Iron, an essential nutrient with limited bioavailability, requires specialized cellular mechanisms for uptake. Although iron uptake into the cytoplasm in the form of heme has been well characterized ...in many bacteria, the subsequent trafficking is poorly understood. The cytoplasmic heme-binding proteins belong to a structurally related family thought to have evolved as "induced fit" ligand-binding macromolecules. One member, Pseudomonas aeruginosa cytoplasmic protein (PhuS), has previously been shown to be important for delivering heme to the iron regulated heme oxygenase (HemO). Spectroscopic investigations of the holo-PhuS complex revealed a dynamic heme environment with overlapping but distinct heme-binding sites with alternative coordinating heme ligands, His-209 or His-212. In the present work we establish a mechanism for how heme is transferred from PhuS to its partner, HemO. Using surface plasmon resonance and isothermal titration calorimetry, we have discovered that holo-PhuS, but not apo-PhuS, forms a 1:1 complex with HemO. Sedimentation velocity and limited proteolysis experiments suggest that heme binding to PhuS induces a conformational rearrangement that drives the protein interaction with HemO. Hydrodynamic analysis reveals that the holo-PhuS displays a more expanded hydrodynamic envelope compared with apo-PhuS, and we propose that this conformational change drives the interaction with HemO. We further demonstrate that replacement of His-212 by Ala disrupts the interaction of holo-PhuS with HemO; in contrast, the His-209-Ala variant can still complex with HemO, albeit more weakly. Together, the present studies reveal a mechanism that couples a heme-dependent conformational switch in PhuS to protein–protein interaction, the subsequent free energy of which drives heme release to HemO.
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Introduction
People with cystic fibrosis (pwCF) require a multidisciplinary care team due to disease complexity. The Cystic Fibrosis Foundation (CFF) notes that pharmacists are recommended, while ...other organizations consider pharmacists required. In 2016, the CFF initiated a grant program for CFF‐accredited care centers and affiliate programs (CFF‐ACCAP) to implement outpatient pharmacy services. The primary objective of this study was to compare surveys regarding pharmacy involvement in CFF‐ACCAP pre‐ and post‐grant implementation.
Methods
This was an IRB‐approved, survey‐based study. The surveys were distributed via the CF pharmacist‐pharmacy technician and center director e‐mail exchanges.
Results
There are currently 244 CFF‐ACCAP and 158 pharmacists. Forty‐two pharmacists completed the 2013 survey and 77 completed the 2023 survey. Practice site shifted from primarily the inpatient (58.5%) to outpatient settings (67.5%; p < .001). Most positions were created in the past 7 years (81%) with 50% currently or previously funded by the CFF grant program. CFF center director response decreased from 2013 to 2023 (106 vs. 48) but centers with a dedicated CF pharmacist increased from 2013 to 2023 (66%–86%; p = .014). In the 2023 survey, we received responses from 17 pharmacy technicians, who were newly included. Most of these technicians (64%) reported working in outpatient clinics.
Conclusions
Since 2013, pharmacy presence has grown at CFF‐ACCAP, partly due to the CFF grant program. Despite pharmacists not being required members of the multidisciplinary care team, their presence is notable in 65% of CFF‐ACCAP centers, where they contribute significantly to improving the care provided for pwCF.
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Influence of initial sediment phosphorus content of the pond sediment on P dose efficiency was examined in a laboratory experiment using four types of sediments collected from ponds located along a ...nutrient gradient in a sewage‐fed fish farm. Each sediment type (500 g) was dispensed in a glass jar with water and treated with single super phosphate (SSP) treatment at 1.25, 2.5, 5.0 and 10.0 mg L−1 in triplicate. Determination of orthophosphate (OP) and soluble reactive phosphorus (SRP) in water and available and total P in sediment showed increased response in relation to dose and time. At a given dose, the rate of increase for all species of phosphate in sediment or water was maximum in the case of local pond (LP) soil followed by stocking pond (SP), facultative pond (FP) and anaerobic pond (AP) soil, suggesting that utililization of phosphate fertilizer was much better under oligotrophic conditions than under eutrophic states. The SSP‐induced OP peak at 10 mg L−1 in LP sediment was similar to that of 5.0 mg L−1 in AP sediment containing 59% enhanced initial phosphate, implying that fertilizer application can be profitably reduced by 18% in the former without limiting the OP level in the water phase. It is concluded that dosage selection of phosphorus fertilizer in aquaculture ponds should be based on an evaluation of the initial P status of the system.
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Gene therapy for hemophilia using adeno-associated virus (AAV) derived vectors can reduce or eliminate patients' disease-related complications and improve their quality of life. Broad implementation ...globally will lead to societal gains and foster health equity. Several vector products each for factor IX (FIX) or factor VIII (FVIII) deficiency are in advanced clinical development. Safety data are reassuring. Efficacy data for up to 8 and 5 years, respectively, vary considerably among vector types and among individuals, but indicate significant reduction in bleeds and factor use. Products will soon be approved for marketing. This review highlights the relevant considerations for implementation of hemophilia gene therapy, specifically across a broad range of socioeconomic backgrounds globally, based on recent publications and our own experience. We address the current efficacy and safety data and relevant aspects of vector immunology. We then discuss pertinent implementation steps including pre-implementation and readiness assessments, considerations on cost, cost-effectiveness and payment models, approaches to education and informed consent, and the operational needs as well as the need for monitoring of health outcomes and implementation outcomes. To prevent a lag or complete lack of establishing access to this life-changing therapy option for all patients with hemophilia worldwide, adaptable pathways supported by collaborative and international efforts of all stakeholders are needed. Keywords: global health, health equity, cost-effectiveness, adeno-associated virus vector, factor VIII, factor IX
The contamination of hazardous metal(loid) is one of the serious environmental and human health risks. This study isolated a total of 40 cadmium (Cd)- and arsenic (As)-resistant bacterial isolates ...from coastal sediments by pour plate technique using tryptic soy agar supplemented with Cd or As (50 mg l⁻¹) for use as metal(loid) bioremediation agents. Out of 40, 4 isolates, RCd3, RCd6, RAs7, and RAs10, showed a relatively higher growth rate in Cd- or As-supplemented culture media which were selected for further study. The selected isolates showed a high minimum inhibitory concentration (60–400 mg l⁻¹for Cd and 400–2200 mg l⁻¹for As), which demonstrated their remarkable Cd and As resistance capabilities. The metal(loid) removal efficiencies (0.032–0.268 μg Cd h⁻¹ mg⁻¹and 0.0003–0.0172 μg As h⁻¹ mg⁻¹wet weight cell) of selected isolates indicated their greater magnitude in absorbing Cd compared to As from water. Phylogenetic analysis of the 16S rDNA sequences revealed that isolates RCd3, RCd6, RAs7, and RAs10 were closely related to Acinetobacter brisouii, Pseudomonas abietaniphila, Exiguobacterium aestuarii, and Planococcus rifietoensis, respectively. Because of high Cd and As resistance and removal efficiency, the selected isolates can survive in a high metal(loid)-contaminated environment and could be a potential tool for bioremediation of high metal(loid)-contaminated effluents to protect the aquatic environment.
Prediction of Juvenile-Onset Myopia Zadnik, Karla; Sinnott, Loraine T; Cotter, Susan A ...
JAMA ophthalmology,
06/2015, Volume:
133, Issue:
6
Journal Article
Peer reviewed
Open access
IMPORTANCE: Myopia (nearsightedness) has its onset in childhood and affects about one-third of adults in the United States. Along with its high prevalence, myopia is expensive to correct and is ...associated with ocular diseases that include glaucoma and retinal detachment. OBJECTIVE: To determine the best set of predictors for myopia onset in school-aged children. DESIGN, SETTING, AND PARTICIPANTS: The Collaborative Longitudinal Evaluation of Ethnicity and Refractive Error (CLEERE) Study was an observational cohort study of ocular development and myopia onset conducted at 5 clinical sites from September 1, 1989, through May 22, 2010. Data were collected from 4512 ethnically diverse, nonmyopic school-aged children from grades 1 through 8 (baseline grades 1 through 6) (ages 6 through 13 years baseline, 6 through 11 years). MAIN OUTCOMES AND MEASURES: We evaluated 13 candidate risk factors for their ability to predict the onset of myopia. Myopia onset was defined as −0.75 diopters or more of myopia in each principal meridian in the right eye as measured by cycloplegic autorefraction at any visit after baseline until grade 8 (age 13 years). We evaluated risk factors using odds ratios from discrete time survival analysis, the area under the curve, and cross validation. RESULTS: A total of 414 children became myopic from grades 2 through 8 (ages 7 through 13 years). Of the 13 factors evaluated, 10 were associated with the risk for myopia onset (P < .05). Of these 10 factors, 8 retained their association in multivariate models: spherical equivalent refractive error at baseline, parental myopia, axial length, corneal power, crystalline lens power, ratio of accommodative convergence to accommodation (AC/A ratio), horizontal/vertical astigmatism magnitude, and visual activity. A less hyperopic/more myopic baseline refractive error was consistently associated with risk of myopia onset in multivariate models (odds ratios from 0.02 to 0.13, P < .001), while near work, time outdoors, and having myopic parents were not. Spherical equivalent refractive error was the single best predictive factor that performed as well as all 8 factors together, with an area under the curve (C statistic) ranging from 0.87 to 0.93 (95% CI, 0.79-0.99). CONCLUSIONS AND RELEVANCE: Future myopia can be predicted in a nonmyopic child using a simple, single measure of refractive error. Future trials for prevention of myopia should target the child with low hyperopia as the child at risk.
PurposeTo model juvenile-onset myopia progression as a function of race/ethnicity, age, sex, parental history of myopia, and time spent reading or in outdoor/sports activity. MethodsSubjects were 594 ...children in the Collaborative Longitudinal Evaluation of Ethnicity and Refractive Error (CLEERE) Study with at least three study visits: one visit with a spherical equivalent (SPHEQ) less myopic/more hyperopic than -0.75 diopter (D), the first visit with a SPHEQ of -0.75 D or more myopia (onset visit), and another after myopia onset. Myopia progression from the time of onset was modeled using cubic models as a function of age, race/ethnicity, and other covariates. ResultsYounger children had faster progression of myopia; for example, the model-estimated 3-year progression in an Asian American child was -1.93 D when onset was at age 7 years compared with -1.43 D when onset was at age 10 years. Annual progression for girls was 0.093 D faster than for boys. Asian American children experienced statistically significantly faster myopia progression compared with Hispanic (estimated 3-year difference of -0.46 D), Black children (-0.88 D), and Native American children (-0.48 D), but with similar progression compared with White children (-0.19 D). Parental history of myopia, time spent reading, and time spent in outdoor/sports activity were not statistically significant factors in multivariate models. ConclusionsYounger age, female sex, and racial/ethnic group were the factors associated with faster myopic progression. This multivariate model can facilitate the planning of clinical trials for myopia control interventions by informing the prediction of myopia progression rates.
Cardiovascular morbidity and mortality as a result of inhaled tobacco products continues to be a global healthcare crisis, particularly in low- and middle-income nations lacking the infrastructure to ...develop and implement effective public health policies limiting tobacco use. Following initiation of public awareness campaigns 50 years ago in the United States, considerable success has been achieved in reducing the prevalence of cigarette smoking and exposure to secondhand smoke. However, there has been a slowing of cessation rates in the United States during recent years, possibly caused by high residual addiction or fatigue from cessation messaging. Furthermore, tobacco products have continued to evolve faster than the scientific understanding of their biological effects. This review considers selected updates on the genetics and epigenetics of smoking behavior and associated cardiovascular risk, mechanisms of atherogenesis and thrombosis, clinical effects of smoking and benefits of cessation, and potential impact of electronic cigarettes on cardiovascular health.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cys2-His2 zinc fingers are one of the most common types of DNA-binding domains. Modifications to zinc-finger binding specificity have recently enabled custom DNA-binding proteins to be designed to a ...wide array of target sequences. We present here a 1.96 Å structure of Aart, a designed six-zinc finger protein, bound to a consensus DNA target site. This is the first structure of a designed protein with six fingers, and was intended to provide insights into the unusual affinity and specificity characteristics of this protein. Most protein−DNA contacts were found to be consistent with expectations, while others were unanticipated or insufficient to explain specificity. Several were unexpectedly mediated by glycerol, water molecules or amino acid−base stacking interactions. These results challenge some conventional concepts of recognition, particularly the finding that triplets containing 5′A, C, or T are typically not specified by direct interaction with the amino acid in position 6 of the recognition helix.
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