Uranium Repartitioning during Microbial Driven Reductive Transformation of U(VI)-Sorbed Schwertmannite and Jarosite.

This study exposes U(VI)-sorbed schwertmannite and jarosite to biotic reductive incubations under field-relevant conditions and examines the changes in aqueous and solid-phase speciation of U, Fe, and S as well as associated microbial communities over 180 days. The chemical, X-ray absorption spectroscopy, X-ray diffraction, and microscopic data demonstrated that the U(VI)-sorbed schwertmannite underwent a rapid reductive dissolution and solid-phase transformation to goethite, during which the surface-sorbed U(VI) was partly reduced and mostly repartitioned to monomeric U(VI)/U(IV) complexes by carboxyl and phosphoryl ligands on biomass or organic substances. Furthermore, the microbial data suggest that these processes were likely driven by the consecutive developments of fermentative and sulfate- and iron- reducing microbial communities.

Cost-effectiveness models for Alzheimer's disease and related dementias: IPECAD modeling workshop cross-comparison challenge.

Introduction: The credibility of model-based economic evaluations of Alzheimer's disease (AD) interventions is central to appropriate decision-making in a policy context. We report on the International PharmacoEconomic Collaboration on Alzheimer's Disease (IPECAD) Modeling Workshop Challenge.

Methods: Two common benchmark scenarios, for the hypothetical treatment of AD mild cognitive impairment (MCI) and mild dementia, were developed jointly by 29 participants.

Cost-Effectiveness of Magnetic Resonance Imaging in Prostate Cancer Screening: A Microsimulation Study.

Objective: This study aimed to assess the cost-effectiveness of magnetic resonance imaging (MRI) with combinations of targeted biopsy (TBx) and systematic biopsy (SBx) for early prostate cancer detection in Sweden.

Methods: A cost-utility analysis was conducted from a lifetime societal perspective using a microsimulation model. Five strategies included no screening and quadrennial screening for men aged 55 to 69 years using SBx alone, TBx on positive MRI (MRI + TBx), combined TBx/SBx on positive MRI (MRI + TBx/SBx), and SBx on negative MRI with TBx/SBx on positive MRI (MRI - SBx, MRI + TBx/SBx).

Molecular Details of a Coupled Binding and Folding Reaction between the Amyloid Precursor Protein and a Folded Domain.

Intrinsically disordered regions in proteins often function as binding motifs in protein-protein interactions. The mechanistic aspects and molecular details of such coupled binding and folding reactions, which involve formation of multiple noncovalent bonds, have been broadly studied theoretically, but experimental data are scarce. Here, using a combination of protein semisynthesis to incorporate phosphorylated amino acids, backbone amide-to-ester modifications, side chain substitutions, and binding kinetics, we examined the interaction between the intrinsically disordered motif of amyloid precursor protein (APP) and the phosphotyrosine binding (PTB) domain of Mint2.

The cost-effectiveness of prostate cancer screening using the Stockholm3 test.

Objectives: The European Randomized Study of Screening for Prostate Cancer found that prostate-specific antigen (PSA) screening reduced prostate cancer mortality, however the costs and harms from screening may outweigh any mortality reduction. Compared with screening using the PSA test alone, using the Stockholm3 Model (S3M) as a reflex test for PSA ≥ 1 ng/mL has the same sensitivity for Gleason score ≥ 7 cancers while the relative positive fractions for Gleason score 6 cancers and no cancer were 0.83 and 0.

XRMA analysis and X-ray diffraction analysis of dental enamel from human permanent teeth exposed to hydrogen peroxide of varying pH.

Background: This investigation shows how 3.3% H2O2, at different pH-values affects the enamel.

Material And Methods: A number of fifteen human premolars were used.

The impact of different prostate-specific antigen (PSA) testing intervals on Gleason score at diagnosis and the risk of experiencing false-positive biopsy recommendations: a population-based cohort study.

Objective: Given a man's current prostate- specific antigen (PSA) level, age and family history of prostate cancer, what are the benefits (decreased risk of higher Gleason score [GS] cancer at diagnosis) and harms (increased risk of false-positive biopsy recommendation) of waiting 1, 2, 3, 4 or 5-8 years until the next PSA test?

Design: Prospective cohort.

Setting: All PSA tested men in Stockholm, Sweden, between 2003 and 2015.

Participants: Men aged 50-74 years with at least two PSA tests between 2003 and 2015 (n=174 636).

A natural history model for planning prostate cancer testing: Calibration and validation using Swedish registry data.

Recent prostate cancer screening trials have given conflicting results and it is unclear how to reduce prostate cancer mortality while minimising overdiagnosis and overtreatment. Prostate cancer testing is a partially observable process, and planning for testing requires either extrapolation from randomised controlled trials or, more flexibly, modelling of the cancer natural history. An existing US prostate cancer natural history model (Gulati et al, Biostatistics 2010;11:707-719) did not model for differences in survival between Gleason 6 and 7 cancers and predicted too few Gleason 7 cancers for contemporary Sweden.

Psychological factors in genital pain: The role of fear-avoidance, pain catastrophizing and anxiety sensitivity among women living in Sweden.

Objectives One in five women under the age of 30 report recurrent genital pain and pain during sexual intercourse. Female genital pain negatively affects sexual and general health, as well as dyadic function and quality of life. Although the current field of research and clinical expertise in general agree upon a biopsychosocial conceptualization, there is still a lack of theoretical models describing the psychosocial mechanisms involved in the development of genital pain.

Binding Kinetics of the Intrinsically Disordered p53 Family Transactivation Domains and MDM2.

Because of their prominent roles in cell-cycle regulation and cancer, the interaction between MDM2 and the intrinsically disordered transactivation domain (TAD) of p53 is exceptionally well-studied. However, although there are numerous computational studies on the interaction mechanism, there is a paucity of experimental data regarding the kinetics and mechanism. We have used stopped flow fluorescence to investigate the binding reaction between MDM2 and TAD from p53 as well as from its paralogs p63 and p73, and in particular, focused on the salt dependence of the interaction.

Incorporation of Metals into Calcite in a Deep Anoxic Granite Aquifer.

Understanding metal scavenging by calcite in deep aquifers in granite is of importance for deciphering and modeling hydrochemical fluctuations and water-rock interaction in the upper crust and for retention mechanisms associated with underground repositories for toxic wastes. Metal scavenging into calcite has generally been established in the laboratory or in natural environments that cannot be unreservedly applied to conditions in deep crystalline rocks, an environment of broad interest for nuclear waste repositories. Here, we report a microanalytical study of calcite precipitated over a period of 17 years from anoxic, low-temperature (14 °C), neutral (pH: 7.

Challenges in assessing the health risks of consuming vegetables in metal-contaminated environments.

A great deal of research has been devoted to the characterization of metal exposure due to the consumption of vegetables from urban or industrialized areas. It may seem comforting that concentrations in crops, as well as estimated exposure levels, are often found to be below permissible limits. However, we show that even a moderate increase in metal accumulation in crops may result in a significant increase in exposure.

Do public nursing home care providers deliver higher quality than private providers? Evidence from Sweden.

Background: Swedish nursing home care has undergone a transformation, where the previous virtual public monopoly on providing such services has been replaced by a system of mixed provision. This has led to a rapidly growing share of private actors, the majority of which are large, for-profit firms. In the wake of this development, concerns have been voiced regarding the implications for care quality.

E-Science technologies in a workflow for personalized medicine using cancer screening as a case study.

Objective: We provide an e-Science perspective on the workflow from risk factor discovery and classification of disease to evaluation of personalized intervention programs. As case studies, we use personalized prostate and breast cancer screenings.

Materials And Methods: We describe an e-Science initiative in Sweden, e-Science for Cancer Prevention and Control (eCPC), which supports biomarker discovery and offers decision support for personalized intervention strategies.

Improved affinity at the cost of decreased specificity: a recurring theme in PDZ-peptide interactions.

The E6 protein from human papillomavirus (HPV) plays an important role during productive infection and is a potential drug target. We have previously designed a high affinity bivalent protein binder for the E6 protein, a fusion between a helix from the E6 associated protein and PDZØ9, an engineered variant (L391F/K392M) of the second PDZ domain from synapse associated protein 97 (SAP97 PDZ2). How the substitutions improve the affinity of SAP97 PDZ2 for HPV E6 is not clear and it is not known to what extent they affect the specificity for cellular targets.

Differential Water Thermodynamics Determine PI3K-Beta/Delta Selectivity for Solvent-Exposed Ligand Modifications.

Phosphoinositide 3-kinases (PI3Ks) are involved in important cellular functions and represent desirable targets for drug discovery efforts, especially related to oncology; however, the four PI3K subtypes (α, β, γ, and δ) have highly similar binding sites, making the design of selective inhibitors challenging. A series of inhibitors with selectivity toward the β subtype over δ resulted in compound 3(S), which has entered a phase I/Ib clinical trial for patients with advanced PTEN-deficient cancer. Interestingly, X-ray crystallography revealed that the modifications making inhibitor 3(S) and related compounds selective toward the β-isoform do not interact directly with either PI3Kβ or PI3Kδ, thereby confounding rationalization of the SAR.

Ligand binding to the PDZ domains of postsynaptic density protein 95.

Cellular scaffolding and signalling is generally governed by multidomain proteins, where each domain has a particular function. Postsynaptic density protein 95 (PSD-95) is involved in synapse formation and is a typical example of such a multidomain protein. Protein-protein interactions of PSD-95 are well studied and include the following three protein ligands: (i)N-methyl-d-aspartate-type ionotropic glutamate receptor subunit GluN2B, (ii) neuronal nitric oxide synthase and (iii) cysteine-rich protein (CRIPT), all of which bind to one or more of the three PDZ domains in PSD-95.

Design of a PDZbody, a bivalent binder of the E6 protein from human papillomavirus.

Chronic infection by high risk human papillomavirus (HPV) strains may lead to cancer. Expression of the two viral oncoproteins E6 and E7 is largely responsible for immortalization of infected cells. The HPV E6 is a small (approximately 150 residues) two domain protein that interacts with a number of cellular proteins including the ubiquitin ligase E6-associated protein (E6AP) and several PDZ-domain containing proteins.

Preparation and optimization of new 4-(2-(indolin-1-yl)-2-oxoethyl)-2-morpholinothiazole-5-carboxylic acid and amide derivatives as potent and selective PI3Kβ inhibitors.

In our continuous efforts to identify and develop novel targeted cancer treatments, a new morpholino-thiazole scaffold active against PI3Kβ has been identified. This Letter reports the optimization of this compound class to develop PI3Kβ isoform-selective inhibitors with suitable pharmacological properties.

Discovery and optimization of pyrimidone indoline amide PI3Kβ inhibitors for the treatment of phosphatase and tensin homologue (PTEN)-deficient cancers.

Compelling molecular biology publications have reported the implication of phosphoinositide kinase PI3Kβ in PTEN-deficient cell line growth and proliferation. These findings supported a scientific rationale for the development of PI3Kβ-specific inhibitors for the treatment of PTEN-deficient cancers. This paper describes the discovery of 2-[2-(2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one (7) and the optimization of this new series of active and selective pyrimidone indoline amide PI3Kβ inhibitors.

The reliability of cardiogenic impedance and correlation with echocardiographic and plethysmographic parameters for predicting CRT time intervals post implantation.

Aims: Encouraging data have been reported on the use of cardiogenic impedance (CI) in cardiac resynchronization therapy (CRT) optimization. The purposes of this study were to: evaluate the stability of certain CI vectors 24 h postimplantation, study the correlation between these CI signals and selected echocardiographic parameters, and examine the possibility of non-invasive calibration of the patient-specific impedance-based prediction model.

Methods And Results: Thirteen patients received a CRT-defibrillator device with monitor capability of the dynamic impedance between several electrodes.

Preparation and optimization of new 4-(morpholin-4-yl)-(6-oxo-1,6-dihydropyrimidin-2-yl)amide derivatives as PI3Kβ inhibitors.

From a HTS campaign, a new series of pyrimidone anilides exemplified by compound 1 has been identified with good inhibitory activity for the PI3Kβ isoform. The structure of compound 1 in PI3Kγ was solved revealing a binding mode in agreement with the SAR observed on PI3Kβ. These compounds displayed inhibition in the nanomolar range in the biochemical assay and were also potent p-Akt inhibitors in a PTEN-deficient PC3 prostate cancer cell line.

Discovery and optimization of new benzimidazole- and benzoxazole-pyrimidone selective PI3Kβ inhibitors for the treatment of phosphatase and TENsin homologue (PTEN)-deficient cancers.

Most of the phosphoinositide-3 kinase (PI3K) kinase inhibitors currently in clinical trials for cancer treatment exhibit pan PI3K isoform profiles. Single PI3K isoforms differentially control tumorigenesis, and PI3Kβ has emerged as the isoform involved in the tumorigenicity of PTEN-deficient tumors. Herein we describe the discovery and optimization of a new series of benzimidazole- and benzoxazole-pyrimidones as small molecular mass PI3Kβ-selective inhibitors.

The transition state of coupled folding and binding for a flexible β-finger.

Flexible and fully disordered protein regions that fold upon binding mediate numerous protein-protein interactions. However, little is known about their mechanism of interaction. One such coupled folding and binding occurs when a flexible region of neuronal nitric oxide synthase adopts a β-finger structure upon binding to its protein ligand, a PDZ [PSD-95 (postsynaptic density protein-95)/Discs large/ZO-1] domain from PSD-95.