A glucose-responsive âclosed-loopâ insulin delivery system mimicking the function of pancreatic cells has tremendous potential to improve quality of life and health in diabetics. Here, we report ...a novel glucose-responsive insulin delivery device using a painless microneedle-array patch (âsmart insulin patchâ) containing glucose-responsive vesicles (GRVs; with an average diameter of 118 nm), which are loaded with insulin and glucose oxidase (GO â) enzyme. The GRVs are self-assembled from hypoxia-sensitive hyaluronic acid (HS-HA) conjugated with 2-nitroimidazole (NI), a hydrophobic component that can be converted to hydrophilic 2-aminoimidazoles through bioreduction under hypoxic conditions. The local hypoxic microenvironment caused by the enzymatic oxidation of glucose in the hyperglycemic state promotes the reduction of HS-HA, which rapidly triggers the dissociation of vesicles and subsequent release of insulin. The smart insulin patch effectively regulated the blood glucose in a mouse model of chemically induced type 1 diabetes. The described work is the first demonstration, to our knowledge, of a synthetic glucose-responsive device using a hypoxia trigger for regulation of insulin release. The faster responsiveness of this approach holds promise in avoiding hyperglycemia and hypoglycemia if translated for human therapy.
Stimuli-triggered drug delivery systems have been increasingly used to promote physiological specificity and on-demand therapeutic efficacy of anticancer drugs. Here we utilize ...adenosine-5'-triphosphate (ATP) as a trigger for the controlled release of anticancer drugs. We demonstrate that polymeric nanocarriers functionalized with an ATP-binding aptamer-incorporated DNA motif can selectively release the intercalating doxorubicin via a conformational switch when in an ATP-rich environment. The half-maximal inhibitory concentration of ATP-responsive nanovehicles is 0.24 μM in MDA-MB-231 cells, a 3.6-fold increase in the cytotoxicity compared with that of non-ATP-responsive nanovehicles. Equipped with an outer shell crosslinked by hyaluronic acid, a specific tumour-targeting ligand, the ATP-responsive nanocarriers present an improvement in the chemotherapeutic inhibition of tumour growth using xenograft MDA-MB-231 tumour-bearing mice. This ATP-triggered drug release system provides a more sophisticated drug delivery system, which can differentiate ATP levels to facilitate the selective release of drugs.
The evolution of a mesophilic aminotransferase, isolated from
Athrobacter citreus, to a thermostable aminotransferase was accomplished via error-prone PCR. After three rounds of mutagenesis, a mutant ...was generated that decreased the biocatalyst loading 3-fold. This improved biocatalyst was engineered further and a new mutant was isolated that was capable of the same performance with 5-fold reduction in biocatalyst loading. Overall, the best mutant (#6) enabled a 3-fold reduction in biocatalyst loading, almost a 5-fold increase in product concentration, and a 5-fold reduction in process cycle time. Through these rounds of mutagenesis enzyme specific activity improved from 5.9 to 1582.8
IU/g with an overall improvement in product yield due to reduced biocatalyst loading. The new mutants were also able to operate at temperatures greater than 50
°C for an extended period of time. A simple cost model was developed to describe the impact of enzyme improvement on product cost.
Recent advances in nanotechnology for diabetes treatment DiSanto, Rocco Michael; Subramanian, Vinayak; Gu, Zhen
Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology,
July/August 2015, Volume:
7, Issue:
4
Journal Article
Peer reviewed
Open access
Nanotechnology in diabetes research has facilitated the development of novel glucose measurement and insulin delivery modalities which hold the potential to dramatically improve quality of life for ...diabetics. Recent progress in the field of diabetes research at its interface with nanotechnology is our focus. In particular, we examine glucose sensors with nanoscale components including metal nanoparticles and carbon nanostructures. The addition of nanoscale components commonly increases glucose sensor sensitivity, temporal response, and can lead to sensors which facilitate continuous in vivo glucose monitoring. Additionally, we survey nanoscale approaches to ‘closed‐loop’ insulin delivery strategies which automatically release insulin in response to fluctuating blood glucose levels (BGLs). ‘Closing the loop’ between BGL measurements and insulin administration by removing the requirement of patient action holds the potential to dramatically improve the health and quality of life of diabetics. Advantages and limitations of current strategies, as well as future opportunities and challenges are also discussed. WIREs Nanomed Nanobiotechnol 2015, 7:548–564. doi: 10.1002/wnan.1329
This article is categorized under:
Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
An enantioselective Overman 3,3-sigmatropic rearrangement on a quinuclidine skeleton was developed for the pilot-plant synthesis of a glycine transporter 1 inhibitor. The first stereocenter was ...produced by a Ru-catalyzed asymmetric transfer hydrogenation process followed by chirality transfer using the Overman rearrangement. The second stereocenter was generated by a diastereoselective hydrogenation reaction.
Purpose
Live surgery (LS) is considered a useful teaching opportunity. The benefits must be balanced with patient safety concerns. To evaluate the rate of complications of a series of urologic LS ...performed by experts during the Congress Challenge in Laparoscopy and Robotics (CILR).
Methods
We present a large, multi-institution, multi-surgeon database that derives from 12 CILR events, from 2004 to 2015 with a total of 224 cases. Radical prostatectomy (RP) was the most common procedure and a selection of complex cases was noted. The primary measure was postoperative complications and use of a Postoperative Morbidity Index (PMI) to allow quantitative weighing of postoperative complications.
Results
From 12 events, the number of cases increased from 11 in 2004 to 27 in 2015 and a total of 27 surgeons. Of 224 cases (164 laparoscopic and 60 robotic), there were 26 (11.6%) complications: 5 grade I, 5 grade II, 3 grade IIIa, 12 grade IIIb and 1 grade V, the latter from laparoscopic cystectomy. Analysis of PMI was 23 times higher from cystectomy compared to RP.
Conclusions
In the setting of live surgery, the overall rate of complications is low considering the complexity of surgeries. The PMI is not higher in more complex procedures, whereas RP seems very safe.
BackgroundNeurofilament light chain (NfL) represents a promising biomarker for axonal injury. We present the first exploratory study on serum NfL in patients with a clinically isolated syndrome (CIS) ...and healthy controls.MethodsWe investigated serum NfL levels in 100 patients with CIS with a short conversion interval to clinically definite multiple sclerosis (MS) (fast converters (FC), median (IQR) conversion time: 110 days (79–139)); 98 patients with non-converting CIS (non-converters (NC), follow-up: 6.5 years (5.3–7.9)); and 92 healthy controls.ResultsNfL levels were higher in FC (24.1 pg/mL (13.5–51.8)) and NC (19.3 pg/mL (13.6–35.2)) than in healthy controls (7.9 pg/mL (5.6–17.2)) (OR=5.85; 95% CI 2.63 to 13.02; p=1.5×10−5 and OR=7.03; 95% CI 2.85 to 17.34; p=2.3×10−5, respectively). When grouping FC and NC, increased serum NfL concentration was also associated with increasing numbers of T2 hyperintense MRI lesions (OR=2.36; 95% CI 1.21 to 4.59; p=0.011), gadolinium-enhancing lesions (OR=2.69; 95% CI 1.13 to 6.41; p=0.026) and higher disability scores (OR=2.54; 95% CI 1.21 to 5.31; p=0.013) at CIS diagnosis.ConclusionsIf replicated in future studies, serum NfL may represent a reliable and easily accessible biomarker of early axonal damage in CIS and MS.
A recent genome wide association study (GWAS) demonstrated that more than 100 genetic variants influence the risk of multiple sclerosis (MS). We investigated what proportion of the general population ...can be considered at high genetic risk of MS, whether genetic information can be used to predict disease development and how the recently found genetic associations have influenced these estimates. We used summary statistics from GWAS in MS to estimate the distribution of risk within a large simulated general population. We profiled MS associated loci in 70 MS patients and 79 healthy controls (HC) and assessed their position within the distribution of risk in the simulated population. The predictive performance of a weighted genetic risk score (wGRS) on disease status was investigated using receiver operating characteristic statistics. When all known variants were considered, 40.8% of the general population was predicted to be at reduced risk, 49% at average, 6.9% at elevated and 3.3% at high risk of MS. Fifty percent of MS patients were at either reduced or average risk of disease. However, they showed a significantly higher wGRS than HC (median 13.47 vs 12.46, p = 4.0810-10). The predictive performance of the model including all currently known MS associations (area under the curve = 79.7%, 95%CI = 72.4%-87.0%) was higher than that of models considering previously known associations. Despite this, considering the relatively low prevalence of MS, the positive predictive value was below 1%. The increasing number of known associated genetic variants is improving our ability to predict the development of MS. This is still unlikely to be clinically useful but a more complete understanding of the complexity underlying MS aetiology and the inclusion of environmental risk factors will aid future attempts of disease prediction.
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