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1.
Insights into the Cooperative Nature of ATP Hydrolysis in Actin Filaments.
Katkar, HH, Davtyan, A, Durumeric, AEP, Hocky, GM, Schramm, AC, De La Cruz, EM, Voth, GA
Biophysical journal. 2018;(8):1589-1602
Abstract
Actin filaments continually assemble and disassemble within a cell. Assembled filaments "age" as a bound nucleotide ATP within each actin subunit quickly hydrolyzes followed by a slower release of the phosphate Pi, leaving behind a bound ADP. This subtle change in nucleotide state of actin subunits affects filament rigidity as well as its interactions with binding partners. We present here a systematic multiscale ultra-coarse-graining approach that provides a computationally efficient way to simulate a long actin filament undergoing ATP hydrolysis and phosphate-release reactions while systematically taking into account available atomistic details. The slower conformational changes and their dependence on the chemical reactions are simulated with the ultra-coarse-graining model by assigning internal states to the coarse-grained sites. Each state is represented by a unique potential surface of a local heterogeneous elastic network. Internal states undergo stochastic transitions that are coupled to conformations of the underlying molecular system. The model reproduces mechanical properties of the filament and allows us to study whether conformational fluctuations in actin subunits produce cooperative filament aging. We find that the nucleotide states of neighboring subunits modulate the reaction kinetics, implying cooperativity in ATP hydrolysis and Pi release. We further systematically coarse grain the system into a Markov state model that incorporates assembly and disassembly, facilitating a direct comparison with previously published models. We find that cooperativity in ATP hydrolysis and Pi release significantly affects the filament growth dynamics only near the critical G-actin concentration, whereas far from it, both cooperative and random mechanisms show similar growth dynamics. In contrast, filament composition in terms of the bound nucleotide distribution varies significantly at all monomer concentrations studied. These results provide new insights, to our knowledge, into the cooperative nature of ATP hydrolysis and Pi release and the implications it has for actin filament properties, providing novel predictions for future experimental studies.
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2.
The Methylerythritol Phosphate Pathway: Promising Drug Targets in the Fight against Tuberculosis.
Wang, X, Dowd, CS
ACS infectious diseases. 2018;(3):278-290
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Abstract
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a severe infectious disease in need of new chemotherapies especially for drug-resistant cases. To meet the urgent requirement of new TB drugs with novel modes of action, the TB research community has been validating numerous targets from several biosynthetic pathways. The methylerythritol phosphate (MEP) pathway is utilized by Mtb for the biosynthesis of isopentenyl pyrophosphate (IPP) and its isomer dimethylallyl pyrophosphate (DMAPP), the universal five-carbon building blocks of isoprenoids. While being a common biosynthetic pathway in pathogens, the MEP pathway is completely absent in humans. Due to its unique presence in pathogens as well as the essentiality of the MEP pathway in Mtb, the enzymes in this pathway are promising targets for the development of new drugs against tuberculosis. In this Review, we discuss three enzymes in the MEP pathway: 1-deoxy-d-xylulose-5-phosphate synthase (DXS), 1-deoxy-d-xylulose-5-phosphate reductoisomerase (IspC/DXR), and 2 C-methyl-d-erythritol 2,4-cyclodiphosphate synthase (IspF), which appear to be the most promising antitubercular drug targets. Structural and mechanistic features of these enzymes are reviewed, as well as selected inhibitors that show promise as antitubercular agents.
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Serum Alkaline Phosphatase, Phosphate, and In-Hospital Mortality in Acute Ischemic Stroke Patients.
Zhong, C, You, S, Chen, J, Zhai, G, Du, H, Luo, Y, Dong, X, Cao, Y, Liu, CF, Zhang, Y
Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 2018;(1):257-266
Abstract
BACKGROUND The clinical impacts of serum alkaline phosphatase (ALP) and phosphate on early death are not fully understood in patients with acute ischemic stroke. We examined the associations between serum ALP, phosphate, and in-hospital mortality after ischemic stroke. METHODS Serum ALP and phosphate were measured in 2944 ischemic stroke patients from 22 hospitals in Suzhou City from December 2013 to May 2014. Cox proportional hazard models and restricted cubic splines were used to estimate the relationships between serum ALP and phosphate (both as categorical and continuous variables) and risk of in-hospital mortality. RESULTS During hospitalization, 111 patients (3.7%) died from all causes. After multivariable adjustment, the hazard ratio (HR) of the highest quartile compared with the lowest quartile of ALP was 2.19 (95% confidence interval [CI], 1.20-4.00) for early death. Restricted cubic spline analysis indicated a significant linear association between ALP and death (P-linearity = .017). A U-shaped association of phosphate with in-hospital mortality was observed (P-nonlinearity = .011). Compared with the third quartile of phosphate (1.08-1.21 mmol/L), HRs of the lowest and highest quartiles for early death were 2.17 (1.15-4.08) and 1.70 (.88-3.30), respectively. Sensitivity analyses further confirmed our findings. CONCLUSIONS We observed a graded relationship between serum ALP levels and risk of early death in patients with acute ischemic stroke. There was a U-shaped association between phosphate and all-cause mortality with significantly increased risk among patients with lower phosphate levels.
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[Novel hormones related to the calcium and phosphate homeostasis in kidney disease].
Mace, ML, Ølgaard, K, Lewin, E
Ugeskrift for laeger. 2018;(21)
Abstract
Calcium and phosphate levels are regulated by a complex interplay between parathyroid hormone (PTH), calcitriol, fibroblast growth factor 23 (FGF23) and its co-receptor αKlotho. Kidney failure causes severe disturbances in the mineral and bone homeostasis resulting in phosphate retention, hypocalcaemia and high plasma levels of FGF23 and PTH, and the patients develop fragile bones and vascular calcifications. Today's treatments aim to lower the levels of phosphate and PTH. Future studies need to clarify, if lowering the FGF23 level or supplementation with αKlotho will improve survival for patients with chronic kidney disease.
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Insights into plant phosphate sensing and signaling.
Ham, BK, Chen, J, Yan, Y, Lucas, WJ
Current opinion in biotechnology. 2018;:1-9
Abstract
Phosphorus (P) is a macronutrient essential for plant growth, therefore, soil P level is critical to crop yield potential in agriculture. As Pi levels limit crop yield under many soil conditions, it is crucial to understand the mechanisms by which plants adapt to low-phosphate (Pi) soil conditions and interact with their soil microbiome to improve crop P use efficiency, in order to ensure global food security. Recent advances have been made towards achieving this goal through advancing our understanding of the plant's response to limiting Pi conditions to maintain P homeostasis. In this review, we assess advances made in local and systemic Pi sensing and signaling, and in the molecular events for Pi absorption, redistribution and plant-symbiont interactions. These findings offer important avenues for bio-engineering of agricultural crops with traits for enhanced Pi acquisition and utilization.
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Phosphate binders as a cause of hypothyroidism in dialysis patients: practical indications from a review of the literature.
Cataldo, E, Columbano, V, Nielsen, L, Gendrot, L, Covella, B, Piccoli, GB
BMC nephrology. 2018;(1):155
Abstract
BACKGROUND Although fatigue is common in dialysis patients, polypharmacy is seldom listed among its causes. In this report, we describe a dialysis patient who developed severe fatigue due to pharmacological interaction between two commonly prescribed drugs, phosphate binders and levothyroxine. CASE PRESENTATION A 65-year old woman, on dialysis for 17 years, complained of fatigue (weight 54 Kg, height 1.55 m, BMI: 23 Kg/m2; malnutrition inflammation index: 10; Charlson index 9). She had been treated with lithium for about 20 years. A heavy smoker, she was obese and diabetic when young, but stopped treatment after weight loss. She had undergone thyroidectomy for papillary carcinoma, left hemicolectomy for colon adenocarcinoma, left quadrantectomy followed by radiotherapy for ductal mammary adenocarcinoma, subtotal parathyroidectomy for tertiary hyperparathyroidism. At the time of this report, she was on thrice-weekly hemodiafiltration (Daugirdas 2 Kt/V: 1.6-1.8). Her recent treatment included spironolactone, amlodipine, perindopril, valproate, lamotrigine, levothyroxine, vitamin D, calcium carbonate, sodium polystyrene and sevelamer. After she questioned her doctor about whether her fatigue might be the result of a drug interaction, levothyroxine interference was identified (TSH, previously normal, increased to 13.07 mU/L, after increasing sevelamer dose, and normalized after change of drug schedule). LITERATURE REVIEW only 5 relevant papers on levothyroxine and phosphate binders on dialysis were found on Pubmed and EMBASE (out of 351 titles retrieved). Information was therefore inferred from studies in normal volunteers or in other diseases. DISCUSSION AND CONCLUSIONS Our case differs from other reports on lower TSH at diagnosis, underlining the need for awareness of the importance of early diagnosis. Integrating the scant literature on dialysis patients with data available in the general population, some working conclusions can be reached: while all phosphate binders potentially interfere with levothyroxine absorption, interference seems to be highest for sevelamer; interference is limited but not excluded by increasing the intervals between drugs; morning fast is usually indicated but, when clashing with the timing of other drugs, a bedtime dose and liquid preparations may be indicated. In the absence of an agreed control schedule, our case supports close monitoring of TSH (1-3 months if unstable, twice-yearly in stable patients).
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HIV, TB, inflammation and other correlates of serum phosphate: A cross-sectional study.
Friis, H, Range, NS, Changalucha, J, PrayGod, G, Jeremiah, K, Faurholt-Jepsen, D, Krarup, HB, Andersen, AB, Kæstel, P, Filteau, S
Clinical nutrition ESPEN. 2018;:38-43
Abstract
BACKGROUND There is little information about serum phosphate levels among patients with pulmonary tuberculosis (TB) and HIV infection. OBJECTIVE We aimed to assess the role of TB, HIV, inflammation and other correlates on serum phosphate levels. METHODS A cross-sectional study was conducted among TB patients and age- and sex-matched non-TB controls. Pulmonary TB patients were categorized as sputum -negative and -positive, based on culture. Age- and sex-matched non-TB controls were randomly selected among neighbours to sputum-positive TB patients. Data on age, sex, alcohol and smoking habits were obtained. HIV status, serum phosphate, and the acute phase reactants C-reactive protein (serum CRP) and α1-acid glycoprotein (serum AGP) were determined. Linear regression analysis was used to identify correlates of serum phosphate. RESULTS Of 1605 participants, 355 (22.1%) were controls and 1250 (77.9%) TB patients, of which 9.9% and 50.4% were HIV-infected. Serum phosphate was determined before start of TB treatment in 44%, and 1-14 days after start of treatment in 56%. Serum phosphate was up to 0.10 mmol/L higher 1-3 days after start of TB treatment, and lowest 4 days after treatment, after which it increased. In multivariable analysis, TB patients had 0.09 (95% CI: 0.05; 0.13) mmol/L higher serum phosphate than controls, and those with HIV had 0.05 (95% CI: 0.01; 0.08) mmol/L higher levels than those without. Smoking was also a positive correlate of serum phosphate, whereas male sex and age were negative correlates. CONCLUSION While HIV and TB are associated with higher serum phosphate, our data suggest that TB treatment is followed by transient reductions in serum phosphate, which may reflect hypophosphataemia in some patients.
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8.
Effect of home bleaching on surface of zinc phosphate cement: A scanning electron microscopic study.
AlZain, SA
Nigerian journal of clinical practice. 2018;(6):807-811
Abstract
CONTEXT The effect of home bleaching on surfaces of dental cements is controversial. AIM: The aim of this study was to microscopically evaluate and compare the effect of different concentrations of carbamide peroxide (CP) home bleaching agents on the surface of zinc phosphate cement. MATERIALS AND METHODS Forty 10 mm × 2 mm specimens of zinc phosphate cement were prepared following the manufacturer's directions. All specimens were immersed in artificial saliva at 37°C for 24 h. The specimens were equally divided into four groups (n = 10). One control group received no CP bleaching. Three experimental groups were exposed to 10%, 16%, and 22% of CP home bleaching agents. The bleaching agents were applied daily for 4 h for 14 days. Specimens were stored in artificial saliva at 37°C for 24 h and then examined under a scanning electron microscope. The surface micromorphology of the specimens was carefully evaluated and compared. RESULTS The zinc oxide particles in the specimens of the control group were tightly packed with well-defined plate-like crystals. When specimens were exposed to 10% CP gels, the particles became flat and irregular with few areas of eroded matrix. When 16% CP gel was used, the crystals became flatter and irregular with rounded edges. Bleaching with 22% CP gel showed little more erosion of the surface of the matrix of the cement. Fewer flat and irregular crystals were observed on the surface of the cement. CONCLUSIONS At-home bleaching using 10%, 16%, and 22% CP may be safely used in the presence of zinc phosphate-luted crown restorations without adverse effects.
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Nitrogen and phosphate metabolism in ectomycorrhizas.
Nehls, U, Plassard, C
The New phytologist. 2018;(4):1047-1058
Abstract
1047 I. Introduction 1047 II. Mobilization of soil N/P by ECM fungi 1048 III. N/P uptake 1048 IV. N/P assimilation 1049 V. N/P storage and remobilization 1049 VI. Hyphal N/P efflux at the plant-fungus interface 1052 VII. Conclusion and research needs 1054 Acknowledgements 1055 References 1055 SUMMARY Nutrient homeostasis is essential for fungal cells and thus tightly adapted to the local demand in a mycelium with hyphal specialization. Based on selected ectomycorrhizal (ECM) fungal models, we outlined current concepts of nitrogen and phosphate nutrition and their limitations, and included knowledge from Baker's yeast when major gaps had to be filled. We covered the entire pathway from nutrient mobilization, import and local storage, distribution within the mycelium and export at the plant-fungus interface. Even when nutrient import and assimilation were broad issues for ECM fungi, we focused mainly on nitrate and organic phosphorus uptake, as other nitrogen/phosphorus (N/P) sources have been covered by recent reviews. Vacuolar N/P storage and mobilization represented another focus point of this review. Vacuoles are integrated into cellular homeostasis and central for an ECM mycelium at two locations: soil-growing hyphae and hyphae of the plant-fungus interface. Vacuoles are also involved in long-distance transport. We further discussed potential mechanisms of bidirectional long-distance nutrient transport (distances from millimetres to metres). A final focus of the review was N/P export at the plant-fungus interface, where we compared potential efflux mechanisms and pathways, and discussed their prerequisites.
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Long-term behaviors of phosphate-based rapid repairing material for concrete shafts in coal mines.
Lei, F, Zhen-Ya, Z, Xiao-Dong, W, Chao, X, Dong-Yuan, H
Journal of applied biomaterials & functional materials. 2018;(3):171-177
Abstract
INTRODUCTION Concrete structures in shaft linings are apt to deteriorate prematurely and therefore prompt restoration is required. In considering this, desulphurization fly ash and machine-made tuff sand are employed to fabricate a phosphate-based rapid repairing material. METHODS The long-term efficiency of the material is evaluated based on combined factors, so drying shrinkage, interfacial bonding strength, corrosion resistance, and combustibility of the specimens are tested and researched in this paper. RESULTS Experimental results showed that, under a dry circumstance, the material goes through a minor expansion at an early stage. It goes into a stage of rapid contraction after one day and a stable contraction after seven days. After 28 days, the total deformation is 67 micro-strains. On the other hand, the fabricated material manifests an excellent mechanical property. The one hour bending strength and compressive strength were 9.2 MPa and 32.6 MPa, respectively. A long-term mine water flushing simulation demonstrates that only 10% bending strength is lost and the corrosion resistance coefficient stays above 0.8, so a very good corrosion resistance is thus achieved. CONCLUSIONS What is more, this repairing material retains its stability even at a high temperature of 1000°C, revealing its good thermo-stability. All these prominent properties make it a good prospective material for real restoration applications.