No abstract

b-amyloid peptide (Ab) is one of the main protein components of senile plaques associated with Alzheimer's disease (AD). Ab readily aggregates to forms fibrils and other aggregated species that have been shown to be toxic in a number of studies. In particular, soluble oligomeric forms are closely related to neurotoxicity. However, the relationship between neurotoxicity and the size of Ab aggregates or oligomers is still under investigation. In this article, we show that different Ab incubation conditions in vitro can affect the rate of Ab fibril formation, the conformation and stability of intermediates in the aggregation pathway, and toxicity of aggregated species formed. When gently agitated, Ab aggregates faster than Ab prepared under quiescent conditions, forming fibrils. The morphology of fibrils formed at the end of aggregation with or without agitation, as observed in electron micrographs, is somewhat different. Interestingly, intermediates or oligomers formed during Ab aggregation differ greatly under agitated and quiescent conditions. Unfolding studies in guanidine hydrochloride indicate that fibrils formed under quiescent conditions are more stable to unfolding in detergent than aggregation associated oligomers or Ab fibrils formed with agitation. In addition, Ab fibrils formed under quiescent conditions were less toxic to differentiated SH-SY5Y cells than the Ab aggregation associated oligomers or fibrils formed with agitation. These results highlight differences between Ab aggregation intermediates formed under different conditions and provide insight into the structure and stability of toxic Ab oligomers.

There is currently great interest in developing microparticles that can enhance the delivery of proteins to macrophages. In this communication, we present a new acid-sensitive polymer for drug delivery, poly(cyclohexane-1,4-diyl acetone dimethylene ketal) (PCADK). PCADK is designed to hydrolyze, after phagocytosis by macrophages, in the acidic environment of the phagosome and enhance the intracellular delivery of phagocytosed therapeutics. Other key attributes of PCADK for drug delivery are its well-characterized degradation products and straightforward synthesis. PCADK hydrolyzes into 1,4-cyclohexanedimethanol, a compound used in food packaging, and acetone, a compound on the FDA GRAS list. PCADK was synthesized using the acetal exchange reaction between 1,4-cyclohexanedimethanol and 2,2-dimethoxypropane, and could be obtained on a multigram scale in one step. The hydrolysis kinetics of the ketal linkages in PCADK were measured by 1 H NMR and were determined to be pH-sensitive, having a half-life of 24.1 days at pH 4.5 and over 4 years at pH 7.4. The therapeutic enzyme superoxide dismutase (SOD), which scavenges reactive oxygen species, was encapsulated into PCADKbased microparticles using a double emulsion procedure. Cell culture experiments demonstrated that PCADKbased microparticles dramatically improved the ability of SOD to scavenge reactive oxygen species produced by macrophages. We anticipate numerous applications of PCADK in drug delivery, based on its acid sensitivity, well-characterized degradation products, and straightforward synthesis.

ObjectiveTo assess clinical profiles of patients with type 2 diabetes in the United Arab Emirates (UAE), including patterns, frequencies, and risk factors of microvascular and macrovascular complications.Research design and methodsFour hundred and ninety patients with type 2 diabetes were enrolled from two major hospitals in Abu Dhabi. The presence of microvascular and macrovascular complications was assessed using logistic regression, and demographic, clinical and laboratory data were collected. Significance was set at p<0.05.ResultsHypertension (83.40%), obesity (90.49%) and dyslipidemia (93.43%) were common type 2 diabetes comorbidities. Most of the patients had relatively poor glycemic control and presented with multiple complications (83.47% of patients had one or more complication), with frequent renal involvement. The most frequent complication was retinopathy (13.26%). However, the pattern of complications varied based on age, where in patients <65 years, a single pattern presented, usually retinopathy, while multiple complications was typically seen in patients >65 years old. Low estimated glomerular filtration rate in combination with disease duration was the most significant risk factor in the development of a diabetic-associated complication especially for coronary artery disease, whereas age, lipid values and waist circumference were significantly associated with the development of diabetic retinopathy.ConclusionsPatients with type 2 diabetes mellitus in the UAE frequently present with comorbidities and complications. Renal disease was found to be the most common comorbidity, while retinopathy was noted as the most common diabetic complication. This emphasizes the need for screening and prevention program toward early, asymptomatic identification of comorbidities and commence treatment, especially for longer disease duration.

Increasing evidence indicates that soluble aggregates of amyloid beta protein (Aβ) are neurotoxic. However, difficulty in isolating these unstable, dynamic species impedes studies of Aβ and other aggregating peptides and proteins. In this study, hydrogen-deuterium exchange (HX) detected by mass spectrometry (MS) was used to measure Aβ(1-40) aggregate distributions without purification or modification that might alter the aggregate structure or distribution. Different peaks in the mass spectra were assigned to monomer, low molecular weight oligomer, intermediate, and fibril based on HX labeling behavior and complementary assays. After 1 h labeling, the intermediates incorporated approximately ten more deuterons relative to fibrils, indicating a more solvent exposed structure of such intermediates. HX-MS also showed that the intermediate species dissociated much more slowly to monomer than did the very low molecular weight oligomers that were formed at very early times in Aβ aggregation. Atomic force microscopy (AFM) measurements revealed the intermediates were roughly spherical with relatively homogenous diameters of 30-50 nm. Quantitative analysis of the HX mass spectra showed that the amount of intermediate species was correlated with Aβ toxicity patterns reported in a previous study under the same conditions. This study also demonstrates the potential of the HX-MS approach to characterizing complex, multicomponent oligomer distributions of aggregating peptides and proteins.

Therapeutics based on small interfering RNA (siRNA) have a great clinical potential; however, delivery problems have limited their clinical efficacy, and new siRNA delivery vehicles are greatly needed. In this report, we demonstrate that submicron particles (800–900 nm) composed of the polyketal PK3 and chloroquine, termed as the PKCNs, can deliver tumor necrosis factor-α (TNF-α) siRNA in vivo to Kupffer cells efficiently and inhibit gene expression in the liver at concentrations as low as 3.5 μg/kg. The high delivery efficiency of the PKCNs arises from the unique properties of PK3, which can protect siRNA from serum nucleases, stimulate cell uptake and trigger a colloid osmotic disruption of the phagosome and release encapsulated siRNA into the cell cytoplasm. We anticipate numerous applications of the PKCNs for siRNA delivery to macrophages, given their high delivery efficiency, and the central role of macrophages in causing diseases such as hepatitis, liver cirrhosis and chronic renal disease.

Type 2 diabetes mellitus (T2DM) is a global public health problem of epidemic proportions, with 60–70% of affected individuals suffering from associated neurovascular complications that act on multiple organ systems. The most common and clinically significant neuropathies of T2DM include uremic neuropathy, peripheral neuropathy, and cardiac autonomic neuropathy. These conditions seriously impact an individual’s quality of life and significantly increase the risk of morbidity and mortality. Although advances in gene sequencing technologies have identified several genetic variants that may regulate the development and progression of T2DM, little is known about whether or not the variants are involved in disease progression and how these genetic variants are associated with diabetic neuropathy specifically. Significant missing heritability data and complex disease etiologies remain to be explained. This article is the first to provide a review of the genetic risk variants implicated in the diabetic neuropathies and to highlight potential commonalities. We thereby aim to contribute to the creation of a genetic-metabolic model that will help to elucidate the cause of diabetic neuropathies, evaluate a patient’s risk profile, and ultimately facilitate preventative and targeted treatment for the individual.

Although the manufacturing processes of contact lenses are well established, the use of additive manufacturing for their fabrication opens many new possibilities to explore. The current study demonstrates the fabrication of personalized smart contract lenses utilizing additive manufacturing. The study includes 3-dimensional (3D) modeling of contact lenses with the assistance of a computer aided designing tool based on standard commercial contact lens dimension, followed by the selection of the suitable materials and 3D printing of contact lenses. The 3D printing parameters were optimized to achieve the desired lens geometries, and a post processing treatment was performed to achieve a smooth surface finish. The study also presents functionalized contact lenses with built-in sensing abilities by utilizing microchannels at the contact lens edges. Tinted contact lenses were printed and nanopatterns were textured onto the contact lens surfaces through holographic laser ablation. 3D printed contact lenses have advantages over conventional contact lenses, offering customized ophthalmic devices and the capability to integrate with optical sensors for diagnostics.