D-brane potentials in the warped resolved conifold and natural inflation

In this paper we obtain a model of Natural Inflation from string theory with a Planckian decay constant. We investigate D-brane dynamics in the background of the warped resolved conifold (WRC) throat approximation of Type IIB string compactifications on Calabi-Yau manifolds. When we glue the throat to a compact bulk Calabi-Yau, we generate a D-brane potential which is a solution to the Laplace equation on the resolved conifold. We can exactly solve this equation, including dependence on the angular coordinates. The solutions are valid down to the tip of the resolved conifold, which is not the case for the more commonly used deformed conifold. This allows us to exploit the effect of the warping, which is strongest at the tip. We inflate near the tip using an angular coordinate of a D5-brane in the WRC which has a discrete shift symmetry, and feels a cosine potential, giving us a model of Natural Inflation, from which it is possible to get a Planckian decay constant whilst maintaining control over the backreaction. This is because the decay constant for a wrapped brane contains powers of the warp factor, and so can be made large, while the wrapping parameter can be kept small enough so that backreaction is under control.Comment: 41 pages, 3 appendices, 1 figure, PDFLaTex; various clarifications added along with a new appendix on b-axions and wrapped D5 branes;version matches the one published in JHE

Determining the neurotransmitter concentration profile at active synapses

Establishing the temporal and concentration profiles of neurotransmitters during synaptic release is an essential step towards understanding the basic properties of inter-neuronal communication in the central nervous system. A variety of ingenious attempts has been made to gain insights into this process, but the general inaccessibility of central synapses, intrinsic limitations of the techniques used, and natural variety of different synaptic environments have hindered a comprehensive description of this fundamental phenomenon. Here, we describe a number of experimental and theoretical findings that has been instrumental for advancing our knowledge of various features of neurotransmitter release, as well as newly developed tools that could overcome some limits of traditional pharmacological approaches and bring new impetus to the description of the complex mechanisms of synaptic transmission

Galectin-9/TIM-3 Interaction Regulates Virus-Specific Primary and Memory CD8+ T Cell Response

In this communication, we demonstrate that galectin (Gal)-9 acts to constrain CD8+ T cell immunity to Herpes Simplex Virus (HSV) infection. In support of this, we show that animals unable to produce Gal-9, because of gene knockout, develop acute and memory responses to HSV that are of greater magnitude and better quality than those that occur in normal infected animals. Interestingly, infusion of normal infected mice with α-lactose, the sugar that binds to the carbohydrate-binding domain of Gal-9 limiting its engagement of T cell immunoglobulin and mucin (TIM-3) receptors, also caused a more elevated and higher quality CD8+ T cell response to HSV particularly in the acute phase. Such sugar treated infected mice also had expanded populations of effector as well as memory CD8+ T cells. The increased effector T cell responses led to significantly more efficient virus control. The mechanisms responsible for the outcome of the Gal-9/TIM-3 interaction in normal infected mice involved direct inhibitory effects on TIM-3+ CD8+ T effector cells as well as the promotion of Foxp3+ regulatory T cell activity. Our results indicate that manipulating galectin signals, as can be achieved using appropriate sugars, may represent a convenient and inexpensive approach to enhance acute and memory responses to a virus infection

Sins of Omission

Little is known about the relative incidence of serious errors of omission versus errors of commission. Objective : To identify the most common substantive medical errors identified by medical record review. Design : Retrospective cohort study. Setting : Twelve Veterans Affairs health care systems in 2 regions. Participants : Stratified random sample of 621 patients receiving care over a 2-year period. Main Outcome Measure : Classification of reported quality problems. Methods : Trained physicians reviewed the full inpatient and outpatient record and described quality problems, which were then classified as errors of omission versus commission. Results : Eighty-two percent of patients had at least 1 error reported over a 13-month period. The average number of errors reported per case was 4.7 (95% confidence intervals [CI]: 4.4, 5.0). Overall, 95.7% (95% CI: 94.9%, 96.4%) of errors were identified as being problems with underuse. Inadequate care for people with chronic illnesses was particularly common. Among errors of omission, obtaining insufficient information from histories and physicals (25.3%), inadequacies in diagnostic testing (33.9%), and patients not receiving needed medications (20.7%) were all common. Out of the 2,917 errors identified, only 27 were rated as being highly serious, and 26 (96%) of these were errors of omission. Conclusions : While preventing iatrogenic injury resulting from medical errors is a critically important part of quality improvement, we found that the overwhelming majority of substantive medical errors identifiable from the medical record were related to people getting too little medical care, especially for those with chronic medical conditions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74567/1/j.1525-1497.2005.0152.x.pd

Characterization of bovine embryos cultured under conditions appropriate for sustaining human naïve pluripotency.

In mammalian preimplantation development, pluripotent cells are set aside from cells that contribute to extra-embryonic tissues. Although the pluripotent cell population of mouse and human embryos can be cultured as embryonic stem cells, little is known about the pathways involved in formation of a bovine pluripotent cell population, nor how to maintain these cells in vitro. The objective of this study was to determine the transcriptomic profile related to bovine pluripotency. Therefore, in vitro derived embryos were cultured in various culture media that recently have been reported capable of maintaining the naïve pluripotent state of human embryonic cells. Gene expression profiles of embryos cultured in these media were compared using microarray analysis and quantitative RT-PCR. Compared to standard culture conditions, embryo culture in 'naïve' media reduced mRNA expression levels of the key pluripotency markers NANOG and POU5F1. A relatively high percentage of genes with differential expression levels were located on the X-chromosome. In addition, reduced XIST expression was detected in embryos cultured in naïve media and female embryos contained fewer cells with H3K27me3 foci, indicating a delay in X-chromosome inactivation. Whole embryos cultured in one of the media, 5iLA, could be maintained until 23 days post fertilization. Together these data indicate that 'naïve' conditions do not lead to altered expression of known genes involved in pluripotency. Interestingly, X-chromosome inactivation and development of bovine embryos were dependent on the culture conditions

Deletion of the WD40 Domain of LRRK2 in Zebrafish Causes Parkinsonism-Like Loss of Neurons and Locomotive Defect

LRRK2 plays an important role in Parkinson's disease (PD), but its biological functions are largely unknown. Here, we cloned the homolog of human LRRK2, characterized its expression, and investigated its biological functions in zebrafish. The blockage of zebrafish LRRK2 (zLRRK2) protein by morpholinos caused embryonic lethality and severe developmental defects such as growth retardation and loss of neurons. In contrast, the deletion of the WD40 domain of zLRRK2 by morpholinos targeting splicing did not induce severe embryonic developmental defects; rather it caused Parkinsonism-like phenotypes, including loss of dopaminergic neurons in diencephalon and locomotion defects. These neurodegenerative and locomotion defects could be rescued by over-expressing zLRRK2 or hLRRK2 mRNA. The administration of L-dopa could also rescue the locomotion defects, but not the neurodegeneration. Taken together, our results demonstrate that zLRRK2 is an ortholog of hLRRK2 and that the deletion of WD40 domain of zLRRK2 provides a disease model for PD

Using classification and regression tree modelling to investigate response shift patterns in dentine hypersensitivity

BACKGROUND: Dentine hypersensitivity (DH) affects people's quality of life (QoL). However changes in the internal meaning of QoL, known as Response shift (RS) may undermine longitudinal assessment of QoL. This study aimed to describe patterns of RS in people with DH using Classification and Regression Trees (CRT) and to explore the convergent validity of CRT with the then-test and ideals approaches. METHODS: Data from an 8-week clinical trial of mouthwashes for dentine hypersensitivity (n = 75) using the Dentine Hypersensitivity Experience Questionnaire (DHEQ) as the outcome measure, were analysed. CRT was used to examine 8-week changes in DHEQ total score as a dependent variable with clinical status for DH and each DHEQ subscale score (restrictions, coping, social, emotional and identity) as independent variables. Recalibration was inferred when the clinical change was not consistent with the DHEQ change score using a minimally important difference for DHEQ of 22 points. Reprioritization was inferred by changes in the relative importance of each subscale to the model over time. RESULTS: Overall, 50.7% of participants experienced a clinical improvement in their DH after treatment and 22.7% experienced an important improvement in their quality of life. Thirty-six per cent shifted their internal standards downward and 14.7% upwards, suggesting recalibration. Reprioritization occurred over time among the social and emotional impacts of DH. CONCLUSIONS: CRT was a useful method to reveal both, the types and nature of RS in people with a mild health condition and demonstrated convergent validity with design based approaches to detect RS

Excessive Biologic Response to IFNβ Is Associated with Poor Treatment Response in Patients with Multiple Sclerosis

Interferon-beta (IFNβ) is used to inhibit disease activity in multiple sclerosis (MS), but its mechanisms of action are incompletely understood, individual treatment response varies, and biological markers predicting response to treatment have yet to be identified.he relationship between the molecular response to IFNβ and treatment response was determined in 85 patients using a longitudinal design in which treatment effect was categorized by brain magnetic resonance imaging as good (n = 70) or poor response (n = 15). Molecular response was quantified using a customized cDNA macroarray assay for 166 IFN-regulated genes (IRGs).The molecular response to IFNβ differed significantly between patients in the pattern and number of regulated genes. The molecular response was strikingly stable for individuals for as long as 24 months, however, suggesting an individual ‘IFN response fingerprint’. Unexpectedly, patients with poor response showed an exaggerated molecular response. IRG induction ratios demonstrated an exaggerated molecular response at both the first and 6-month IFNβ injections.MS patients exhibit individually unique but temporally stable biological responses to IFNβ. Poor treatment response is not explained by the duration of biological effects or the specific genes induced. Rather, individuals with poor treatment response have a generally exaggerated biological response to type 1 IFN injections. We hypothesize that the molecular response to type I IFN identifies a pathogenetically distinct subset of MS patients whose disease is driven in part by innate immunity. The findings suggest a strategy for biologically based, rational use of IFNβ for individual MS patients

Use of a health information exchange system in the emergency care of children

<p>Abstract</p> <p>Background</p> <p>Children may benefit greatly in terms of safety and care coordination from the information sharing promised by health information exchange (HIE). While information exchange capability is a required feature of the certified electronic health record, we known little regarding how this technology is used in general and for pediatric patients specifically.</p> <p>Methods</p> <p>Using data from an operational HIE effort in central Texas, we examined the factors associated with actual system usage. The clinical and demographic characteristics of pediatric ED encounters (n = 179,445) were linked to the HIE system user logs. Based on the patterns of HIE system screens accessed by users, we classified each encounter as: no system usage, basic system usage, or novel system usage. Using crossed random effects logistic regression, we modeled the factors associated with basic and novel system usage.</p> <p>Results</p> <p>Users accessed the system for 8.7% of encounters. Increasing patient comorbidity was associated with a 5% higher odds of basic usage and 15% higher odds for novel usage. The odds of basic system usage were lower in the face of time constraints and for patients who had not been to that location in the previous 12 months.</p> <p>Conclusions</p> <p>HIE systems may be a source to fulfill users' information needs about complex patients. However, time constraints may be a barrier to usage. In addition, results suggest HIE is more likely to be useful to pediatric patients visiting ED repeatedly. This study helps fill an existing gap in the study of technological applications in the care of children and improves knowledge about how HIE systems are utilized.</p