In situ structures of the genome and genome-delivery apparatus in a single-stranded RNA virus.

Packaging of the genome into a protein capsid and its subsequent delivery into a host cell are two fundamental processes in the life cycle of a virus. Unlike double-stranded DNA viruses, which pump their genome into a preformed capsid, single-stranded RNA (ssRNA) viruses, such as bacteriophage MS2, co-assemble their capsid with the genome; however, the structural basis of this co-assembly is poorly understood. MS2 infects Escherichia coli via the host 'sex pilus' (F-pilus); it was the first fully sequenced organism and is a model system for studies of translational gene regulation, RNA-protein interactions, and RNA virus assembly. Its positive-sense ssRNA genome of 3,569 bases is enclosed in a capsid with one maturation protein monomer and 89 coat protein dimers arranged in a T = 3 icosahedral lattice. The maturation protein is responsible for attaching the virus to an F-pilus and delivering the viral genome into the host during infection, but how the genome is organized and delivered is not known. Here we describe the MS2 structure at 3.6 Å resolution, determined by electron-counting cryo-electron microscopy (cryoEM) and asymmetric reconstruction. We traced approximately 80% of the backbone of the viral genome, built atomic models for 16 RNA stem-loops, and identified three conserved motifs of RNA-coat protein interactions among 15 of these stem-loops with diverse sequences. The stem-loop at the 3' end of the genome interacts extensively with the maturation protein, which, with just a six-helix bundle and a six-stranded β-sheet, forms a genome-delivery apparatus and joins 89 coat protein dimers to form a capsid. This atomic description of genome-capsid interactions in a spherical ssRNA virus provides insight into genome delivery via the host sex pilus and mechanisms underlying ssRNA-capsid co-assembly, and inspires speculation about the links between nucleoprotein complexes and the origins of viruses

Population Aging and Intergenerational Transfers: Introducing Age into National Accounts

In all societies intergenerational transfers are large and have an important influence on inequality and growth. The development of each generation of youth depends on the resources that it receives from productive members of society for health, education, and sustenance. The well-being of the elderly depends on familial support and a variety of social programs. The National Transfer Accounts (NTA) system provides a comprehensive approach to measuring all reallocations of income across age and time at the aggregate level. It encompasses reallocations achieved through capital accumulation and transfers, distinguishing those mediated by public institutions from those relying on private institutions. This paper introduces the methodology and presents preliminary results emphasizing economic support systems in Taiwan and the United States. As the two economies differ in their demographic configuration, their level of development, and their old-age support systems, comparing them will shed light on the economic implications of population aging under alternative institutional arrangements.

Malaria parasite translocon structure and mechanism of effector export.

The putative Plasmodium translocon of exported proteins (PTEX) is essential for transport of malarial effector proteins across a parasite-encasing vacuolar membrane into host erythrocytes, but the mechanism of this process remains unknown. Here we show that PTEX is a bona fide translocon by determining structures of the PTEX core complex at near-atomic resolution using cryo-electron microscopy. We isolated the endogenous PTEX core complex containing EXP2, PTEX150 and HSP101 from Plasmodium falciparum in the 'engaged' and 'resetting' states of endogenous cargo translocation using epitope tags inserted using the CRISPR-Cas9 system. In the structures, EXP2 and PTEX150 interdigitate to form a static, funnel-shaped pseudo-seven-fold-symmetric protein-conducting channel spanning the vacuolar membrane. The spiral-shaped AAA+ HSP101 hexamer is tethered above this funnel, and undergoes pronounced compaction that allows three of six tyrosine-bearing pore loops lining the HSP101 channel to dissociate from the cargo, resetting the translocon for the next threading cycle. Our work reveals the mechanism of P. falciparum effector export, and will inform structure-based design of drugs targeting this unique translocon

Nonlinear Waves in Disordered Diatomic Granular Chains

We investigate the propagation and scattering of highly nonlinear waves in disordered granular chains composed of diatomic (two-mass) units of spheres that interact via Hertzian contact. Using ideas from statistical mechanics, we consider each diatomic unit to be a "spin", so that a granular chain can be viewed as a spin chain composed of units that are each oriented in one of two possible ways. Experiments and numerical simulations both reveal the existence of two different mechanisms of wave propagation: In low-disorder chains, we observe the propagation of a solitary pulse with exponentially decaying amplitude. Beyond a critical level of disorder, the wave amplitude instead decays as a power law, and the wave transmission becomes insensitive to the level of disorder. We characterize the spatio-temporal structure of the wave in both propagation regimes and propose a simple theoretical interpretation for such a transition. Our investigation suggests that an elastic spin chain can be used as a model system to investigate the role of heterogeneities in the propagation of highly nonlinear waves.Comment: 10 pages, 8 figures (some with multiple parts), to appear in Physical Review E; summary of changes: new title, one new figure, additional discussion of several points (including both background and results

Из опыта формирования творческой активности у школьников среднего звена при изучении геометрического материала

BACKGROUND:Current research suggests that while patients are becoming more engaged across the health delivery spectrum, this involvement occurs most often at the pre-preparation stage to identify 'high-level' priorities in health ecosystem priority setting, and at the preparation phase for health research. OBJECTIVE:The purpose of this systematic rapid review of the literature is to describe the evidence that does exist in relation to patient and public engagement priority setting in both health ecosystem and health research. DATA SOURCES:HealthStar (via OVID); CINAHL; Proquest Databases; and Scholar's Portal. STUDY ELIGIBILITY CRITERIA:i) published in English; ii) published within the timeframe of 2007-Current (10 years) unless the report/article was formative in synthesizing key considerations of patient engagement in health ecosystem and health research priority setting; iii) conducted in Canada, the US, Europe, UK, Australia/New Zealand, or Scandinavian countries. STUDY APPRAISAL AND SYNTHESIS:i) Is the research valid, sound, and applicable?; ii) what outcomes can we potentially expect if we implement the findings from this research?; iii) will the target population (i.e., health researchers and practitioners) be able to use this research?. A summary of findings from each of the respective processes was synthesized to highlight key information that would support decision-making for researchers when determining the best priority setting process to apply for their specific patient-oriented research. RESULTS:Seventy articles from the UK, US, Canada, Netherlands and Australia were selected for review. Results were organized into two tiers of public and patient engagement in prioritization: Tier 1-Deliberative and Tier 2-Consultative. Highly structured patient and public engagement planning activities include the James Lind Alliance Priority Setting Partnerships (UK), Dialogue Method (Netherlands), Global Evidence Mapping (Australia), and the Deep Inclusion Method/CHoosing All Together (US). LIMITATIONS:The critical study limitations include challenges in comprehensively identifying the patient engagement literature for review, bias in article selection due to the identified scope, missed information due to a more limited use of exhaustive search strategies (e.g., in-depth hand searching), and the heterogeneity of reported study findings. CONCLUSION:The four public and patient engagement priority setting processes identified were successful in setting priorities that are inclusive and objectively based, specific to the priorities of stakeholders engaged in the process. The processes were robust, strategic and aimed to promote equity in patient voices. Key limitations identified a lack of evaluation data on the success and extent in which patients were engaged. Issues pertaining to feasibility of stakeholder engagement, coordination, communication and limited resources were also considered

Neutrino dimuon production and the dynamical determination of strange parton distributions

Utilizing recent neutrino dimuon production measurement from NuTeV the assumptions on the determination of the strangeness content of the nucleon within the dynamical approach to parton distributions are investigated. The data are found to be in good agreement with the predictions derived from our (GJR08) dynamical parton distributions, which have been generated entirely radiatively starting from vanishing strange input distributions at an optimally chosen low resolution scale. Further, the data induce an asymmetry in the strange sea which is found to be small and positive in agreement with previous results.Comment: 6 pages, 2 figure

Acupressure for agitation in nursing home residents with dementia: study protocol for a randomized controlled trial

BACKGROUND: Agitation is prevalent among people with dementia (PWD) in nursing homes. It frustrates both the PWD and their caregivers. Acupressure is a non-pharmacological intervention whose effectiveness is supported by preliminary studies. However, there is still a dearth of evidence to explain its effect for clinical use and further research. The present study is being conducted primarily to investigate the effects of acupressure as compared with sham-acupressure and usual care. METHODS/DESIGN: This study is a multicenter, assessor/participant/statistician-blinded, parallel group, randomized controlled trial taking place in Hong Kong nursing homes. We have been recruiting PWD over 65 years of age in nursing homes, who are experiencing agitation; 99 participants will be recruited in order to demonstrate a significant effect difference (that is, f =0.27) with a power of 0.8 and a significance level of 0.05 among the three groups. Participants are assigned by permuted block randomization into three groups in a 1:1:1 ratio. In the acupressure group, participants receive acupressure at the Fengchi (GB20), Baihui (GV20), Shenmen (HT7), Niguan (PC6) and Yingtang (EX-HN3) acupoints. In the sham-acupressure group, participants receive pressure on five non-acupoints. In the usual-care group, participants receive no intervention apart from the care provided by the nursing homes. Participants assigned to the sham-acupressure and usual-care groups receive free acupressure, like those in the acupressure group, after completion of the study. The whole study lasts for 30 weeks, and its primary outcome measure is agitation. The general estimated equation model will be used to compare the effects among groups and time points. The trial is currently recruiting participants. DISCUSSION: This trial will provide a higher quality of evidence than previous studies on the use of acupressure for agitation in PWD. It will also provide newer evidence on acupressure in the population of PWD with agitation for clinical application and further research, including the effect on moderating stress, the delayed effect, the added effect on the placebo, and the effect on moderating the participant’s use of psychotropic drugs. TRIAL REGISTRATION: Centre for Clinical Trials Clinical Trials Registry: CUHK_CCT00347 (Registration date: 13 December 2012)

Designed beta-hairpins inhibit LDH5 oligomerization and enzymatic activity

Lactate dehydrogenase 5 (LDH5) is overexpressed in metastatic tumors and is an attractive target for anticancer therapy. Small-molecule drugs have been developed to target the substrate/cofactor sites of LDH5, but none has reached the clinic to date, and alternative strategies remain almost unexplored. Combining rational and computer-based approaches, we identified peptidic sequences with high affinity toward a β-sheet region that is involved in protein-protein interactions (PPIs) required for the activity of LDH5. To improve stability and potency, these sequences were grafted into a cyclic cell-penetrating β-hairpin peptide scaffold. The lead grafted peptide, cGmC9, inhibited LDH5 activity in vitro in low micromolar range and more efficiently than the small-molecule inhibitor GNE-140. cGmC9 inhibits LDH5 by targeting an interface unlikely to be inhibited by small-molecule drugs. This lead will guide the development of new LDH5 inhibitors and challenges the landscape of drug discovery programs exclusively dedicated to small molecules. </p

The Strange Parton Distribution of the Nucleon: Global Analysis and Applications

The strangeness degrees of freedom in the parton structure of the nucleon are explored in the global analysis framework, using the new CTEQ6.5 implementation of the general mass perturbative QCD formalism of Collins. We systematically determine the constraining power of available hard scattering experimental data on the magnitude and shape of the strange quark and anti-quark parton distributions. We find that current data favor a distinct shape of the strange sea compared to the isoscalar non-strange sea. A new reference parton distribution set, CTEQ6.5S0, and representative sets spanning the allowed ranges of magnitude and shape of the strange distributions, are presented. Some applications to physical processes of current interest in hadron collider phenomenology are discussed.Comment: 19 pages; revised version submitted to JHE