Lipid and Protein Transfer between Nanolipoprotein Particles and Supported Lipid Bilayers.

A nanolipoprotein particle (NLP) is a lipid bilayer disc stabilized by two amphipathic "scaffold" apolipoproteins. It has been most notably utilized as a tool for solubilizing a variety of membrane proteins while preserving structural and functional properties. Transfer of functional proteins from NLPs into model membrane systems such as supported lipid bilayers (SLBs) would enable new opportunities, for example, two-dimensional protein crystallization and studies on protein-protein interactions. This work used fluorescence microscopy and atomic force microscopy to investigate the interaction between NLPs and SLBs. When incubated with SLBs, NLPs were found to spontaneously deliver lipid and protein cargo. The impact of membrane composition on lipid exchange was explored, revealing a positive correlation between the magnitude of lipid transfer and concentration of defects in the target SLB. Incorporation of lipids capable of binding specifically to polyhistidine tags encoded into the apolipoproteins also boosted transfer of NLP cargo. Optimal conditions for lipid and protein delivery from NLPs to SLBs are proposed based on interaction mechanisms

The present and future of serum diagnostic tests for testicular germ cell tumours

Testicular germ cell tumours (GCTs) are the most common malignancy occurring in young adult men and the incidence of these tumours is increasing. Current research priorities in this field include improving overall survival for patients classified as being 'poor-risk' and reducing late effects of treatment for patients classified as 'good-risk'. Testicular GCTs are broadly classified into seminomas and nonseminomatous GCTs (NSGCTs). The conventional serum protein tumour markers α-fetoprotein (AFP), human chorionic gonadotrophin (hCG) and lactate dehydrogenase (LDH) show some utility in the management of testicular malignant GCT. However, AFP and hCG display limited sensitivity and specificity, being indicative of yolk sac tumour (AFP) and choriocarcinoma or syncytiotrophoblast (hCG) subtypes. Furthermore, LDH is a very nonspecific biomarker. Consequently, seminomas and NSGCTs comprising a pure embryonal carcinoma subtype are generally negative for these conventional markers. As a result, novel universal biomarkers for testicular malignant GCTs are required. MicroRNAs are short, non-protein-coding RNAs that show much general promise as biomarkers. MicroRNAs from two 'clusters', miR-371–373 and miR-302–367, are overexpressed in all malignant GCTs, regardless of age (adult or paediatric), site (gonadal or extragonadal) and subtype (seminomas, yolk sac tumours or embryonal carcinomas). A panel of four circulating microRNAs from these two clusters (miR-371a-3p, miR-372-3p, miR-373-3p and miR-367-3p) is highly sensitive and specific for the diagnosis of malignant GCT, including seminoma and embryonal carcinoma. In the future, circulating microRNAs might be useful in diagnosis, disease monitoring and prognostication of malignant testicular GCTs, which might also reduce reliance on serial CT scanning. For translation into clinical practice, important practical considerations now need addressing.The authors would like to acknowledge grant funding from CwCUK/GOSHCC (M.J.M. N.C. grant W1058), SPARKS (M.J.M. N.C. grant 11CAM01), CRUK (N.C. grant A13080) MRC (M.J.M. grant MC_EX_G0800464) and National Health Service funding to the Royal Marsden/Institute of Cancer Research National Institute for Health Research Biomedical Research Centre for Cancer (R.A.H.). The authors also thank the Max Williamson Fund, the Josh Carrick Foundation and The Perse Preparatory School, Cambridge for support.This is the author accepted manuscript. The final version is available fromNature Publishing Group via https://doi.org/10.1038/nrurol.2016.17

Large-scale Spatiotemporal Spike Patterning Consistent with Wave Propagation in Motor Cortex

Aggregate signals in cortex are known to be spatiotemporally organized as propagating waves across the cortical surface, but it remains unclear whether the same is true for spiking activity in individual neurons. Furthermore, the functional interactions between cortical neurons are well documented but their spatial arrangement on the cortical surface has been largely ignored. Here we use a functional network analysis to demonstrate that a subset of motor cortical neurons in non-human primates spatially coordinate their spiking activity in a manner that closely matches wave propagation measured in the beta oscillatory band of the local field potential. We also demonstrate that sequential spiking of pairs of neuron contains task-relevant information that peaks when the neurons are spatially oriented along the wave axis. We hypothesize that the spatial anisotropy of spike patterning may reflect the underlying organization of motor cortex and may be a general property shared by other cortical areas

Majorana Zero Modes in 1D Quantum Wires Without Long-Ranged Superconducting Order

We show that long-ranged superconducting order is not necessary to guarantee the existence of Majorana fermion zero modes at the ends of a quantum wire. We formulate a concrete model which applies, for instance, to a semiconducting quantum wire with strong spin-orbit coupling and Zeeman splitting coupled to a wire with algebraically-decaying superconducting fluctuations. We solve this model by bosonization and show that it supports Majorana fermion zero modes. We argue that a large class of models will also show the same phenomenon. We discuss the implications for experiments on spin-orbit coupled nanowires coated with superconducting film and for LaAlO3/SrTiO3 interfaces.Comment: 14 pages. Figures added and a discussion of the effects of quantum phase slips. References Added. Fourth author adde

Nanodelivery of a functional membrane receptor to manipulate cellular phenotype.

Modification of membrane receptor makeup is one of the most efficient ways to control input-output signals but is usually achieved by expressing DNA or RNA-encoded proteins or by using other genome-editing methods, which can be technically challenging and produce unwanted side effects. Here we develop and validate a nanodelivery approach to transfer in vitro synthesized, functional membrane receptors into the plasma membrane of living cells. Using β2-adrenergic receptor (β2AR), a prototypical G-protein coupled receptor, as an example, we demonstrated efficient incorporation of a full-length β2AR into a variety of mammalian cells, which imparts pharmacologic control over cellular signaling and affects cellular phenotype in an ex-vivo wound-healing model. Our approach for nanodelivery of functional membrane receptors expands the current toolkit for DNA and RNA-free manipulation of cellular function. We expect this approach to be readily applicable to the synthesis and nanodelivery of other types of GPCRs and membrane receptors, opening new doors for therapeutic development at the intersection between synthetic biology and nanomedicine

Boundary Layers of Accretion Disks: Wave-Driven Transport and Disk Evolution

Astrophysical objects possessing a material surface (white dwarfs, young stars, etc.) may accrete gas from the disc through the so-called surface boundary layer (BL), in which the angular velocity of the accreting gas experiences a sharp drop. Acoustic waves excited by the supersonic shear in the BL play an important role in mediating the angular momentum and mass transport through that region. Here we examine the characteristics of the angular momentum transport produced by the different types of wave modes emerging in the inner disc, using the results of a large suite of hydrodynamic simulations of the BLs. We provide a comparative analysis of the transport properties of different modes across the range of relevant disc parameters. In particular, we identify the types of modes which are responsible for the mass accretion onto the central object. We find the correlated perturbations of surface density and radial velocity to provide an important contribution to the mass accretion rate. Although the wave-driven transport is intrinsically non-local, we do observe a clear correlation between the angular momentum flux injected into the disc by the waves and the mass accretion rate through the BL. We find the efficiency of angular momentum transport (normalized by thermal pressure) to be a weak function of the flow Mach number. We also quantify the wave-driven evolution of the inner disc, in particular the modification of the angular frequency profile in the disc. Our results pave the way for understanding wave-mediated transport in future three-dimensional, magnetohydrodynamic studies of the BLs.Comment: 16 pages, 9 figures, submitted to MNRA

Magnetized Rotating Isothermal Winds

We consider the general problem of a Parker-type non-relativistic isothermal wind from a rotating and magnetic star. Using the magnetohydrodynamics (MHD) code athena++, we construct an array of simulations in the stellar rotation rate $\Omega_\ast$ and the isothermal sound speed $c_T$, and calculate the mass, angular momentum, and energy loss rates across this parameter space. We also briefly consider the three dimensional case, with misaligned magnetic and rotation axes. We discuss applications of our results to the spindown of normal stars, highly-irradiated exoplanets, and to nascent highly-magnetic and rapidly-rotating neutron stars born in massive star core collapse.8Comment: 19 pages, 13 figures; v2: published version after minor revision

Direct acoustic profiling of DNA hybridisation using HSV type 1 viral sequences

We describe the detection of specific, conserved DNA sequences of herpes simplex virus (HSV) type 1 by means of a novel, high sensitivity acoustic biosensor. Repeated assays on planar and polymeric carboxylic acid- and biotin-presenting surface chemistries enabled statistical comparison of assay specificity and sensitivity and evaluation of assay Z-factor scores. Using a three minute hybridisation with NeutrAvidin capture for signal enhancement, it was possible to detect HSV viral nucleic acids at 5.2 6 10211 M concentration. c The Royal Society of Chemistry 200

SOST Inhibits Prostate Cancer Invasion.

Inhibitors of Wnt signaling have been shown to be involved in prostate cancer (PC) metastasis; however the role of Sclerostin (Sost) has not yet been explored. Here we show that elevated Wnt signaling derived from Sost deficient osteoblasts promotes PC invasion, while rhSOST has an inhibitory effect. In contrast, rhDKK1 promotes PC elongation and filopodia formation, morphological changes characteristic of an invasive phenotype. Furthermore, rhDKK1 was found to activate canonical Wnt signaling in PC3 cells, suggesting that SOST and DKK1 have opposing roles on Wnt signaling in this context. Gene expression analysis of PC3 cells co-cultured with OBs exhibiting varying amounts of Wnt signaling identified CRIM1 as one of the transcripts upregulated under highly invasive conditions. We found CRIM1 overexpression to also promote cell-invasion. These findings suggest that bone-derived Wnt signaling may enhance PC tropism by promoting CRIM1 expression and facilitating cancer cell invasion and adhesion to bone. We concluded that SOST and DKK1 have opposing effects on PC3 cell invasion and that bone-derived Wnt signaling positively contributes to the invasive phenotypes of PC3 cells by activating CRIM1 expression and facilitating PC-OB physical interaction. As such, we investigated the effects of high concentrations of SOST in vivo. We found that PC3-cells overexpressing SOST injected via the tail vein in NSG mice did not readily metastasize, and those injected intrafemorally had significantly reduced osteolysis, suggesting that targeting the molecular bone environment may influence bone metastatic prognosis in clinical settings