Adeno-associated virus (AAV)-mediated CRISPR-Cas9 editing holds promise to treat many diseases. The immune response to bacterial-derived Cas9 has been speculated as a hurdle for AAV-CRISPR therapy. ...However, immunological consequences of AAV-mediated Cas9 expression have thus far not been thoroughly investigated in large mammals. We evaluate Cas9-specific immune responses in canine models of Duchenne muscular dystrophy (DMD) following intramuscular and intravenous AAV-CRISPR therapy. Treatment results initially in robust dystrophin restoration in affected dogs but also induces muscle inflammation, and Cas9-specific humoral and cytotoxic T-lymphocyte (CTL) responses that are not prevented by the muscle-specific promoter and transient prednisolone immune suppression. In normal dogs, AAV-mediated Cas9 expression induces similar, though milder, immune responses. In contrast, other therapeutic (micro-dystrophin and SERCA2a) and reporter (alkaline phosphatase, AP) vectors result in persistent expression without inducing muscle inflammation. Our results suggest Cas9 immunity may represent a critical barrier for AAV-CRISPR therapy in large mammals.
Sleep disturbances and dementia are two common and significant health problems in older adults. Investigations suggest that sleep disturbances might increase the risk of dementia. The aim of the ...present study was to systematically review and meta-analyze the predictive roles of overall sleep disturbances, their subtypes (e.g., insomnia, sleep disordered breathing SDB), and other sleep problems (e.g., excessive daytime sleepiness, sleep-related movement disorder, circadian rhythm sleep disorder, and nonspecific sleep problems) in incident all-cause dementia and Alzheimer's disease (AD) and vascular dementia subtypes. We performed a systematic search of the PubMed, EMBase, ISI Web of Science, and PsycINFO databases for longitudinal studies that were published up to October 28, 2016. A total of 12,926 papers were retrieved. Eighteen longitudinal studies that included 246,786 subjects at baseline and 25,847 dementia cases after an average 9.49 y of follow-up were eligible for inclusion. Compared with individuals without sleep disturbances, subjects who reported sleep disturbances had a higher risk of incident all-cause dementia, AD, and vascular dementia. The subgroup analysis showed that insomnia increased the risk of AD but not vascular or all-cause dementia. In contrast, SDB was associated with a higher incidence of all-cause dementia, AD, and vascular dementia. This meta-analysis suggests that sleep disturbances may predict the risk of incident dementia. Moreover, insomnia was associated only with incident AD, and SDB was a risk factor of all-cause dementia, AD, and vascular dementia. However, sleep disturbances were evaluated mainly based on self-reports, and some confounders may mediate the relationship between sleep disturbances and dementia. Therefore, the results should be further validated. In summary, these findings may help identify individuals who are at risk for dementia and optimize early prevention strategies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Increasing evidence suggests that abnormal regulation of neurotrophic factors is involved in the etiology and pathogenesis of Autism Spectrum Disorder (ASD). However, clinical data on neurotrophic ...factor levels in children with ASD were inconsistent. Therefore, we performed a systematic review of peripheral blood neurotrophic factors levels in children with ASD, and quantitatively summarized the clinical data of peripheral blood neurotrophic factors in ASD children and healthy controls. A systematic search of PubMed and Web of Science identified 31 studies with 2627 ASD children and 4418 healthy controls to be included in the meta-analysis. The results of random effect meta-analysis showed that the peripheral blood levels of brain-derived neurotrophic factor (Hedges' g = 0.302; 95% CI = 0.014 to 0.591; P = 0.040) , nerve growth factor (Hedges' g = 0.395; 95% CI = 0.104 to 0.686; P = 0.008) and vascular endothelial growth factor (VEGF) (Hedges' g = 0.097; 95% CI = 0.018 to 0.175; P = 0.016) in children with ASD were significantly higher than that of healthy controls, whereas blood neurotrophin-3 (Hedges' g = - 0.795; 95% CI = - 1.723 to 0.134; P = 0.093) and neurotrophin-4 (Hedges' g = 0.182; 95% CI = - 0.285 to 0.650; P = 0.445) levels did not show significant differences between cases and controls. Taken together, these results clarified circulating neurotrophic factor profile in children with ASD, strengthening clinical evidence of neurotrophic factor aberrations in children with ASD.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Pulp mill wastewater was treated using the coagulation-flocculation process with aluminum chloride as the coagulant and a modified natural polymer, starch-
g-PAM-
g-PDMC polyacrylamide and poly ...(2-methacryloyloxyethyl) trimethyl ammonium chloride, as the flocculant. A novel approach with a combination of response surface methodology (RSM) and uniform design (UD) was employed to evaluate the effects and interactions of three main influential factors, coagulant dosage, flocculant dosage and pH, on the treatment efficiency in terms of the supernatant turbidity and lignin removals as well as the water recovery. The optimal conditions obtained from the compromise of the three desirable responses, supernatant turbidity removal, lignin removal and water recovery efficiency, were as follows: coagulant dosage of 871 mg/L, flocculant dosage of 22.3 mg/L and pH 8.35. Confirmation experiments demonstrated that such a combination of the UD and RSM is a powerful and useful approach for optimizing the coagulation-flocculation process for the pulp mill wastewater treatment.
► A modified natural polymer, was used as flocculant to treat pulp mill wastewater. ► A novel approach combining RSM and UD was used to optimize the process. ► Experiments demonstrated that such a combination is an effective and powerful.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Mantle cell lymphoma (MCL) is a lymphoproliferative disorder lacking reliable therapies. PI3K pathway contributes to the pathogenesis of MCL, serving as a potential target. However, idelalisib, an ...FDA-approved drug targeting PI3Kδ, has shown intrinsic resistance in MCL treatment. Here we report that a p300/CBP inhibitor, A-485, could overcome resistance to idelalisib in MCL cells in vitro and in vivo. A-485 was discovered in a combinational drug screening from an epigenetic compound library containing 45 small molecule modulators. We found that A-485, the highly selective catalytic inhibitor of p300 and CBP, was the most potent compound that enhanced the sensitivity of MCL cell line Z-138 to idelalisib. Combination of A-485 and idelalisib remarkably decreased the viability of three MCL cell lines tested. Co-treatment with A-485 and idelalisib in Maver-1 and Z-138 MCL cell xenograft mice for 3 weeks dramatically suppressed the tumor growth by reversing the unsustained inhibition in PI3K downstream signaling. We further demonstrated that p300/CBP inhibition decreased histone acetylation at RTKs gene promoters and reduced transcriptional upregulation of RTKs, thereby inhibiting the downstream persistent activation of MAPK/ERK signaling, which also contributed to the pathogenesis of MCL. Therefore, additional inhibition of p300/CBP blocked MAPK/ERK signaling, which rendered maintaining activation to PI3K-mTOR downstream signals p-S6 and p-4E-BP1, thus leading to suppression of cell growth and tumor progression and eliminating the intrinsic resistance to idelalisib ultimately. Our results provide a promising combination therapy for MCL and highlight the potential use of epigenetic inhibitors targeting p300/CBP to reverse drug resistance in tumor.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Quercetin is one of the most abundant dietary flavonoid compounds, and its mechanism for combating age-related neurodegenerative diseases is unclear. In this study, quercetin (35 and 70 mg kg
−1
, ...orally administered for 4 weeks) was administered to 7-month-old aging mice (senescence-accelerated mouse prone 8 mice). As a result, it was found that quercetin could improve spatial learning and memory impairment displayed by aging mice in the Morris water maze. The results of immunoblotting reflected the protein expressions of the longevity factor (sirtuin1), inflammasomes (NLRP3 and ASC), synaptic marker (PSD95) and neurotrophic factors (BDNF and NGF) in the hippocampus of the brain. It indicated that the intervention of quercetin could increase the expression of sirtuin1 and prevent neuroinflammation, which was evident from the decrease in the protein levels of the astrocyte marker (GFAP) and inflammatory factors (cleaved-caspase 1, IL-1β and IL-18). In addition, quercetin could reduce the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) in the hippocampus of aging mice. Current data indicated that quercetin might improve neuroinflammation in aging mice by regulating the Sirtuin1/NLRP3 pathway.
Quercetin is one of the most abundant dietary flavonoid compounds, and its mechanism for combating age-related neurodegenerative diseases is unclear.
Electroactive microbial cells have evolved unique extracellular electron transfer to conduct the reactions via redox outer‐membrane (OM) proteins. However, the electron transfer mechanism at the ...interface of OM proteins and nanomaterial remains unclear. In this study, the mechanism for the electron transfer at biological/inorganic interface is investigated by integrating molecular modeling with electrochemical and spectroscopic measurements. For this purpose, a model system composed of OmcA, a typical OM protein, and the hexagonal tungsten trioxide (h‐WO3) with good biocompatibility is selected. The interfacial electron transfer is dependent mainly on the special molecular configuration of OmcA and the microenvironment of the solvent exposed active center. Also, the apparent electron transfer rate can be tuned by site‐directed mutagenesis at the axial ligand of the active center. Furthermore, the equilibrium state of the OmcA/h‐WO3 systems suggests that their attachment is attributed to the limited number of residues. The electrochemical analysis of OmcA and its variants reveals that the wild type exhibits the fastest electron transfer rate, and the transient absorption spectroscopy further shows that the axial histidine plays an important role in the interfacial electron transfer process. This study provides a useful approach to promote the site‐directed mutagenesis and nanomaterial design for bioelectrocatalytic applications.
This work used molecular modeling and experimental measurements to explore electron transfer between bacterial cytochromes and nanomaterials. The results highlight the importance of outer‐membrane protein configuration and active center microenvironment in governing electron transfer processes. Site‐directed mutagenesis can adjust electron transfer rates, enhancing the understanding of microbe‐nanostructure interactions for improved biotic‐linked‐abiotic bioelectrocatalytic system design.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Motivated by recent experimental observation of photonic spin Hall effect at metasurfaces, we study lateral Goos-Hänchen (GH) and transverse Imbert-Fedorov (IF) shifts of an arbitrarily polarized ...light beam totally reflected from metasurfaces, in terms of stationary phase method and energy flux method. The intriguing phenomenon is that the gradient in phase discontinuity results in anomalous reflection and refraction, and the GH and IF shifts can be thus controlled from negative to positive values by changing the sign of phase discontinuity. The tunable GH and IF shifts have potential applications in nano-optics, with the development of novel functionalities and performances of metasurfaces.
Since nitrate causes severe ecological and health risks, nitrate contamination of drinking water sources has become one of the most important water quality concerns all over the world. Photocatalytic ...reduction of nitrate to molecular nitrogen presents a promising approach to remove nitrate from drinking water sources. However, harmful intermediates like NO2−, NO, NO2 and N2O are usually formed, and metal loading or hole scavengers are generally needed to reduce the recombination of photo-generated electrons and holes, which will cause secondary pollution to drinking water. In this work, an efficient, selective and sustainable bioelectro-photocatalytic nitrate-reducing system by utilizing commercial TiO2 nanoparticles P25 as the photocatalyst and bio-electrons from microbial metabolism as the hole scavenger is reported. In this system, bio-electrons extracted from organic substrates in bioanode are transferred to the photocathode through an external circuit for hole quenching. With the utilization of the residual photogenerated electrons, nitrate is completely reduced to nitrogen without accumulation of harmful nitrite or ammonium. The experimental results and the mechanistic analysis using the first-principles density functional theory calculations demonstrate that toxic by-products like nitrite or ammonium will not be accumulated in this system. Thus, this approach has a great potential for sustainable remediation of nitrate-contaminated drinking water sources.
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•Bioelectro-photocatalytic system had a high selectivity for reduction of NO3− to N2.•Bio-electrons served as hole scavenger in the photocatalytic reaction.•Experimental results and chemical calculations showed no accumulation of byproducts.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
•The small-molecule inhibitors targeting CD47/SIRPα axis, a promising phagocytosis checkpoint in cancer therapy, are reviewed for the first time.•In addition to targeting the interaction of ...CD47/SIRPα, compounds regulating CD47 at transcriptional, translational and posttranslational levels are summarized.•Challenges followed by the corresponding strategies are proposed for further development of small-molecule inhibitors targeting CD47/SIRPα axis.
Immunotherapy has become an indispensable part of cancer treatment. A pivotal phagocytosis checkpoint, named cluster of differentiation 47 (CD47), which functions as ‘don’t eat me’ signal to protect cells from phagocytosis upon interaction with signal regulatory protein alpha (SIRPα) on macrophages, has recently attracted much attention. Numerous antibodies targeting the CD47/SIRPα axis have shown encouraging efficacy in clinical trials. Meanwhile, studies on small-molecule inhibitors that interfere with CD47/SIRPα interaction or regulate CD47 expression are also in full swing. In this review, we summarize the small-molecule inhibitors interrupting the binding of CD47/SIRPα and regulating CD47 at the transcriptional, translational, and post-translational modification (PTM) levels. We provide perspectives and strategies for targeting the CD47/SIRPα phagocytosis checkpoint.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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