Stereodivergent cyclopropanation of unactivated alkenes with heme proteins

Cyclopropyl motifs are present in a variety of compounds important to pharmaceutical, agrochemical, and fragrance industries. The asymmetric synthesis of cyclopropanes is often performed under harsh conditions with toxic, precious metal chiral catalysts. In 2013, the first example of biocatalytic alkene cyclopropanation was reported, using an engineered cytochrome P450 enzyme [1]. Since then, several heme proteins were reported to cyclopropanate a variety of styrenyl alkenes [2], but none have been shown to asymmetrically cyclopropanate more challenging substrates such as unactivated, aliphatic alkenes using the native iron-heme cofactor. Here we report that heme proteins can cyclopropanate unactivated alkenes and that stereoselectivity and activity can be tuned by directed evolution. A few rounds of site-saturation mutagenesis and screening yielded four protein variants with high enantio- and diastereoselectivity for complementary isomers, enabling stereodivergent synthesis of aliphatic cyclopropanes. These iron-porphyrin proteins are fully genetically encoded, and the reactions can be performed under mild, aqueous conditions with whole cells or purified protein. The protein enhances the activity of the native iron-heme cofactor, giving access to a broad array of cyclopropanated products. This example showcases the ability to quickly and efficiently engineer proteins for non-natural biocatalytic function. [1] P.S. Coelho, E.M. Brustad, A. Kannan, F.H. Arnold, Olefin cyclopropanation via carbene transfer catalyzed by engineered cytochrome P450 enzymes., Science. 339 (2013) 307–10. [2] O.F. Brandenberg, R. Fasan, F.H. Arnold, Exploiting and engineering hemoproteins for abiological carbene and nitrene transfer reactions, Curr. Opin. Biotechnol. 38 (2017) in press

Assessing reproducibility for radiographic measurement of leg length inequality after total hip replacement

Leg length inequality (LLI) as a result of total hip replacement can cause considerable morbidity. Although LLI was described when the technique was popularised in the 1960s, it remains a significant challenge to arthroplasty surgeons. This study reviews the established practice for the measurement of LLI on plain antero-posterior radiograph, and compares these techniques to two methods used locally. The radiographs of 35 patients were measured using four techniques. All four methods yielded an interclass correlation co-efficient of ≥0.90 for inter reader reliability. This study shows that the four methods are comparable for reliability, while a composite method, measuring from the centre of femoral rotation to the inferior teardrop and then to the lesser trochanter, has the added advantage of providing extra information on component position as well as an overall measure of LLI

Diffusion as mixing mechanism in granular materials

We present several numerical results on granular mixtures. In particular, we examine the efficiency of diffusion as a mixing mechanism in these systems. The collisions are inelastic and to compensate the energy loss, we thermalize the grains by adding a random force. Starting with a segregated system, we show that uniform agitation (heating) leads to a uniform mixture of grains of different sizes. We define a characteristic mixing time, $\tau_{mix}$, and study theoretically and numerically its dependence on other parameters like the density. We examine a model for bidisperse systems for which we can calculate some physical quantities. We also examine the effect of a temperature gradient and demonstrate the appearance of an expected segregation.Comment: 15 eps figures, include

Financial toxicity in adults with cancer: Adverse outcomes and noncompliance

Purpose Because of the escalating cost of cancer care coupled with high insurance deductibles, premiums, and uninsured populations, patients with cancer are affected by treatmentrelated financial harm, known as financial toxicity. The purpose of this study was to describe individuals reporting financial toxicity and to identify rates of and reasons for affordability-related treatment noncompliance. Methods From May 2010 to November 2015, adult patients (age $ 18 years) with cancer were identified from a Health Registry/Cancer Survivorship Cohort. Financial toxicity was defined as agreement with the phrase"You have to pay for more medical care than you can afford" from the Patient Satisfaction Questionnaire-18. Logistic regression and Fisher exact tests were used to compare groups. Results Of 1,988 participants, 524 (26%) reported financial toxicity. Patients reporting financial toxicity were more likely age 65 years or younger, female, nonwhite, non-English speaking, not married, less educated, and to have received a diagnosis more recently (all P,.001). Participants with financial toxicity were more likely to report noncompliance with medication, owing to inability to afford prescription drugs (relative risk [RR], 3.55; 95% CI, 2.53 to 4.98), and reported forgoing mental health care (RR, 3.89; 95% CI, 2.04 to 7.45), doctor's visits (RR, 2.98; 95% CI, 1.97 to 4.51), and medical tests (RR, 2.54; 95% CI, 1.49 to 4.34). The most endorsed reasons for delayed care were not having insurance coverage and being unable to afford household expenses. Conclusion More than25%of adultswith cancer reportedfinancial toxicity thatwas associatedwith an increased riskfor medicalnoncompliance.Financial toxicity remains a major issue in cancer care, and efforts are needed to ensure patients experiencing high levels offinancial toxicity are able to access recommended care

A nonlinear hydrodynamical approach to granular materials

We propose a nonlinear hydrodynamical model of granular materials. We show how this model describes the formation of a sand pile from a homogeneous distribution of material under gravity, and then discuss a simulation of a rotating sandpile which shows, in qualitative agreement with experiment, a static and dynamic angle of repose.Comment: 17 pages, 14 figures, RevTeX4; minor changes to wording and some additional discussion. Accepted by Phys. Rev.

Measurement of νˉμ\bar{\nu}_{\mu} and νμ\nu_{\mu} charged current inclusive cross sections and their ratio with the T2K off-axis near detector

We report a measurement of cross section $\sigma(\nu_{\mu}+{\rm nucleus}\rightarrow\mu^{-}+X)$ and the first measurements of the cross section $\sigma(\bar{\nu}_{\mu}+{\rm nucleus}\rightarrow\mu^{+}+X)$ and their ratio $R(\frac{\sigma(\bar \nu)}{\sigma(\nu)})$ at (anti-)neutrino energies below 1.5 GeV. We determine the single momentum bin cross section measurements, averaged over the T2K $\bar{\nu}/\nu$-flux, for the detector target material (mainly Carbon, Oxygen, Hydrogen and Copper) with phase space restricted laboratory frame kinematics of $\theta_{\mu}$500 MeV/c. The results are $\sigma(\bar{\nu})=\left( 0.900\pm0.029{\rm (stat.)}\pm0.088{\rm (syst.)}\right)\times10^{-39}$ and $\sigma(\nu)=\left( 2.41\ \pm0.022{\rm{(stat.)}}\pm0.231{\rm (syst.)}\ \right)\times10^{-39}$in units of cm$^{2}$/nucleon and$R\left(\frac{\sigma(\bar{\nu})}{\sigma(\nu)}\right)= 0.373\pm0.012{\rm (stat.)}\pm0.015{\rm (syst.)}$.Comment: 18 pages, 8 figure

Functional and genetic analysis of regulatory regions of coliphage H-19B: location of shiga-like toxin and lysis genes suggest a role for phage functions in toxin release

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74784/1/j.1365-2958.1998.00890.x.pd

A review of symptomatic leg length inequality following total hip arthroplasty

Leg length inequality (LLI) following total hip replacement is a complication which features increasingly in the recent literature. The definition of LLI is complicated by lack of consensus regarding radiological measurement, clinical measurement and the incomplete relationship between LLI and associated symptoms. This paper reviews 79 reports relating to LLI post hip replacement, detailing definitions and classification and highlighting patient populations prone to symptomatic LLI. While there is no universal definition of LLI, there is a broad consensus that less than 10 mm of difference on AP view plain radiographs is clinically acceptable. There are few techniques described that consistently produce a postoperative LLI of less than this magnitude. Where postoperative LLI exists, lengthening appears to cause more problems than shortening. In cases of mild LLI, non-surgical management produces adequate outcomes in the majority of cases, with functional LLI cases doing better than those with true LLI. Operative correction is effective in half of cases, even where nerve palsy is present, and remains an important option of last resort. Poor outcomes in patients with LLI may be minimised if individuals at risk are identified and counselled appropriately

The Polygenic and Monogenic Basis of Blood Traits and Diseases

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation. Analysis of blood cell traits in the UK Biobank and other cohorts illuminates the full genetic architecture of hematopoietic phenotypes, with evidence supporting the omnigenic model for complex traits and linking polygenic burden with monogenic blood diseases