Mendelian randomization analysis of C-reactive protein on colorectal cancer risk

Background: Chronic inflammation is a risk factor for colorectal cancer (CRC). Circulating C-reactive protein (CRP) is also moderately associated with CRC risk. However, observational studies are susceptible to unmeasured confounding or reverse causality. Using genetic risk variants as instrumental variables, we investigated the causal relationship between genetically elevated CRP concentration and CRC risk, using a Mendelian randomization approach. Methods: Individual-level data from 30 480 CRC cases and 22 844 controls from 33 participating studies in three international consortia were used: the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT) and the Colon Cancer Family Registry (CCFR). As instrumental variables, we included 19 single nucleotide polymorphisms (SNPs) previously associated with CRP concentration. The SNP-CRC associations were estimated using a logistic regression model adjusted for age, sex, principal components and genotyping phases. An inverse-variance weighted method was applied to estimate the causal effect of CRP on CRC risk. Results: Among the 19 CRP-associated SNPs, rs1260326 and rs6734238 were significantly associated with CRC risk (P = 7.5 × 10-4, and P = 0.003, respectively). A genetically predicted one-unit increase in the log-transformed CRP concentrations (mg/l) was not associated with increased risk of CRC [odds ratio (OR) = 1.04; 95% confidence interval (CI): 0.97, 1.12; P = 0.256). No evidence of association was observed in subgroup analyses stratified by other risk factors. Conclusions: In spite of adequate statistical power to detect moderate association, we found genetically elevated CRP concentration was not associated with increased risk of CRC among individuals of European ancestry. Our findings suggested that circulating CRP is unlikely to be a causal factor in CRC development

A quantitative analysis of complexity of human pathogen-specific CD4 T cell responses in healthy M. tuberculosis infected South Africans

Author Summary: Human pathogen-specific immune responses are tremendously complex and the techniques to study them ever expanding. There is an urgent need for a quantitative analysis and better understanding of pathogen-specific immune responses. Mycobacterium tuberculosis (Mtb) is one of the leading causes of mortality due to an infectious agent worldwide. Here, we were able to quantify the Mtb-specific response in healthy individuals with Mtb infection from South Africa. The response is highly diverse and 66 epitopes are required to capture 80% of the total reactivity. Our study also show that the majority of the identified epitopes are restricted by multiple HLA alleles. Thus, technical advances are required to capture and characterize the complete pathogen-specific response. This study demonstrates further that the approach combining identified epitopes into "megapools" allows capturing a large fraction of the total reactivity. This suggests that this technique is generally applicable to the characterization of immunity to other complex pathogens. Together, our data provide for the first time a quantitative analysis of the complex pathogen-specific T cell response and provide a new understanding of human infections in a natural infection setting

Maximizing and stabilizing luminescence from halide perovskites with potassium passivation

Metal halide perovskites are of great interest for various high-performance optoelectronic applications. The ability to tune the perovskite bandgap continuously by modifying the chemical composition opens up applications for perovskites as coloured emitters, in building-integrated photovoltaics, and as components of tandem photovoltaics to increase the power conversion efficiency. Nevertheless, performance is limited by non-radiative losses, with luminescence yields in state-of-the-art perovskite solar cells still far from 100 per cent under standard solar illumination conditions. Furthermore, in mixed halide perovskite systems designed for continuous bandgap tunability2 (bandgaps of approximately 1.7 to 1.9 electronvolts), photoinduced ion segregation leads to bandgap instabilities. Here we demonstrate substantial mitigation of both non-radiative losses and photoinduced ion migration in perovskite films and interfaces by decorating the surfaces and grain boundaries with passivating potassium halide layers. We demonstrate external photoluminescence quantum yields of 66 per cent, which translate to internal yields that exceed 95 per cent. The high luminescence yields are achieved while maintaining high mobilities of more than 40 square centimetres per volt per second, providing the elusive combination of both high luminescence and excellent charge transport. When interfaced with electrodes in a solar cell device stack, the external luminescence yield—a quantity that must be maximized to obtain high efficiency—remains as high as 15 per cent, indicating very clean interfaces. We also demonstrate the inhibition of transient photoinduced ion-migration processes across a wide range of mixed halide perovskite bandgaps in materials that exhibit bandgap instabilities when unpassivated. We validate these results in fully operating solar cells. Our work represents an important advance in the construction of tunable metal halide perovskite films and interfaces that can approach the efficiency limits in tandem solar cells, coloured-light-emitting diodes and other optoelectronic applications.M.A.-J. thanks Nava Technology Limited and Nyak Technology Limited for their funding and technical support. Z.A.-G. acknowledges funding from a Winton Studentship, and ICON Studentship from the Lloyd’s Register Foundation. This project has received funding from the European Union’s Seventh Framework Programme (FP7/2007-2013) under REA grant agreement number PIOF-GA-2013-622630, the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement number 756962), and the Royal Society and Tata Group (UF150033). We thank the Engineering and Physical Sciences Research Council (EPSRC) for support. XMaS is a mid-range facility at the European Synchrotron Radiation Facility supported by the EPSRC and we are grateful to the XMaS beamline team staff for their support. We thank Diamond Light Source for access to beamline I09 and staff member T.-L. Lee as well as U. Cappel for assistance during the HAXPES measurements. S.C., C.D. and G.D. acknowledge funding from the ERC under grant number 25961976 PHOTO EM and financial support from the European Union under grant number 77 312483 ESTEEM2. M.A. thanks the president of the UAE’s Distinguished Student Scholarship Program, granted by the Ministry of Presidential Affairs. H.R. and B.P. acknowledge support from the Swedish research council (2014-6019) and the Swedish foundation for strategic research. E.M.H. and T.J.S. were supported by the Netherlands Organization for Scientific Research under the Echo grant number 712.014.007

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The Clebsch–Gordan Coefficients and Their Application to Magnetic Resonance

The Clebsch–Gordan coefficients are extremely useful in magnetic resonance theory, yet have an infamous perceived level of complexity by many students. The Clebsch–Gordan coefficients are used to determine both the matrix elements of the spherical tensor operators and the total angular momentum states of a system of component angular momenta. Full derivations of these coefficients are rarely worked through step by step. Instead, students are provided with tables accompanied by little or no explanation of where the values in it originated from. This lack of direction is often a source of confusion for students. For this reason, we work through two common examples of the application of the Clebsch–Gordan coefficients to magnetic resonance experiments. In the first, we determine the components of the magnetic resonance Hamiltonian of ranks 0, 1, and 2 and use these to identify the secular portion of the static, heteronuclear dipolar Hamiltonian. In the second, we derive the singlet and triplet states that arise from the interaction of two identical spin- particles

Electron-decoupled MAS DNP with N@C60

Frequency-chirped microwaves decouple electron- and 13C-spins in magic-angle spinning N@C60:C60 powder, improving DNP-enhanced 13C NMR signal intensity by 12% for 7 s polarization, and 5% for 30 s polarization. This electron decoupling demonstration is a step toward utilizing N@C60 as a controllable electron-spin source for magic-angle spinning magnetic resonance experiments.ISSN:1463-9084ISSN:1463-907

Characterization of Frequency-Chirped Dynamic Nuclear Polarization in Rotating Solids

Continuous wave (CW) dynamic nuclear polarization (DNP) is used with magic angle spinning (MAS) to enhance the typically poor sensitivity of nuclear magnetic resonance (NMR) by orders of magnitude. In a recent publication we show that further enhancement is obtained by using a frequency-agile gyrotron to chirp incident microwave frequency through the electron resonance frequency during DNP transfer. Here we characterize the effect of chirped MAS DNP by investigating the sweep time, sweep width, center-frequency, and electron Rabi frequency of the chirps. We show the advantages of chirped DNP with a trityl nitroxide biradical, and a lack of improvement with chirped DNP using AMUPol, a nitroxide biradical. Frequency-chirped DNP on a model system of urea in a cryoprotecting matrix yields an enhancement of 142, 21% greater than that obtained with CW DNP. We then go beyond this model system and apply chirped DNP to intact human cells. In human Jurkat cells, frequency-chirped DNP improves enhancement by 24% over CW DNP. The characterization of the chirped DNP effect reveals instrument limitations on sweep time and sweep width, promising even greater increases in sensitivity with further technology development. These improvements in gyrotron technology, frequency-agile methods, and in cell applications are expected to play a significant role in the advancement of MAS DNP.<br /

Dynamic Nuclear Polarization Nuclear Magnetic Resonance in Human Cells Using Fluorescent Polarizing Agents

Solid state nuclear magnetic resonance (NMR) enables atomic-resolution characterization of the molecular structure and dynamics within complex heterogeneous samples, but it is typically insensitive. Dynamic nuclear polarization (DNP) increases the NMR signal intensity by orders of magnitude and can be performed in combination with magic angle spinning (MAS) for sensitive, high-resolution spectroscopy. Here we report MAS DNP experiments, for the first time, within intact human cells with >40-fold DNP enhancement and a sample temperature of <6 K. In addition to cryogenic MAS results at <6 K, we also show in-cell DNP enhancements of 57-fold at 90 K. In-cell DNP is demonstrated using biradicals and sterically shielded monoradicals as polarizing agents. A novel trimodal polarizing agent is introduced for DNP, which contains a nitroxide biradical, a targeting peptide for cell penetration, and a fluorophore for subcellular localization with confocal microscopy. The fluorescent polarizing agent provides in-cell DNP enhancements of 63-fold at a concentration of 2.7 mM. These experiments pave the way for structural characterization of biomolecules in an endogenous cellular context

Targeting EPO and EPO receptor pathways in anemia and dysregulated erythropoiesis.

INTRODUCTION: Recombinant human erythropoietin (rhEPO) is a first-line therapeutic for the anemia of chronic kidney disease, cancer chemotherapy, AIDS (Zidovudine therapy), and lower-risk myelodysplastic syndrome. However, rhEPO frequently elevates hypertension, is costly, and may affect cancer progression. Potentially high merit therefore exists for defining new targets for anti-anemia agents within erythropoietin (EPO) and EPO receptor (EPOR) regulatory circuits. AREAS COVERED: EPO production by renal interstitial fibroblasts is subject to modulation by several regulators of hypoxia-inducible factor 2a (HIF2a) including Iron Response Protein-1, prolyl hydroxylases, and HIF2a acetylases, each of which holds potential as anti-anemia drug targets. The cell surface receptor for EPO (EPOR) preassembles as a homodimer, together with Janus Kinase 2 (JAK2), and therefore it remains attractive to develop novel agents that trigger EPOR complex activation (activating antibodies, mimetics, small-molecule agonists). Additionally, certain downstream transducers of EPOR/JAK2 signaling may be druggable, including Erythroferrone (a hepcidin regulator), a cytoprotective Spi2a serpin, and select EPOR-associated protein tyrosine phosphatases. EXPERT OPINION: While rhEPO (and biosimilars) are presently important mainstay erythropoiesis-stimulating agents (ESAs), impetus exists for studies of novel ESAs that fortify HIF2a\u27s effects, act as EPOR agonists, and/or bolster select downstream EPOR pathways to erythroid cell formation. Such agents could lessen rhEPO dosing, side effects, and/or costs