Evaluation of Next Generation Capillary-Channeled Polymer Fibers and the Implementation of C-CP Fiber Modification Modalities on Non-Fiber Substrates

Developing new stationary phases for liquid chromatography is continuing to drive high performance liquid chromatography (HPLC) into the future. In this regard the Marcus’ group has been leveraging the continued advances of Capillary-Channeled Polymer (C-CP) fibers in an attempt to meet the demand of high throughput biomarcomolecule chromatography. Separation mechanisms studied include: ion-exchange (IC), reversed phase (RP), affinity, hydrophobic interaction chromatography (HIC). In this work, the next generation of C-CP fiber stationary phases was thoroughly evaluated with respect to hydrodynamic concerns relating to protein chromatography. Traditionally C-CP fibers have eight channels that run co-linearly along the length of the fiber. Packed C-CP fibers form a network of pseudo-open capillary structures through channels interdigitating. The fibers studied have a much higher surface area to volume ratio compared to circular fibers with similar diameters. The open tubular network has an added bonus of operating at low back pressures. C-CP fibers are non-porous with regards to biomarcomolecules, resulting in fast mass transfer kinetics causing no significant C-term band broadening. The next generation of C-CP fiber has been developed with three larger more ridged channels. This design allows for tighter packing densities without compromising channel integrity. This advancement allows the fibers to operate at higher linear velocities leading to a separation of a six-protein suit (ribonuclease A, cytochrome C, lysozyme, transferrin, bovine serum albumin, and α-chimotrypsinogen) under reversed phase conditions. Surface modification of the C-CP fibers has been accomplished with a variety of techniques, both through covalent and physical adsorption modification. Of particular interest to this work is the Lipid Tethered Ligand (LTL) surface modification modality, which has seen excellent success when employed on polypropylene C-CP fibers. LTLs functionalize a surface with ion-exchange or affinity ligands through hydrophobic physical adsorption to augment the available surface chemistry in a quick and simple flow-through system. In the work presented here, the LTL system was applied to the most commonly used polymer resin, polystyrene-divinylbenzene. The effectiveness of LTL loading, stability, and kinetics on PS-DVB was evaluated. Ligand availability was evaluated with both biotin-LTL for the extraction of streptavidin and iminodiacetic acid-LTL for the extraction of methylene blue

Exonic mutations in cell–cell adhesion may contribute to CADASIL-related CSVD pathology

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a condition caused by mutations in NOTCH3 and results in a phenotype characterised by recurrent strokes, vascular dementia and migraines. Whilst a genetic basis for the disease is known, the molecular mechanisms underpinning the pathology of CADASIL are still yet to be determined. Studies conducted at the Genomics Research Centre (GRC) have also identified that only 15–23% of individuals clinically suspected of CADASIL have mutations in NOTCH3. Based on this, whole exome sequencing was used to identify novel genetic variants for CADASIL-like cerebral small-vessel disease (CSVD). Analysis of functionally important variants in 50 individuals was investigated using overrepresentation tests in Gene ontology software to identify biological processes that are potentially affected in this group of patients. Further investigation of the genes in these processes was completed using the TRAPD software to identify if there is an increased number (burden) of mutations that are associated with CADASIL-like pathology. Results from this study identified that cell–cell adhesion genes were positively overrepresented in the PANTHER GO-slim database. TRAPD burden testing identified n = 15 genes that had a higher number of rare (MAF 0.8) mutations compared to the gnomAD v2.1.1 exome control dataset. Furthermore, these results identified ARVCF, GPR17, PTPRS, and CELSR1 as novel candidate genes in CADASIL-related pathology. This study identified a novel process that may be playing a role in the vascular damage related to CADASIL-related CSVD and implicated n = 15 genes in playing a role in the disease.</p

Acute Metabolic Responses to Glucose and Fructose Supplementation in Healthy Individuals : A Double-Blind Randomized Crossover Placebo-Controlled Trial

The aim of this study was to investigate the impact of glucose (Glu), fructose (Fru), glucose and fructose (GluFru) and sucralose on blood glucose response in healthy individuals. Fifteen healthy individuals (five females, age of 25.4 ± 2.5 years, BMI of 23.7 ± 1.7 kg/m2 with a body mass (BM) of 76.3 ± 12.3 kg) participated in this double-blind randomized crossover placebo-controlled trial. Participants received a mixture of 300 mL of water with 1 g/kg BM of Glu, 1 g/kg BM of Fru, 0.5 g/kg BM of GluFru (each), and 0.2 g sucralose as a placebo. Peak BG values Glu were reached after 40 ± 13 min (peak BG: 141 ± 20 mg/dL), for Fru after 36 ± 22 min (peak BG: 98 ± 7 mg/dL), for GluFru after 29 ± 8 min (BG 128 ± 18 mg/dL), and sucralose after 34 ± 27 min (peak BG: 83 ± 5 mg/dL). Significant differences regarding the time until peak BG were found only between Glu and GluFru supplementation (p = 0.02). Peak blood glucose levels were significantly lower following the ingestion of Fru compared to the supplementation of Glu and GluFru (p p = 0.23). All conditions led to a significantly higher peak BG value compared to sucralose (p p = 0.002), Fru and GluFru (both p p = 0.051). Insulin levels were significantly higher in all conditions at peak compared to sucralose (p < 0.0001). The findings of this study prove the feasibility of combined carbohydrate supplementations for many applications in diabetic or healthy exercise cohorts

Acute Changes in Heart Rate Variability to Glucose and Fructose Supplementation in Healthy Individuals : A Double-Blind Randomized Crossover Placebo-Controlled Trial

SIMPLE SUMMARY: In this study, we investigated the cardio-autonomic stress responses to the ingestion of liquid glucose, fructose, a combination thereof and a placebo in healthy individuals at rest. The cardio-autonomic response was more pronounced in all groups with carbohydrates compared to placebo indicating an increased cardio-autonomic stress response resulting in a reduced heart-rate variability. When investigating different levels of blood glucose, the findings showed a significant decline in heart-rate variability with increasing blood glucose levels. This was also seen with severely low levels of blood glucose. The speed of how quick blood glucose increased and decreased also impacted the cardio-autonomic response which further deteriorated heart-rate variability. These findings indicate that healthy human’s autonomic system responds quickly to changes in their blood glucose. ABSTRACT: Background: It is unknown how different types of carbohydrates alter the cardio-autonomic system in healthy individuals. Therefore, the aim of this study was to investigate how heart-rate variability changes to single dose ingestion of glucose, fructose, glucose and fructose, and an artificial sweetener (sucralose). Methods: In a double-blind randomized crossover placebo-controlled setting, 15 participants received all study-specific substances in liquid form. During each 2-h visit, venous blood glucose was measured in a 5-min interval while heart-rate variability was measured continuously via Holter-electrocardiograph. Results: Ingestion of different types of carbohydrates and sucralose showed significant differences for heart rate (p < 0.001), SDNN (p < 0.008), RMSSD (p < 0.001), pNN50 (p < 0.001) and blood pressure (p < 0.001). Different glucose levels significantly altered parameters of heart-rate variability and blood pressure (all p < 0.001), while the rate of change in blood glucose led to changes in heart rate variability, but not in heart rate (p = 0.25) or blood pressure (p = 0.99). Conclusions: Ingestion of different types of carbohydrates lead to reductions in heart-rate variability compared to a placebo. Blood glucose values above or below 70–90 mg/dL decreased heart rate variability while this was also seen for rapid glucose changes, yet not as pronounced. Healthy individuals should be conscious about carbohydrate intake while maintaining blood glucose levels between 70–90 mg/dL

Target Zones in History and Theory: Lessons from an Austro-Hungarian Experiment (1896-1914)

The first known experiment with an exchange rate band took place in Austria- Hungary between 1896 and 1914. The rationale for introducing this policy rested on precisely those intuitions that the modern literature has emphasized: the band was designed to secure both exchange rate stability and monetary policy autonomy. However, unlike more recent experiences, such as the ERM, this policy was not undermined by credibility problems. The episode provides an ideal testing ground for some important ideas in modern macroeconomics: specifically, can formal rules, when faithfully adhered to, provide policy makers with some advantages such as short term autonomy? First, we find that a credible band has a "microeconomic" influence on exchange rate stability. By reducing uncertainty, a credible fluctuation band improves the quality of expectations, a channel that has been neglected in the modern literature. Second, we show that the standard test of the basic target zone model is flawed and develop an alternative methodology. We believe that these findings shed a new light on the economics of exchange rate bands