Designing siRNA That Distinguish between Genes That Differ by a Single Nucleotide

Small interfering RNAs (siRNAs), the guides that direct RNA interference (RNAi), provide a powerful tool to reduce the expression of a single gene in human cells. Ideally, dominant, gain-of-function human diseases could be treated using siRNAs that specifically silence the mutant disease allele, while leaving expression of the wild-type allele unperturbed. Previous reports suggest that siRNAs can be designed with single nucleotide specificity, but no rational basis for the design of siRNAs with single nucleotide discrimination has been proposed. We systematically identified siRNAs that discriminate between the wild-type and mutant alleles of two disease genes: the human Cu, Zn superoxide dismutase (SOD1) gene, which contributes to the progression of hereditary amyotrophic lateral sclerosis through the gain of a toxic property, and the huntingtin (HTT) gene, which causes Huntington disease when its CAG-repeat region expands beyond approximately 35 repeats. Using cell-free RNAi reactions in Drosophila embryo lysate and reporter assays and microarray analysis of off-target effects in cultured human cells, we identified positions within an siRNA that are most sensitive to mismatches. We also show that purine:purine mismatches imbue an siRNA with greater discriminatory power than other types of base mismatches. siRNAs in which either a G:U wobble or a mismatch is located in the “seed” sequence, the specialized siRNA guide region responsible for target binding, displayed lower levels of selectivity than those in which the mismatch was located 3′ to the seed; this region of an siRNA is critical for target cleavage but not siRNA binding. Our data suggest that siRNAs can be designed to discriminate between the wild-type and mutant alleles of many genes that differ by just a single nucleotide

Perspectives of patients and healthcare professionals on mHealth for asthma self-management

Copyright ©ERS 2017. Mobile healthcare (mHealth) has the potential to revolutionise the self-management of long-term medical conditions such as asthma. A user-centred design is integral if mHealth is to be embraced by patients and healthcare professionals. The aim of this study was to determine the perspectives of individuals with asthma and healthcare professionals on the use of mHealth for asthma self-management. We used a sequential exploratory mixed methods design; focus groups informed the development of questionnaires, which were disseminated to individuals with asthma and healthcare professionals. Focus group participants (18 asthma patients and five healthcare professionals) identified 12 potential uses of mHealth. Questionnaire results showed that individuals with asthma (n=186) most frequently requested an mHealth system to monitor asthma over time (72%) and to collect data to present to healthcare teams (70%). In contrast, healthcare professionals (n=63) most frequently selected a system alerting patients to deteriorating asthma control (86%) and advising them when to seek medical attention (87%). Individuals with asthma were less likely than healthcare professionals (p < 0.001) to believe that assessing medication adherence and inhaler technique could improve asthma control. Our data provide strong support for mHealth for asthma self-management, but highlight fundamental differences between the perspectives of patients and healthcare professionals

Search for eccentric black hole coalescences during the third observing run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass M&gt;70 M⊙) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities 0&lt;e≤0.3 at 0.33 Gpc−3 yr−1 at 90\% confidence level

Ultralight vector dark matter search using data from the KAGRA O3GK run

Among the various candidates for dark matter (DM), ultralight vector DM can be probed by laser interferometric gravitational wave detectors through the measurement of oscillating length changes in the arm cavities. In this context, KAGRA has a unique feature due to differing compositions of its mirrors, enhancing the signal of vector DM in the length change in the auxiliary channels. Here we present the result of a search for U(1)B−L gauge boson DM using the KAGRA data from auxiliary length channels during the first joint observation run together with GEO600. By applying our search pipeline, which takes into account the stochastic nature of ultralight DM, upper bounds on the coupling strength between the U(1)B−L gauge boson and ordinary matter are obtained for a range of DM masses. While our constraints are less stringent than those derived from previous experiments, this study demonstrates the applicability of our method to the lower-mass vector DM search, which is made difficult in this measurement by the short observation time compared to the auto-correlation time scale of DM

How Academic Administrators Shape Experiential Learning Curriculum Based on Employer Feedback

This generic qualitative inquiry was guided by the following research question: How do academic administrators of the Association to Advance Collegiate Schools of Business AACSB accredited business schools shape experiential learning curriculum based on employer feedback regarding workplace readiness and employability? The study explored experiences of academic administrators regarding the use of employers' feedback in terms of incorporating experiential learning into the business curriculum. This generic qualitative inquiry utilized semi-structured interviews with 13 academic administrators of AACSB accredited universities in the United States. Data collected from the interviews were transcribed and were analyzed using NVivo macOS version 11 software, resulting in six key themes. Findings of the study indicate that (a) employers and universities are partnering to create experiential learning curriculum; (b) real-world projects are being incorporated into curriculum although internships are also encouraged; (c) the faculty, not academic administrators drive curriculum decisions; (d) trends in employer feedback are required before implementation is considered; (e) employer feedback is focused on workplace readiness skills not course content, concepts, or industry knowledge; and (f) there are still challenges regarding faculty willingness to address employer feedback through experiential learning curriculum

Engaging Community-Based Cancer Physicians: Experience of the Memorial Sloan Kettering Cancer Center Cancer Alliance.

BACKGROUND: The proliferation of relationships between community health systems and academic medical centers has created a need to identify effective components of these models. This article reports on frontline physician experiences, with one such relationship established through the Memorial Sloan Kettering Cancer Center (MSK) Cancer Alliance. MSK created the Alliance with the goals of rapidly bringing the newest standards of care into community settings and increasing patient access to clinical trials in their local communities. METHODS: Alliance leadership administered a 10-question anonymous survey to physicians treating patients with cancer across the 3 Alliance member health systems: Hartford HealthCare Cancer Institute, Lehigh Valley Cancer Institute, and Miami Cancer Institute at Baptist Health South Florida. The purpose of the survey was to identify opportunities to improve physician engagement. RESULTS: There were 103 clinician respondents across Alliance members, of which 87 reported participation in a disease management team and were included in the final analysis. Most respondents reported high value from Alliance activities, such as attending MSK tumor boards (94%) and lecture series (96%), among those who reported them applicable. Across all respondents, most reported satisfaction with engagement opportunities, such as MSK physician participation in their institution\u27s meetings (76%). When asked where they would like to see increased engagement, the most commonly reported response was for more lecture series (45%). Most respondents (88%) reported that the Alliance led to practice change, either for themselves or for other clinicians at their institution. Many attributed this practice change to MSK disease-specific process measures. CONCLUSIONS: The activities most valued by community physicians were heavily physician relationship-based. The encouraging experience of the MSK Cancer Alliance suggests that activities involving physician investment may be effective for promoting practice change in the context of cross-institution relationships. Future research is needed in this area