Evidence That Cytochrome \u3cem\u3eb\u3csub\u3e5\u3c/sub\u3e\u3c/em\u3e Acts as a Redox Donor in CYP17A1 Mediated Androgen Synthesis

Cytochrome P450 17A1 (CYP17A1) is an important drug target for castration resistant prostate cancer. It is a bi-functional enzyme, catalyzing production of glucocorticoid precursors by hydroxylation of pregnene-nucleus, and androgen biosynthesis by a second C--C lyase step, at the expense of glucocorticoid production. Cytochrome b5(cyt b5) is known to be a key regulator of the androgen synthesis reaction in vivo, by a mechanism that is not well understood. Two hypotheses have been proposed for the mechanism by which cyt b5 increases androgen biosynthesis. Cyt b5 could act as an allosteric effector, binding to CYP17A1 and either changing its selective substrate affinity or altering the conformation of the P450 to increase the catalytic rate or decrease unproductive uncoupling channels. Alternatively, cyt b5 could act as a redox donor for supply of the second electron in the P450 cycle, reducing the oxyferrous complex to form the reactive peroxo-intermediate. To understand the mechanism of lyase enhancement by cyt b5, we generated a redox-inactive form of cyt b5, in which the heme is replaced with a Manganese-protoporphyrin IX (Mn-b5), and investigated enhancement of androgen producing lyase reaction by CYP17A1. Given the critical significance of a stable membrane anchor for all of the proteins involved and the need for controlled stoichiometric ratios, we employed the Nanodisc system for this study. The redox inactive form was observed to have no effect on the lyase reaction, while reactions with the normal heme-iron containing cyt b5 were enhanced ∼5 fold as compared to reactions in the absence of cyt b5. We also performed resonance Raman measurements on ferric CYP17A1 bound to Mn-b5. Upon addition of Mn-b5 to Nanodisc reconstituted CYP17A1, we observed clear evidence for the formation of a b5-CYP17A1 complex, as noted by changes in the porphyrin modes and alteration in the proximal Fe--S vibrational frequency. Thus, although Mn-b5 binds to CYP17A1, it is unable to enhance the lyase reaction, strongly suggesting that cyt b5 has a redox effector role in enhancement of the CYP17A1 mediated lyase reaction necessary for androgen synthesis

On global models for isolated rotating axisymmetric charged bodies; uniqueness of the exterior field

A relatively recent study by Mars and Senovilla provided us with a uniqueness result for the exterior vacuum gravitational field generated by an isolated distribution of matter in axial rotation in equilibrium in General Relativity. The generalisation to exterior electrovacuum gravitational fields, to include charged rotating objects, is presented here.Comment: LaTeX, 21 pages, uses iopart styl

Conformal Ricci collineations of static spherically symmetric spacetimes

Conformal Ricci collineations of static spherically symmetric spacetimes are studied. The general form of the vector fields generating conformal Ricci collineations is found when the Ricci tensor is non-degenerate, in which case the number of independent conformal Ricci collineations is \emph{fifteen}; the maximum number for 4-dimensional manifolds. In the degenerate case it is found that the static spherically symmetric spacetimes always have an infinite number of conformal Ricci collineations. Some examples are provided which admit non-trivial conformal Ricci collineations, and perfect fluid source of the matter

The Costs And Benefits Of A Finance Lab

Technology has revolutionized the practice of finance.  In order to provide business students a current and relevant education, schools in the U.S. and abroad are increasingly adopting the latest technology in the instruction of finance.  A finance lab typically provides real-time or delayed market data, simulation and risk analysis software, and Bloomberg terminals to illustrate various financial concepts and to train students in the use of technology.  This paper discusses numerous important constituents of a finance lab, their costs and benefits, and some potential funding sources

Excess α-synuclein compromises phagocytosis in iPSC-derived macrophages

To examine the pathogenic role of α-synuclein (αS) in Parkinson's Disease, we have generated induced Pluripotent Stem Cell lines from early onset Parkinson's Disease patients with SNCA A53T and SNCA Triplication mutations, and in this study have differentiated them to PSC-macrophages (pMac), which recapitulate many features of their brain-resident cousins, microglia. We show that SNCA Triplication pMac, but not A53T pMac, have significantly increased intracellular αS versus controls and release significantly more αS to the medium. SNCA Triplication pMac, but not A53T pMac, show significantly reduced phagocytosis capability and this can be phenocopied by adding monomeric αS to the cell culture medium of control pMac. Fibrillar αS is taken up by pMac by actin-rearrangement-dependent pathways, and monomeric αS by actin-independent pathways. Finally, pMac degrade αS and this can be arrested by blocking lysosomal and proteasomal pathways. Together, these results show that macrophages are capable of clearing αS, but that high levels of exogenous or endogenous αS compromise this ability, likely a vicious cycle scenario faced by microglia in Parkinson's disease

Sintering of calcium phosphates with a femtosecond pulsed laser for hard tissue engineering

The authors acknowledge support from the sponsors of this work; the EPSRC LUMIN (EP/K020234/1) and EU-Marie-Curie-IAPP LUSTRE (324538) projects.Direct laser sintering on hard tissues is likely to open new pathways for personalised medicine. To minimise irradiation damage of the surrounding soft tissues, lasers operating at wavelengths that are ‘safe’ for the tissues and biomaterials with improved optical properties are required. In this work laser sintering is demonstrated with the use of an ultrafast, femtosecond (100 fs) pulsed laser operating at a wavelength of 1045 nm and two existing calcium phosphate minerals (brushite and hydroxyapatite) which have been improved after doping with iron (10 mol%). Femtosecond laser irradiation caused transformation of the Fe3+-doped brushite and Fe3+-doped HAp samples into β-calcium pyrophosphate and calcium-iron-phosphate, respectively, with simultaneous evidence for microstructural sintering and densification. After estimating the temperature profile at the surface of the samples we suggest that soft tissues over 500 μm from the irradiated zone would be safe from thermal damage. This novel laser processing provides a means to control the phase constitution and the morphology of the finished surfaces. The porous structure of β-pyrophosphate might be suitable for applications in bone regeneration by supporting osteogenic cell activity while, the densified Fe3+-rich calcium-iron-phosphate may be promising for applications like dental enamel restoration.PostprintPeer reviewe

Ricci Collineations for type B warped space-times

We present the general structure of proper Ricci Collineations (RC) for type B warped space-times. Within this framework, we give a detailed description of the most general proper RC for spherically symmetric metrics. As examples, static spherically symmetric and Friedmann-Robertson-Walker space-times are considered.Comment: 18 pages, Latex, To appear in GR

Unbiased Metagenomic Sequencing for Pediatric Meningitis in Bangladesh Reveals Neuroinvasive Chikungunya Virus Outbreak and Other Unrealized Pathogens.

The burden of meningitis in low-and-middle-income countries remains significant, but the infectious causes remain largely unknown, impeding institution of evidence-based treatment and prevention decisions. We conducted a validation and application study of unbiased metagenomic next-generation sequencing (mNGS) to elucidate etiologies of meningitis in Bangladesh. This RNA mNGS study was performed on cerebrospinal fluid (CSF) specimens from patients admitted in the largest pediatric hospital, a World Health Organization sentinel site, with known neurologic infections (n = 36), with idiopathic meningitis (n = 25), and with no infection (n = 30), and six environmental samples, collected between 2012 and 2018. We used the IDseq bioinformatics pipeline and machine learning to identify potentially pathogenic microbes, which we then confirmed orthogonally and followed up through phone/home visits. In samples with known etiology and without infections, there was 83% concordance between mNGS and conventional testing. In idiopathic cases, mNGS identified a potential bacterial or viral etiology in 40%. There were three instances of neuroinvasive Chikungunya virus (CHIKV), whose genomes were >99% identical to each other and to a Bangladeshi strain only previously recognized to cause febrile illness in 2017. CHIKV-specific qPCR of all remaining stored CSF samples from children who presented with idiopathic meningitis in 2017 (n = 472) revealed 17 additional CHIKV meningitis cases, exposing an unrecognized meningitis outbreak. Orthogonal molecular confirmation, case-based clinical data, and patient follow-up substantiated the findings. Case-control CSF mNGS surveys can complement conventional diagnostic methods to identify etiologies of meningitis, conduct surveillance, and predict outbreaks. The improved patient- and population-level data can inform evidence-based policy decisions.IMPORTANCE Globally, there are an estimated 10.6 million cases of meningitis and 288,000 deaths every year, with the vast majority occurring in low- and middle-income countries. In addition, many survivors suffer from long-term neurological sequelae. Most laboratories assay only for common bacterial etiologies using culture and directed PCR, and the majority of meningitis cases lack microbiological diagnoses, impeding institution of evidence-based treatment and prevention strategies. We report here the results of a validation and application study of using unbiased metagenomic sequencing to determine etiologies of idiopathic (of unknown cause) cases. This included CSF from patients with known neurologic infections, with idiopathic meningitis, and without infection admitted in the largest children's hospital of Bangladesh and environmental samples. Using mNGS and machine learning, we identified and confirmed an etiology (viral or bacterial) in 40% of idiopathic cases. We detected three instances of Chikungunya virus (CHIKV) that were >99% identical to each other and to a strain previously recognized to cause systemic illness only in 2017. CHIKV qPCR of all remaining stored 472 CSF samples from children who presented with idiopathic meningitis in 2017 at the same hospital uncovered an unrecognized CHIKV meningitis outbreak. CSF mNGS can complement conventional diagnostic methods to identify etiologies of meningitis, and the improved patient- and population-level data can inform better policy decisions

Report of the Task Force on Enhancing technology use in agriculture insurance

Pradhan Mantri Fasal Bima Yojana (PMFBY) is a flagship scheme of the Government of India to provide insurance coverage and financial support to farmers in the event of failure of any of the notified crops, unsown area and damage to harvest produce as a result of natural calamities, pests and diseases to stabilise the income of farmers, and to encourage them to adopt modern agricultural practices. The scheme is a considerable improvement over all previous insurance schemes in India and is heavily subsidised by the state and central governments. The scheme aims to cover 50 percent of the farming households within next 3 years. During its implementation in the last one season, several challenges relating to enrolment, yield estimation, loss assessment, and claim settlement were reported by farmers, insurance companies as well as the state governments. It was also noted that several technological opportunities existed for possibly leveraging support to the Indian crop insurance program for enhanced efficiency and effectiveness. NITI Aayog of the Government of India, therefore, constituted a Task Force to deliberate on this subject and identify such potential opportunities. This report summarises the recommendations of the Task Force. The Task Force constituted to address the issue of technology support to crop insurance comprised the following 5 sub-groups: (1) Remote Sensing & Drones; (2) Decision Support Systems, Crop Modelling & Integrated Approaches; (3) IT/ICT in Insurance; (4) Crop Cutting Experiments (CCEs); and (5) Technologies for Livestock and Aquaculture Insurance. Each sub-group had several discussions with experts in the respective areas, and submitted draft reports. More than 100 experts related to professional research agencies, insurance industry, banks, and the government contributed to these discussions. Technological options available in the country and abroad were considered by all groups. The Task Force together with the sub-groups then deliberated on key issues and formulated its recommendations as presented in this report. During the discussions it was realised that there were many administrative and institutional issues that needed to be addressed in PMFBY. However, the focus of the Task Force was on its main mandate, technology use in crop insurance. We hope these recommendations would help the Indian crop insurance sector take full advantage of the technological options suggested so as to increase its efficacy and effectiveness leading to reduced agrarian distress in the country

Genetic basis for variation in plasma IL-18 levels in persons with chronic hepatitis C virus and human immunodeficiency virus-1 infections

Inflammasomes are multi-protein complexes integrating pathogen-triggered signaling leading to the generation of pro-inflammatory cytokines including interleukin-18 (IL-18). Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections are associated with elevated IL-18, suggesting inflammasome activation. However, there is marked person-to-person variation in the inflammasome response to HCV and HIV. We hypothesized that host genetics may explain this variation. To test this, we analyzed the associations of plasma IL-18 levels and polymorphisms in 10 genes in the inflammasome cascade. About 1538 participants with active HIV and/or HCV infection in three ancestry groups are included. Samples were genotyped using the Illumina Omni 1-quad and Omni 2.5 arrays. Linear regression analyses were performed to test the association of variants with log IL-18 including HCV and HIV infection status, and HIV RNA in each ancestry group and then meta-analyzed. Eleven highly correlated single-nucleotide polymorphisms (r²=0.98–1) in the IL-18-BCO2 region were significantly associated with log IL-18; each T allele of rs80011693 confers a decrease of 0.06 log pg ml⁻¹ of IL-18 after adjusting for covariates (rs80011693; rs111311302 β=−0.06, P-value=2.7 × 10⁻⁴). In conclusion, genetic variation in IL-18 is associated with IL-18 production in response to HIV and HCV infection, and may explain variability in the inflammatory outcomes of chronic viral infections