Plants utilise ancient conserved peptide upstream open reading frames in stress-responsive translational regulation.

The regulation of protein synthesis plays an important role in the growth and development of all organisms. Upstream open reading frames (uORFs) are commonly found in eukaryotic messenger RNA transcripts and typically attenuate the translation of associated downstream main ORFs (mORFs). Conserved peptide uORFs (CPuORFs) are a rare subset of uORFs, some of which have been shown to conditionally regulate translation by ribosome stalling. Here, we show that Arabidopsis CPuORF19, CPuORF46 and CPuORF47, which are ancient in origin, regulate translation of any downstream ORF, in response to the agriculturally significant environmental signals, heat stress and water limitation. Consequently, these CPuORFs represent a versatile toolkit for inducible gene expression with broad applications. Finally, we note that different classes of CPuORFs may operate during distinct phases of translation, which has implications for the bioengineering of these regulatory factors.

C-X-C Motif Chemokine Ligand 9 and Its CXCR3 Receptor Are the Salt and Pepper for T Cells Trafficking in a Mouse Model of Gaucher Disease.

Gaucher disease is a lysosomal storage disease, which happens due to mutations in GBA1/Gba1 that encodes the enzyme termed as lysosomal acid ß-glucosidase. The major function of this enzyme is to catalyze glucosylceramide (GC) into glucose and ceramide. The deficiency of this enzyme and resultant abnormal accumulation of GC cause altered function of several of the innate and adaptive immune cells. For example, augmented infiltration of T cells contributes to the increased production of pro-inflammatory cytokines, (e.g., IFNγ, TNFα, IL6, IL12p40, IL12p70, IL23, and IL17A/F). This leads to tissue damage in a genetic mouse model (Gba19V/-) of Gaucher disease. The cellular mechanism(s) by which increased tissue infiltration of T cells occurs in this disease is not fully understood. Here, we delineate role of the CXCR3 receptor and its exogenous C-X-C motif chemokine ligand 9 (CXCL9) in induction of increased tissue recruitment of CD4+ T and CD8+ T cells in Gaucher disease. Intracellular FACS staining of macrophages (Mϕs) and dendritic cells (DCs) from Gba19V/- mice showed elevated production of CXCL9. Purified CD4+ T cells and the CD8+ T cells from Gba19V/- mice showed increased expression of CXCR3. Ex vivo and in vivo chemotaxis experiments showed CXCL9 involvement in the recruitment of Gba19V/- T cells. Furthermore, antibody blockade of the CXCL9 receptor (CXCR3) on T cells caused marked reduction in CXCL9- mediated chemotaxis of T cells in Gba19V/- mice. These data implicate abnormalities of the CXCL9-CXCR3 axis leading to enhanced tissue recruitment of T cells in Gaucher disease. Such results provide a rationale for blockade of the CXCL9/CXCR3 axis as potential new therapeutic targets for the treatment of inflammation in Gaucher disease.

The long-term effects of a family based economic empowerment intervention (Suubi+Adherence) on suppression of HIV viral loads among adolescents living with HIV in southern Uganda: Findings from 5-year cluster randomized trial.

BACKGROUND: The rapid scale-up of HIV therapy across Africa has failed to adequately engage adolescents living with HIV (ALWHIV). Retention and viral suppression for this group (ALWHIV) is 50% lower than for adults. Indeed, on the African continent, HIV remains the single leading cause of mortality among adolescents. Strategies tailored to the unqiue developmental and social vulnerabilities of this group are urgently needed to enhance successful treatment. METHODS: We carried out a five-year longitudinal cluster randomized trial (ClinicalTrials.gov ID: NCT01790373) with adolescents living with HIV (ALWHIV) ages 10 to 16 years clustered at health care clinics to test the effect of a family economic empowerment (EE) intervention on viral suppression in five districuts in Uganda. In total, 39 accredited health care clinics from study districts with existing procedures tailored to adolescent adherence were eligible to participate in the trial. We used data from 288 youth with detectable HIV viral loads (VL) at baseline (158 -intervention group from 20 clinics, 130 -non-intervention group from 19 clinics). The primary end point was undetectable plasma HIV RNA levels, defined as < 40 copies/ml. We used Kaplan-Meier (KM) analysis and Cox proportional hazard models to estimate intervention effects. FINDINGS: The Kaplan-Meier (KM) analysis indicated that an incidence of undetectable VL (0.254) was significantly higher in the intervention condition compared to 0.173 (in non-intervention arm) translated into incidence rate ratio of 1.468 (CI: 1.064-2.038), p = 0.008. Cox regression results showed that along with the family-based EE intervention (adj. HR = 1.446, CI: 1.073-1.949, p = 0.015), higher number of medications per day had significant positive effects on the viral suppression (adj.HR = 1.852, CI: 1.275-2.690, p = 0.001). INTERPRETATION: A family economic empowerment intervention improved treatment success for ALWHIV in Uganda. Analyses of cost effectiveness and scalability are needed to advance incorporation of this intervention into routine practice in low and middle-income countries.

Using Systems Thinking to Implement the QSEN Informatics Competency.

There is an urgent need to improve the use and usability of the electronic health record (EHR) in health care to prevent undue patient harm. Professional development educators can use systems thinking and the QSEN competency, Informatics, to educate nurses about such things as nurse-sensitive indicators in preventing medical errors. This article presents teaching tips in using systems thinking to champion communication technologies that support error prevention (betterment). [J Contin Educ Nurs. 2019;50(9):392-397.].

Comparing Educational Outcomes of Online Module-Based Technology with and without Simulation on Attitudes Toward Care of the Dying in Second Semester BSN Students.

BACKGROUND: Opportunities to provide competent and compassionate End-of Life (EOL) care to patients and families are limited for nursing students. METHOD: A mixed methods approach was used to explore the students' attitudes towards caring for an EOL patient in two groups: an on-line-module only group and an on-line module plus simulation group. RESULTS: Statistically significant effect of time was found across the two conditions (F [1, 69] = 7.83, p = .007), indicating that scores on the FATCOD-B significantly improved regardless of the condition over time. The qualitative responses indicated that the simulation experience was more impactful than the on-line module. CONCLUSIONS: Innovative education modalities described in the study may assist in preparing the future workforce for the myriad of demands related to health, life, and death.

Adverse event reporting following simulation encounters in accelerated and traditional bachelor nursing students.

OBJECTIVE: This study was to investigate the differences in the types, frequency, and perspectives of self-reported adverse events reported following simulation encounters between students enrolled in two Bachelor of Science in Nursing (BSN) programs: accelerated option (AO-BSN) or traditional (T-BSN) and by role (participant or observer) during simulation. METHODS: This study analyzed 6994 adverse event reports entered by students through the simulated adverse event reporting system. RESULTS: The AO-BSN students reported a higher percentage of adverse events coded as errors. In contrast the T-BSN students reported more near misses and sentinel events. Further, the T-BSN students significantly reported more fall related errors, while AO-BSN students reported more confidentiality breach errors. Participants reported more medication errors, whereas observers reported more airway and fall categorized errors. CONCLUSION: The vantage from which adverse events are viewed and educational track appear to alter slightly the perceptions of the precipitating factors leading to committed or observed adverse events.

A Protective Association between SNAP Participation and Educational Outcomes Among Children of Economically Strained Households.

With the recent cuts to the Supplemental Nutrition Assistance Program (SNAP), more information is needed to assess the impact these policies have on vulnerable children. As such, this study assesses the potential moderating effect of SNAP participation on the association between material deprivation and educational outcomes among children living in poverty (n = 10 971, and n = 14 928). SNAP participation was found to moderate the association between material deprivation and grade retention, indicating that SNAP may be contributing to grade retention among children living in poverty, which can have positive lifelong consequences.

Complement drives glucosylceramide accumulation and tissue inflammation in Gaucher disease.

Gaucher disease is caused by mutations in GBA1, which encodes the lysosomal enzyme glucocerebrosidase (GCase). GBA1 mutations drive extensive accumulation of glucosylceramide (GC) in multiple innate and adaptive immune cells in the spleen, liver, lung and bone marrow, often leading to chronic inflammation. The mechanisms that connect excess GC to tissue inflammation remain unknown. Here we show that activation of complement C5a and C5a receptor 1 (C5aR1) controls GC accumulation and the inflammatory response in experimental and clinical Gaucher disease. Marked local and systemic complement activation occurred in GCase-deficient mice or after pharmacological inhibition of GCase and was associated with GC storage, tissue inflammation and proinflammatory cytokine production. Whereas all GCase-inhibited mice died within 4-5 weeks, mice deficient in both GCase and C5aR1, and wild-type mice in which GCase and C5aR were pharmacologically inhibited, were protected from these adverse effects and consequently survived. In mice and humans, GCase deficiency was associated with strong formation of complement-activating GC-specific IgG autoantibodies, leading to complement activation and C5a generation. Subsequent C5aR1 activation controlled UDP-glucose ceramide glucosyltransferase production, thereby tipping the balance between GC formation and degradation. Thus, extensive GC storage induces complement-activating IgG autoantibodies that drive a pathway of C5a generation and C5aR1 activation that fuels a cycle of cellular GC accumulation, innate and adaptive immune cell recruitment and activation in Gaucher disease. As enzyme replacement and substrate reduction therapies are expensive and still associated with inflammation, increased risk of cancer and Parkinson disease, targeting C5aR1 may serve as a treatment option for patients with Gaucher disease and, possibly, other lysosomal storage diseases.

Determining pathogen and indicator levels in class B municipal organic residuals used for land application.

Biosolids are nutrient-rich organic residuals that are currently used to amend soils for food production. Treatment requirements to inactivate pathogens for production of Class A biosolids are energy intensive. One less energy intensive alternative is to treat biosolids to Class B standards, but it could result in higher pathogen loads. Quantitative microbial risk assessments models have been developed on land application of Class B biosolids but contain many uncertainties because of limited data on specific pathogen densities and the use of fecal indicator organisms as accurate surrogates of pathogen loads. To address this gap, a 12-mo study of the levels and relationships between , , and human adenovirus (HAdV) with fecal coliform, somatic, and F-RNA coliphage levels in Class B biosolids from nine wastewater treatment plants throughout the United States was conducted. Results revealed that fecal coliform, somatic, and F-RNA coliphage densities were consistent throughout the year. More important, results revealed that HAdV ( = 2.5 × 10 genome copies dry g) and ( = 4.14 × 10 cysts dry g) were in all biosolids samples regardless of treatment processes, location, or season. oocysts were also detected (38% positive; range: 0-1.9 × 10 oocysts dry g), albeit sporadically. Positive correlations among three fecal indicator organisms and HAdV, but not protozoa, were also observed. Overall, this study reveals that high concentrations of enteric pathogens (e.g., , , and HAdV) are present in biosolids throughout the United States. Microbial densities found can further assist management and policymakers in establishing more accurate risk assessment models associated with land application of Class B biosolids.

Site matters: winning the hearts and minds of patients in a cardiology clinic.

BACKGROUND: In medical care settings, mental health symptoms of depression and distress are associated with poor medical outcomes, yet they are often underrecognized. OBJECTIVE: Authors sought to examine the effect of having immediate mental-health screening in the cardiology clinic. METHOD: The Patient Health Questionnaire and the Impact of Event Scale were used to screen for depression and distress in 316 patients at an urban cardiology clinic. Because of poor follow-up rates, a psychiatrist was placed on the premises of the cardiology clinic to facilitate referrals. RESULTS: Placing a psychiatrist within the cardiology clinic significantly improved the rate of successful referrals. CONCLUSION: Because 45 patients (14%) endorsed suicidal thoughts, authors conclude that mental health screening programs should include an immediate evaluation by a clinician.

Six core competencies and seven deadly sins: a virtues-based approach to the new guidelines for graduate medical education.

As part of efforts afoot to improve the overall quality of physician training, the Accreditation Council for Graduate Medical Education (ACGME) has endorsed a set of competencies that will be the blueprint for outcomes-based graduate medical education for years to come. While the spirit of this new law is taking shape, the letter remains largely unwritten. To bridge this gap, administrators of programs from all specialties must determine how the core competencies will be taught, evaluated, modeled, and enforced within their respective programs. This paper summarizes these challenges, in particular for surgical programs, and focuses constructively on the modeling/enforcement approach, describing key characteristics that programs should pursue and cultivate (virtues) as well as the signal prohibitions (vices) that both trainees and trainers must avoid. Regardless of specialty or programmatic particulars, virtues and vices may be used to define a context in which general competencies may be understood, and yield operational guidance upon which ultimate discussions of evaluation, remediation, and graduation may be predicated.