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1.
Artigo em Inglês | MEDLINE | ID: mdl-31898798

RESUMO

As long-standing clinical problems, a series of complicated infections are more difficult to treat due to the development of antibiotic resistance, especially caused by methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium (VRE), and multidrug-resistant Mycobacterium tuberculosis (M. tuberculosis). Moreover, the treatment options available to against these infections are also becoming increasingly limited. Linezolid is the first synthetic oxazolidinone antibiotic with a unique mechanism of action, and its efficacy against Gram-positive bacteria has been clearly demonstrated. However, the limitations of linezolid alone for the treatment of these complicated infections have been reported in the recent years. Combination therapy may be a good approach to enhance efficacy and prevent the development of resistance. In this review, the results of multiple linezolid combination therapies from in vitro, animal studies, and clinical cases for the treatment of MRSA, VRE, and multidrug-resistant M. tuberculosis strains will be discussed, and thus provide more relevant information for clinician in clinical practice.

2.
R Soc Open Sci ; 6(11): 191154, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31827849

RESUMO

Peanut meal (PM) has recently emerged as a potential protein source for wood adhesives, owing to superior features such as high availability, renewability and eco-friendliness. However, the poor properties of unmodified PM-based wood adhesives, compared with their petroleum-derived counterparts, limit their use in high-performance applications. In order to promote the application of PM-based wood adhesives in plywood industry, urea (U) and epichlorohydrin (ECH) were used to enhance the properties of the adhesives and the modification mechanism was investigated. PM-based wood adhesives made with U and ECH were shown to possess sufficient water resistance and exhibited higher apparent viscosity and solid content than without. Fourier-transform infrared spectroscopy results suggested that U denatured PM protein and expose more reactive groups, allowing ECH to react better with U-treated PM protein to form a dense, cross-linked network which was the main reason for the improvement of the properties. The crystallinity increased from 2.7% to 11% compared with the control, indicating that the molecular structure of the resultant adhesive modified by U and ECH became more regular and compact owing to the cross-linked network structure. Thermogravimetry tests showed that decomposition temperature of the protein skeleton structure increased from 307°C to 314°C after U and ECH modification. Scanning electron microscopy images revealed that using U and ECH for adhesives resulted in a smooth protein surface which prevented moisture penetration and improved water resistance. PM-based adhesives thus represent potential candidates to replace petroleum-derived adhesives in the plywood industry, which will effectively promote the rapid development of eco-friendly adhesives and increase the added value of PM.

3.
Biomed Pharmacother ; 123: 109736, 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31855738

RESUMO

Myelodysplastic syndrome (MDS) is a heterogeneously cloned hematopoietic stem cell malignancy with a high risk of developing acute myeloid leukemia (AML). 4-amino-2-trifluoromethyl-phenyl resinate (ATPR), a novel all-trans retinoic acid (ATRA) derivative designed in our group, was proved to be a tumor inhibitor in diverse types of cancer cells in vitro. However, little has been known about the effects of ATPR on MDS. To analyze if and to what extent it's anti-tumor activity on MDS, we performed CCK-8, Flow Cytometry, Wright-Giemsa staining, qRT-PCR, and Western blot to analyze the SKM-1 cells state after ATPR treatment in multiplex detection angles. As expected, our results proved that ATPR could effectively induce cell differentiation and reduce cell proliferation of SKM-1 cell lines. Subsequently, to further analyze the potential mechanisms, we applied Label-free proteomic techniques to discover relevant protein that may be involved. Most notably, a series of factors related to RNA behavioral regulation were changed. Among them, we demonstrated that DEAD-box RNA helicase DDX23 was abnormally ablated in MDS patients and could be restored after ATPR treatment in vitro. Besides, our results suggested that ATPR-induced SKM-1 cell maturation was counteracted when knockdown DDX23, underscoring that DDX23 might be involved. In conclusion, we confirmed that ATPR could induce SKM-1 cells differentiation and its positive influence of DDX23 may provide a new idea to relieve MDS.

4.
World Neurosurg ; 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31866456

RESUMO

BACKGROUND: Percutaneous endoscopic lumbar discectomy (PELD) has been widely used to treat various types of lumbar disc herniation, it has the advantages of less trauma, faster recovery, lower costs and higher percentage of patient satisfaction compared with open surgery. However, the treatment of lumbar spinal stenosis (LSS) is still regarded as a challenging task for percutaneous full-endoscopic surgery, especially for the elderly with multiple comorbidities and complex pathological factors. OBJECTIVE: To introduce a technique of percutaneous full-endoscopic lumbar foraminoplasty and decompression (PFELFD) by using a visualization-reamer for treating elderly lateral recess and foraminal stenosis and evaluate its efficacy and safety. METHODS: A retrospective review was conducted on 65 consecutive elderly patients (30 males and 35 females) with lateral recess and foraminal stenosis who underwent PFELFD from January 2017 to September 2017. The Visual Analog Scale (VAS) and Oswestry Disability Index (ODI) were used for the evaluation of pain relief and neurological improvement. RESULTS: The mean age was 71.58 years (range 65-89 years). The mean follow-up period was 16.12 months (range, 12-20 months). The mean operative time was 98.59 min per level (range, 55-120 min). The mean intraoperative perspective frequency was 3.21 times (range, 2-6 times). The mean hospital stay after the procedure was 2.18 days (range, 1-4 days). The back and leg VAS, ODI all over the time-points in the postoperative period were significantly lower than preoperative (P < 0.01). At the final follow-up review, the modified MacNab criteria were rated as follows: excellent in 47 patients (72.31%), good in 12 patients (16.92%), fair in 3 patients (4.62%), and poor in 4 patients (6.15%). Therefore, excellent or good results were obtained in 89.23% of the patients. CONCLUSIONS: PFELFD using a visualization-reamer is an effective and safe treatment for elderly lumbar lateral recess and foraminal stenosis. It improves the safety and efficiency of decompression and reduces intraoperative fluoroscopy.

5.
Macromol Biosci ; : e1900303, 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31867845

RESUMO

Self-healing hydrogels as wound dressings still face challenges in infection prevention, especially in the dressing of mass wounds, due to their inflexibility and the slow formation of the protective film on the wound. Therefore, designing a spray-filming (rapid-forming) hydrogel that can serve as a bacterial barrier is of particular significance in the development of wound dressings. Here, a self-healing hydrogel based on adipic acid dihydrazide-modified gelatin (Gel-ADH) and monoaldehyde-modified sodium alginate(SA-mCHO) is prepared. Using dynamic, Schiff base bonds, the hydrogels exhibit excellent self-healing properties. Moreover, the gelation time of SA-mCHO/Gel-ADH (SG) hydrogels is shortened to 2-21 s, resulting in rapid filming by spraying the two precursor solutions. In addition, the rapid spray-filming ability might offer sufficient flexibility and rapidity for dealing with mass and irregular wounds. Notably, the bacterial barrier experiments show that the SG hydrogel films could form an effective barrier to Staphylococcus aureus and Candida albicans for 12 h. Therefore, SG hydrogels could be used in wound dressings and they show great promise in applications associated with mass and irregular traumas.

6.
Adv Healthc Mater ; : e1901155, 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31867893

RESUMO

Timely diagnosis of acute myocardial infarction (AMI) strongly impacts the survival rate of patients. The authors report the development of a two-shell hollow silica contrast agent useful for ultrasound (US) imaging, which is able to provide ultra-early diagnosis of AMI. To target the characterization of fast blood flow and high blood pressure in the heart, two shells of hollow silica are adopted with opposite polarities, which assemble based on amino and perfluorodecyl silanes. The external amino silane facilitates the attachment of disease-targeted groups, while the internal perfluorodecyl silane provides great US imaging contrast. The material also possesses superior water dispersity, controllable morphology, low toxicity, and biodegradability both in vitro and in vivo, thus promoting its applications in the ultra-early diagnosis of AMI in rats, and is particularly useful for delineation of myocardial necrosis sites.

7.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(6): 840-846, 2019 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-31880115

RESUMO

OBJECTIVE: To investigate the regulatory effect and its mechanism of chrysophanol (CP) on renal injury and immune response in immunoglobin A (IgA) nephropathy rats. METHODS: IgA nephropathy rat model was established by the method of lipopolysaccharide + bovine serum protein + carbon tetrachloride. Then the rats were randomly divided into 5 groups: control group, IgA group, IgA+low, medium and high dose of CP groups(2.5, 5 and 10 mg/kg for each group respectively). IgA+CP groups were intraperitoneally injected with different doses of chrysophanol once a day for 4 weeks, and the control group and IgA group were given isovolumetric saline. Urine protein content, serum creatinine and urea nitrogen were detected at 24 h after the administration of drugs. Kidney histopathological damage and apoptosis were measured by HE and TUNEL staining. The expression levels of Caspase-3 and Caspase-9 were detected by RT-PCR and Western blot; The contents of malondialdehyde (MDA), superoxide dismutase (SOD) and (glutathione peroxidase, Gpx) were detected by enzyme-linked immunosorbent assay (ELISA). The expression of interleukin-1ß, -6 (IL-1ß, IL-6) and tumor necrosis factor (TNF-α) in serum and kidney tissue were measured by ELISA and Western blot, respectively. The mRNA and protein expression levels of toll-like receptro 4 (TLR4), nuclear factor-κB P65 (NF-κB P65) were also detected by RT-PCR and Western blot, and vascular cell adherin molecule (VCAM-1) protein level was deteted by Western blot. RESULTS: In IgA nephropathy rats, the administration of CP reduced proteinuria, serum creatinine and urea nitrogen in a dose-dependent manner (P < 0.01). It also improved the pathological damage of kidney tissue, reduced the apoptosis rate (P < 0.01), and decreased the mRNA and protein expression levels of apoptosis-related proteins Caspase-3 and Caspase-9 (P < 0.01). CP inhibited MDA production while increased the activities of antioxidant enzymes Gpx and SOD (P < 0.01), and decreased the levels of serum and protein expression of IL-1ß, IL-6 and TNF-α (P < 0.01), as well as the expression levels of TLR4, NF-κB P65 and VCAM-1 (P < 0.01). CONCLUSION: Chrysophanol could play a protective role in IgA nephropathy rats, and its mechanism may be related to alleviating kidney injury and regulating immune response.

8.
Clin Respir J ; 2019 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-31876095

RESUMO

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is associated with poor prognosis in non-small cell lung cancer (NSCLC) patients. There are limited data about the impact of severe-to-very severe COPD on prognosis in patients with NSCLC receiving first-line chemotherapy. OBJECTIVES: To investigate whether severe-to-very severe COPD impacted survival of patients with NSCLC receiving first-line chemotherapy. METHODS: A retrospective review was performed on 513 consecutive NSCLC patients receiving first-line chemotherapy between February 2014 and May 2018. Prognostic impact of severe-to-very severe COPD was analysed using regression analyses. RESULTS: Totally 258 NSCLC patients (118 non-COPD, 96 mild-to-moderate COPD and 44 severe-to-very severe COPD) were evaluated retrospectively. Kaplan-Meier analysis showed that the median overall survival times in the severe-to-very severe COPD, mild-to-moderate COPD and non-COPD groups were 14.0 months [95% confidence interval (CI): 11.0-17.0], 18 months (95% CI: 14.8-21.2) and 19 months (95% CI: 15.3-22.7), respectively. The difference was significant between patients with severe-to-very severe COPD and those without COPD (χ2  = 6.8, P = 0.009) and between patients with severe-to-very severe COPD and those with mild-to-moderate COPD (χ2  = 4.0, P = 0.045). Multivariate analysis showed that survival time was significantly shorter in the severe-to-very severe COPD group than in the non-COPD group (adjusted hazard ratio: 1.876, 95% CI: 1.161-3.030, P = 0.01) and mild-to-moderate COPD group (adjusted hazard ratio: 1.782, 95% CI: 1.046-3.034, P = 0.033). CONCLUSION: Severe-to-very severe COPD may worsen the prognosis of NSCLC patients who received first-line chemotherapy.

9.
Gene ; : 144196, 2019 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-31669648

RESUMO

Accumulating evidence has indicated the important roles of circular RNAs (circRNAs) in different tumors. However, their detailed regulatory mechanisms in glioma are not fully understood. In this study, the functional role of a novel circRNA, circ-EZH2, was investigated by cell counting kit-8 (CCK-8), colony formation, flow cytometry, and transwell experiments. The regulatory mechanism of circ-EZH2 was explored by bioinformatics analysis, quantitative real-time PCR (qRT-PCR), Western blot and dual-luciferase reporter assay. We identified that circ-EZH2 was overexpressed in glioma tissues and cell lines. Further studies revealed that ectopic expression of circ-EZH2 significantly promoted cell growth, migration and invasion but inhibited cell apoptosis. By contrast, silencing of circ-EZH2 induced the opposite effects. Additionally, we found circ-EZH2 served as a miRNA sponge for miR-1265 to release its suppression on DDAH1 and CBX3. Rescue assays further revealed that the oncogenic function of circ-EZH2 was partly dependent on its modulation of DDAH1 and CBX3. Our study unraveled a novel molecular pathway in glioma and may provide a new perspective for the treatment of glioma.

10.
Int J Radiat Biol ; : 1-9, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31692404

RESUMO

Purpose: Heavy-ion beams and γ-rays are popular physical mutagenesis to generate mutations in higher plants. It has been found that they show different mutation frequencies and spectrums of phenotype induction, however, the characteristics of heavy-ion beams on genetic polymorphism have not been clarified by comparing with γ-rays.Materials and methods: In the present study, seeds of Arabidopsis thaliana were exposed to carbon-ion beams (with linear energy transfer (LET) of 50 keV/µm) and γ-rays (with average LET of 0.2 keV/µm) irradiation. By using inter-simple sequence repeat (ISSR) and random amplified polymorphic DNA (RAPD) analysis, the genetic polymorphism of both M1 and M3 plants were investigated, respectively.Results: Carbon-ion beams induced relatively higher polymorphism rate in both M1 and M3 generation than γ-rays: the polymorphism rates of M1 plants derived from carbon-ion beams irradiation are 12.87% (ISSR-C) and 9.01% (RAPD-C), while are 7.67% (ISSR-γ) and 1.45% (RAPD-γ) of plants derived from γ-rays. In M3 generation, the polymorphism rates of ISSR-C, RAPD-C, ISSR-γ, and RAPD-γ are 17.64%, 22.79%, 12.10%, and 2.82%, respectively.Conclusions: In summary, the exposure to carbon-ion beams and γ-rays lead to the change of genomic DNA of A. thaliana, which could be tested in M1 plants and M3 plants by ISSR and RAPD technology. So, both carbon-ion beams and γ-rays can induce variations of genetic polymorphisms in M1 plants and M3 plants. The genetic polymorphisms of M1 plants and M3 plants induced by carbon-ion beams are higher than γ-rays, indicating that heavy-ion beams irradiations mutation breeding is more advantageous than conventional ionizing radiations. Average molecular polymorphism of M1 plants is lower than M3 mutants, by nearly 4.77% (ISSR-C), 13.78% (RAPD-C), 4.43% (ISSR-γ), and 1.37% (RAPD-γ). We hope our study will provide basic information for understanding the effects of carbon-ion beams and γ-rays for plant mutation breeding.

11.
BMC Evol Biol ; 19(1): 203, 2019 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-31694538

RESUMO

BACKGROUND: The flood of genomic data to help build and date the tree of life requires automation at several critical junctures, most importantly during sequence assembly and alignment. It is widely appreciated that automated alignment protocols can yield inaccuracies, but the relative impact of various sources error on phylogenomic analysis is not yet known. This study employs an updated mammal data set of 5162 coding loci sampled from 90 species to evaluate the effects of alignment uncertainty, substitution models, and fossil priors on gene tree, species tree, and divergence time estimation. Additionally, a novel coalescent likelihood ratio test is introduced for comparing competing species trees against a given set of gene trees. RESULTS: The aligned DNA sequences of 5162 loci from 90 species were trimmed and filtered using trimAL and two filtering protocols. The final dataset contains 4 sets of alignments - before trimming, after trimming, filtered by a recently proposed pipeline, and further filtered by comparing ML gene trees for each locus with the concatenation tree. Our analyses suggest that the average discordance among the coalescent trees is significantly smaller than that among the concatenation trees estimated from the 4 sets of alignments or with different substitution models. There is no significant difference among the divergence times estimated with different substitution models. However, the divergence dates estimated from the alignments after trimming are more recent than those estimated from the alignments before trimming. CONCLUSIONS: Our results highlight that alignment uncertainty of the updated mammal data set and the choice of substitution models have little impact on tree topologies yielded by coalescent methods for species tree estimation, whereas they are more influential on the trees made by concatenation. Given the choice of calibration scheme and clock models, divergence time estimates are robust to the choice of substitution models, but removing alignments deemed problematic by trimming algorithms can lead to more recent dates. Although the fossil prior is important in divergence time estimation, Bayesian estimates of divergence times in this data set are driven primarily by the sequence data.

13.
Can J Cardiol ; 35(11): 1546-1556, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31679624

RESUMO

BACKGROUND: Endothelial progenitor cell (EPC) therapy has been suggested as a major breakthrough in the treatment of ischemic diseases. However, the molecular mechanism that underlies EPC functional regulation is still unclear. METHODS: We examined the angiogenic capacity of EPCs in a hindlimb ischemia model of wild-type and ClC-3 knockout mice. RESULTS: Mice lacking of ClC-3 exhibited reduced blood flow recovery and neovascularization in ischemic muscles 7 and 14 days after hind limb ischemia. Moreover, compared with wild-type EPCs, the hindlimb blood reperfusion in mice receiving ClC-3 knockout EPCs was significantly impaired, accompanied by reduced EPC homing and retention. In vitro, EPCs derived from ClC-3 knockout mice displayed impaired migratory, adhesive, and angiogenic activity. CXC chemokine receptor 4 (CXCR4) expression was significantly reduced in EPC from ClC-3 knockout mice compared with wild-type. Moreover, the expression and phosphorylation of Janus kinase 2 (JAK-2), a downstream signalling of CXCR4, was also reduced in ClC-3 knockout EPC, indicating that CXCR4/JAK-2 signalling is dysregulated by ClC-3 deficiency. Consistent with this assumption, the migratory capacity of wild-type EPCs was attenuated by either CXCR4 antagonist AMD3100 or JAK-2 inhibitor AG490. More importantly, the impaired migratory capacity of ClC-3 knockout EPCs was rescued by overexpression of CXCR4. CONCLUSIONS: ClC-3 plays a critical role in the angiogenic capacity of EPCs and EPC-mediated neovascularization of ischemic tissues. Disturbance of CXCR4/JAK-2 signalling may contribute to the functional impairment of ClC-3 deficient EPCs. Thus, ClC-3 may be a potential therapeutic target for modulating neovascularization in ischemic diseases.

14.
JMIR Mhealth Uhealth ; 7(11): e14452, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31682586

RESUMO

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a major public health burden. Self-management of diabetes including maintaining a healthy lifestyle is essential for glycemic control and to prevent diabetes complications. Mobile-based health data can play an important role in the forecasting of blood glucose levels for lifestyle management and control of T2DM. OBJECTIVE: The objective of this work was to dynamically forecast daily glucose levels in patients with T2DM based on their daily mobile health lifestyle data including diet, physical activity, weight, and glucose level from the day before. METHODS: We used data from 10 T2DM patients who were overweight or obese in a behavioral lifestyle intervention using mobile tools for daily monitoring of diet, physical activity, weight, and blood glucose over 6 months. We developed a deep learning model based on long short-term memory-based recurrent neural networks to forecast the next-day glucose levels in individual patients. The neural network used several layers of computational nodes to model how mobile health data (food intake including consumed calories, fat, and carbohydrates; exercise; and weight) were progressing from one day to another from noisy data. RESULTS: The model was validated based on a data set of 10 patients who had been monitored daily for over 6 months. The proposed deep learning model demonstrated considerable accuracy in predicting the next day glucose level based on Clark Error Grid and ±10% range of the actual values. CONCLUSIONS: Using machine learning methodologies may leverage mobile health lifestyle data to develop effective individualized prediction plans for T2DM management. However, predicting future glucose levels is challenging as glucose level is determined by multiple factors. Future study with more rigorous study design is warranted to better predict future glucose levels for T2DM management.

15.
Opt Express ; 27(21): 29639-29648, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31684221

RESUMO

Realization of the highly efficient hybrid atom-photon gates is vital to the quantum interface that integrates atoms and superconducting resonators. Here we propose a scheme to realize the hybrid state transfer and controlled-PHASE gate based on Raman chirped shortcut to adiabatic passage. The scheme is fast to protect the quantum state from the decoherence effects in the hybrid interface, as well as is robust due to the geometric phase. We show that this two-qubit gate is more resilient than the Raman pulse and Raman chirped adiabatic passage against the variations in the vacuum coupling strength and two-photon detuning. Its fast and robust features make it especially suitable for long-term storage and optical readout of superconducting qubits, and moreover, entanglement swapping between two disparate components.

16.
Int J Biol Macromol ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31726167

RESUMO

The occurrence of Maillard reaction in protein - polysaccharide coacervated microcapsules and its effects on microcapsule properties were investigated. Vitamin E microcapsules were prepared by soybean protein isolate - chitosan coacervation at 50 °C, 70 °C, or 90 °C for 12 h in the presence of maltose. Chromatic and furosine measurements revealed that Maillard reaction occurred in the microcapsules and was favored by high incubation temperatures. The three coacervation temperatures did not destroy the microcapsule structure, but improved the microencapsulation efficiency and microencapsulation yield instead. The microcapsules exhibited decreased aggregation and the increased absolute zeta potential and particle size were believed contribute to this improvement. Stability analysis demonstrated that the microcapsules possessed enhanced resistance to dissolution in water and improved storage stability than control microcapsules. It is concluded that coacervation at a temperature high enough to initiate Maillard reaction is a promising way to improve the physiochemical properties of protein - polysaccharide coacervated microcapsules.

17.
Colloids Surf B Biointerfaces ; : 110641, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31759778

RESUMO

Rapid hemostasis is crucial to saving the lives of traumatic patients in emergency medical treatment. To improve the hemostatic performance of the gelatin microspheres (GMs) in vivo and in vitro, in the study, porous gelatin microspheres (PGMs) were prepared through water-in-oil emulsion method combined with vacuum freeze-drying after cross-linking with glutaraldehyde and prefreeze in liquid nitrogen. Owing to the porous structure and rough surface, the obtained PGMs were effective to induce red blood cells aggregation and promote fibrin generation, which led to improved hemostatic potential than GMs in blood coagulation time, whole blood clotting rate, and the hemostatic efficiency of rabbit liver wound and ear vein cut models tests. The potent hemostatic effect of the PGMs could be attributed to the synergistic effects of the physiological blood coagulation activated by negatively charged surface and physical barriers reinforced by fibrin. Moreover, PGMs with high water absorption rate and porous structure showed better hemostatic performance than commercial hemostatic powder (chitosan hemostasis power and Yunnan Baiyao) in vitro and in vivo. Cytotoxicity tests with bone marrow mesenchymal stem cells of murine showed that PGMs with excellent cytocompatibility were conducive to cell proliferation. Therefore, it could be concluded that PGMs were more suitable for rapid hemostasis than GMs and had a great potential for hemostatic applications.

18.
Acta Biomater ; 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31760222

RESUMO

Natural and synthetic hydrogels have been widely investigated as biomaterial scaffolds to promote tissue repair and regeneration. Nevertheless, the scaffold alone is often insufficient to drive new tissue growth, instead requiring continuous delivery of therapeutics, such as proteins or other biomolecules that work in concert with structural support provided by the scaffold. However, because of the high-water content, hydrogels tend to be permeable and cause rapid release of the encapsulated drug, which could lead to serious complications from local overdose and may result in the significant waste of encapsulated therapeutic(s). To this end, we designed an oligonucleotide-functionalized hydrogel that can provide sustained and controlled delivery of therapeutics for up to 4 weeks. To prove this concept, we successfully achieved sustained release (for over 28 days) of model anti-Nogo receptor (anti-NgR) RNA aptamer from oligonucleotide-functionalized hyaluronic acid-based hydrogel by changing the complementarity between the short antisense sequences and the aptamer. Furthermore, the released aptamer successfully blocked neuro-inhibitory effects of myelin-derived inhibitors and promoted neurite outgrowth from rat dorsal root ganglia in vitro. Because antisense sequences can be designed to bind to proteins, peptides, and aptamer, our oligonucleotide-functionalized hydrogel offers a promising therapeutic delivery system to obtain controlled release (both bolus and sustained) of various therapeutics for the treatment of complex diseases and injury models, such as spinal cord injury. STATEMENT OF SIGNIFICANCE: Producing a therapeutic effect often requires the administration of multiple injections with high dosages. This regimen causes discomfort to the patient and raises cost of treatment. Additionally, systemic delivery of therapeutics often results in adverse effects; therefore, local delivery at the site of injury is desirable. Therefore, in this study, we designed an oligonucleotide-functionalized biomaterial platform using ssDNA oligonucleotides (immobile species) as antisense sequences to increase residence time and fine-tune the release of anti-nogo receptor aptamer (mobile species) for spinal cord injury application. Because antisense sequences can be designed to bind proteins, peptides, and aptamer, our hydrogel offers a promising delivery system to obtain controlled release of various therapeutics for the treatment of complex diseases and injury models.

19.
Proc Natl Acad Sci U S A ; 116(44): 22353-22358, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31611414

RESUMO

An Australian estuarine isolate of Penicillium sp. MST-MF667 yielded 3 tetrapeptides named the bilaids with an unusual alternating LDLD chirality. Given their resemblance to known short peptide opioid agonists, we elucidated that they were weak (K i low micromolar) µ-opioid agonists, which led to the design of bilorphin, a potent and selective µ-opioid receptor (MOPr) agonist (K i 1.1 nM). In sharp contrast to all-natural product opioid peptides that efficaciously recruit ß-arrestin, bilorphin is G protein biased, weakly phosphorylating the MOPr and marginally recruiting ß-arrestin, with no receptor internalization. Importantly, bilorphin exhibits a similar G protein bias to oliceridine, a small nonpeptide with improved overdose safety. Molecular dynamics simulations of bilorphin and the strongly arrestin-biased endomorphin-2 with the MOPr indicate distinct receptor interactions and receptor conformations that could underlie their large differences in bias. Whereas bilorphin is systemically inactive, a glycosylated analog, bilactorphin, is orally active with similar in vivo potency to morphine. Bilorphin is both a unique molecular tool that enhances understanding of MOPr biased signaling and a promising lead in the development of next generation analgesics.

20.
Rev Sci Instrum ; 90(9): 095102, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31575248

RESUMO

In this paper, we demonstrate the use of a surface condensation sensor board for characterizing interior space in a damp heat chamber. The sensor board is approximately 18 in. × 12 in. in dimension. A total of 324 sense electrodes are designed on the board. The uniform gap between the sense electrodes is 250 µm throughout the surface area of the board. First, the surface leakage current of the sensor board is characterized with other commercially available humidity sensors. The relationship of leakage current to humidity is determined. Surface leakage current is spatially measured inside the chamber, and localized condensation spots are identified at 85 °C/85%RH stress condition. The main goal of this article is to characterize interior space and identify less-risky locations prior to qualification of semiconductor components, optical subassemblies, and optical modules.

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