Multiplexed capillary electrophoresis system

The use of capillary electrophoresis (CE) has greatly improved DNA sequencing rates compared to conventional slab gel electrophoresis. Part of the improvement in speed, however, has been offset by the loss of the ability (inherent in slab gels) to accommodate multiple lanes in a single run. Highly multiplexed capillary electrophoresis, by making possible hundreds or even thousands of parallel sequencing runs, represents an attractive approach to overcoming the current throughput limitations of existing DNA sequencing instrumentation

Multiplex capillary electrophoresis system

The use of capillary electrophoresis (CE) has greatly improved DNA sequencing rates compared to conventional slab gel electrophoresis. Part of the improvement in speed, however, has been offset by the loss of the ability (inherent in slab gels) to accommodate multiple lanes in a single run. Highly multiplexed capillary electrophoresis, by making possible hundreds or even thousands of parallel sequencing runs, represents an attractive approach to overcoming the current throughput limitations of existing DNA sequencing instrumentation

Making Sense of the Legendre Transform

The Legendre transform is an important tool in theoretical physics, playing a critical role in classical mechanics, statistical mechanics, and thermodynamics. Yet, in typical undergraduate or graduate courses, the power of motivation and elegance of the method are often missing, unlike the treatments frequently enjoyed by Fourier transforms. We review and modify the presentation of Legendre transforms in a way that explicates the formal mathematics, resulting in manifestly symmetric equations, thereby clarifying the structure of the transform algebraically and geometrically. Then we bring in the physics to motivate the transform as a way of choosing independent variables that are more easily controlled. We demonstrate how the Legendre transform arises naturally from statistical mechanics and show how the use of dimensionless thermodynamic potentials leads to more natural and symmetric relations.Comment: 11 pages, 3 figure

Targeting hypoxia-inducible factor-1α (HIF-1α) in combination with antiangiogenic therapy: a phase I trial of bortezomib plus bevacizumab.

PurposeWe hypothesized that bortezomib, an agent that suppresses HIF-1α transcriptional activity, when combined with bevacizumab, would obviate the HIF-1α resistance pathway. The objectives of this phase I trial were to assess safety and biological activity of this combination.Experimental designPatients with advanced, refractory malignancies were eligible. Patients received bevacizumab and bortezomib (3-week cycle) with dose expansions permitted if responses were seen and for assessing correlates. Pharmacodynamic assessment included plasma VEGF, VEGFR2, 20S proteasome inhibition, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and HIF-1α tumor expression.ResultsNinety-one patients were treated (median=6 prior treatments). The FDA-approved doses of both drugs were safely reached, and the recommended phase 2 dose (RP2D) is bevacizumab 15 mg/kg with bortezomib 1.3 mg/m(2). Four patients attained partial response (PR) and seven patients achieved stable disease (SD) ≥ 6 months (Total SD ≥ 6 months/PR=11 (12%)). The most common drug-related toxicities included thrombocytopenia (23%) and fatigue (19%). DCE-MRI analysis demonstrated no dose-dependent decreases in K(trans) although analysis was limited by small sample size (N=12).ConclusionCombination bevacizumab and bortezomib is well-tolerated and has demonstrated clinical activity in patients with previously treated advanced malignancy. Pharmacodynamic assessment suggests that inhibition of angiogenic activity was achieved

Blade Loading Effects on Axial Turbine Tip Leakage Vortex Dynamics and Loss

umerical simulations have been carried out to define the loss generation mechanisms associated with tip leakage in un-shrouded axial turbines. Tip clearance vortex dynamics are a dominant feature of two mechanisms important in determining this loss: (i) decreased swirl velocity due to vortex line contraction in regions of decreasing axial velocity, i.e., adverse pressure gradient and (ii) vortex breakdown and reverse flow in the vortex core. The mixing losses behave differently from the conventional view of flow exiting a turbine tip clearance. More specifically, it is shown, through both control volume arguments and computations, that as a swirling leakage flow passes through a pressure rise, such as in the aft portion of the suction side of a turbine blade, the mixed-out loss can either decrease or increase. For turbines the latter typically occurs if the deceleration is large enough to initiate vortex breakdown, and it is demonstrated that this is the case in modern turbines. The effect of blade pressure distribution on clearance losses is illustrated through computational examination of two turbine blades, one with forward loading at the tip and one with aft loading. A 15% difference in leakage loss is found between the two, due to lower clearance vortex deceleration (lower core static pressure rise) with forward loading, and hence lower vortex breakdown loss. Additional computational experiments, carried out to define the effects of blade loading, incidence, and solidity, are found to be consistent with the proposed ideas linking blade pressure distribution, vortex breakdown and turbine tip leakage loss

A Prospective Study of Periodontal Disease and Risk of Gastric and Duodenal Ulcer in Male Health Professionals

OBJECTIVES: Periodontal disease has been associated with higher circulating levels of inflammatory markers and conditions associated with chronic inflammation, including vascular disease, diabetes mellitus, and cancer. Limited data exist on the relationship between periodontal disease and gastric and duodenal ulcer. METHODS: We conducted a prospective cohort study of 49,120 men in the Health Professionals Follow-up Study, aged 40–75 years at enrollment in 1986. Biennially, we assessed periodontal disease, tooth loss, and other risk factors for gastric and duodenal ulcer. We validated diagnoses of gastric and duodenal ulcer through medical record review. We used Cox proportional hazards modeling, adjusting for potential confounders, to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: We documented 138 cases of gastric ulcer and 124 cases of duodenal ulcer with available information on Helicobacter pylori status over 24 years of follow-up. After adjustment for risk factors, including smoking and regular use of aspirin and non-steroidal anti-inflammatory drugs, men with periodontal disease with bone loss had a multivariate HR of ulcer of 1.62 (95% CI, 1.24–2.12). Periodontal disease appeared to be associated with a similar risk of developing ulcers that were H. pylori negative (HR 1.75; 95% CI, 1.26–2.43) than H. pylori positive (HR 1.40; 95% CI, 0.87-2.24), as well as ulcers in the stomach (HR 1.75; 95% CI, 1.21–2.53) than ulcers in the duodenum (HR 1.47; 95% CI, 0.98–2.19). CONCLUSIONS: Periodontal disease is associated with an increased risk of incident gastric and duodenal ulcer. This relationship may be mediated by alterations in the oral and gastrointestinal microbiome and/or systemic inflammatory factors

Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors: a prospective cohort study

Objective To examine the association between chronic use of proton pump inhibitors (PPIs) and risk of hip fracture

The diet-derived short chain fatty acid propionate improves beta-cell function in humans and stimulates insulin secretion from human islets in vitro

Aims: Diet-derived short chain fatty acids (SCFAs) improve glucose homeostasis in vivo, but the role of individual SCFAs and their mechanisms of action have not been defined. This study evaluated the effects of increasing colonic delivery of the SCFA propionate on β-cell function in humans and the direct effects of propionate on isolated human islets in vitro. Materials and Methods: For 24 weeks human subjects ingested an inulin-propionate ester that delivers propionate to the colon. Acute insulin, GLP-1 and non-esterified fatty acid (NEFA) levels were quantified pre- and post-supplementation in response to a mixed meal test. Expression of the SCFA receptor FFAR2 in human islets was determined by western blotting and immunohistochemistry. Dynamic insulin secretion from perifused human islets was quantified by radioimmunoassay and islet apoptosis was determined by quantification of caspase 3/7 activities. Results: Colonic propionate delivery in vivo was associated with improved β-cell function with increased insulin secretion that was independent of changes in GLP-1 levels. Human islet β-cells expressed FFAR2 and propionate potentiated dynamic glucose-stimulated insulin secretion in vitro, an effect that was dependent on signalling via protein kinase C. Propionate also protected human islets from apoptosis induced by the NEFA sodium palmitate and inflammatory cytokines. Conclusions: Our results indicate that propionate has beneficial effects on β-cell function in vivo, and in vitro analyses demonstrated that it has direct effects to potentiate glucose-stimulated insulin release and maintain β-cell mass through inhibition of apoptosis. These observations support ingestion of propiogenic dietary fibres to maintain healthy glucose homeostasis