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The Nordic Geodetic Commission (NKG) has launched a joint NKG GNSS Analysis Centre that aims to routinely produce high qualityGNSS solutions for the common needs of the NKG and the Nordic and Baltic countries. A consistent and densified velocity field is needed for the constraining of the gla-cial isostatic adjustment (GIA) modelling that is a key component of maintaining the national reference frame realisations in the area. We described the methods of the NKG GNSS Analysis Centre including the defined processing setup for the local analysis centres (LAC) and for the combination centres.We analysed the results of the first 2.5 years (2014.5-2016). The results showed that different subnets were consistent with the combined solution within 1-2 mm level. We observed the so called network effect affecting our reference frame alignment. However, the accuracy of the reference frame alignment was on a few millimetre level in the area of the main interest (Nordic and Baltic Countries). TheNKGGNSS AC was declared fully operational in April 2017.

A insulina é o hormônio responsável pela regulação da glicemia sanguínea, encarregada de sinalizar a entrada da glicose na célula. Quando há a deficiência desse hormônio, seja por defeito na sua secreção, quantidade de receptores ou falha pós-estímulo, gera uma hiperglicemia, ocasionando o diabetes mellitus tipo 2. A vitamina D funciona como um hormônio, e está envolvida em diversas funções do corpo humano, dentre elas o metabolismo da glicose e insulina. Para uma melhor compreensão foi realizada uma pesquisa através de um levantamento bibliográfico nas bases de dados PubMed, SciELO e Lilacs, com objetivo de elucidar a relação entre a vitamina D e a resistência à insulina. Devido a presença de receptores de vitamina D em diversos tecidos do corpo, tem sido bastante discutido os efeitos e a relação dessa vitamina em mecanismos que induzem ao DM2. Estudos demonstram que a hipovitaminose D, geralmente, está presente em portadores de diabetes, e que essa deficiência altera mecanismos que predispõe a ação ineficiente da insulina. Em contrapartida, relatam que a suplementação de vitamina D melhora tanto a glicemia em jejum, quanto a sensibilidade à insulina nos tecidos.

Reversible and irreversible amyloids are two diverging cases of protein (mis)folding associated with the cross-β motif in the protein folding and aggregation energy landscape. Yet, the molecular origins responsible for the formation of reversible vs irreversible amyloids have remained unknown. Here we provide evidence at the atomic level of distinct folding motifs for irreversible and reversible amyloids derived from a single protein sequence: human lysozyme. We compare the 2.8 Å structure of irreversible amyloid fibrils determined by cryo-electron microscopy helical reconstructions with molecular insights gained by solid-state NMR spectroscopy on reversible amyloids. We observe a canonical cross-β-sheet structure in irreversible amyloids, whereas in reversible amyloids, there is a less-ordered coexistence of β-sheet and helical secondary structures that originate from a partially unfolded lysozyme, thus carrying a "memory" of the original folded protein precursor. We also report the structure of hen egg-white lysozyme irreversible amyloids at 3.2 Å resolution, revealing another canonical amyloid fold, and reaffirming that irreversible amyloids undergo a complete conversion of the native protein into the cross-β structure. By combining atomic force microscopy, cryo-electron microscopy and solid-state NMR, we show that a full unfolding of the native protein precursor is a requirement for establishing irreversible amyloid fibrils., (© 2024. The Author(s).)

The investigation of triggers causing the onset and intensification of Northern Hemisphere Glaciation (NHG) during the late Pliocene is essential for understanding the global climate system, with important implications for projecting future climate changes. Despite their critical roles in the global climate system, influences of land-ocean interactions on high-latitude ice sheets remain largely unexplored. Here, we present a high-resolution Asian dust record from Ocean Drilling Program Site 1208 in the North Pacific, which lies along the main route of the westerlies. Our data indicate that atmosphere-land-ocean interactions affected aeolian dust emissions through modulating moisture and vegetation in dust source regions, highlighting a critical role of terrestrial systems in initiating the NHG as early as 3.6 Myr ago. Combined with additional multi-proxy and model results, we further show that westerly wind strength was enhanced, mainly at low-to-middle tropospheric levels, during major glacial events at about 3.3 and 2.7 Myr ago. We suggest that coupled responses of Earth's surface dynamics and atmospheric circulation in the Plio-Pleistocene likely involved feedbacks related to changes in paleogeography, ocean circulation, and global climate., (© 2024. The Author(s).)

Adhesive type 1 pili from uropathogenic Escherichia coli strains are filamentous, supramolecular protein complexes consisting of a short tip fibrillum and a long, helical rod formed by up to several thousand copies of the major pilus subunit FimA. Here, we reconstituted the entire type 1 pilus rod assembly reaction in vitro, using all constituent protein subunits in the presence of the assembly platform FimD, and identified the so-far uncharacterized subunit FimI as an irreversible assembly terminator. We provide a complete, quantitative model of pilus rod assembly kinetics based on the measured rate constants of FimD-catalyzed subunit incorporation. The model reliably predicts the length distribution of assembled pilus rods as a function of the ratio between FimI and the main pilus subunit FimA and is fully consistent with the length distribution of membrane-anchored pili assembled in vivo. The results show that the natural length distribution of adhesive pili formed via the chaperone-usher pathway results from a stochastic chain termination reaction. In addition, we demonstrate that FimI contributes to anchoring the pilus to the outer membrane and report the crystal structures of (i) FimI in complex with the assembly chaperone FimC, (ii) the FimI-FimC complex bound to the N-terminal domain of FimD, and (iii) a ternary complex between FimI, FimA and FimC that provides structural insights on pilus assembly termination and pilus anchoring by FimI., (© 2023. The Author(s).)

High-resolution ice core records from coastal Antarctica are particularly useful to inform our understanding of environmental changes and their drivers. Here, we present a decadally resolved record of sea-salt sodium (a proxy for open-ocean area) and non-sea salt calcium (a proxy for continental dust) from the well-dated Roosevelt Island Climate Evolution (RICE) core, focusing on the time period between 40-26 ka BP. The RICE dust record exhibits an abrupt shift towards a higher mean dust concentration at 32 ka BP. Investigating existing ice-core records, we find this shift is a prominent feature across Antarctica. We propose that this shift is linked to an equatorward displacement of Southern Hemisphere westerly winds. Subsequent to the wind shift, data suggest a weakening of Southern Ocean upwelling and a decline of atmospheric CO 2 to lower glacial values, hence making this shift an important glacial climate event with potentially important insights for future projections., (© 2023. Springer Nature Limited.)

Invasive species cause environmental degradation, decrease biodiversity, and alter ecosystem function. Invasions can also drive changes in vector-borne and zoonotic diseases by altering important traits of wildlife hosts or disease vectors. Managing invasive species can restore biodiversity and ecosystem function, but it may have cascading effects on hosts, parasites, and human risk of infection. Water hyacinth, Eichhornia crassipes, is an extremely detrimental invader in many sites of human schistosome transmission, especially in Lake Victoria, where hyacinth is correlated with high snail abundance and hotspots of human schistosome infection. Hyacinth is often managed via removal or in situ destruction, but the effects of these strategies on snail intermediate hosts and schistosomes are not known. We evaluated the effects of water hyacinth invasion and these management strategies on the dynamics of human schistosomes, Schistosoma mansoni, and snails, Biomphalaria glabrata, in experimental mesocosms over 17 weeks. We hypothesized that hyacinth, which is inedible to snails, would affect snail growth, reproduction, and cercariae production through the balance of its competitive effects on edible algae and its production of edible detritus. We predicted that destruction would create a pulse of edible detrital resources, thereby increasing snail growth, reproduction, and parasite production. Conversely, we predicted that removal would have small or negligible effects on snails and schistosomes, because it would alleviate competition on edible algae without generating a resource pulse. We found that hyacinth invasion suppressed algae, changed the timing of peak snail abundance, and increased total production of human-infectious cercariae ~6-fold relative to uninvaded controls. Hyacinth management had complex effects on algae, snails, and schistosomes. Removal increased algal growth and snail abundance (but not biomass), and slightly reduced schistosome production. In contrast, destruction increased snail biomass (but not abundance), indicating increases in body size. Destruction caused the greatest schistosome production (10-fold more than the control), consistent with evidence that larger snails with greater access to food are most infectious. Our results highlight the dynamic effects of invasion and management on a globally impactful human parasite and its intermediate host. Ultimately, preventing or removing hyacinth invasions would simultaneously benefit human and environmental health outcomes., (© 2022 The Ecological Society of America.)

Antarctica is one of the most vulnerable regions to climate change on Earth and studying the past and present responses of this polar marine ecosystem to environmental change is a matter of urgency. Sedimentary ancient DNA (sedaDNA) analysis can provide such insights into past ecosystem-wide changes. Here we present authenticated (through extensive contamination control and sedaDNA damage analysis) metagenomic marine eukaryote sedaDNA from the Scotia Sea region acquired during IODP Expedition 382. We also provide a marine eukaryote sedaDNA record of ~1 Mio. years and diatom and chlorophyte sedaDNA dating back to ~540 ka (using taxonomic marker genes SSU, LSU, psbO). We find evidence of warm phases being associated with high relative diatom abundance, and a marked transition from diatoms comprising <10% of all eukaryotes prior to ~14.5 ka, to ~50% after this time, i.e., following Meltwater Pulse 1A, alongside a composition change from sea-ice to open-ocean species. Our study demonstrates that sedaDNA tools can be expanded to hundreds of thousands of years, opening the pathway to the study of ecosystem-wide marine shifts and paleo-productivity phases throughout multiple glacial-interglacial cycles., (© 2022. The Author(s).)

Ice loss in the Southern Hemisphere has been greatest over the past 30 years in West Antarctica. The high sensitivity of this region to climate change has motivated geologists to examine marine sedimentary records for evidence of past episodes of West Antarctic Ice Sheet (WAIS) instability. Sediments accumulating in the Scotia Sea are useful to examine for this purpose because they receive iceberg-rafted debris (IBRD) sourced from the Pacific- and Atlantic-facing sectors of West Antarctica. Here we report on the sedimentology and provenance of the oldest of three cm-scale coarse-grained layers recovered from this sea at International Ocean Discovery Program Site U1538. These layers are preserved in opal-rich sediments deposited ∼1.2 Ma during a relatively warm regional climate. Our microCT-based analysis of the layer's in-situ fabric confirms its ice-rafted origin. We further infer that it is the product of an intense but short-lived episode of IBRD deposition. Based on the petrography of its sand fraction and the Phanerozoic 40 Ar/ 39 Ar ages of hornblende and mica it contains, we conclude that the IBRD it contains was likely sourced from the Weddell Sea and/or Amundsen Sea embayment(s) of West Antarctica. We attribute the high concentrations of IBRD in these layers to "dirty" icebergs calved from the WAIS following its retreat inland from its modern grounding line. These layers also sit at the top of a ∼366-m thick Pliocene and early Pleistocene sequence that is much more dropstone-rich than its overlying sediments. We speculate this fact may reflect that WAIS mass-balance was highly dynamic during the ∼41-kyr (inter)glacial world., (© 2022. The Authors.)

The Southern Ocean paleoceanography provides key insights into how iron fertilization and oceanic productivity developed through Pleistocene ice-ages and their role in influencing the carbon cycle. We report a high-resolution record of dust deposition and ocean productivity for the Antarctic Zone, close to the main dust source, Patagonia. Our deep-ocean records cover the last 1.5 Ma, thus doubling that from Antarctic ice-cores. We find a 5 to 15-fold increase in dust deposition during glacials and a 2 to 5-fold increase in biogenic silica deposition, reflecting higher ocean productivity during interglacials. This antiphasing persisted throughout the last 25 glacial cycles. Dust deposition became more pronounced across the Mid-Pleistocene Transition (MPT) in the Southern Hemisphere, with an abrupt shift suggesting more severe glaciations since ~0.9 Ma. Productivity was intermediate pre-MPT, lowest during the MPT and highest since 0.4 Ma. Generally, glacials experienced extended sea-ice cover, reduced bottom-water export and Weddell Gyre dynamics, which helped lower atmospheric CO 2 levels., (© 2022. The Author(s).)

Emerging ice-sheet modeling suggests once initiated, retreat of the Antarctic Ice Sheet (AIS) can continue for centuries. Unfortunately, the short observational record cannot resolve the tipping points, rate of change, and timescale of responses. Iceberg-rafted debris data from Iceberg Alley identify eight retreat phases after the Last Glacial Maximum that each destabilized the AIS within a decade, contributing to global sea-level rise for centuries to a millennium, which subsequently re-stabilized equally rapidly. This dynamic response of the AIS is supported by (i) a West Antarctic blue ice record of ice-elevation drawdown >600 m during three such retreat events related to globally recognized deglacial meltwater pulses, (ii) step-wise retreat up to 400 km across the Ross Sea shelf, (iii) independent ice sheet modeling, and (iv) tipping point analysis. Our findings are consistent with a growing body of evidence suggesting the recent acceleration of AIS mass loss may mark the beginning of a prolonged period of ice sheet retreat and substantial global sea level rise., (© 2021. The Author(s).)

The ATP hydrolysis transition state of motor proteins is a weakly populated protein state that can be stabilized and investigated by replacing ATP with chemical mimics. We present atomic-level structural and dynamic insights on a state created by ADP aluminum fluoride binding to the bacterial DnaB helicase from Helicobacter pylori. We determined the positioning of the metal ion cofactor within the active site using electron paramagnetic resonance, and identified the protein protons coordinating to the phosphate groups of ADP and DNA using proton-detected 31 P, 1 H solid-state nuclear magnetic resonance spectroscopy at fast magic-angle spinning > 100 kHz, as well as temperature-dependent proton chemical-shift values to prove their engagements in hydrogen bonds. 19 F and 27 Al MAS NMR spectra reveal a highly mobile, fast-rotating aluminum fluoride unit pointing to the capture of a late ATP hydrolysis transition state in which the phosphoryl unit is already detached from the arginine and lysine fingers., (© 2021. The Author(s).)

Progress in NMR in general and in biomolecular applications in particular is driven by increasing magnetic-field strengths leading to improved resolution and sensitivity of the NMR spectra. Recently, persistent superconducting magnets at a magnetic field strength (magnetic induction) of 28.2 T corresponding to 1200 MHz proton resonance frequency became commercially available. We present here a collection of high-field NMR spectra of a variety of proteins, including molecular machines, membrane proteins, viral capsids, fibrils and large molecular assemblies. We show this large panel in order to provide an overview over a range of representative systems under study, rather than a single best performing model system. We discuss both carbon-13 and proton-detected experiments, and show that in 13 C spectra substantially higher numbers of peaks can be resolved compared to 850 MHz while for 1 H spectra the most impressive increase in resolution is observed for aliphatic side-chain resonances., (© 2021. The Author(s).)

The highly infectious disease COVID-19 caused by the Betacoronavirus SARS-CoV-2 poses a severe threat to humanity and demands the redirection of scientific efforts and criteria to organized research projects. The international COVID19-NMR consortium seeks to provide such new approaches by gathering scientific expertise worldwide. In particular, making available viral proteins and RNAs will pave the way to understanding the SARS-CoV-2 molecular components in detail. The research in COVID19-NMR and the resources provided through the consortium are fully disclosed to accelerate access and exploitation. NMR investigations of the viral molecular components are designated to provide the essential basis for further work, including macromolecular interaction studies and high-throughput drug screening. Here, we present the extensive catalog of a holistic SARS-CoV-2 protein preparation approach based on the consortium's collective efforts. We provide protocols for the large-scale production of more than 80% of all SARS-CoV-2 proteins or essential parts of them. Several of the proteins were produced in more than one laboratory, demonstrating the high interoperability between NMR groups worldwide. For the majority of proteins, we can produce isotope-labeled samples of HSQC-grade. Together with several NMR chemical shift assignments made publicly available on covid19-nmr.com , we here provide highly valuable resources for the production of SARS-CoV-2 proteins in isotope-labeled form., Competing Interests: CH was employed by Signals GmbH & Co. KG. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Altincekic, Korn, Qureshi, Dujardin, Ninot-Pedrosa, Abele, Abi Saad, Alfano, Almeida, Alshamleh, de Amorim, Anderson, Anobom, Anorma, Bains, Bax, Blackledge, Blechar, Böckmann, Brigandat, Bula, Bütikofer, Camacho-Zarco, Carlomagno, Caruso, Ceylan, Chaikuad, Chu, Cole, Crosby, de Jesus, Dhamotharan, Felli, Ferner, Fleischmann, Fogeron, Fourkiotis, Fuks, Fürtig, Gallo, Gande, Gerez, Ghosh, Gomes-Neto, Gorbatyuk, Guseva, Hacker, Häfner, Hao, Hargittay, Henzler-Wildman, Hoch, Hohmann, Hutchison, Jaudzems, Jović, Kaderli, Kalniņš, Kaņepe, Kirchdoerfer, Kirkpatrick, Knapp, Krishnathas, Kutz, zur Lage, Lambertz, Lang, Laurents, Lecoq, Linhard, Löhr, Malki, Bessa, Martin, Matzel, Maurin, McNutt, Mebus-Antunes, Meier, Meiser, Mompeán, Monaca, Montserret, Mariño Perez, Moser, Muhle-Goll, Neves-Martins, Ni, Norton-Baker, Pierattelli, Pontoriero, Pustovalova, Ohlenschläger, Orts, Da Poian, Pyper, Richter, Riek, Rienstra, Robertson, Pinheiro, Sabbatella, Salvi, Saxena, Schulte, Schiavina, Schwalbe, Silber, Almeida, Sprague-Piercy, Spyroulias, Sreeramulu, Tants, Tārs, Torres, Töws, Treviño, Trucks, Tsika, Varga, Wang, Weber, Weigand, Wiedemann, Wirmer-Bartoschek, Wirtz Martin, Zehnder, Hengesbach and Schlundt.)

The Hepatitis C virus nonstructural protein 5A (NS5A) is a membrane-associated protein involved in multiple steps of the viral life cycle. Direct-acting antivirals (DAAs) targeting NS5A are a cornerstone of antiviral therapy, but the mode-of-action of these drugs is poorly understood. This is due to the lack of information on the membrane-bound NS5A structure. Herein, we present the structural model of an NS5A AH-linker-D1 protein reconstituted as proteoliposomes. We use highly sensitive proton-detected solid-state NMR methods suitable to study samples generated through synthetic biology approaches. Spectra analyses disclose that both the AH membrane anchor and the linker are highly flexible. Paramagnetic relaxation enhancements (PRE) reveal that the dimer organization in lipids requires a new type of NS5A self-interaction not reflected in previous crystal structures. In conclusion, we provide the first characterization of NS5A AH-linker-D1 in a lipidic environment shedding light onto the mode-of-action of clinically used NS5A inhibitors., (© 2020 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Sea-level rise due to ice loss in the Northern Hemisphere in response to insolation and greenhouse gas forcing is thought to have caused grounding-line retreat of marine-based sectors of the Antarctic Ice Sheet (AIS) 1-3 . Such interhemispheric sea-level forcing may explain the synchronous evolution of global ice sheets over ice-age cycles. Recent studies that indicate that the AIS experienced substantial millennial-scale variability during and after the last deglaciation 4-7 (roughly 20,000 to 9,000 years ago) provide further evidence of this sea-level forcing. However, global sea-level change as a result of mass loss from ice sheets is strongly nonuniform, owing to gravitational, deformational and Earth rotational effects 8 , suggesting that the response of AIS grounding lines to Northern Hemisphere sea-level forcing is more complicated than previously modelled 1,2,6 . Here, using an ice-sheet model coupled to a global sea-level model, we show that AIS dynamics are amplified by Northern Hemisphere sea-level forcing. As a result of this interhemispheric interaction, a large or rapid Northern Hemisphere sea-level forcing enhances grounding-line advance and associated mass gain of the AIS during glaciation, and grounding-line retreat and mass loss during deglaciation. Relative to models without these interactions, the inclusion of Northern Hemisphere sea-level forcing in our model increases the volume of the AIS during the Last Glacial Maximum (about 26,000 to 20,000 years ago), triggers an earlier retreat of the grounding line and leads to millennial-scale variability throughout the last deglaciation. These findings are consistent with geologic reconstructions of the extent of the AIS during the Last Glacial Maximum and subsequent ice-sheet retreat, and with relative sea-level change in Antarctica 3-7,9,10 .

RNA helicases of the DEAH/RHA family are involved in many essential cellular processes, such as splicing or ribosome biogenesis, where they remodel large RNA-protein complexes to facilitate transitions to the next intermediate. DEAH helicases couple adenosine triphosphate (ATP) hydrolysis to conformational changes of their catalytic core. This movement results in translocation along RNA, which is held in place by auxiliary C-terminal domains. The activity of DEAH proteins is strongly enhanced by the large and diverse class of G-patch activators. Despite their central roles in RNA metabolism, insight into the molecular basis of G-patch-mediated helicase activation is missing. Here, we have solved the structure of human helicase DHX15/Prp43, which has a dual role in splicing and ribosome assembly, in complex with the G-patch motif of the ribosome biogenesis factor NKRF. The G-patch motif binds in an extended conformation across the helicase surface. It tethers the catalytic core to the flexibly attached C-terminal domains, thereby fixing a conformation that is compatible with RNA binding. Structures in the presence or absence of adenosine diphosphate (ADP) suggest that motions of the catalytic core, which are required for ATP binding, are still permitted. Concomitantly, RNA affinity, helicase, and ATPase activity of DHX15 are increased when G-patch is bound. Mutations that detach one end of the tether but maintain overall binding severely impair this enhancement. Collectively, our data suggest that the G-patch motif acts like a flexible brace between dynamic portions of DHX15 that restricts excessive domain motions but maintains sufficient flexibility for catalysis., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

The future response of the Antarctic ice sheet to rising temperatures remains highly uncertain. A useful period for assessing the sensitivity of Antarctica to warming is the Last Interglacial (LIG) (129 to 116 ky), which experienced warmer polar temperatures and higher global mean sea level (GMSL) (+6 to 9 m) relative to present day. LIG sea level cannot be fully explained by Greenland Ice Sheet melt (∼2 m), ocean thermal expansion, and melting mountain glaciers (∼1 m), suggesting substantial Antarctic mass loss was initiated by warming of Southern Ocean waters, resulting from a weakening Atlantic meridional overturning circulation in response to North Atlantic surface freshening. Here, we report a blue-ice record of ice sheet and environmental change from the Weddell Sea Embayment at the periphery of the marine-based West Antarctic Ice Sheet (WAIS), which is underlain by major methane hydrate reserves. Constrained by a widespread volcanic horizon and supported by ancient microbial DNA analyses, we provide evidence for substantial mass loss across the Weddell Sea Embayment during the LIG, most likely driven by ocean warming and associated with destabilization of subglacial hydrates. Ice sheet modeling supports this interpretation and suggests that millennial-scale warming of the Southern Ocean could have triggered a multimeter rise in global sea levels. Our data indicate that Antarctica is highly vulnerable to projected increases in ocean temperatures and may drive ice-climate feedbacks that further amplify warming., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

The deployment of small unmanned aircraft systems (UAS) to collect routine in situ vertical profiles of the thermodynamic and kinematic state of the atmosphere in conjunction with other weather observations could significantly improve weather forecasting skill and resolution. High-resolution vertical measurements of pressure, temperature, humidity, wind speed and wind direction are critical to the understanding of atmospheric boundary layer processes integral to air-surface (land, ocean and sea ice) exchanges of energy, momentum, and moisture; how these are affected by climate variability; and how they impact weather forecasts and air quality simulations. We explore the potential value of collecting coordinated atmospheric profiles at fixed surface observing sites at designated times using instrumented UAS. We refer to such a network of autonomous weather UAS designed for atmospheric profiling and capable of operating in most weather conditions as a 3D Mesonet. We outline some of the fundamental and high-impact science questions and sampling needs driving the development of the 3D Mesonet and offer an overview of the general concept of operations. Preliminary measurements from profiling UAS are presented and we discuss how measurements from an operational network could be realized to better characterize the atmospheric boundary layer, improve weather forecasts, and help to identify threats of severe weather.

Cardiotonic steroids (CTS) are Na⁺/K⁺-ATPase (NKA) ligands that are elevated in volume-expanded states and associated with cardiac and renal dysfunction in both clinical and experimental settings. We test the hypothesis that the CTS telocinobufagin (TCB) promotes renal dysfunction in a process involving signaling through the NKA α-1 in the following studies. First, we infuse TCB (4 weeks at 0.1 µg/g/day) or a vehicle into mice expressing wild-type (WT) NKA α-1, as well as mice with a genetic reduction (~40%) of NKA α-1 (NKA α-1 +/- ). Continuous TCB infusion results in increased proteinuria and cystatin C in WT mice which are significantly attenuated in NKA α-1 +/- mice (all p < 0.05), despite similar increases in blood pressure. In a series of in vitro experiments, 24-h treatment of HK2 renal proximal tubular cells with TCB results in significant dose-dependent increases in both Collagens 1 and 3 mRNA (2-fold increases at 10 nM, 5-fold increases at 100 nM, p < 0.05). Similar effects are seen in primary human renal mesangial cells. TCB treatment (100 nM) of SYF fibroblasts reconstituted with cSrc results in a 1.5-fold increase in Collagens 1 and 3 mRNA ( p < 0.05), as well as increases in both Transforming Growth factor beta (TGFb, 1.5 fold, p < 0.05) and Connective Tissue Growth Factor (CTGF, 2 fold, p < 0.05), while these effects are absent in SYF cells without Src kinase. In a patient study of subjects with chronic kidney disease, TCB is elevated compared to healthy volunteers. These studies suggest that the pro-fibrotic effects of TCB in the kidney are mediated though the NKA-Src kinase signaling pathway and may have relevance to volume-overloaded conditions, such as chronic kidney disease where TCB is elevated.

The western Indian Ocean has been warming faster than any other tropical ocean during the 20 th century, and is the largest contributor to the global mean sea surface temperature (SST) rise. However, the temporal pattern of Indian Ocean warming is poorly constrained and depends on the historical SST product. As all SST products are derived from the International Comprehensive Ocean-Atmosphere dataset (ICOADS), it is challenging to evaluate which product is superior. Here, we present a new, independent SST reconstruction from a set of Porites coral geochemical records from the western Indian Ocean. Our coral reconstruction shows that the World War II bias in the historical sea surface temperature record is the main reason for the differences between the SST products, and affects western Indian Ocean and global mean temperature trends. The 20 th century Indian Ocean warming pattern portrayed by the corals is consistent with the SST product from the Hadley Centre (HadSST3), and suggests that the latter should be used in climate studies that include Indian Ocean SSTs. Our data shows that multi-core coral temperature reconstructions help to evaluate the SST products. Proxy records can provide estimates of 20 th century SST that are truly independent from the ICOADS data base.

Reconstructing the dynamic response of the Antarctic ice sheets to warming during the Last Glacial Termination (LGT; 18,000-11,650 yrs ago) allows us to disentangle ice-climate feedbacks that are key to improving future projections. Whilst the sequence of events during this period is reasonably well-known, relatively poor chronological control has precluded precise alignment of ice, atmospheric and marine records, making it difficult to assess relationships between Antarctic ice-sheet (AIS) dynamics, climate change and sea level. Here we present results from a highly-resolved 'horizontal ice core' from the Weddell Sea Embayment, which records millennial-scale AIS dynamics across this extensive region. Counterintuitively, we find AIS mass-loss across the full duration of the Antarctic Cold Reversal (ACR; 14,600-12,700 yrs ago), with stabilisation during the subsequent millennia of atmospheric warming. Earth-system and ice-sheet modelling suggests these contrasting trends were likely Antarctic-wide, sustained by feedbacks amplified by the delivery of Circumpolar Deep Water onto the continental shelf. Given the anti-phase relationship between inter-hemispheric climate trends across the LGT our findings demonstrate that Southern Ocean-AIS feedbacks were controlled by global atmospheric teleconnections. With increasing stratification of the Southern Ocean and intensification of mid-latitude westerly winds today, such teleconnections could amplify AIS mass loss and accelerate global sea-level rise.

Proxy-based indicators of past climate change show that current global climate models systematically underestimate Holocene-epoch climate variability on centennial to multi-millennial timescales, with the mismatch increasing for longer periods. Proposed explanations for the discrepancy include ocean-atmosphere coupling that is too weak in models, insufficient energy cascades from smaller to larger spatial and temporal scales, or that global climate models do not consider slow climate feedbacks related to the carbon cycle or interactions between ice sheets and climate. Such interactions, however, are known to have strongly affected centennial- to orbital-scale climate variability during past glaciations, and are likely to be important in future climate change. Here we show that fluctuations in Antarctic Ice Sheet discharge caused by relatively small changes in subsurface ocean temperature can amplify multi-centennial climate variability regionally and globally, suggesting that a dynamic Antarctic Ice Sheet may have driven climate fluctuations during the Holocene. We analysed high-temporal-resolution records of iceberg-rafted debris derived from the Antarctic Ice Sheet, and performed both high-spatial-resolution ice-sheet modelling of the Antarctic Ice Sheet and multi-millennial global climate model simulations. Ice-sheet responses to decadal-scale ocean forcing appear to be less important, possibly indicating that the future response of the Antarctic Ice Sheet will be governed more by long-term anthropogenic warming combined with multi-centennial natural variability than by annual or decadal climate oscillations.

Our understanding of the deglacial evolution of the Antarctic Ice Sheet (AIS) following the Last Glacial Maximum (26,000-19,000 years ago) is based largely on a few well-dated but temporally and geographically restricted terrestrial and shallow-marine sequences. This sparseness limits our understanding of the dominant feedbacks between the AIS, Southern Hemisphere climate and global sea level. Marine records of iceberg-rafted debris (IBRD) provide a nearly continuous signal of ice-sheet dynamics and variability. IBRD records from the North Atlantic Ocean have been widely used to reconstruct variability in Northern Hemisphere ice sheets, but comparable records from the Southern Ocean of the AIS are lacking because of the low resolution and large dating uncertainties in existing sediment cores. Here we present two well-dated, high-resolution IBRD records that capture a spatially integrated signal of AIS variability during the last deglaciation. We document eight events of increased iceberg flux from various parts of the AIS between 20,000 and 9,000 years ago, in marked contrast to previous scenarios which identified the main AIS retreat as occurring after meltwater pulse 1A and continuing into the late Holocene epoch. The highest IBRD flux occurred 14,600 years ago, providing the first direct evidence for an Antarctic contribution to meltwater pulse 1A. Climate model simulations with AIS freshwater forcing identify a positive feedback between poleward transport of Circumpolar Deep Water, subsurface warming and AIS melt, suggesting that small perturbations to the ice sheet can be substantially enhanced, providing a possible mechanism for rapid sea-level rise.

The intricacy of multiple feedback loops in the pathways downstream of Akt allows this kinase to control multiple cellular processes in the cardiovascular system and precludes inferring consequences of its activation in specific pathological conditions. Akt1, the major Akt isoform in the heart and vasculature, has a protective role in the endothelium during atherosclerosis. However, Akt1 activation may also have detrimental consequences in the cardiovascular system. Mice lacking both the high-density lipoprotein receptor SR-BI (scavenger receptor class B type I) and ApoE (apolipoprotein E), which promotes clearance of remnant lipoproteins, are a model of severe dyslipidemia and spontaneous myocardial infarction. We found that Akt1 was activated in these mice, and this activation correlated with cardiac dysfunction, hypertrophy, and fibrosis; increased infarct area; cholesterol accumulation in macrophages and atherosclerosis; and reduced life span. Akt1 activation was associated with inflammation, oxidative stress, accumulation of oxidized lipids, and increased abundance of CD36, a major sensor of oxidative stress, and these events created a positive feedback loop that exacerbated the consequences of oxidative stress. Genetic deletion of Akt1 in this mouse model resulted in decreased mortality, alleviation of multiple complications of heart disease, and reduced occurrence of spontaneous myocardial infarction. Thus, interference with Akt1 signaling in vivo could be protective and improve survival under dyslipidemic conditions by reducing oxidative stress and responses to oxidized lipids.

We demonstrate a simplified approach toward active polarization control in coherently combined laser architectures. By leveraging optical phase dithers applied by a phase controller, polarization error signals are generated for an entire laser array from a single beam sample of the combined output, enabling closed-loop polarization locking of non-polarization-maintaining fibers. The concept is shown to be compatible with both hill-climbing and synchronous multidither phase control methods. Simultaneous phase locking and polarization locking was demonstrated for a five-fiber array with >99% phasing efficiency and >20 dB polarization extinction ratio.

Objectives: Intraoral exposure to dental restorations can cause contact allergy that may induce carcinogenesis. We investigated the relationship of intraoral metal contact allergy to epithelial carcinogenesis., Methods: The prevalence of positive patch test reactions to dental restoration metals in 65 prospectively enrolled patients with newly or previously diagnosed oral squamous cell carcinoma (SCC) was compared to that in 48 control patients. The relative risk of oral SCC was estimated by calculating odds ratios for exposure to dental metals resulting in allergy., Results: Of the 65 patients with oral SCC, 34% were allergic to at least 1 adjacent metal. They were 1.57 times as likely as control patients to have metal contact allergy (odds ratio, 1.57; 95% confidence interval, 0.65 to 3.80) and more than 3 times as likely to react to mercury (odds ratio, 3.20; 95% confidence interval, 0.42 to 33.20)., Conclusions: Patients with oral SCC who have metal dental restorations should undergo patch testing and possible removal of the restorations if their reactions are positive.

We demonstrate a method for single-detector coherent sensing and automated coalignment of group delays in a coherently combined laser array, enabling robust coherent combining of broadband sources despite initial path mismatches exceeding the laser coherence length. The method is based on Fourier-domain filtering of the coherently combined laser beam to extract error signals, and it is equally applicable to controlling both spatial and temporal misalignments.

Integrins mediate cell adhesion, migration, and survival by connecting intracellular machinery with the surrounding extracellular matrix. Previous studies demonstrated the importance of the interaction between β(3) integrin and VEGF type 2 receptor (VEGFR2) in VEGF-induced angiogenesis. Here we present in vitro evidence of the direct association between the cytoplasmic tails (CTs) of β(3) and VEGFR2. Specifically, the membrane-proximal motif around (801)YLSI in VEGFR2 mediates its binding to non-phosphorylated β(3)CT, accommodating an α-helical turn in integrin bound conformation. We also show that Y(747) phosphorylation of β(3) enhances the above interaction. To demonstrate the importance of β(3) phosphorylation in endothelial cell functions, we synthesized β(3)CT-mimicking Y(747) phosphorylated and unphosphorylated membrane permeable peptides. We show that a peptide containing phospho-Y(747) but not F(747) significantly inhibits VEGF-induced signaling and angiogenesis. Moreover, phospho-Y(747) peptide exhibits inhibitory effect only in WT but not in β(3) integrin knock-out or β(3) integrin knock-in cells expressing β(3) with two tyrosines substituted for phenylalanines, demonstrating its specificity. Importantly, these peptides have no effect on fibroblast growth factor receptor signaling. Collectively these data provide novel mechanistic insights into phosphorylation dependent cross-talk between integrin and VEGFR2.

The timing of the last maximum extent of the Antarctic ice sheets relative to those in the Northern Hemisphere remains poorly understood. We develop a chronology for the Weddell Sea sector of the East Antarctic Ice Sheet that, combined with ages from other Antarctic ice-sheet sectors, indicates that the advance to and retreat from their maximum extent was within dating uncertainties synchronous with most sectors of Northern Hemisphere ice sheets. Surface climate forcing of Antarctic mass balance would probably cause an opposite response, whereby a warming climate would increase accumulation but not surface melting. Our new data support teleconnections involving sea-level forcing from Northern Hemisphere ice sheets and changes in North Atlantic deep-water formation and attendant heat flux to Antarctic grounding lines to synchronize the hemispheric ice sheets.

A three-stage Yb-fiber amplifier emitted 1.43 kW of single-mode power when seeded with a 25 GHz linewidth master oscillator (MO). The amplified output was polarization stabilized and phase locked using active heterodyne phase control. A low-power sample of the output beam was coherently combined to a second fiber amplifier with 90% visibility. The measured combining efficiency agreed with estimated decoherence effects from fiber nonlinearity, linewidth, and phase-locking accuracy. This is the highest-power fiber laser that has been coherently locked using any method that allows brightness scaling.

Background: The study was conducted to evaluate ethinyl estradiol (EE) or ibuprofen (IBU) compared to placebo (PL) on spotting and bleeding (S/B) and a postcoital test (PCT) in women using the levonorgestrel subcutaneous implant. Women experiencing excessive S/B were enrolled in a multicenter prospective randomized study using EE, IBU or PL., Outcome Measures: Duration of S/B and a PCT were evaluated. Statistical analysis used a general linear model procedure with Duncan's multiple range tests for individual variables., Results: One hundred seven women were evaluated, and there was no difference in the duration of bleeding among the three therapies, while the mean number of spotting days were 1.8 for EE and 2.8 for PL (p=.04). There was no effect of IBU on S/B. No effect on cervical mucus or sperm was found between treatments., Conclusion: There was a decrease in spotting but no effect on bleeding with EE compared to PL.

Batch and column biosorption of La(3+) (lanthanum) and Eu(3+) (europium) was studied using protonated Sargassum polycystum biomass. The ion exchange sorption mechanism was confirmed by the proportional release of protons and by the total normality of the solution, which remained constant during the process. Equilibrium isotherms were determined for the binary systems, La/H and Eu/H for a total normality of 3 meq g(-1), which produced separation factors of 2.7 and 4.7, respectively, demonstrating a higher affinity of the biomass towards europium. Column runs with a single metal feed were used to estimate the intra-particle mass transfer coefficients for La and Eu (6.0 x 10(-4) and 3.7 x 10(-4) min(-1), respectively). Modeling batch and column binary systems with proton as the common ion was able to predict reasonably well the behavior of a ternary system containing protons. The software FEMLAB was used for solving the set of coupled partial differential equations. Moreover, a series of consecutive sorption/desorption runs demonstrated that the metal could be recovered and the biomass reused in multiple cycles by using 0.1N HCl with no apparent loss in the biosorbent metal uptake capacity.

A suite of synthetic hydraphile ion channels has been used to probe the possibility of cation-pi interactions between the channel and the phospholipid bilayer. The hydraphiles selected for this study contained either no sidearm, aliphatic sidearms or aromatic sidearms that varied in electron-richness. An ion selective electrode (ISE) method was used to evaluate the ion transport ability of these hydraphiles across synthetic bilayers. Transport was dependent on sidearm identity. Ion transport activity for the aromatic sidechained compounds was greatest when the sidearms were electron rich and vesicles were prepared from 100% DOPC (trimethylammonium cation headgroup, overall neutral). When the lipid headgroups were made more negative by changing the composition from DOPC to 70 : 30 (w/w) DOPC : DOPA, transport by the aromatic-sidechained channels was reduced. Fluorescence studies showed that when the lipid composition changed, the headgroups experienced a different polarity, suggesting reorientation. The data are in accord with a stabilizing cation-pi interaction between the aromatic sidearm of the hydraphile channel and the ammonium phospholipid headgroup.

Hydraphile compounds have been prepared in which certain of the amine nitrogens have been replaced by amide residues. The amide bonds are present either in the sidearm, the side chain, or the central relay. Sodium cation transport through phospholipid vesicles mediated by each hydraphile was assessed. All of the amide-containing hydraphiles showed increased levels of Na(+) transport compared to the parent compound, but the most dramatic rate increase was observed for sidearm amine to amide replacement. We attribute this enhancement to stabilization of the sidearm in the bilayer to achieve a better conformation for ion conduction. Biological studies of the amide hydraphiles with E. coli and B. subtilis showed significant toxicity only with the latter. Further, the consistency between the efficacies of ion transport and toxicity previously observed for non-amidic hydraphiles was not in evidence.

Purpose: To compare the efficacy and safety of diclofenac sodium 0.1% eyedrops packaged in an Abak multidose container without preservative (Dicloabak) with the reference product, sodium merthiolate-preserved diclofenac sodium 0.1% eyedrops, in controlling postoperative inflammation after cataract surgery., Methods: The multicenter, controlled, randomized, single-masked study included 194 patients (Dicloabak 96, preserved diclofenac 98) scheduled to have cataract surgery by phacoemulsification with foldable intraocular lens. All were evaluated preoperatively and postoperatively after 1, 7, and 28 days. Postoperative inflammation was measured by the total score of anterior chamber cells and flare. Ocular plin, conjunctival hyperemia and ciliary flush were also assessed. Postoperative patient assessments also included visual acuity, objective tolerance by slit-lamp, fluorescein test, and subjective evaluation of local tolerance., Results: There was no statistically significant difference between the groups in the total score of flare and cells or the degree of conjunctival hyperemia and ciliary flush at any study visit. Dicloabak was demonstrated to be not inferior to preserved diclofenac at all assessment times. The overall assessment of local tolerance was similar for both study medications., Conclusions: Preservative suppression did not alter diclofenac efficacy. Results support the good safety profile of both formulations when dosed three times daily for 4 weeks in absence of concomitant use of drugs potentially toxic for cornea. Preservative-free formulations like Dicloabak should be preferred to generic diclofenac formulations including other ingredients and may improve the safety profile of this topical nonsteroid anti-inflammatory drug.

Dialkyldiaza-18-crown-6 lariat ethers having twin n-octyl, n-decyl, n-dodecyl, n-tetradecyl, n-hexadecyl, 1-oxodecyl and 1-oxododecyl side arms were prepared and studied. Cation transport in liposomes mediated by these compounds showed discontinuous activity that correlated with toxicity to the bacteria E. coli and B. Subtilis, and the yeast S. Cerevisiae. Transport, toxicity and membrane depolarization studies all suggest that side chain length affords very different interactions in a bilayer membrane compared with bulk phases. An explanation for activity in terms of carrier transport and restricted transverse relaxation is proposed.

A small library of hydraphiles has been prepared that incorporates either 1,4-phenylenedioxy or 2,6-naphthalenedioxy within the spacer chains. The side chains attached to the distal macrocycles in these tris(macrocyclic) compounds are either n-dodecyl or benzyl. The presence of the arenes subunits significantly affect sodium cation release from vesicles. The efficacy of ion transport is paralleled by the toxicity of these compounds to Bacillus subtilis.

A library of "hydraphile" synthetic ion channel analogues that differ in overall length from approximately 28-58 A has been prepared. A new and convenient ion-selective electrode (ISE) method was used to assay Na(+) release. Liposomes were formed from three different phospholipids: 1,2-dimyristoleoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), and 1,2-dierucoyl-sn-glycero-3-phosphocholine (DEPC). The acyl chains of the lipids comprise cis-unsaturated 14:1, 18:1, or 22:1 residues, respectively. Sodium release was measured for each liposome system with each of the synthetic channels. Peak activity was observed for shorter channels in liposomes formed from DMPC and for longer channels in DEPC. A separate study was then conducted in DMPC liposomes in the presence of the putative membrane-thickening agents cholesterol and decane. Peak activity was clearly shifted to longer channel lengths upon addition of 20 or 40 mol % cholesterol or n-decane to the liposome preparation.

Previous sodium ion transport results obtained by NMR methods are compared with those obtained by a new ISE technique and are found to correlate well with each other and with the biological activity against E. coli and B. subtilis.

The synthetic peptide, R(2)N-COCH(2)OCH(2)CO-Gly-Gly-Gly-Pro-Gly-Gly-Gly-OR', was shown to be selective for Cl(-) over K(+) when R is n-octadecyl and R' is benzyl. Nineteen heptapeptides have now been prepared in which the N-terminal and C-terminal residues have been varied. All of the N-terminal residues are dialkyl but the C-terminal chains are esters, 2 degrees amides, or 3 degrees amides. The compounds having varied N-terminal anchors and C-terminal benzyl groups are as follows: 1, R = n-propyl; 2, R = n-hexyl; 3, R = n-octyl; 4, R = n-decyl; 5, R = n-dodecyl; 6, R = n-tetradecyl; 7, R = n-hexadecyl; 8, R = n-octadecyl. Compounds 9-19 have R = n-octadecyl and C-terminal residues as follows: 9, OR' = OCH(2)CH(3); 10, OR' = OCH(CH(3))(2); 11, OR' = O(CH(2))(6)CH(3); 12, OR' = OCH(2)-c-C(6)H(11); 13, OR' = O(CH(2))(9)CH(3); 14, OR' = O (CH(2))(17)CH(3); 15, NR'(2) = N[(CH(2))(6)CH(3)](2); 16, NHR' = NH(CH(2))(9)CH(3); 17, NR'(2) = N[(CH(2))(9)CH(3)](2); 18, NHR' = NH(CH(2))(17)CH(3); 19, NR'(2) = N[(CH(2))(17)CH(3)](2). The highest anion transport activities were observed as follows. For the benzyl esters whose N-terminal residues were varied, i.e.1-8, compound 3 was most active. For the C(18) anchored esters 10-14, n-heptyl ester 11 was most active. For the C(18) anchored, C-terminal amides 15-19, di-n-decylamide 17 was most active. It was concluded that both the C- and N-terminal anchors were important for channel function in the bilayer but that activity was lost unless only one of the two anchoring groups was dominant.

The selective precipitation of xylanase from an aqueous phase containing mixtures of xylanase and cellulase was studied using an ionic surfactant as precipitating ligand and a polar organic solvent as recovery solvent. Of four ionic surfactants tested, sodium di-(2-ethylhexyl) sulfosuccinate (AOT) showed a complete removal of xylanase at pH 4.5. The recovery of xylanase from the xylanase-AOT complex was a strong function of the type and the volume of the polar solvent and of the concentration of sodium acetate buffer in the final aqueous solution used to solubilize the recovered xylanase. With ethanol as a recovery solvent, a recovery of xylanase activity of 78 +/- 10% was obtained. The cellulase activity in the recovered xylanase was below the detection limit. The results demonstrate that an ionic surfactant can recover enzymes from aqueous solutions without loss in their activity., (Copyright 2004 Wiley Periodicals, Inc.)

Gallium was removed selectively from aqueous solutions containing zinc or aluminum using sodium di-(n-octyl) phosphinate as a ligand (NaL). At low pH or low mole ratios, the gallium was removed by complexation with the ligand as GaL(3(S)), while the zinc or the aluminum remained in the solution. Nearly complete separation of gallium was obtained. By increasing the amount of ligand or by increasing the pH, the zinc or aluminum remaining in the solution was then removed as a solid complex: ZnL(2(S)) or AlL(3(S)), respectively. At a pH between 1.5 and 2 and a mole ratio ligand to total metals of 0.75 for zinc solutions and 1.0 for aluminum solutions, more than 98% of the gallium was selectively removed with a high molar selectivity, alpha(Ga/Zn) and alpha(Ga/Al), respectively. Over 95% of gallium was recovered from the solid GaL(3(S)) complex by treatment of the complex with a 3M NaOH solution and diethyl ether. The gallium was concentrated in the aqueous solution to 4 times its initial concentration and the ligand was extracted into the ether phase. After evaporation of the ether, 95% of the ligand was regenerated in its sodium form as a solid.