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Ma C.,Tsinghua University | Woolford J.L.,Jr
Nature Structural and Molecular Biology | Year: 2017

A key step in ribosome biogenesis is the nuclear export of pre-ribosomal particles. Nmd3, a highly conserved protein in eukaryotes, is a specific adaptor required for the export of pre-60S particles. Here we used cryo-electron microscopy (cryo-EM) to characterize Saccharomyces cerevisiae pre-60S particles purified with epitope-tagged Nmd3. Our structural analysis indicates that these particles belong to a specific late stage of cytoplasmic pre-60S maturation in which ribosomal proteins uL16, uL10, uL11, eL40 and eL41 are deficient, but ribosome assembly factors Nmd3, Lsg1, Tif6 and Reh1 are present. Nmd3 and Lsg1 are located near the peptidyl-transferase center (PTC). In particular, Nmd3 recognizes the PTC in its near-mature conformation. In contrast, Reh1 is anchored to the exit of the polypeptide tunnel, with its C terminus inserted into the tunnel. These findings pinpoint a structural checkpoint role for Nmd3 in PTC assembly, and provide information about functional and mechanistic roles of these assembly factors in the maturation of the 60S ribosomal subunit. © 2017 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

Ticau S.,Howard Hughes Medical Institute | Correa I.R.,Jr
Nature Structural and Molecular Biology | Year: 2017

The opening and closing of two ring-shaped Mcm2–7 DNA helicases is necessary to license eukaryotic origins of replication, although the mechanisms controlling these events are unclear. The origin-recognition complex (ORC), Cdc6 and Cdt1 facilitate this process by establishing a topological link between each Mcm2–7 hexamer and origin DNA. Using colocalization single-molecule spectroscopy and single-molecule Förster resonance energy transfer (FRET), we monitored ring opening and closing of Saccharomyces cerevisiae Mcm2–7 during origin licensing. The two Mcm2–7 rings were open during initial DNA association and closed sequentially, concomitant with the release of their associated Cdt1. We observed that ATP hydrolysis by Mcm2–7 was coupled to ring closure and Cdt1 release, and failure to load the first Mcm2–7 prevented recruitment of the second Mcm2–7. Our findings identify key mechanisms controlling the Mcm2–7 DNA-entry gate during origin licensing, and reveal that the two Mcm2–7 complexes are loaded via a coordinated series of events with implications for bidirectional replication initiation and quality control. © 2017 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

Case C.,Jr.
Current Hematologic Malignancy Reports | Year: 2017

The Radiation Injury Treatment Network (RITN) began in 2006 with the ambitious vision to provide a resource to help with the surge of casualties following a mass casualty incident with marrow toxic injuries. Through the efforts of the National Marrow Donor Program and American Society for Blood and Marrow Transplantation with the support of the Office of Naval Research, the initial 13 hospitals and cancer centers have grown to 76, training over 13,500 hospital staff and conducted, funded, and supported 580 disaster exercises testing preparedness. After a decade, there is more to do, but much laudatory work has been accomplished. © 2017 The Author(s)

BACKGROUND:: In 2008, the National Heart, Lung, and Blood Institute convened an Implementation Science Work Group to assess evidence-based strategies for effectively implementing clinical practice guidelines. This was part of a larger effort to update existing clinical practice guidelines on cholesterol, blood pressure, and overweight/obesity. OBJECTIVES:: Review evidence from the published implementation science literature and identify effective or promising strategies to enhance the adoption and implementation of clinical practice guidelines. METHODS:: This systematic review was conducted on 4 critical questions, each focusing on the adoption and effectiveness of 4 intervention strategies: (1) reminders, (2) educational outreach visits, (3) audit and feedback, and (4) provider incentives. A scoping review of the Rx for Change database of systematic reviews was used to identify promising guideline implementation interventions aimed at providers. Inclusion and exclusion criteria were developed a priori for each question, and the published literature was initially searched up to 2012, and then updated with a supplemental search to 2015. Two independent reviewers screened the returned citations to identify relevant reviews and rated the quality of each included review. RESULTS:: Audit and feedback and educational outreach visits were generally effective in improving both process of care (15 of 21 reviews and 12 of 13 reviews, respectively) and clinical outcomes (7 of 12 reviews and 3 of 5 reviews, respectively). Provider incentives showed mixed effectiveness for improving both process of care (3 of 4 reviews) and clinical outcomes (3 reviews equally distributed between generally effective, mixed, and generally ineffective). Reminders showed mixed effectiveness for improving process of care outcomes (27 reviews with 11 mixed and 3 generally ineffective results) and were generally ineffective for clinical outcomes (18 reviews with 6 mixed and 9 generally ineffective results). Educational outreach visits (2 of 2 reviews), reminders (3 of 4 reviews), and provider incentives (1 of 1 review) were generally effective for cost reduction. Educational outreach visits (1 of 1 review) and provider incentives (1 of 1 review) were also generally effective for cost-effectiveness outcomes. Barriers to clinician adoption or adherence to guidelines included time constraints (8 reviews/overviews); limited staffing resources (2 overviews); timing (5 reviews/overviews); clinician skepticism (5 reviews/overviews); clinician knowledge of guidelines (4 reviews/overviews); and higher age of the clinician (1 overview). Facilitating factors included guideline characteristics such as format, resources, and end-user involvement (6 reviews/overviews); involving stakeholders (5 reviews/overviews); leadership support (5 reviews/overviews); scope of implementation (5 reviews/overviews); organizational culture such as multidisciplinary teams and low-baseline adherence (9 reviews/overviews); and electronic guidelines systems (3 reviews). CONCLUSION:: The strategies of audit and feedback and educational outreach visits were generally effective in improving both process of care and clinical outcomes. Reminders and provider incentives showed mixed effectiveness, or were generally ineffective. No general conclusion could be reached about cost effectiveness, because of limitations in the evidence. Important gaps exist in the evidence on effectiveness of implementation interventions, especially regarding clinical outcomes, cost effectiveness and contextual issues affecting successful implementation. © 2017 by the American College of Cardiology Foundation and the American Heart Association, Inc.

Minami S.S.,University of California at San Francisco | Farese R.V.,Jr
Nature Medicine | Year: 2014

Haploinsufficiency of the progranulin (PGRN) gene (GRN) causes familial frontotemporal lobar degeneration (FTLD) and modulates an innate immune response in humans and in mouse models. GRN polymorphism may be linked to late-onset Alzheimer's disease (AD). However, the role of PGRN in AD pathogenesis is unknown. Here we show that PGRN inhibits amyloid β (Aβ) deposition. Selectively reducing microglial expression of PGRN in AD mouse models impaired phagocytosis, increased plaque load threefold and exacerbated cognitive deficits. Lentivirus-mediated PGRN overexpression lowered plaque load in AD mice with aggressive amyloid plaque pathology. Aβ plaque load correlated negatively with levels of hippocampal PGRN, showing the dose-dependent inhibitory effects of PGRN on plaque deposition. PGRN also protected against Aβ toxicity. Lentivirus-mediated PGRN overexpression prevented spatial memory deficits and hippocampal neuronal loss in AD mice. The protective effects of PGRN against Aβ deposition and toxicity have important therapeutic implications. We propose enhancing PGRN as a potential treatment for PGRN-deficient FTLD and AD.

Lopes B.,Rio Of Janeiro Corneal Tomography And Biomechanics Study Group | Ambrosio R.,Jr
Cornea | Year: 2014

PURPOSE:: The aim of this study was to compare corneal densitometry measured by Scheimpflug tomography in normal and keratoconic eyes and to assess the differences in densitometry values among the stages of keratoconus.METHODS:: Keratoconic and normal corneas were examined using the Pentacam. Corneal densitometry was measured over a 12-mm diameter area, divided by annular concentric zones and depths. Keratoconus was classified according to the topographic keratoconus classification.CONCLUSIONS:: The densitometry map reveals that light backscatter was higher in the central portion of the anterior keratoconic cornea than in the normal cornea. The densitometry level is higher in more advanced stages.RESULTS:: We enrolled 1 eye randomly selected from each of 172 patients with normal corneas (N) and 98 patients with bilateral keratoconus (KC). There were significant differences between the groups for densitometry measurements in 2 annuli: central 2.0 mm in diameter (N = 16.85 ± 2.42, KC = 18.93 ± 2.78, P = 0.0001) and annulus 2.0 to 6.0 mm in diameter (N = 15.18 ± 2.18, KC = 16.16 ± 1.71, P = 0.005), and total diameter (N = 24.89 ± 6.18, KC = 16.71 ± 2.3, P = 0.033). Divided by layers, the inner parts of anterior (120 μm), central (from 120 μm to the last 60 μm), and posterior (last 60 μm) layers were also higher in the KC group (P < 0.001). There were differences according to the stages of KC for corneal densitometry of the central annuli at total thickness, anterior and central layers. More advanced cases presented a higher backscatter (P < 0.05). The anterior layer presented the smallest overlap between groups and KC stages. © 2014 by Lippincott Williams & Wilkins.

Suri R.S.,Center Hospitalier Of Luniversite Of Montreal | Lockridge R.S.,Jr.
Clinical Journal of the American Society of Nephrology | Year: 2014

Background and objectives Patients receiving hemodialysis often perceive their caregivers are overburdened. We hypothesizethat increasinghemodialysis frequencywould resultin higherpatient perceptionsofburden on their unpaid caregivers. Design, setting, participants, & measurements In two separate trials, 245 patients were randomized to receive in-center daily hemodialysis (6 days/week) or conventional hemodialysis (3 days/week) while 87 patients were randomized to receive home nocturnal hemodialysis (6 nights/week) or home conventional hemodialysis for 12 months. Changes in overall mean scores over time in the 10-question Cousineau perceived burden scale were compared. Results In total, 173 of 245 (70%) and 80 of 87 (92%) randomized patients in the Daily and Nocturnal Trials, respectively, reported having an unpaid caregiver at baseline or during follow-up. Relative to in-center conventional dialysis, the 12-month change in mean perceived burden score with in-center daily hemodialysis was -2.1 (95% confidence interval, -9.4 to +5.3; P=0.58). Relative to home conventional dialysis, the 12-month change in mean perceived burden score with home nocturnal dialysis was +6.1 (95% confidence interval, -0.8 to +13.1; P=0.08). After multiple imputation for missing data in the Nocturnal Trial, the relative difference between home nocturnal and home conventional hemodialysis was +9.4(95% confidence interval, +0.55 to +18.3; P=0.04). In the Nocturnal Trial, changes in perceived burden were inversely correlated with adherence to dialysis treatments (Pearson r=-0.35; P=0.02). Conclusion Relative to conventional hemodialysis, in-center daily hemodialysis did not result in higher perceptions of caregiver burden. There was a trend to higher perceived caregiver burden among patients randomized to home nocturnal hemodialysis. These findings may have implications for the adoption of and adherence to frequent nocturnal hemodialysis. © 2014 by the American Society of Nephrology.

Salem N.,Jr. | Eggersdorfer M.,DSM Nutritional Products Inc.
Current Opinion in Clinical Nutrition and Metabolic Care | Year: 2015

PURPOSE OF REVIEW: To delineate the available sources of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) for human consumption and to determine if the available supply is capable of supplying the nutrient levels recommended by expert bodies. RECENT FINDINGS: There are converging opinions among experts, professional organizations and health professionals that a recommendation for a daily individual consumption of 500 mg of EPA/DHA would provide health benefits, and this translates to an annual human consumption of 1.3 million metric tons. Current human consumption of EPA/DHA is estimated to be only a small fraction of this amount and many people may suffer from suboptimal health as a result of low intake. EPA and DHA originate in the phytoplankton and are made available in the human food chain mainly through fish and other seafood. SUMMARY: The fish catch is not elastic and in fact has long since reached a plateau. Aquaculture has grown rapidly, but most of the fish oil produced is currently being used to support aquaculture feed and so this would appear to limit aquaculture growth - or at least the growth in availability of fish sources of EPA/DHA. Vegetable oil-derived alpha-linolenic acid, though relatively plentiful, is converted only at a trace level in humans to DHA and not very efficiently to EPA, and so cannot fill this gap. Microbial EPA/DHA production can in the future be increased, although this oil is likely to remain more expensive than fish oil. Plant sources of EPA and DHA have now been produced in the laboratory via transgenic means and will eventually clear regulatory hurdles for commercialization, but societal acceptance remains in question. The purpose of this review is to discuss the various sources of omega-3 fatty acids within the context of the potential world demand for these nutrients. In summary, it is concluded that fish and vegetable oil sources will not be adequate to meet future needs, but that algal oil and terrestrial plants modified genetically to produce EPA and DHA could provide for the increased world demand. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Joyal J.-S.,McGill University | Gobeil F.,Jr
Nature Medicine | Year: 2014

Neurons have an important role in retinal vascular development. Here we show that the G protein–coupled receptor (GPCR) coagulation factor II receptor-like 1 (F2rl1, previously known as Par2) is abundant in retinal ganglion cells and is associated with new blood vessel formation during retinal development and in ischemic retinopathy. After stimulation, F2rl1 in retinal ganglion cells translocates from the plasma membrane to the cell nucleus using a microtubule-dependent shuttle that requires sorting nexin 11 (Snx11). At the nucleus, F2rl1 facilitates recruitment of the transcription factor Sp1 to trigger Vegfa expression and, in turn, neovascularization. In contrast, classical plasma membrane activation of F2rl1 leads to the expression of distinct genes, including Ang1, that are involved in vessel maturation. Mutant versions of F2rl1 that prevent nuclear relocalization but not plasma membrane activation interfere with Vegfa but not Ang1 expression. Complementary angiogenic factors are therefore regulated by the subcellular localization of a receptor (F2rl1) that governs angiogenesis. These findings may have implications for the selectivity of drug actions based on the subcellular distribution of their targets.

Spaide R.F.,Vitreous | Ryan E.H.,Jr.
American Journal of Ophthalmology | Year: 2015

Purpose To evaluate potential accumulation of fluid in the outer choroid in eyes with central serous chorioretinopathy. Design Retrospective observational case series. Methods Patients in 2 community-based retinal practices were evaluated for hyporeflective areas in the outer choroid consistent with collections of fluid using enhanced depth imaging optical coherence tomography. Eligible patients were examined over the preceding 2 years, had a history of central serous chorioretinopathy, and did not have a history of choroidal neovascularization or photodynamic therapy. Results In the New York group there were 131 eyes of 70 patients who had a mean age of 56.3 (± 12.5) years, and 88 (67.2%) had hyporeflective regions consistent with posterior loculation of fluid in the macular region. In the Minnesota data set there were 91 eyes of 48 patients who had a mean age of 47.9 (± 9.9) years and hyporeflective regions consistent with posterior loculation of fluid was present in 59 (64.8%). In the entire group the mean subfoveal choroidal thickness of those without loculated fluid was 344 μm, as compared with 498 μm with loculated fluid (P <.001). The areas of loculated fluid were hyporeflective, were larger topographically than the large choroidal vessels, had an angular inner border, and did not have a bounding vascular wall. Conclusions Posterior loculation of fluid is a common finding in central serous chorioretinopathy, but it has a different pattern and distribution than do collections of fluid in the outer choroid and suprachoroidal space as seen in other forms of choroidal effusion. © 2015 Elsevier Inc.

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