Sensory neuron differentiation is regulated by Notch signaling in the trigeminal placode

AbstractTrigeminal sensory neurons develop from the neural crest and neurogenic placodes, and have been studied as a principal model of sensory neuron formation. While the Notch pathway has been extensively characterized in central nervous system development and other developmental processes, it has not been well characterized in sensory neurogenesis. Here we studied the functional role of Notch signaling in the trigeminal ophthalmic (opV) placode, a prime model of sensory neurogenesis. To establish a good spatiotemporal description of Notch pathway genes in the chick trigeminal placode, a stage-specific expression analysis was conducted, showing that expression of most Notch pathway genes and effectors are expressed in the placode, with expression primarily being confined to ectodermal cells. Expression was highest at stages of peak neuronal differentiation. To test the function of Notch signaling in opV placode cell differentiation, Notch receptor cleavage was blocked using the gamma-secretase inhibitor, DAPT, or signaling was activated by misexpression of the Notch intracellular domain (NICD). Notch activation resulted in a significant reduction in sensory neurogenesis. Cells remained in the ectoderm and did not differentiate. Expression of the opV specification marker Pax3 was also lost in targeted cells. DAPT exposure resulted in a dramatic increase in neurogenesis without increasing proliferation, where many differentiated cells were found in the mesenchyme and, surprisingly, within the ectoderm. This is the first result clearly showing prolific neuronal differentiation in the ectoderm of the trigeminal placodes after experimental manipulation of a molecular signaling pathway, thus identifying Notch signaling as a primary regulator of the sensory neuron fate in the opV placode

Alcohol consumption and cardiovascular outcomes in patients with nonalcoholic fatty liver disease: A population-based cohort study

Low-level alcohol consumption is associated with reduced cardiovascular disease (CVD) in the general population. It is unclear whether this association is seen in patients with nonalcoholic fatty liver disease (NAFLD) who have an increased risk of CVD. We examined the association between alcohol consumption and CVD-related outcomes in subjects with NAFLD from a general population cohort. Subjects participating in the 1994-1995 Busselton Health survey underwent clinical and biochemical assessment. NAFLD was identified using the Fatty Liver Index of \u3e60, and alcohol consumption quantified using a validated questionnaire. CVD hospitalizations and death during the ensuing 20 years were ascertained using the Western Australian data linkage system. A total of 659 of 4,843 patients were diagnosed with NAFLD. The average standard drinks per week was 8.0 for men and 4.0 for women. Men consuming 8-21 drinks per week had a 38% (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.43-0.90) lower risk of CVD hospitalization as compared with men consuming 1-7 drinks per week. With both men and women combined, consumption of 8-21 drinks per week was associated with a 32% (HR 0.68, 95% CI 0.49-0.93) reduction in CVD hospitalization in minimally adjusted and 29% (HR 0.71, 95% CI 0.51-0.99) in fully adjusted models. No protective association was observed with binge drinking. There was no association between alcohol consumption and CVD death. Conclusion: Low to moderate alcohol consumption is associated with fewer CVD hospitalizations but not CVD death in subjects with NAFLD

Healthy Sleep Leads to Improved Nutrition and Exercise in College Females

Diet, sleep quality, and exercise are important determinants of physical, mental, and emotional health. College students are particularly vulnerable to impaired health, as they experience multiple unique stressors associated with college life that impact their ability to engage in healthy sleep, diet, and exercise habits. Our results found that exercise significantly mediated the association between sleep quality and diet. Improved sleep habits may increase a young woman\u27s ability and desire to exercise, thus impacting her diet and nutrition. Findings suggest that clinicians can use a person\u27s motivation in any one domain, or multiple domains, to impact other health domains

Tailoring the surface charge of dextran-based polymer coated SPIONs for modulated stem cell uptake and MRI contrast

Tracking stem cells in vivo using non-invasive techniques is critical to evaluate the efficacy and safety of stem cell therapies. Superparamagnetic iron oxide nanoparticles (SPIONs) enable cells to be tracked using magnetic resonance imaging (MRI), but to obtain detectable signal cells need to be labelled with a sufficient amount of iron oxide. For the majority of SPIONs, this can only be obtained with the use of transfection agents, which can adversely affect cell health. Here, we have synthesised a library of dextran-based polymer coated SPIONs with varying surface charge from −1.5 mV to +18.2 mV via a co-precipitation approach and investigated their ability to be directly internalised by stem cells without the need for transfection agents. The SPIONs were colloidally stable in physiological solutions. The crystalline phase of the particles was confirmed with powder X-ray diffraction and their magnetic properties were characterised using SQUID magnetometry and magnetic resonance. Increased surface charge led to six-fold increase in uptake of particles into stem cells and higher MRI contrast, with negligible change in cell viability. Cell tracking velocimetry was shown to be a more accurate method for predicting MRI contrast of stem cells compared to measuring iron oxide uptake through conventional bulk iron quantification

Closed String Tachyon Condensation on Twisted Circles

We study IIA/B string theory compactified on twisted circles. These models possess closed string tachyons and reduce to type 0B/A theory in a special limit. Using methods of gauged linear sigma models and mirror symmetry we construct a conformal field theory which interpolates between these models and flat space via an auxiliary Liouville direction. Interpreting motion in the Liouville direction as renormalization group flow, we argue that the end point of tachyon condensation in all these models (including 0B/A theory) is supersymmetric type II theory. We also find a zero-slope limit of these models which is best described in a T-dual picture as a type II NS-NS fluxbrane. In this limit tachyon condensation is an interesting and well posed problem in supergravity. We explicitly determine the tachyon as a fluctuation of supergravity fields, and perform a rudimentary numerical analysis of the relevant flows.Comment: 21 pages plus appendices (12 pages), harvmac, 1 fig, v2: minor changes and references added, v3: minor changes version published in JHE

Sympathetic-transduction in untreated hypertension

Transduction of muscle sympathetic nerve activity (MSNA) into vascular tone varies with age and sex. Older normotensive men have reduced sympathetic transduction so that a given level of MSNA causes less arteriole vasoconstriction. Whether sympathetic transduction is altered in hypertension (HTN) is not known. We investigated whether sympathetic transduction is impaired in untreated hypertensive men compared to normotensive controls. Eight untreated hypertensive men and 10 normotensive men (age 50 ± 15 years vs. 45 ± 12 years (mean ± SD); p = 0.19, body mass index (BMI) 24.7 ± 2.7 kg/m(2) vs. 26.0 ± 4.2 kg/m(2); p = 0.21) were recruited. MSNA was recorded from the peroneal nerve using microneurography; beat-to-beat blood pressure (BP; Finapres) and heart rate (ECG) were recorded simultaneously at rest for 10 min. Sympathetic-transduction was quantified using a previously described method. The relationship between MSNA burst area and subsequent diastolic BP was measured for each participant with the slope of the regression indicating sympathetic transduction. MSNA was higher in the hypertensive group compared to normotensives (73 ± 17 bursts/100 heartbeats vs. 49 ± 19 bursts/100 heart bursts; p = 0.007). Sympathetic-transduction was lower in the hypertensive versus normotensive group (0.04%/mmHg/s vs. 0.11%/mmHg/s, respectively; R = 0.622; p = 0.006). In summary, hypertensive men had lower sympathetic transduction compared to normotensive individuals suggesting that higher levels of MSNA are needed to cause the same level of vasoconstrictor tone

An ultrasensitive reverse transcription polymerase chain reaction assay to detect asymptomatic low-density Plasmodium falciparum and Plasmodium vivax infections in small volume blood samples.

BackgroundHighly sensitive, scalable diagnostic methods are needed to guide malaria elimination interventions. While traditional microscopy and rapid diagnostic tests (RDTs) are suitable for the diagnosis of symptomatic malaria infection, more sensitive tests are needed to screen for low-density, asymptomatic infections that are targeted by interventions aiming to eliminate the entire reservoir of malaria infection in humans.MethodsA reverse transcription polymerase chain reaction (RT- PCR) was developed for multiplexed detection of the 18S ribosomal RNA gene and ribosomal RNA of Plasmodium falciparum and Plasmodium vivax. Simulated field samples stored for 14 days with sample preservation buffer were used to assess the analytical sensitivity and specificity. Additionally, 1750 field samples from Southeastern Myanmar were tested both by RDT and ultrasensitive RT-PCR.ResultsLimits of detection (LoD) were determined under simulated field conditions. When 0.3 mL blood samples were stored for 14 days at 28 °C and 80% humidity, the LoD was less than 16 parasites/mL for P. falciparum and 19.7 copies/µL for P. vivax (using a plasmid surrogate), about 10,000-fold lower than RDTs. Of the 1739 samples successfully evaluated by both ultrasensitive RT-PCR and RDT, only two were RDT positive while 24 were positive for P. falciparum, 108 were positive for P. vivax, and 127 were positive for either P. vivax and/or P. falciparum using ultrasensitive RT-PCR.ConclusionsThis ultrasensitive RT-PCR method is a robust, field-tested screening method that is vastly more sensitive than RDTs. Further optimization may result in a truly scalable tool suitable for widespread surveillance of low-level asymptomatic P. falciparum and P. vivax parasitaemia

Ricci flow and black holes

Gradient flow in a potential energy (or Euclidean action) landscape provides a natural set of paths connecting different saddle points. We apply this method to General Relativity, where gradient flow is Ricci flow, and focus on the example of 4-dimensional Euclidean gravity with boundary S^1 x S^2, representing the canonical ensemble for gravity in a box. At high temperature the action has three saddle points: hot flat space and a large and small black hole. Adding a time direction, these also give static 5-dimensional Kaluza-Klein solutions, whose potential energy equals the 4-dimensional action. The small black hole has a Gross-Perry-Yaffe-type negative mode, and is therefore unstable under Ricci flow. We numerically simulate the two flows seeded by this mode, finding that they lead to the large black hole and to hot flat space respectively, in the latter case via a topology-changing singularity. In the context of string theory these flows are world-sheet renormalization group trajectories. We also use them to construct a novel free energy diagram for the canonical ensemble.Comment: 31 pages, 14 color figures. v2: Discussion of the metric on the space of metrics corrected and expanded, references adde

Cost-effectiveness of genotype-guided and dual antiplatelet therapies in acute coronary syndrome.

BackgroundThe choice of antiplatelet therapy after acute coronary syndrome (ACS) is complicated: Ticagrelor and prasugrel are novel alternatives to clopidogrel, patients with some genotypes may not respond to clopidogrel, and low-cost generic formulations of clopidogrel are available.ObjectiveTo determine the most cost-effective strategy for dual antiplatelet therapy after percutaneous coronary intervention for ACS.DesignDecision-analytic model.Data sourcesPublished literature, Medicare claims, and life tables.Target populationPatients having percutaneous coronary intervention for ACS.Time horizonLifetime.PerspectiveSocietal.InterventionFive strategies were examined: generic clopidogrel, prasugrel, ticagrelor, and genotyping for polymorphisms of CYP2C19 with carriers of loss-of-function alleles receiving either ticagrelor (genotyping with ticagrelor) or prasugrel (genotyping with prasugrel) and noncarriers receiving clopidogrel.Outcome measuresDirect medical costs, quality-adjusted life years(QALYs), and incremental cost-effectiveness ratios (ICERs).Results of base-case analysisThe clopidogrel strategy produced$179 301 in costs and 9.428 QALYs. Genotyping with prasugrel was superior to prasugrel alone, with an ICER of$35 800 per QALY relative to clopidogrel. Genotyping with ticagrelor was more effective than genotyping with prasugrel ($30 200 per QALY relative to clopidogrel). Ticagrelor was the most effective strategy($52 600 per QALY relative to genotyping with ticagrelor).Results of sensitivity analysisStronger associations between genotype and thrombotic outcomes rendered ticagrelor substantially less cost-effective ($104 800 per QALY). Genotyping with prasugrel was the preferred therapy among patients who could not tolerate ticagrelor.LimitationNo randomized trials have directly compared genotyping strategies or prasugrel with ticagrelor.ConclusionGenotype-guided personalization may improve the cost-effectiveness of prasugrel and ticagrelor after percutaneous coronary intervention for ACS, but ticagrelor for all patients may bean economically reasonable alternative in some settings

How should performance in EBUS mediastinal staging in lung cancer be measured?

There has been a paradigm shift in mediastinal staging algorithms in non-small cell lung cancer over the last decade in the United Kingdom (UK). This has seen endoscopic nodal staging (predominantly endobronchial ultrasound, EBUS) almost replace surgical staging (predominantly mediastinoscopy) as the pathological staging procedure of first choic