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Research supported by US NSF grants 0850413 and 1014506, and the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013) / ERC Grant Agreement No. 320750. The UK NERC and BGS funded the recovery of Core MD04-2822. Core MD04-2822 from the Rockall Trough has apparent sedimentation rates of ∼ 1 m/kyr during the last deglaciation (Termination I). Component magnetization directions indicate a magnetic excursion at 16.3 m depth in the core, corresponding to an age of 26.5 ka, implying an excursion duration of ∼350 years. Across Termination I, the mean grain size of sortable silt implies reduced bottom-current velocity in the Younger Dryas and Heinrich Stadial (HS)-1A, and increased velocities during the Bølling-Allerød warm period. Standard bulk magnetic parameters imply fining of magnetic grain size from the mid-Younger Dryas (∼12 ka) until ∼ 8 ka. First-order reversal curves (FORCs) were analyzed using ridge extraction to differentiate single domain (SD) from background (detrital) components. Principal component analysis (FORC-PCA) was then used to discriminate three end members corresponding to SD, pseudo-single domain (PSD) and multidomain (MD) magnetite. The fining of bulk magnetic grain size from 12 to 8 ka is due to reduction in concentration of detrital (PSD+MD) magnetite, superimposed on a relatively uniform concentration of SD magnetite produced by magnetotactic bacteria. The decrease in PSD+MD magnetite concentration from 12 to 8 ka is synchronized with increase in benthic δ13C, and with major (∼70 m) regional sea-level rise, and may therefore be related to detrital sources on the shelf that had reduced influence as sea level rose, and to bottom-water reorganization as Northern Source Water (NSW) replaced Southern Source Water (SSW). Publisher PDF

Cystic fibrosis results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-dependent protein kinase A (PKA) and ATP-regulated chloride channel. Here, we demonstrate that nucleoside diphosphate kinase B (NDPK-B, NM23-H2) forms a functional complex with CFTR. In airway epithelia forskolin/IBMX significantly increases NDPK-B co-localisation with CFTR whereas PKA inhibitors attenuate complex formation. Furthermore, an NDPK-B derived peptide (but not its NDPK-A equivalent) disrupts the NDPK-B/CFTR complex in vitro (19-mers comprising amino acids 36-54 from NDPK-B or NDPK-A). Overlay (Far-Western) and Surface Plasmon Resonance (SPR) analysis both demonstrate that NDPK-B binds CFTR within its first nucleotide binding domain (NBD1, CFTR amino acids 351-727). Analysis of chloride currents reflective of CFTR or outwardly rectifying chloride channels (ORCC, DIDS-sensitive) showed that the 19-mer NDPK-B peptide (but not its NDPK-A equivalent) reduced both chloride conductances. Additionally, the NDPK-B (but not NDPK-A) peptide also attenuated acetylcholine-induced intestinal short circuit currents. In silico analysis of the NBD1/NDPK-B complex reveals an extended interaction surface between the two proteins. This binding zone is also target of the 19-mer NDPK-B peptide, thus confirming its capability to disrupt NDPK-B/CFTR complex. We propose that NDPK-B forms part of the complex that controls chloride currents in epithelia.

Perovskites in the ternary system PbTiO₃ (PT)–PbZrO₃ (PZ)–Pb(Fe₀.₅Nb₀.₅)O₃ (PFN) have attracted close interest because they can display simultaneous ferroelectric, magnetic and ferroelastic properties. Those with the most sensitive response to external fields are likely to have compositions near the morphotropic phase boundary (MPB) which lies close to the binary join Pb(Zr₀.₅₃Ti₀.₄₇)O₃ (PZT)–PFN. In the present study, the strength and dynamics of strain coupling behaviour which accompanies the development of ferroelectricity and (anti)ferromagnetism in ceramic PZT–PFN samples have been investigated by resonant ultrasound spectroscopy. Elastic softening ahead of the cubic–tetragonal transition does not fit with models based on dispersion of the soft mode or relaxor characteristics but is attributed, instead, to coupling between acoustic modes and a central peak mode from correlated relaxations and/or microstructure dynamics. Softening of the shear modulus through the transition by up to ~50 % fits with the expected pattern for linear/quadratic strain/order parameter coupling at an improper ferroelastic transition and close to tricritical evolution for the order parameter. Superattenuation of acoustic resonances in a temperature interval of ~100 K below the transition point is indicative of mobile ferroelastic twin walls. By way of contrast, the first-order tetragonal–monoclinic transition involves only a small change in the shear modulus and is not accompanied by significant changes in acoustic dissipation. The dominant feature of the elastic and anelastic properties at low temperatures is a concave-up variation of the shear modulus and relatively high loss down to the lowest temperature, which appears to be the signature of materials with substantial local strain heterogeneity and a spectrum of strain relaxation times. No evidence of magnetoelastic coupling has been found, in spite of the samples displaying ferromagnetism below ~550 K and possible spin glass ordering below ~50 K. For the important multiferroic perovskite ceramics with compositions close to the MPB of ternary PT-PZ-PFN, there must be some focus in future on the role of strain heterogeneity.

Resonant Ultrasound Spectroscopy has been used to characterize elastic and anelastic anomalies in a polycrystalline sample of multiferroic Pb(Fe0.5Nb0.5)O3 (PFN). Elastic softening begins at ~550 K, which is close to the Burns temperature marking the development of dynamical polar nanoregions. A small increase in acoustic loss at ~425 K coincides with the value of T* reported for polar nanoregions starting to acquire a static or quasi-static component. Softening of the shear modulus by ~30–35% through ~395–320 K, together with a peak in acoustic loss, is due to classical strain/order parameter coupling through the cubic → tetragonal → monoclinic transition sequence of ferroelectric/ferroelastic transitions. A plateau of high acoustic loss below ~320 K is due to the mobility under stress of a ferroelastic microstructure but, instead of the typical effects of freezing of twin wall motion at some low temperature, there is a steady decrease in loss and increase in elastic stiffness below ~85 K. This is attributed to freezing of a succession of strain-coupled defects with a range of relaxation times and is consistent with a report in the literature that PFN develops a tweed microstructure over a wide temperature interval. No overt anomaly was observed near the expected Néel point, ~145 K, consistent with weak/absent spin/lattice coupling but heat capacity measurements showed that the antiferromagnetic transition is actually smeared out or suppressed. Instead, the sample is weakly ferromagnetic up to ~560 K, though it has not been possible to exclude definitively the possibility that this could be due to some magnetic impurity. Overall, evidence from the RUS data is of a permeating influence of static and dynamic strain relaxation effects which are attributed to local strain heterogeneity on a mesoscopic length scale. These, in turn, must have a role in determining the magnetic properties and multiferroic character of PFN.

This work was supported in part by a grant from the Engineering and Physical Sciences Research Council (EP/I036079/1) which is gratefully acknowledged. The RUS facilities in Cambridge were established with support from the Natural Environment Research Council (grant numbers NE/B505738/1 and NE/F17081/1). HS and SED acknowledge support from the Winton Programme for the Physics of Sustainability, and HS acknowledges support from the Funai Foundation for Information Technology. Funding to support this research (to RJH) was also obtained from the European Union's Seventh Framework Programme (FP/2007-2013)/ ERC grant agreement 3207500. Resonant Ultrasound Spectroscopy has been used to characterize elastic and anelastic anomalies in a polycrystalline sample of multiferroic Pb(Fe0.5Nb0.5)O3 (PFN). Elastic softening begins at ~550 K, which is close to the Burns temperature marking the development of dynamical polar nanoregions. A small increase in acoustic loss at ~425 K coincides with the value of T* reported for polar nanoregions starting to acquire a static or quasi-static component. Softening of the shear modulus by ~30–35% through ~395–320 K, together with a peak in acoustic loss, is due to classical strain/order parameter coupling through the cubic → tetragonal → monoclinic transition sequence of ferroelectric/ferroelastic transitions. A plateau of high acoustic loss below ~320 K is due to the mobility under stress of a ferroelastic microstructure but, instead of the typical effects of freezing of twin wall motion at some low temperature, there is a steady decrease in loss and increase in elastic stiffness below ~85 K. This is attributed to freezing of a succession of strain-coupled defects with a range of relaxation times and is consistent with a report in the literature that PFN develops a tweed microstructure over a wide temperature interval. No overt anomaly was observed near the expected Néel point, ~145 K, consistent with weak/absent spin/lattice coupling but heat capacity measurements showed that the antiferromagnetic transition is actually smeared out or suppressed. Instead, the sample is weakly ferromagnetic up to ~560 K, though it has not been possible to exclude definitively the possibility that this could be due to some magnetic impurity. Overall, evidence from the RUS data is of a permeating influence of static and dynamic strain relaxation effects which are attributed to local strain heterogeneity on a mesoscopic length scale. These, in turn, must have a role in determining the magnetic properties and multiferroic character of PFN. Publisher PDF

Dynamin superfamily molecular motors use guanosine triphosphate (GTP) as a source of energy for membrane-remodeling events. We found that knockdown of nucleoside diphosphate kinases (NDPKs) NM23-H1/H2, which produce GTP through adenosine triphosphate (ATP)–driven conversion of guanosine diphosphate (GDP), inhibited dynamin-mediated endocytosis. NM23-H1/H2 localized at clathrin-coated pits and interacted with the proline-rich domain of dynamin. In vitro, NM23-H1/H2 were recruited to dynamin-induced tubules, stimulated GTP-loading on dynamin, and triggered fission in the presence of ATP and GDP. NM23-H4, a mitochondria-specific NDPK, colocalized with mitochondrial dynamin-like OPA1 involved in mitochondria inner membrane fusion and increased GTP-loading on OPA1. Like OPA1 loss of function, silencing of NM23-H4 but not NM23-H1/H2 resulted in mitochondrial fragmentation, reflecting fusion defects. Thus, NDPKs interact with and provide GTP to dynamins, allowing these motor proteins to work with high thermodynamic efficiency.

Overexpression of the nm23H1 gene has been associated with the suppression of metastasis in several solid tumors. However, in colorectal carcinoma and neuroblastoma, increased levels of nm23 H1 nucleoside diphosphate kinase A (NDPKA) mRNA are associated with tumorigenesis. To determine the role of nm23 H1/NDPKA in the prostate, normal and/or malignant tissue samples from 29 consecutive patients were studied. Levels of nm23 H1/NDPKA mRNA and nm23 H1/NDPKA mRNA protein were determined in tissue from 18 and 27 patients, respectively. In all, 16 of the 18 tumor samples expressed increased levels of nm23 H1/NDPKA mRNA as compared with those measured in normal tissue. The level of nm23 H1/NDPKA mRNA was >10-fold higher in a metastatic lymph node than in normal prostate tissue. All cancer specimens and areas of prostatic intraepithelial neoplasia showed immunoreactivity with the nm23 H1/NDPKA antibody; however, normal prostatic tissue was unreactive. These findings suggest that overexpression of the nm23 H1/NDPKA gene occurs frequently in adenocarcinomas of the prostate and may be an early event in prostate cancer tumorigenesis.