MR‐REX: molecular replacement by cooperative conformational search and occupancy optimization on low‐accuracy protein models

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144619/1/ayd2rr5144.pd

Modeling the Hydration Layer around Proteins: HyPred

AbstractProtein hydration plays an integral role in determining protein function and stability. We develop a simple method with atomic level precision for predicting the solvent density near the surface of a protein. A set of proximal radial distribution functions are defined and calculated for a series of different atom types in proteins using all-atom, explicit solvent molecular dynamic simulations for three globular proteins. A major improvement in predicting the hydration layer is found when the protein is held immobile during the simulations. The distribution functions are used to develop a model for predicting the hydration layer with sub-1-Ångstrom resolution without the need for additional simulations. The model and the distribution functions for a given protein are tested in their ability to reproduce the hydration layer from the simulations for that protein, as well as those for other proteins and for simulations in which the protein atoms are mobile. Predictions for the density of water in the hydration shells are then compared with high occupancy sites observed in crystal structures. The accuracy of both tests demonstrates that the solvation model provides a basis for quantitatively understanding protein solvation and thereby predicting the hydration layer without additional simulations

Rapid Absorption of Naloxone from Eye Drops

Naloxone as emergency treatment for opioid overdosing can be administered via several routes. However, the available administration methods are invasive or may be associated with incomplete or slow naloxone absorption. We evaluated pharmacokinetics and local tolerance of naloxone ocular drops in healthy beagle dogs. Naloxone administration as eye drops produced fast absorption with time to maximum plasma concentration (t(max)) achieved in 14 to 28 min, high plasma exposure (C-max 10.3 ng/mL to 12.7 ng/mL), and good bioavailability (41% to 56%). No signs of ocular irritability were observed in the scored ocular tolerability parameters, and the reactions of dogs suggesting immediate ocular discomfort after the dosing were sporadic and short lasting. Slight and transient increase in the intraocular pressure and transient decrease in the tear production were recorded. The results suggest that eye drops may provide a fast and an effective non-invasive route for naloxone administration to reverse opioid overdosing, and clinical studies in the human are warranted.Peer reviewe

Rapid Absorption of Naloxone from Eye Drops

Naloxone as emergency treatment for opioid overdosing can be administered via several routes. However, the available administration methods are invasive or may be associated with incomplete or slow naloxone absorption. We evaluated pharmacokinetics and local tolerance of naloxone ocular drops in healthy beagle dogs. Naloxone administration as eye drops produced fast absorption with time to maximum plasma concentration (tmax) achieved in 14 to 28 min, high plasma exposure (Cmax 10.3 ng/mL to 12.7 ng/mL), and good bioavailability (41% to 56%). No signs of ocular irritability were observed in the scored ocular tolerability parameters, and the reactions of dogs suggesting immediate ocular discomfort after the dosing were sporadic and short lasting. Slight and transient increase in the intraocular pressure and transient decrease in the tear production were recorded. The results suggest that eye drops may provide a fast and an effective non-invasive route for naloxone administration to reverse opioid overdosing, and clinical studies in the human are warranted

Rapid Absorption of Naloxone from Eye Drops

Naloxone as emergency treatment for opioid overdosing can be administered via several routes. However, the available administration methods are invasive or may be associated with incomplete or slow naloxone absorption. We evaluated pharmacokinetics and local tolerance of naloxone ocular drops in healthy beagle dogs. Naloxone administration as eye drops produced fast absorption with time to maximum plasma concentration (tmax) achieved in 14 to 28 min, high plasma exposure (Cmax 10.3 ng/mL to 12.7 ng/mL), and good bioavailability (41% to 56%). No signs of ocular irritability were observed in the scored ocular tolerability parameters, and the reactions of dogs suggesting immediate ocular discomfort after the dosing were sporadic and short lasting. Slight and transient increase in the intraocular pressure and transient decrease in the tear production were recorded. The results suggest that eye drops may provide a fast and an effective non-invasive route for naloxone administration to reverse opioid overdosing, and clinical studies in the human are warranted

Templateâ based protein structure prediction in CASP11 and retrospect of Iâ TASSER in the last decade

We report the structure prediction results of a new composite pipeline for templateâ based modeling (TBM) in the 11th CASP experiment. Starting from multiple structure templates identified by LOMETS based metaâ threading programs, the QUARK ab initio folding program is extended to generate initial fullâ length models under strong constraints from template alignments. The final atomic models are then constructed by Iâ TASSER based fragment reassembly simulations, followed by the fragmentâ guided molecular dynamic simulation and the MQAPâ based model selection. It was found that the inclusion of QUARKâ TBM simulations as an intermediate modeling step could help improve the quality of the Iâ TASSER models for both Easy and Hard TBM targets. Overall, the average TMâ score of the first Iâ TASSER model is 12% higher than that of the best LOMETS templates, with the RMSD in the same threadingâ aligned regions reduced from 5.8 to 4.7 à . Nevertheless, there are nearly 18% of TBM domains with the templates deteriorated by the structure assembly pipeline, which may be attributed to the errors of secondary structure and domain orientation predictions that propagate through and degrade the procedures of template identification and final model selections. To examine the record of progress, we made a retrospective report of the Iâ TASSER pipeline in the last five CASP experiments (CASP7â 11). The data show no clear progress of the LOMETS threading programs over PSIâ BLAST; but obvious progress on structural improvement relative to threading templates was witnessed in recent CASP experiments, which is probably attributed to the integration of the extended ab initio folding simulation with the threading assembly pipeline and the introduction of atomicâ level structure refinements following the reduced modeling simulations. Proteins 2016; 84(Suppl 1):233â 246. © 2015 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134137/1/prot24918.pd

Cadmium in Fertilizers. Risk to human health and the environment

The aim of this report was to estimate impacts of cadmium in phosphorus fertilizers on a cadmium content and cadmium balance of the cultivated soil, and to assess related human health and environmental risks under Finnish conditions. The assessment was performed by applying, as appropriate, the EU principles on risk assessment of New and Existing Substances, and the guidance document prepared by Environmental Resources Management Limited for the risk assessment of cadmium in fertilizers. The work was carried out on the basis of the available literature and other information relating to the occurrence of cadmium in the environment in Finland, harmful environmental influences of cadmium, as well as its adverse health effects. Based on the cadmium mass balances hundred-year scenarios were calculated at three different cadmium levels in P-fertilizers: 1) the present Finnish average cadmium level in fertilizers (i.e. 2.5 mg Cd/kg P), 2) the cadmium level corresponding to the national limit (i.e. 50 mg Cd/kg P), and 3) the cadmium level corresponding to an average European value (138 mg Cd/kg P). At present, cadmium concentrations in the Finnish cultivated soils pose a risk to soil organisms. Also, the leaching of cadmium from the arable land is causing a risk to the aquatic environment. However, if the use of the low cadmium P-fertilizers will be continued in Finland, it will result in a balance between cadmium inputs and outputs or even in a gradual decrease in the cadmium concentrations of soil, crops and leachates. The use of P-fertilizers containing cadmium at a level of the Finnish national limit value and, especially at a level of the average European content, would increase the risk to the environment. At present, a part of the elderly population in Finland is at risk from adverse health effects caused by cadmium. These risk groups consist of people whose dietary intake of cadmium has increased by using much of kidneys, liver, mushrooms, or molluscs in their diet, people whose gastrointestinal absorption of cadmium has increased because of deficiency of iron and heavy smokers. In these risk groups, the estimated urinary level of cadmium can be associated with high risk of kidney dysfunction and bone effects. An increase in the cadmium content of P-fertilizers would increase the size of the risk groups considerably

Plasma 25-Hydroxyvitamin D Concentration and Risk of Islet Autoimmunity

We examined the association between plasma 25-hydroxyvitamin D [25(OH)D] concentration and islet autoimmunity (IA) and whether vitamin D gene polymorphisms modify the effect of 25(OH)D on IA risk. We followed 8,676 children at increased genetic risk of type 1 diabetes at six sites in the U.S. and Europe. We defined IA as positivity for at least one autoantibody (GADA, IAA, or IA-2A) on two or more visits. We conducted a risk set sampled nested case-control study of 376 IA case subjects and up to 3 control subjects per case subject. 25(OH)D concentration was measured on all samples prior to, and including, the first IA positive visit. Nine polymorphisms in VDR, CYP24A, CYP27B1, GC, and RXRA were analyzed as effect modifiers of 25(OH)D. Adjusting for HLA-DR-DQ and ancestry, higher childhood 25(OH)D was associated with lower IA risk (odds ratio = 0.93 for a 5 nmol/L difference; 95% CI 0.89, 0.97). Moreover, this association was modified by VDR rs7975232 (interaction P = 0.0072), where increased childhood 25(OH)D was associated with a decreasing IA risk based upon number of minor alleles: 0 (1.00; 0.93, 1.07), 1 (0.92; 0.89, 0.96), and 2 (0.86; 0.80, 0.92). Vitamin D and VDR may have a combined role in IA development in children at increased genetic risk for type 1 diabetes.Peer reviewe

Asukaslähtöisen perusparantamisen kehitystarpeet. IKE-esitutkimus

Asunto-osakeyhtiöiden kiinteistöjen peruskorjaus- ja -parannustarve kasvaa lähivuosina ja -vuosikymmeninä erittäin voimakkaasti. Jotta ikääntyvät talot ja niissä olevat kodit vastaavat paremmin erilaisten asukasryhmien muuttuvia tarpeita ja vaatimuksia, tuotantokeskeisestä peruskorjaamisesta on päästävä asukaslähtöiseen perusparantamiseen. Tässä Ihmisten ja kiinteistöjen elämänsyklit (IKE)-esitutkimuksessa on selvitetty asuinkiinteistöjen perusparantamisen kipupisteitä ja hyviä käytäntöjä erityisesti asukkaiden yksilöllisten tarpeiden ja kokemusten näkökulmasta. Lisäksi on arvioitu perusparannushankkeiden läpiviemisen ja prosessin hallinnan sekä viestinnän ja vuorovaikutuksen nykytilaa ja kehittämistarpeita. Asuinkiinteistöjen asukaslähtöisen perusparantamisen keskeisimmiksi kehitystarpeiksi tutkimuksessa nousevat asunto-osakeyhtiöiden strategisen elinkaarijohtamisen, asuinkiinteistöjen kuntoindeksin, asiakaslähtöisen tuotteistetun palvelu- ja yhteistoimintaprosessin, ennakoivan ja vuorovaikutteisen viestinnän, korjausrakentamisen teollisten menetelmien, yksilöllisten rahoitusratkaisujen sekä korjausrakentamisalan eri toimijoiden asiakaslähtöisen toimintatavan kehittäminen. IKE-esitutkimuksen mukaan kehittämisen tavoitteeksi tulee asettaa asukkaiden, asunto-osakeyhtiön ja ammattilaisten välinen tuotteistettu yhteistoiminta- ja palveluprosessi, jossa osapuolet korjaavat ja kehittävät kotitaloa yhdessä. Prosessin tulee tähdätä kotitalon ja sen asukkaiden yksilöllisten tavoitteiden läpinäkyvyyteen, vaiheiden käytännönläheiseen ja ymmärrettävään esittämiseen sekä asukaslähtöiseen toteuttamistapaan. Tavoitteet toteutetaan palveluliiketoimintana, jolloin kullekin osapuolelle on määritelty selkeät roolit ja vastuut. Osapuolet kohtaavat sovittuina ajankohtina määrittämään yhteisiä tavoitteita ja tarkentamaan niitä. Korjausrakentamisen tuotteita tarjoavien rakennusosa- ja tuotevalmistajien ja palveluntarjoajien tulee suunnitella tuotteensa osaksi asukaslähtöistä prosessia