846 research outputs found
IFITM3 restricts influenza A virus entry by blocking the formation of fusion pores following virus-endosome hemifusion
Interferon-induced transmembrane proteins (IFITMs) inhibit infection of diverse enveloped viruses, including the influenza A virus (IAV) which is thought to enter from late endosomes. Recent evidence suggests that IFITMs block virus hemifusion (lipid mixing in the absence of viral content release) by altering the properties of cell membranes. Consistent with this mechanism, excess cholesterol in late endosomes of IFITM-expressing cells has been reported to inhibit IAV entry. Here, we examined IAV restriction by IFITM3 protein using direct virus-cell fusion assay and single virus imaging in live cells. IFITM3 over-expression did not inhibit lipid mixing, but abrogated the release of viral content into the cytoplasm. Although late endosomes of IFITM3-expressing cells accumulated cholesterol, other interventions leading to aberrantly high levels of this lipid did not inhibit virus fusion. These results imply that excess cholesterol in late endosomes is not the mechanism by which IFITM3 inhibits the transition from hemifusion to full fusion. The IFITM3\u27s ability to block fusion pore formation at a post-hemifusion stage shows that this protein stabilizes the cytoplasmic leaflet of endosomal membranes without adversely affecting the lumenal leaflet. We propose that IFITM3 interferes with pore formation either directly, through partitioning into the cytoplasmic leaflet of a hemifusion intermediate, or indirectly, by modulating the lipid/protein composition of this leaflet. Alternatively, IFITM3 may redirect IAV fusion to a non-productive pathway, perhaps by promoting fusion with intralumenal vesicles within multivesicular bodies/late endosomes
Implementation of Brain Breaks((R)) in the Classroom and Effects on Attitudes toward Physical Activity in a Macedonian School Setting
The purpose of this study was to explore the effects of Brain Break((R)) activities on interest and motivation for physical activity among schoolchildren and the contribution of such activities on learning for health and holistic development. The study sample was comprised of 283 participants, primary school students from 3rd to 5th grades from two public schools in the Republic of Macedonia. Six experimental and six control groups were included in the study. Interventions in classroom settingsbased Brain Break((R)) video exercises were introduced in the experimental group during a period of three months. Students\u27 attitudes toward physical activity were tested using a self-report survey instrument entitled Attitudes toward Physical Activity Scale (APAS) before and after intervention. Applied factor analyses were completed and the results of these analysis support APAS validity and the successful use of this application in the measurement of the learning experience, self-awareness, self-efficacy, and self-confidence in developing physical fitness. Learning was enhanced by using video exercises. Information presented in this paper is meaningful for the promotion of better exercise habits and the holistic approach to better health by using personal motivation and motivation provided by others. The results from repeated ANCOVA suggest positive effects of the applied Brain Break((R)) video exercises as an interventional program. The study confirms the effect of application of Brain Break((R)) video exercises on children\u27s attitudes for physical activity, motivation for PA, internalization of movement habits as personal good
Pendidikan kesihatan dan jasmani: satu pernyataan konsensus sejagat baru / Christopher R. Edginton, Ming-kai Chin and Eng Hoe Wee
Perubahan yang ketara di dalam pendidikan jasmani telah berlaku dalam masa 40 tahun dengan
transisi daripada orentasi tradisional kemahiran sukan kepada penekanan yang lebih luas ke atas
kecergasan berasaskan kesihatan dan aktiviti fizikal sepanjang hayat. (Bocarro et al., 2008; Jago et
al., 2009; McKenzie & Kahan, 2008). Namun, di merata dunia, program-program pendidikan
jasmani sedang dikurangkan, dihadkan dan/atau sewenang-wenangnya dihapuskan daripada
kurikulum sekolah rendah dan menengah (Hardman & Marshall, 2009; Puhse & Gerber, 2005).
Adalah bertambah jelas bahawa nilai program-program pendidikan jasmani sedang diuji di seluruh
dunia
Comprehensive identification of host modulators of HIV-1 replication using multiple orthologous RNAi reagents
RNAi screens have implicated hundreds of host proteins as HIV-1 dependency factors (HDFs). While informative, these early studies overlap poorly due to false positives and false negatives. To ameliorate these issues, we combined information from the existing HDF screens together with new screens performed with multiple orthologous RNAi reagents (MORR). In addition to being traditionally validated, the MORR screens and the historical HDF screens were quantitatively integrated by the adaptation of an established analysis program, RIGER, for the collective interpretation of each gene\u27s phenotypic significance. False positives were addressed by the removal of poorly expressed candidates through gene expression filtering, as well as with GESS, which identifies off-target effects. This workflow produced a quantitatively integrated network of genes that modulate HIV-1 replication. We further investigated the roles of GOLGI49, SEC13, and COG in HIV-1 replication. Collectively, the MORR-RIGER method minimized the caveats of RNAi screening and improved our understanding of HIV-1-host cell interactions
The Impact of Brain Breaks Classroom-Based Physical Activities on Attitudes toward Physical Activity in Polish School Children in Third to Fifth Grade
The purpose of this study was to examine the effectiveness of the Brain Breaks® Physical Activity Solutions in changing attitudes toward physical activity of school children in a community in Poland. In 2015, a sample of 326 pupils aged 9–11 years old from 19 classes at three selected primary schools were randomly assigned to control and experimental groups within the study. During the classes, children in the experimental group performed physical activities two times per day in three to five minutes using Brain Breaks® videos for four months, while the control group did not use the videos during the test period. Students’ attitudes toward physical activities were assessed before and after the intervention using the “Attitudes toward Physical Activity Scale”. Repeated measures of ANOVA were used to examine the change from pre- to post-intervention. Overall, a repeated measures ANOVA indicated time-by-group interaction effects in ‘Self-efficacy on learning with video exercises’, F(1.32) = 75.28, p = 0.00, η2 = 0.19. Although the changes are minor, there were benefits of the intervention. It may be concluded that HOPSports Brain Breaks® Physical Activity Program contributes to better self-efficacy on learning while using video exercise of primary school children
Evaluating implementation of LEAPS, a youth-led early childhood care and education intervention in rural Pakistan: Protocol for a stepped wedge cluster-randomized trial
Background: The Sustainable Development Goals (SDGs) highlight the importance of investments in early childhood care and education (ECCE) and youth development. Given Pakistan\u27s large young population, and gender and urban-rural inequalities in access to education, training, and employment, such investments offer opportunities. LEAPS is a youth-led ECCE program that trains female youth, 18-24 years, as Community Youth Leaders (CYLs) to deliver high-quality ECCE for children, 3.5-5.5 years, in rural Sindh, Pakistan.Methods: We use a stepped wedge cluster-randomized trial to evaluate implementation of LEAPS. Ninety-nine clusters will be randomized to receive the intervention in one of three 7-month steps (33 clusters/step). The primary outcome is children\u27s school readiness (indexed by the total score on the International Development and Early Learning Assessment (IDELA)). Secondary child outcomes are children\u27s IDELA domain scores and executive functions. Data are collected in cross-sectional surveys of 1089 children (11 children/cluster from 99 clusters) aged 4.5-5.5 years at four timepoints (baseline and at the end of each step). Additionally, we will enroll three non-randomized youth participant open cohorts, one per step (33 CYLs: 66 comparison youth per cohort; 99:198 in total). Youth cohorts will be assessed at enrollment and every 7 months thereafter to measure secondary outcomes of youth personal and professional development, depressive symptoms, and executive functions. A non-randomized school cohort of 330 LEAPS students (10 students/cluster from 33 clusters) will also be enrolled and assessed during Step 1 after intervention rollout and at endline. The quality of the learning environment will be assessed in each LEAPS ECCE center and in a comparison center at two timepoints midway following rollout and at endline. A concurrent mixed-methods implementation evaluation will assess program fidelity and quality, and the extent to which a technical support strategy is successful in strengthening systems for program expansion. A cost evaluation will assess cost per beneficiary. Data collection for implementation and cost evaluations will occur in Step 3.Discussion: Youth-led models for ECCE offer a promising approach to support young children and youth. This study will contribute to the evidence as a means to promote sustainable human development across multiple SDG targets.Trial registration: ClinicalTrials.gov NCT03764436 . Registered on December 5, 2018
Teaching cancer imaging in the era of precision medicine: Looking at the big picture
The role of imaging in cancer diagnosis and treatment has evolved at the same rapid pace as cancer management. Over the last twenty years, with the advancement of technology, oncology has become a multidisciplinary field that allows for researchers and clinicians not only to create individualized treatment options for cancer patients, but also to evaluate patients\u27 response to therapy with increasing precision. Familiarity with these concepts is a requisite for current and future radiologists, as cancer imaging studies represent a significant and growing component of any radiology practice, from tertiary cancer centers to community hospitals. In this review we provide the framework to teach cancer imaging in the era of genomic oncology. After reading this article, readers should be able to illustrate the basics cancer genomics, modern cancer genomics, to summarize the types of systemic oncologic therapies available, their patterns of response and their adverse events, to discuss the role of imaging in oncologic clinical trials and the role of tumor response criteria and to display the future directions of oncologic imaging
Anakinra reduces blood pressure and renal fibrosis in one kidney/DOCA/salt-induced hypertension
OBJECTIVE: To determine whether a clinically-utilised IL-1 receptor antagonist, anakinra, reduces renal inflammation, structural damage and blood pressure (BP) in mice with established hypertension. METHODS: Hypertension was induced in male mice by uninephrectomy, deoxycorticosterone acetate (2.4mg/d,s.c.) and replacement of drinking water with saline (1K/DOCA/salt). Control mice received uninephrectomy, a placebo pellet and normal drinking water. 10days post-surgery, mice commenced treatment with anakinra (75mg/kg/d, i.p.) or vehicle (0.9% saline, i.p.) for 11 days. Systolic BP was measured by tail cuff while qPCR, immunohistochemistry and flow cytometry were used to measure inflammatory markers, collagen and immune cell infiltration in the kidneys. RESULTS: By 10 days post-surgery, 1K/DOCA/salt-treated mice displayed elevated systolic BP (148.3+/-2.4mmHg) compared to control mice (121.7+/-2.7mmHg; n=18, P\u3c0.0001). The intervention with anakinra reduced BP in 1K/DOCA/salt-treated mice by approximately 20mmHg (n=16, P\u3c0.05), but had no effect in controls. In 1K/DOCA/salt-treated mice, anakinra modestly reduced ( approximately 30%) renal expression of some (CCL5, CCL2; n=7-8; P\u3c0.05) but not all (ICAM-1, IL-6) inflammatory markers, and had no effect on immune cell infiltration (n=7-8, P \u3e 0.05). Anakinra reduced renal collagen content (n=6, P\u3c0.01) but paradoxically appeared to exacerbate the renal and glomerular hypertrophy (n=8-9, P\u3c0.001) that accompanied 1K/DOCA/salt-induced hypertension. CONCLUSION: Despite its anti-hypertensive and renal anti-fibrotic actions, anakinra had minimal effects on inflammation and leukocyte infiltration in mice with 1K/DOCA/salt-induced hypertension. Future studies will assess whether the anti-hypertensive actions of anakinra are mediated by protective actions in other BP-regulating or salt-handling organs such as the arteries, skin and brain
Characterization of Drug-Resistant Lipid-Dependent Differentially Detectable Mycobacterium tuberculosis
An estimated 15-20% of patients who are treated for pulmonary tuberculosis (TB) are culture-negative at the time of diagnosis. Recent work has focused on the existence of differentially detectable Mycobacterium tuberculosis (Mtb) bacilli that do not grow under routine solid culture conditions without the addition of supplementary stimuli. We identified a cohort of TB patients in Lima, Peru, in whom acid-fast bacilli could be detected by sputum smear microscopy, but from whom Mtb could not be grown in standard solid culture media. When we attempted to re-grow Mtb from the frozen sputum samples of these patients, we found that 10 out of 15 could be grown in a glycerol-poor/lipid-rich medium. These fell into the following two groups: a subset that could be regrown in glycerol after lipid-resuscitation , and a group that displayed a heritable glycerol-sensitive phenotype that were unable to grow in the presence of this carbon source. Notably, all of the glycerol-sensitive strains were found to be multidrug resistant. Although whole-genome sequencing of the lipid-resuscitated strains identified 20 unique mutations compared to closely related strains, no single genetic lesion could be associated with this phenotype. In summary, we found that lipid-based media effectively fostered the growth of Mtb from a series of sputum smear-positive samples that were not culturable in glycerol-based Lowenstein-Jensen or 7H9 media, which is consistent with Mtb\u27s known preference for non-glycolytic sources during infection. Analysis of the recovered strains demonstrated that both genetic and non-genetic mechanisms contribute to the observed differential capturability, and suggested that this phenotype may be associated with drug resistance
Mono-anionic phosphopeptides produced by unexpected histidine alkylation exhibit high plk1 polo-box domain-binding affinities and enhanced antiproliferative effects in hela cells
Binding of polo-like kinase 1 (Plk1) polo-box domains (PBDs) to phosphothreonine (pThr)/phosphoserine (pSer)-containing sequences is critical for the proper function of Plk1. Although high-affinity synthetic pThr-containing peptides provide starting points for developing PBD-directed inhibitors, to date the efficacy of such peptides in whole cell assays has been poor. This potentially reflects limited cell membrane permeability arising, in part, from the di-anionic nature of the phosphoryl group or its mimetics. In our current article we report the unanticipated on-resin N(τ)-alkylation of histidine residues already bearing a N(π)- alkyl group. This resulted in cationic imidazolium-containing pThr peptides, several of which exhibit single-digit nanomolar PBD-binding affinities in extracellular assays and improved antimitotic efficacies in intact cells. We enhanced the cellular efficacies of these peptides further by applying bio-reversible pivaloyloxymethyl (POM) phosphoryl protection. New structural insights presented in our current study, including the potential utility of intramolecular charge masking, may be useful for the further development of PBD-binding peptides and peptide mimetics.National Institutes of Health (U.S.) (Grants ES015339 and GM104047
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