart and diaphragm or impaired wirehang performance. However, the glycogen content of skeletal muscle was reduced by the addition of clenbuterol in the absence of CI-MPR, as was lysosomal vacuolation, which correlated with increased AKT signaling. In summary, β2-agonist treatment enhanced CI-MPR-mediated uptake and trafficking of GAA in mice with Pompe disease, and a similarly enhanced benefit might be expected in other lysosomal storage disorders. [ABSTRACT FROM AUTHOR]

A sintering method, which is called low-temperature instantaneous liquid-phase sintering with addition of Sn, is exploited to fabricate Terfenol-D sintered compacts. In this work, the influences of powder size, Sn content, compaction pressure, and sintering technique on the magnetic and mechanical properties have been investigated. A large magnetostriction (λ∥) of 546 ppm at 12 kOe is obtained for the sintered compact fabricated at the following conditions: a powder size <75 μm, a Sn content of 8:100, a compaction pressure of 1.0 GPa, and sintering at 250 °C for 150 s in the rapid thermal processor. In addition, the sintered compact fabricated by this means possesses higher oxidation resistance and its hard brittleness improves. [ABSTRACT FROM AUTHOR]

Background: D-Tagatose 3-epimerase epimerizes d-fructose to yield d-psicose, which is a rare sugar that exists in small quantities in nature and is difficult to synthesize chemically. We aim to explore potential industrial biocatalysts for commercial-scale manufacture of this rare sugar. A d-tagatose 3-epimerase from Rhodobacter sphaeroides (RsDTE) has recently been identified as a d-tagatose 3-epimerase that can epimerize d-fructose to yield d-psicose with a high conversion rate. Results: The purified RsDTE by Ni-affinity chromatography, ionic exchange chromatography and gel filtration forms a tetramer in solution. The maximal activity was in Tris-HCl buffer pH 8.5, and the optimal temperature was at 35 °C. The product, d-psicose, was confirmed using HPLC and NMR. Crystals of RsDTE were obtained using crystal kits and further refined under crystallization conditions such as 10% PEG 8000,0.1 M HEPES pH 7.5, and 8% ethylene glycol at 20 °C using the sitting-drop vapor diffusion method. The RsDTE homology model showed that it possessed the characteristic TIM-barrel fold. Four residues, Glu156, Asp189, Gln215 and Glu250, forms a hydrogen bond network with the active Mn(II) for the hydride transfer reaction. These residues may constitute the catalytic tetrad of RsDTE. The residues around O1, O2 and O3 of the substrates were conserved. However, the binding-site residues are different at O4, O5 and O6. Arg118 formed the unique hydrogen bond with O4 of d-fructose which indicates RsDTE's preference of d-fructose more than any other family enzymes. Conclusions: RsDTE possesses a different metal-binding site. Arg118, forming unique hydrogen bond with O4 of d-fructose, regulates the substrate recognition. The research on d-tagatose 3-epimerase or d-psicose 3-epimerase enzymes attracts enormous commercial interest and would be widely used for rare sugar production in the future. [ABSTRACT FROM AUTHOR]

Distributed feedback (DFB) lasing is observed in a metallic cavity, which consists of a gold grating and a polymer membrane. The gold grating is prepared by evaporating a 25 nm thin film of gold on the photoresist grating fabricated by interference lithography. A 150 nm thick polymer membrane is directly attached on the gold grating, forming a suspended membrane supported by the grating ridge. The assembly method decreases the metallic contact area, which makes the mode more photonic and thereby reduces the ohmic loss of the metal. Low threshold DFB lasing can be achieved when the sample is optically pumped. The fabrication technique provides a facile way to realize plasmonic DFB polymer lasers. [ABSTRACT FROM AUTHOR]

Background/Aims: Atherosclerosis is a multifactorial chronic disease and is the main cause of death and impairment in the world. Endothelial injury and apoptosis play a crucial role in the onset and development of atherosclerosis. MicroRNAs (miRNAs) have been proven to be involved in the pathogenesis of atherosclerosis. However, studies of the functional role of apoptosis-related miRNAs in the endothelium during atherogenesis are limited. Methods: Cell injury and apoptosis were measured in five types of cells transfected with miR-1185 or cotransfected with miR-1185 and its inhibitor. Bioinformatics analysis and a luciferase reporter assay were used to confirm the targets of miR-1185. The effects of the targets of miR-1185 on endothelial apoptosis were determined using small-interfering RNA. Results: In this study, we first report that miR-1185 significantly promoted apoptosis in endothelial cells but not in vascular smooth muscle cells and macrophages. A mechanistic analysis showed that ultraviolet irradiation resistance-associated gene (UVRAG) and krev1 interaction trapped gene 1 (KRIT1), targets of miR-1185, mediated miR-1185-induced endothelial cell apoptosis. Conclusion: The results revealed the impact of miR-1185 on endothelial apoptosis, suggesting that miR-1185 may be a potential target for the prevention and treatment of atherosclerosis. [ABSTRACT FROM AUTHOR]

Background/Aims: Atherosclerosis is a multifactorial chronic disease and is the main cause of death and impairment in the world. Endothelial injury and apoptosis play a crucial role in the onset and development of atherosclerosis. MicroRNAs (miRNAs) have been proven to be involved in the pathogenesis of atherosclerosis. However, studies of the functional role of apoptosis-related miRNAs in the endothelium during atherogenesis are limited. Methods: Cell injury and apoptosis were measured in five types of cells transfected with miR-1185 or co-transfected with miR-1185 and its inhibitor. Bioinformatics analysis and a luciferase reporter assay were used to confirm the targets of miR-1185. The effects of the targets of miR-1185 on endothelial apoptosis were determined using small-interfering RNA. Results: In this study, we first report that miR-1185 significantly promoted apoptosis in endothelial cells but not in vascular smooth muscle cells and macrophages. A mechanistic analysis showed that ultraviolet irradiation resistance-associated gene (UVRAG) and krev1 interaction trapped gene 1 (KRIT1), targets of miR-1185, mediated miR-1185-induced endothelial cell apoptosis. Conclusion: The results revealed the impact of miR-1185 on endothelial apoptosis, suggesting that miR-1185 may be a potential target for the prevention and treatment of atherosclerosis. [ABSTRACT FROM AUTHOR]

Multi-wavelength polymer lasers are produced with one-dimensional beat structures fabricated with multiple gratings at the same substrate location using interference lithography. As a distributed feedback cavity, the beat structure is equivalent to a linear superposition of multiple grating cavities. Each emission wavelength is determined by the corresponding grating cavity, which implies that interaction between different cavities is very weak. For a beat structure consisting of three gratings, emission peaks at 558 nm, 565 nm, and 569 nm originate from 350-nm, 362-nm, and 374-nm cavities, with thresholds of 14.5μJ/cm2, 15.0μJ/cm2, and 13.5μJ/cm2, respectively. This technique provides an alternative way to design compact polymer lasers. [ABSTRACT FROM AUTHOR]

Background: The maintenance of nucleus pulposus (NP) viability in vitro is difficult. The annulus fibrosus (AF) pathway reflects one nutrient transport channel and may have an important effect on NP viability in disc organ cultures. The present study describes a feasible disc pre-treatment involving the AF and investigates its efficacy in improving NP bioactivity in an in vitro disc bioreactor culture.Methods: Rabbit discs that were randomly assigned to the experimental group (EG) were pretreated via the surgical removal and controlled trypsinization of the outer AF. The discs in the control group (CG) did not receive any special treatment. All discs were organ-cultured in a self-developed bioreactor. Solute transport into the central NP was measured using a methylene blue solution. On days 7 and 14, histological properties, cell viability, cell membrane damage, gene expression and matrix composition within the NP in these two groups were compared with each other and with the corresponding parameters of fresh NP samples. Additionally, the structures of the outer AF and the cartilage endplate (CEP) following pre-treatment were also assessed.Results: The outer AF in the EG became disorganized, but no specific changes occurred in the CEP or the inner AF following pre-treatment. The discs in the EG exhibited increased penetration of methylene blue into the central NP. On days 7 and 14, the NP bioactivity in the EG was improved compared with that of the CG in terms of cell viability, cell membrane damage, gene expression profile and matrix synthesis. Moreover, cell viability and matrix synthesis parameters in the EG were more similar to those of fresh samples than they were to the same parameters in the CG on day 14.Conclusions: Using this disc pre-treatment, i.e., the surgical removal and controlled trypsinization of the outer AF, NP bioactivity was better maintained for up to 14 days in an in vitro disc bioreactor culture. [ABSTRACT FROM AUTHOR]

Dual-wavelength laser emission is achieved by using an active/inactive/active sandwich-like structure, which can be conveniently fabricated using spin coating technique. Poly [(9, 9-dioctylfluorenyl- 2, 7-diyl)-alt-co-(1, 4-benzo-(2, 1', 3) -thiadiazole)] and polyvinyl alcohol are employed as the active and the inactive materials, respectively. Two laser wavelengths are simultaneously observed, which are attributed to the difference of the surrounding refractive index of two active waveguides in the sandwich-like structure. Each wavelength is controlled by the respective waveguide structure, meaning that multi-wavelength laser can be designed by stacking the active/inactive layer pair. These results provide more flexibility to design compact laser sources. [ABSTRACT FROM AUTHOR]

Elevated serum free fatty acids (FFAs) levels play an important role in the development of insulin resistance (IR) and diabetes. We investigated the dynamic changes and the underlying regulatory mechanism of postprandial FFA profile in hyperlipidemia (HLP) and their relation with insulin sensitivity in both humans and mice. We found that serum stearic acid (SA) is the only fatty acid that is increased dramatically in the postprandial state. The elevation of SA is due to increased insulin-stimulated de novo synthesis mediated by sterol regulatory element--binding protein-1c (SREBP-1c)/acetyl-CoA carboxylase/fatty acid synthase/elongation of long-chain fatty acid family member 6 (ELOVL6) and the elongation of palmitic acid (PA) catalyzed by ELOVL6. Downregulation of SREBP-1c or ELOVL6 by small interfering RNA can reduce SA synthesis in liver and serum SA level, followed by amelioration of IR in HLP mice. However, inhibition of SREBP-1c is more effective in improving IR than suppression of ELOVL6, which resulted in accumulation of PA. In summary, increased postprandial SA is caused by the insulin-stimulated SREBP-1c pathway and elongation of PA in HLP. Reduction of postprandial SA is a good candidate for improving IR, and SREBP-1c is potentially a better target to prevent IR and diabetes by decreasing SA. [ABSTRACT FROM AUTHOR]

Small-diameter (<4 mm) vascular constructs are urgently needed for patients requiring replacement of their peripheral vessels. However, successful development of constructs remains a significant challenge. In this study, we successfully developed small-diameter vascular constructs with high patency using our integrally designed computer-controlled bioreactor system. This computer-controlled bioreactor system can confer physiological mechanical stimuli and fluid flow similar to physiological stimuli to the cultured grafts. The medium circulating system optimizes the culture conditions by maintaining fixed concentration of O2 and CO2 in the medium flow and constant delivery of nutrients and waste metabolites, as well as eliminates the complicated replacement of culture medium in traditional vascular tissue engineering. Biochemical and mechanical assay of newly developed grafts confirm the feasibility of the bioreactor system for small-diameter vascular engineering. Furthermore, the computer-controlled bioreactor is superior for cultured cell proliferation compared with the traditional non-computer- controlled bioreactor. Specifically, our novel bioreactor system may be a potential alternative for tissue engineering of large-scale small-diameter vascular vessels for clinical use. [ABSTRACT FROM AUTHOR]

Infantile Pompe disease progresses to a lethal cardiomyopathy in absence of effective treatment. Enzyme-replacement therapy (ERT) with recombinant human acid α-glucosidase (rhGAA) has been effective in most patients with Pompe disease, but efficacy was reduced by high-titer antibody responses. Immunomodulatory gene therapy with a low dose adeno-associated virus (AAV) vector (2 × 1010 particles) containing a liver-specific regulatory cassette significantly lowered immunoglobin G (IgG), IgG1, and IgE antibodies to GAA in Pompe disease mice, when compared with mock-treated mice (P < 0.05). AAV-LSPhGAApA had the same effect on GAA-antibody production whether it was given prior to, following, or simultaneously with the initial GAA injection. Mice given AAV-LSPhGAApA had significantly less decrease in body temperature (P < 0.001) and lower anaphylactic scores (P < 0.01) following the GAA challenge. Mouse mast cell protease-1 (MMCP-1) followed the pattern associated with hypersensitivity reactions (P < 0.05). Regulatory T cells (Treg) were demonstrated to play a role in the tolerance induced by gene therapy as depletion of Treg led to an increase in GAA-specific IgG (P < 0.001). Treg depleted mice were challenged with GAA and had significantly stronger allergic reactions than mice given gene therapy without subsequent Treg depletion (temperature: P < 0.01; symptoms: P < 0.05). Ubiquitous GAA expression failed to prevent antibody formation. Thus, immunomodulatory gene therapy could provide adjunctive therapy in lysosomal storage disorders treated by enzyme replacement. [ABSTRACT FROM AUTHOR]

Glycogen storage disease type Ia (GSD-Ia) profoundly impairs glucose release by the liver due to glucose-6-phosphatase (G6Pase) deficiency. An adeno-associated virus (AAV) containing a small human G6Pase transgene was pseudotyped with AAV8 (AAV2/8) to optimize liver tropism. Survival was prolonged in 2-week-old G6Pase (–/–) mice by 600-fold fewer AAV2/8 vector particles (vp), in comparison to previous experiments involving this model (2 × 109 vp; 3 × 1011 vp/kg). When the vector was pseudotyped with AAV1, survival was prolonged only at a higher dose (3 × 1013 vp/kg). The AAV2/8 vector uniquely prevented hypoglycemia during fasting and fully corrected liver G6Pase deficiency in GSD-Ia mice and dogs. The AAV2/8 vector has prolonged survival in three GSD-Ia dogs to >11 months, which validated this strategy in the large animal model for GSD-Ia. Urinary biomarkers, including lactate and 3-hydroxybutyrate, were corrected by G6Pase expression solely in the liver. Glycogen accumulation in the liver was reduced almost to the normal level in vector-treated GSD-Ia mice and dogs, as was the hepatocyte growth factor (HGF) in GSD-Ia mice. These preclinical data demonstrated the efficacy of correcting hepatic G6Pase deficiency, and support the further preclinical development of AAV vector–mediated gene therapy for GSD-Ia.Molecular Therapy (2008); 16 4 665–672 doi:10.1038/mt.2008.15 [ABSTRACT FROM AUTHOR]