An Improvement of Lambda Calculus Using WoeOffset

The implications of unstable technology have been far-reaching and pervasive. In fact, few information theorists would disagree with the analysis of the lookaside buffer. WoeOffset, our new methodology for wireless theory, is the solution to all of these problems

Deducing Receptor Signaling Parameters from In Vivo Analysis: LuxN/AI-1 Quorum Sensing in Vibrio harveyi

SummaryQuorum sensing, a process of bacterial cell-cell communication, relies on production, detection, and response to autoinducer signaling molecules. LuxN, a nine-transmembrane domain protein from Vibrio harveyi, is the founding example of membrane-bound receptors for acyl-homoserine lactone (AHL) autoinducers. We used mutagenesis and suppressor analyses to identify the AHL-binding domain of LuxN and discovered LuxN mutants that confer both decreased and increased AHL sensitivity. Our analysis of dose-response curves of multiple LuxN mutants pins these inverse phenotypes on quantifiable opposing shifts in the free-energy bias of LuxN for occupying its kinase and phosphatase states. To understand receptor activation and to characterize the pathway signaling parameters, we exploited a strong LuxN antagonist, one of fifteen small-molecule antagonists we identified. We find that quorum-sensing-mediated communication can be manipulated positively and negatively to control bacterial behavior and, more broadly, that signaling parameters can be deduced from in vivo data

Ectopic LTαβ Directs Lymphoid Organ Neogenesis with Concomitant Expression of Peripheral Node Addressin and a HEV-restricted Sulfotransferase

Lymph node (LN) function depends on T and B cell compartmentalization, antigen presenting cells, and high endothelial venules (HEVs) expressing mucosal addressin cell adhesion molecule (MAdCAM-1) and peripheral node addressin (PNAd), ligands for naive cell entrance into LNs. Luminal PNAd expression requires a HEV-restricted sulfotransferase (HEC-6ST). To investigate LTαβ's activities in lymphoid organogenesis, mice simultaneously expressing LTα and LTβ under rat insulin promoter II (RIP) control were compared with RIPLTα mice in a model of lymphoid neogenesis and with LTβ−/− mice. RIPLTαβ pancreata exhibited massive intra-islet mononuclear infiltrates that differed from the more sparse peri-islet cell accumulations in RIPLTα pancreata: separation into T and B cell areas was more distinct with prominent FDC networks, expression of lymphoid chemokines (CCL21, CCL19, and CXCL13) was more intense, and L-selectin+ cells were more frequent. In contrast to the predominant abluminal PNAd pattern of HEV in LTβ−/− MLN and RIPLTα pancreatic infiltrates, PNAd was expressed at the luminal and abluminal aspects of HEV in wild-type LN and in RIPLTαβ pancreata, coincident with HEC-6ST. These data highlight distinct roles of LTα and LTαβ in lymphoid organogenesis supporting the notion that HEC-6ST–dependent luminal PNAd is under regulation by LTαβ

Add-on lenses in the treatment of residual refractive error

The survey was funded by a grant from the Office of the First Minister and Deputy First Minister of Northern Ireland.In a sample of young people in Northern Ireland (N=819), we examine the relationships between the quality of experience with police officers and police legitimacy. We examine potential pathways through which experiences may either support or undermine the legitimacy of the police, and thus cooperation and compliance with them. We find evidence that perceptions of the police as having goals that align with those of wider society, and as being fair in general, mediate relations between the quality of encounters and legitimacy, which in turn mediates the relation with cooperation and compliance. Identification with wider society was not a reliable mediator, contrary to our predictions based on the Group Engagement Model. Moreover, our analysis of the structure of police fairness perceptions finds no support for the distinction between procedural and distributive police fairness as usually conceived. Implications for the social psychological understanding of legitimate authority are discussed.Publisher PDFPeer reviewe

Hot topics, urgent priorities, and ensuring success for racial/ethnic minority young investigators in academic pediatrics.

BackgroundThe number of racial/ethnic minority children will exceed the number of white children in the USA by 2018. Although 38% of Americans are minorities, only 12% of pediatricians, 5% of medical-school faculty, and 3% of medical-school professors are minorities. Furthermore, only 5% of all R01 applications for National Institutes of Health grants are from African-American, Latino, and American Indian investigators. Prompted by the persistent lack of diversity in the pediatric and biomedical research workforces, the Academic Pediatric Association Research in Academic Pediatrics Initiative on Diversity (RAPID) was initiated in 2012. RAPID targets applicants who are members of an underrepresented minority group (URM), disabled, or from a socially, culturally, economically, or educationally disadvantaged background. The program, which consists of both a research project and career and leadership development activities, includes an annual career-development and leadership conference which is open to any resident, fellow, or junior faculty member from an URM, disabled, or disadvantaged background who is interested in a career in academic general pediatrics.MethodsAs part of the annual RAPID conference, a Hot Topic Session is held in which the young investigators spend several hours developing a list of hot topics on the most useful faculty and career-development issues. These hot topics are then posed in the form of six "burning questions" to the RAPID National Advisory Committee (comprised of accomplished, nationally recognized senior investigators who are seasoned mentors), the RAPID Director and Co-Director, and the keynote speaker.Results/conclusionsThe six compelling questions posed by the 10 young investigators-along with the responses of the senior conference leadership-provide a unique resource and "survival guide" for ensuring the academic success and optimal career development of young investigators in academic pediatrics from diverse backgrounds. A rich conversation ensued on the topics addressed, consisting of negotiating for protected research time, career trajectories as academic institutions move away from an emphasis on tenure-track positions, how "non-academic" products fit into career development, racism and discrimination in academic medicine and how to address them, coping with isolation as a minority faculty member, and how best to mentor the next generation of academic physicians

Leukocyte Subset Changes in Response to a 164-km Road Cycle Ride in a Hot Environment

International Journal of Exercise Science 9(1): 34-46, 2016. The purpose of this observational study was to determine the circulating leukocyte subset response to completing the 2013 Hotter’N Hell Hundred recreational 164-km road cycle event in a hot and humid environmental condition. Twenty-eight men and four women were included in this study. Whole blood samples were obtained 1-2 hours before (PRE) and immediately after (POST) the event. Electronic sizing/sorting and cytometry were used to determine complete blood counts (CBC) including neutrophil, monocyte, and lymphocyte subsets. The concentration of circulating total leukocytes (103·µL-1) increased 134% from PRE to POST with the greatest increase in neutrophils (319%, p\u3c0.0001). Circulating monocytes (including macrophages) increased 24% (p=0.004) and circulating lymphocytes including B and T cells increased 53% (p\u3c0.0001). No association was observed between rolling time or relative intensity and leukocyte subset. Completing the Hotter n’ Hell Hundred (HHH), a 100 mile recreational cycling race in extreme (hot and humid) environmental conditions, induces a substantial increase in total leukocytes in circulation. The contribution of increases in specific immune cell subsets is not equal, with neutrophils increasing to greater than 4-fold starting values from PRE to POST race. It is likely that exercise in stressful environmental conditions affects the complement of circulating immune cells, although activational state and characterization of specific leukocyte subsets remains unclear. The observed increase in circulating cell sub-populations suggests that the circulating immune surveillance system may be acutely affected by exercise in hot and humid conditions

Pharmacists’ use of guidelines for the supply of non-prescription medicines: a cross-sectional survey

Objectives: Guidelines support best practice for healthcare practice. In Australia, some non-prescription medicines are only accessible after consultation with a pharmacist and are known as Pharmacist Only medicines. Guidelines for providing some Pharmacist Only medicines are available, however, it is currently unknown if and how these guidelines are used in practice.// The objective was to characterise pharmacists’, intern pharmacists and pharmacy students’ use of guidelines for Pharmacist Only medicines.// Methods: A cross-sectional electronic survey of Australian registered pharmacists, intern pharmacists and pharmacy students was administered in July 2020. Questions explored the participants’ use of Pharmacist Only medicine guidelines (available both in print and online; available online only) in the preceding 12 months. Data were analysed descriptively (i.e. frequencies, percentages).// Key findings: In total, 574 eligible respondents completed the survey. Overall, 396 (69%) reported accessing the online and in-print guidelines in the previous 12 months with 185 (33%) accessing online-only guidelines. The guideline on emergency contraception was used the most out of all guidelines in the past 12 months (278, 48%). Overall, respondents reported accessing guidelines to update knowledge, check their practice reflected best practice and content familiarisation. Respondents’ reasons for not accessing guidelines were due to respondents stating they did not need the information or that they had previously accessed the guidelines more than 12 months ago. These reasons varied between respondent groups.// Conclusions: Access and use of the Pharmacist Only medicines guidelines varied between pharmacists, interns and students. Further understanding of the influences of the use of these guidelines will help inform professional bodies on how best to develop guidelines to increase consistent use in practice and implement interventions to increase use./

Use of a reference text by pharmacists, intern pharmacists and pharmacy students: a national cross-sectional survey

Background: Reference texts assist pharmacists by addressing knowledge gaps and enabling evidence-based decisions when providing patient care. It is unknown whether reference text utilisation patterns differ between pharmacists, intern pharmacists and pharmacy students. To describe and compare the self-reported use and perceptions of a reference text, namely the national formulary, by pharmacists, intern pharmacists and pharmacy students. // Methods: Registered pharmacists, intern pharmacists and pharmacy students living in Australia were surveyed in July 2020. The survey was electronic and self-administered. Questions considered self-reported use of a specific reference text in the preceding 12 months. // Key findings: There were 554 eligible responses out of 774 who commenced the survey: 430 (78%) pharmacists, 45 (8%) intern pharmacists and 79 (14%) pharmacy students. Most participants (529/554, 96%) reported historical use of the text, though pharmacists were significantly less likely than intern pharmacists and students to use it frequently (52/422, 12% versus 16/43, 37% versus 23/76, 30%, P < 0.001). Pharmacists (44%, 177/404) reported using the text as a tool to resolve a situation when providing a service or patient care (177/404, 44%) or as a teaching resource (150/404, 38%). In contrast, intern pharmacists and students most commonly use these to familiarise themselves with the contents (30/43, 70%; 46/76, 61%) or update their knowledge (34/43, 79%; 53/76, 70%). // Conclusions: Access and use patterns varied significantly across career stages. A broader understanding of the use of reference texts may help develop interventions to optimise the content and usability. Varying usage patterns across the groups may inform the tailoring of texts for future use

Discovery and characterization of artifactual mutations in deep coverage targeted capture sequencing data due to oxidative DNA damage during sample preparation

As researchers begin probing deep coverage sequencing data for increasingly rare mutations and subclonal events, the fidelity of next generation sequencing (NGS) laboratory methods will become increasingly critical. Although error rates for sequencing and polymerase chain reaction (PCR) are well documented, the effects that DNA extraction and other library preparation steps could have on downstream sequence integrity have not been thoroughly evaluated. Here, we describe the discovery of novel C > A/G > T transversion artifacts found at low allelic fractions in targeted capture data. Characteristics such as sequencer read orientation and presence in both tumor and normal samples strongly indicated a non-biological mechanism. We identified the source as oxidation of DNA during acoustic shearing in samples containing reactive contaminants from the extraction process. We show generation of 8-oxoguanine (8-oxoG) lesions during DNA shearing, present analysis tools to detect oxidation in sequencing data and suggest methods to reduce DNA oxidation through the introduction of antioxidants. Further, informatics methods are presented to confidently filter these artifacts from sequencing data sets. Though only seen in a low percentage of reads in affected samples, such artifacts could have profoundly deleterious effects on the ability to confidently call rare mutations, and eliminating other possible sources of artifacts should become a priority for the research community.National Human Genome Research Institute (U.S.) (HG03067-05

Task 2: ShARe/CLEF eHealth evaluation lab 2014

This paper reports on Task 2 of the 2014 ShARe/CLEF eHealth evaluation lab which extended Task 1 of the 2013 ShARe/CLEF eHealth evaluation lab by focusing on template lling of disorder attributes. The task was comprised of two subtasks: attribute normalization (task 2a) and cue identication (task 2b).We instructed participants to develop a system which either kept or updated a default attribute value for each task. Participant systems were evaluated against a blind reference standard of 133 discharge summaries using Accuracy (task 2a) and F-score (task 2b). In total, ten teams participated in task 2a, and three teams in task 2b. For task 2a and 2b, the HITACHI team systems (run 2) had the highest performances, with an overall average average accuracy of 0.868 and F1-score (strict) of 0.676, respectively