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We study a parameter estimation problem which arises from measurements with QUANTOM, a measurement facility utilizing Prompt-Gamma Neutron Activation Analysis (PGNAA) to analyze elemental masses in 200-l nuclear waste drums. The presence of neutron flux measurements in QUANTOM offers additional information for elemental composition reconstruction, motivating an alternative to the standard iterative approach. Therefore, the measurement is modelled using approximate models for neutron and photon transport. We introduce a mathematical formulation for solving the resulting parameter estimation problem of QUANTOM measurements and employ an adjoint-based method to determine the elemental composition. Uniqueness of solutions in this context is studied, and the results offer novel insights for PGNAA applications.

The Skagerrak basin represents the main sink area for fine-grained sediment in the North Sea region and constitutes a natural deposition center for sediments that are supplied from the Atlantic, the Baltic Sea and the surrounding continental margins and coasts. However, the exact sources and their proportional contributions to the North Sea sediments and to the Skagerrak deposits are not well understood. To trace the predominant sources of the sediment and to gain a better understanding of the sedimentary processes in the North Sea and the Skagerrak basin, radiogenic Sr, Nd, and Hf isotope signatures and clay mineral compositions of the detrital clay fraction of surface sediment samples from the North Sea, the Scandinavian margins and the Baltic Sea were measured. The results indicate that the major source for Skagerrak clay-size sediments is the northern North Sea but Scandinavia as well as the southern North Sea including the southern England coast also contribute material. Seabed and coastal erosion in the northern North Sea are enhanced by the inflowing Atlantic Currents, which provide the Skagerrak with high amounts of clay size sediments. In contrast, the southern North Sea, the Baltic Sea and mid-European rivers such as Weser, Elbe and Ems are only minor contributors. As Skagerrak deposits are dominated by clay sized material (up to 60%), the reconstructed sediment processes in this study deviate from findings in previous sediment budget studies, which were based on both clay and silt fraction and indicated predominant influences from the southern North Sea. These results highlight that coastal and seabed erosion in the North Sea is a previously underestimated source of fine-grained sediments for depocenters in the entire North Sea. With regard to climate change, the global sea-level rise will likely enhance erosional processes and can therefore significantly influence the sediment budget of the entire North Sea.

Glycosaminoglycans (GAGs) play a key role in a variety of biological processes in the extracellular matrix (ECM) via interactions with their protein targets. Due to their high flexibility, periodicity and electrostatics-driven interactions, GAG-containing complexes are very challenging to characterize both experimentally and in silico. In this study, we, for the first time, systematically analyzed the interactions of endostatin, a proteolytic fragment of collagen XVIII known to be anti-angiogenic and anti-tumoral, with heparin (HP) and representative heparan sulfate (HS) oligosaccharides of various lengths, sequences and sulfation patterns. We first used conventional molecular docking and a docking approach based on a repulsive scaling–replica exchange molecular dynamics technique, as well as unbiased molecular dynamic simulations, to obtain dynamically stable GAG binding poses. Then, the corresponding free energies of binding were calculated and the amino acid residues that contribute the most to GAG binding were identified. We also investigated the potential influence of Zn2+ on endostatin–HP complexes using computational approaches. These data provide new atomistic details of the molecular mechanism of HP’s binding to endostatin, which will contribute to a better understanding of its interplay with proteoglycans at the cell surface and in the extracellular matrix.

Abstract The Amazon River accounts for 20% of global freshwater runoff and supplies vital trace metals to the Atlantic Ocean. Suspended particles within its plume are thought to partially dissolve, constituting a large potential source of metals, which is, however, not well constrained. Here we used combined neodymium (Nd) and hafnium (Hf) isotopes to disprove the release of Nd and Hf from particles as the cause of the observed dissolved concentration increases and isotopic variability across the plume. Instead, the changes reflect admixture of nearby Pará River freshwater with exceptionally high dissolved Nd and Hf concentrations contributing 45–100% of the riverine fraction to the southern and outer estuary. This result led us to develop an empirical relationship between riverine Nd concentration and pH to revise the global dissolved riverine Nd flux, which accordingly is at least three times higher than commonly used estimates. Future work should focus on contributions of low-pH rivers to global metal fluxes.

ABSTRACTAs small and stable high-affinity antigen binders, VHHs boast attractive characteristics both for therapeutic use in various disease indications, and as versatile reagents in research and diagnostics. To further increase the versatility of VHHs, we explored the VHH scaffold in a structure-guided approach to select regions where the introduction of an N-glycosylation N-X-T sequon and its associated glycan should not interfere with protein folding or epitope recognition. We expressed variants of such glycoengineered VHHs in the Pichia pastoris GlycoSwitchM5 strain, allowing us to pinpoint preferred sites at which Man5GlcNAc2-glycans can be introduced at high site occupancy without affecting antigen binding. A VHH carrying predominantly a Man5GlcNAc2 N-glycan at one of these preferred sites showed highly efficient, glycan-dependent uptake by Mf4/4 macrophages in vitro and by alveolar lung macrophages in vivo, illustrating one potential application of glyco-engineered VHHs: a glycan-based targeting approach for lung macrophage endolysosomal system delivery. The set of optimal artificial VHH N-glycosylation sites identified in this study can serve as a blueprint for targeted glyco-engineering of other VHHs, enabling site-specific functionalization through the rapidly expanding toolbox of synthetic glycobiology.

Abstract The development of stable barium (Ba) isotope measurements provides a novel tool to investigate the geochemical cycling of Ba in the ocean and its sediments. In sediment pore waters, gradients of dissolved Ba concentrations result from various diagenetic processes. The distribution and fractionation of Ba isotopes in the pore waters are expected to further improve our understanding of these early diagenetic control mechanisms. Here, we present pore water profiles of dissolved stable Ba isotopic signatures (δ138Bapw) from shallow water sediments covering the entire Pearl River Estuary (PRE) in Southern China. We find pronounced depth‐dependent Ba isotope variations generally showing a shift from heavy to light δ138Bapw signatures from the sediment surface down to 15 cm depth. These gradients are well reproduced by a diffusion‐reaction model, which generates an apparent fractionation factor (138ε) of −0.60 ± 0.10‰ pointing to preferential removal of low‐mass Ba isotopes from the pore water during solution‐solid phase interactions. Consequently, the combined diagenetic processes induce the highest δ138Bapw values of +0.5 to +0.7‰ in the pore waters of the topmost sediment layer. Although the detrital fraction dominates the Ba content in the PRE surface sediments, the determined gradients of pore water Ba isotopes, together with concentration variations of Ba and other redox‐sensitive elements such as manganese (Mn), show that non‐detrital excess Ba carriers including Mn oxides and authigenic barite clearly affect the post‐depositional Ba dynamics. Stable Ba isotopes are thus a potentially powerful tracer of Ba geochemistry during early sediment diagenesis in estuarine depositional environments.

Barium (Ba) isotopes are a promising new tracer for riverine freshwater input to the ocean and marine biogeochemical cycling. However, many processes that affect Ba cycling at continental margins have not yet been investigated with respect to Ba isotope fractionation. Here, we present a comprehensive data set of Ba concentration and isotope data for water column, pore water and sediment samples from Kiel Bight, a seasonally stratified and hypoxic fjord in the southwestern Baltic Sea. The surface water Ba concentration and Ba isotope inventory of the water column can generally be explained by mixing of riverine freshwater and Atlantic seawater. However, the deep-water below the seasonal pycnocline (10 - 15 m water depth) is characterized by a pronounced positive Ba concentration anomaly (up to 915 nM) that is accompanied by a δ138Ba of ~+0.25 ‰, which is lighter than expected from the seawater-freshwater mixing line (Ba: 77 nM, δ138Ba: +0.32 ‰ at a salinity of 18). Pore water profiles indicate a Ba flux across the sediment-water interface, which contributes to the enrichment in isotopically light Ba in the deep-water. Pore waters of surface sediments and deep-waters are oversaturated with respect to barite. Therefore, barite dissolution is unlikely to account for the benthic Ba flux. Water column Ba concentrations closely correlate with those of the nutrients phosphate and silica, which are removed from surface waters by biological processes and recycled from the sediment by diffusion across the sediment-water interface. As nutrient-to-Ba ratios differ among sites and from those observed in open-marine systems, we propose that Ba is removed from surface waters by adsorption onto biogenic particles (rather than assimilation) and regenerated within surface sediments upon organic matter degradation. Pore water data for subsurface sediments in Kiel Bight indicate preferential transfer of isotopically heavy Ba into an authigenic phase during early diagenesis. Quantifying the burial flux associated with this authigenic Ba phase along continental margins could potentially help to settle the isotopic imbalance between known Ba source and sink fluxes in the ocean.

Abstract Objective To assess the biomechanical effects of different prosthetic/implant configurations and load directions on 3-unit fixed prostheses supported by short dental implants in the posterior mandible using validated 3-D finite element (FE) models. Methods Models represented an atrophic mandible, missing the 2nd premolar, 1st and 2nd molars, and rehabilitated with either two short implants (implant length-IL = 8 mm and 4 mm) supporting a 3-unit dental bridge or three short implants (IL = 8 mm, 6 mm and 4 mm) supporting zirconia prosthesis in splinted or single crowns design. Load simulations were performed in ABAQUS (Dassault Systèmes, France) under axial and oblique (30°) force of 100 N to assess the global stiffness and forces within the implant prosthesis. Local stresses within implant/prosthesis system and strain energy density (SED) within surrounding bone were determined and compared between configurations. Results The global stiffness was around 1.5 times higher in splinted configurations vs. single crowns, whereby off-axis loading lead to a decrease of 39%. Splinted prostheses exhibited a better stress distribution than single crowns. Local stresses were larger and distributed over a larger area under oblique loads compared to axial load direction. The forces on each implant in the 2-implant-splinted configurations increased by 25% compared to splinted crowns on 3 implants. Loading of un-splinted configurations resulted in increased local SED magnitude. Conclusion Splinting of adjacent short implants in posterior mandible by the prosthetic restoration has a profound effect on the magnitude and distribution of the local stress peaks in peri-implant regions. Replacing each missing tooth with an implant is recommended, whenever bone supply and costs permit.

Climate change is subject to lively public discussions. Especially the question of whether climate change is manmade is a central point of contention. Since climatic processes are interleaved and complex, it is difficult to evaluate public, political or scientific statements. In this work, we look at mathematical models behind climate processes on a simplified level. We present a simple model of the Earth?s energy budged developed by high school students themselves during a project week. The model allows the students to compute the global Earth?s surface temperature and effects of varying solar activity and land surface changes. More precisely, the model describing the energy budget of the Earth forms a systems of partial differential equations and can be linked to compartment models. We show how this mathematically challenging question can be didactically reduced in such a way that students can be enabled to develop, solve and extend compartment models independently without having been taught the theoretical background. We implemented this course as an interactive online workshop and present our experiences with gifted student groups. We believe that our material presents an opportunity to demonstrate the power of mathematical modeling, to understand natural phenomena, and to critically reflect on discussions.

To enable collaborative modeling activities online digital tools are essential. In this paper we present a holistic and adaptable concept for the development and implementation of modeling activities – which could especially be fruitful in times of homeschooling and distance learning. The concept is based on two digital tools: Jupyter Notebooks and a communication platform with video conferences.We carried out this concept in the context of two types of modeling activities: guided modeling days, where the students work on previously prepared and didactically developed digital learning material, and modeling weeks, in which the students work on open problems from research and industry very freely. In this paper the usage of Jupyter Notebook in modeling activities is presented and illustrated with the example of the optimization of a solar power plant. On top, we share our experiences in online modeling activities with high-school students in Germany.

Abstract Reactive iron (Fe) oxides in marine sediments may represent a source of bioavailable Fe to the ocean via reductive dissolution and sedimentary Fe release or can promote organic carbon preservation and long‐term burial. Furthermore, enrichments of reactive Fe (sum of Fe oxides, carbonates and sulfides normalized to total Fe) in ancient sediments are utilized as a paleo‐proxy for anoxic conditions. Considering the general importance of reactive Fe oxides in marine biogeochemistry, it is important to quantify their terrestrial sources and fate at the land‐ocean interface. We applied sequential Fe extractions to sediments from the Amazon shelf to investigate the transformation of river‐derived Fe oxides during early diagenesis. We found that ∼22% of the Amazon River‐derived Fe oxides are converted to Fe‐containing clay minerals in Amazon shelf sediments. The incorporation of reactive Fe into authigenic clay minerals (commonly referred to as reverse weathering) is substantiated by the relationship between Fe oxide loss and potassium (K) uptake from sedimentary pore waters, which is in agreement with the previously reported Fe/K stoichiometry of authigenic clay minerals. Mass balance calculations suggest that widely applied sequential extractions do not separate Fe‐rich authigenic clay minerals from reactive Fe oxides and carbonates. We conclude that the balance between terrestrial supply of reactive Fe and reverse weathering in continental margin sediments has to be taken into account in the interpretation of sedimentary Fe speciation data.

Fluorescent proteins are essential reporters in cell and molecular biology. Here, we found that red-fluorescent proteins possess an alternative translation initiation site that produces a short functional protein isoform in both prokaryotes and eukaryotes. The short isoform creates significant background fluorescence that biases the outcome of expression studies. In this study, we identified the short protein isoform, traced its origin, and determined the extent of the issue within the family of red fluorescent protein. Our analysis showed that the short isoform defect of the red fluorescent protein family may affect the interpretation of many published studies. We provided a re-engineered mCherry variant that lacks background expression as an improved tool for imaging and protein expression studies.

This study sought to discover whether and how biological parameters can predict leadership behavior in the following leadership-related tasks: a face-to-face negotiation (Study 1), an individual problem-solving case (Study 2), and a group-based problem-solving case (Study 3). We replicated previous work by Mehta, Mor, Yap and Prasad in testing the dual-hormone hypothesis related to testosterone increase and cortisol decrease (Study 1), but our findings do not provide evidence to support the dual-hormone hypothesis. In Study 2, we found that high openness was a significant predictor in the individual problem-solving case. The results from Study 3 indicated that higher openness was related to a better score on the group exercise. Our findings did not support the dual-hormone model, and we did not find support for the seller-specific effect reported in Mehta et al. The original study included 64 participants with complete hormone data, while our replicational study involved 114 participants with complete hormone data.

Early stages of atherosclerosis may develop in childhood due to hyperlipidemia. The aims are to investigate the prevalence of familiar hypercholesterolemia in 6 to 12-year-old children and to study the deviation in cholesterol measures. Anthropometric data and venous blood were collected from children participating in the Health Oriented Pedagogical Project (HOPP). Out of 18 children with TC > 6.0 mmol/L, 15 were tested genetically and none diagnosed with FH. The prevalence of TC > 6.0 mmol/L declined from 1.3% in 2015 to 0.5% in 2016. The mean TC was 4.30 mmol/L both years, which is lower than in earlier studies. Usage of a single TC measurement and a threshold of TC > 6.0 mmol/L in screening children for FH, may not be a good screening strategy. While lipid values have a good reliability across 2 measurements, there are variations in individual TC levels across 1 year.

Abstract Background Finding reliable information on one of more than 7000 rare diseases is a major challenge for those affected. Since rare diseases are defined only by the prevalence criterion, a multitude of heterogeneous diseases are included. Common to all, however, are difficulties regarding information access. Even though various quantitative studies have analyzed the use of different information sources for specific rare diseases, little is known about the use of information sources for different rare diseases, how users rate these information sources based on their experiences, and how the use and importance of these information sources change over time. Methods Fifty-five patients with a variety of rare diseases and 13 close relatives participated in qualitative interviews. For these interviews, a semi-structured guideline was developed, piloted, and revised. Data analysis involved a qualitative content analysis developed by Philipp Mayring. Results The participants considered internet as the most important and widespread information source, especially for early information. Although patients have difficulty dealing with information obtained online, they consider online searching a quick and practical option to gather information. During the course of the disease, personal contact partners, especially self-help associations and specialized doctors, become more important. This is also because information provided online is sometimes insufficiently detailed to answer their information needs, which can be complemented by information from doctors and self-help. Conclusions People rarely use just one type of source, but rather refer to different sources and informants. The source used depends on the type of information sought as well as other person-related factors such as preexisting knowledge and the disease stage. To improve people’s information searching and connect them with medical specialists in rare diseases, a central information portal on rare diseases might be a suitable access point to provide free and quality assured information for patients, caregivers, and physicians. This would allow not only patients but also doctors to find quality assured information on symptoms and therapies as well as patient associations and specialized doctors.

Summary: Small-molecule tankyrase 1 and tankyrase 2 (TNKS1/2) inhibitors are effective antitumor agents in selected tumor cell lines and mouse models. Here, we characterized the response signatures and the in-depth mechanisms for the antiproliferative effect of tankyrase inhibition (TNKSi). The TNKS1/2-specific inhibitor G007-LK was used to screen 537 human tumor cell lines and a panel of particularly TNKSi-sensitive tumor cell lines was identified. Transcriptome, proteome, and bioinformatic analyses revealed the overall TNKSi-induced response signatures in the selected panel. TNKSi-mediated inhibition of wingless-type mammary tumor virus integration site/β-catenin, yes-associated protein 1 (YAP), and phosphatidylinositol-4,5-bisphosphate 3-kinase/AKT signaling was validated and correlated with lost expression of the key oncogene MYC and impaired cell growth. Moreover, we show that TNKSi induces accumulation of TNKS1/2-containing β-catenin degradasomes functioning as core complexes interacting with YAP and angiomotin proteins during attenuation of YAP signaling. These findings provide a contextual and mechanistic framework for using TNKSi in anticancer treatment that warrants further comprehensive preclinical and clinical evaluations.

The upwelling area off Peru is characterized by exceptionally high rates of primary productivity, mainly dominated by diatoms, which require dissolved silicic acid (dSi) to construct their frustules. The silicon isotope compositions of dissolved silicic acid (δ30SidSi) and biogenic silica (δ30SibSi) in the ocean carry information about dSi utilization, dissolution, and water mass mixing. Diatoms are preserved in the underlying sediments and can serve as archives for past nutrient conditions. However, the factors influencing the Si isotope fractionation between diatoms and seawater are not fully understood. More δ30SibSi data in today’s ocean are required to validate and improve the understanding of paleo records. Here, we present the first δ30SibSi data (together with δ30SidSi) from the water column in the Peruvian Upwelling region. Samples were taken under strong upwelling conditions and the bSi collected from seawater consisted of more than 98% diatoms. The δ30SidSi signatures in the surface waters were higher (+1.7‰ to +3.0‰) than δ30SibSi (+1.0‰ to +2‰) with offsets between diatoms and seawater (Δ30Si) ranging from −0.4‰ to −1.0‰. In contrast, δ30SidSi and δ30SibSi signatures were similar in the subsurface waters of the oxygen minimum zone (OMZ) as a consequence of a decrease in δ30SidSi. A strong relationship between δ30SibSi and [dSi] in surface water samples supports that dSi utilization of the available pool (70 and 98%) is the main driver controlling δ30SibSi. A comparison of δ30SibSi samples from the water column and from underlying core-top sediments (δ30SibSi_sed.) in the central upwelling region off Peru (10°S and 15°S) showed good agreement (δ30SibSi_sed. = +0.9‰ to +1.7‰), although we observed small differences in δ30SibSi depending on the diatom size fraction and diatom assemblage. A detailed analysis of the diatom assemblages highlights apparent variability in fractionation among taxa that has to be taken into account when using δ30SibSi data as a paleo proxy for the reconstruction of dSi utilization in the region.

ABSTRACT Osteoporosis is the most common bone disease and is conventionally classified as a decrease of total bone mass. Current diagnosis of osteoporosis is based on clinical risk factors and dual energy X‐ray absorptiometry (DEXA) scans, but changes in bone quantity (bone mass) and quality (trabecular structure, material properties, and tissue composition) are not distinguished. Yet, osteoporosis is known to cause a deterioration of the trabecular network, which might be related to changes at the tissue scale—the material properties. The goal of the current study was to use a previously established test method to perform a thorough characterization of the material properties of individual human trabeculae from femoral heads in cyclic tensile tests in a close to physiologic, wet environment. A previously developed rheological model was used to extract elastic, viscous, and plastic aspects of material behavior. Bone morphometry and tissue mineralization were determined with a density calibrated micro‐computed tomography (μCT) set‐up. Osteoporotic trabeculae neither showed a significantly changed material or mechanical behavior nor changes in tissue mineralization, compared with age‐matched healthy controls. However, donors with osteopenia indicated significantly reduced apparent yield strain and elastic work with respect to osteoporosis, suggesting possible initial differences at disease onset. Bone morphometry indicated a lower bone volume to total volume for osteoporotic donors, caused by a smaller trabecular number and a larger trabecular separation. A correlation of age with tissue properties and bone morphometry revealed a similar behavior as in osteoporotic bone. In the range studied, age does affect morphometry but not material properties, except for moderately increased tissue strength in healthy donors and moderately increased hardening exponent in osteoporotic donors. Taken together, the distinct changes of trabecular bone quality in the femoral head caused by osteoporosis and aging could not be linked to suspected relevant changes in material properties or tissue mineralization. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

The global silicon (Si) cycle plays a critical role in regulating the biological pump and the carbon cycle in the oceans. A promising tool to reconstruct past dissolved silicic acid (DSi) concentrations is the silicon isotope signature of radiolaria (δ30Sirad), siliceous zooplankton that dwells at subsurface and intermediate water depths. However, to date, only a few studies on sediment δ30Sirad records are available. To investigate its applicability as a paleo proxy, we compare the δ30Sirad of different radiolarian taxa and mixed radiolarian samples from surface sediments off Peru to the DSi distribution and its δ30Si signatures (δ30SiDSi) along the coast between the equator and 15°S. Three different radiolarian taxa were selected according to their specific habitat depths of 0–50 m (Acrosphaera murrayana), 50–100 m (Dictyocoryne profunda/truncatum), and 200–400 m (Stylochlamydium venustum). Additionally, samples containing a mix of species from the bulk assemblage covering habitat depths of 0 to 400 m have been analyzed for comparison. We find distinct δ30Sirad mean values of +0.70 ± 0.17‰ (Acro; 2 SD), +1.61 ± 0.20 ‰ (Dictyo), +1.19 ± 0.31 ‰ (Stylo) and +1.04 ± 0.19 ‰ (mixed radiolaria). The δ30Si values of all individual taxa and the mixed radiolarian samples indicate a significant (p < 0.05) inverse relationship with DSi concentrations of their corresponding habitat depths. However, only δ30Si of A. murrayana are correlated to DSi concentrations under normally prevailing upwelling conditions. The δ30Si of Dictyocoryne sp., Stylochlamydium sp., and mixed radiolaria are significantly correlated to the lower DSi concentrations either associated with nutrient depletion or shallower habitat depths. Furthermore, we calculated the apparent Si isotope fractionation between radiolaria and DSi (Δ30Si ∼ 30ε = δ 30Sirad − δ 30SiDSi) and obtained values of −1.18 ± 0.17 ‰ (Acro), −0.05 ± 0.25 ‰ (Dictyo), −0.34 ± 0.27 ‰ (Stylo), and −0.62 ± 0.26 ‰ (mixed radiolaria). The significant differences in Δ30Si between the order of Nassellaria (A. murrayana) and Spumellaria (Dictyocoryne sp. and Stylochlamydium sp.) may be explained by order-specific Si isotope fractionation during DSi uptake, similar to species-specific fractionation observed for diatoms. Overall, our study provides information on the taxon-specific fractionation factor between radiolaria and seawater and highlights the importance of taxonomic identification and separation to interpret down-core records.

During the Miocene, the Central American seaway was not closed, allowing low-salinity Pacific water to potentially weaken the Atlantic circulation. A new, continuous Nd isotope record shows that there was no direct intermediate water mass export from the Caribbean to the Florida Strait and thus, the Atlantic circulation could strengthen.

The sluggish water mass transport in the deeper North Pacific Ocean complicates the assessment of formation, spreading and mixing of surface, intermediate and deep-water masses based on standard hydrographic parameters alone. Geochemical tracers sensitive to water mass provenance and mixing allow to better characterize the origin and fate of the prevailing water masses. Here, we present dissolved neodymium (Nd) isotope compositions (εNd) and concentrations ([Nd]) obtained along a longitudinal transect at ∼180°E from ∼7°S to ∼50°N. The strongest contrast in Nd isotope signatures is observed in equatorial regions between surface waters (εNd ∼0 at 4.5°N) and Lower Circumpolar Deep Water (LCDW) prevailing at 4500 m depth (εNd = −6.7 at 7.2°N). The Nd isotope compositions of equatorial surface and subsurface waters are strongly influenced by regional inputs from the volcanic rocks surrounding the Pacific, which facilitates the identification of the source regions of these waters and seasonal changes in their advection along the equator. Highly radiogenic weathering inputs from Papua-New-Guinea control the εNd signature of the equatorial surface waters and strongly alter the εNd signal of Antarctic Intermediate Water (AAIW) by sea water-particle interactions leading to an εNd shift from −5.3 to −1.7 and an increase in [Nd] from 8.5 to 11.0 pmol/kg between 7°S and 15°N. Further north in the open North Pacific, mixing calculations based on εNd, [Nd] and salinity suggest that this modification of the AAIW composition has a strong impact on intermediate water εNd signatures of the entire region allowing for improved identification of the formation regions and pathways of North Pacific Intermediate Water (NPIW). The deep-water Nd isotope signatures indicate a southern Pacific origin and subsequent changes along its trajectory resulting from a combination of water mass mixing, vertical processes and Nd release from seafloor sediments, which precludes Nd isotopes as quantitative tracers of deep-water mass mixing. Moreover, comparison with previously reported data indicates that the Nd isotope signatures and concentrations below 100 m depth essentially remained stable over the past decades, which suggests constant impacts of water mass advection and mixing as well as of non-conservative vertical exchange and bottom release.

Summary: C-Mannosylation is a relatively rare form of protein glycosylation involving the attachment of an α-mannopyranosyl residue to C-2 of the indole moiety of the amino acid tryptophan. This type of linkage was initially discovered in RNase 2 from human urine but later confirmed to be present in many other important proteins. Based on NMR experiments and extensive molecular dynamics simulations on the hundred microsecond timescale we demonstrate that, for isolated glycopeptides and denatured RNase 2, the C-linked mannopyranosyl residue exists as an ensemble of conformations, among which 1C4 is the most abundant. However, for native RNase 2, molecular dynamics and NMR studies revealed that the mannopyranosyl residue favors a specific conformation, which optimally stabilizes the protein fold through a network of hydrogen bonds and which leads to a significant reduction of the protein dynamics on the microsecond timescale. Our findings contribute to the understanding of the biological role of C-mannosylation.

The chloroplast is a central part of plant cells, as this is the organelle where the photosynthesis, fixation of inorganic carbon, and other key functions related to fatty acid synthesis and amino acid synthesis occur. Since this organelle should be an integral part of any genome-scale metabolic model for a microalgae or a higher plant, it is of great interest to generate a detailed and standardized chloroplast model. Additionally, we see the need for a novel type of sub-model template, or organelle model, which could be incorporated into a larger, less specific genome-scale metabolic model, while allowing for minor differences between chloroplast-containing organisms. The result of this work is the very first standardized chloroplast model, iGR774, consisting of 788 reactions, 764 metabolites, and 774 genes. The model is currently able to run in three different modes, mimicking the chloroplast metabolism of three photosynthetic microalgae-Nannochloropsis gaditana, Chlamydomonas reinhardtii and Phaeodactylum tricornutum. In addition to developing the chloroplast metabolic network reconstruction, we have developed multiple software tools for working with this novel type of sub-model in the COBRA Toolbox for MATLAB, including tools for connecting the chloroplast model to a genome-scale metabolic reconstruction in need of a chloroplast, for switching the model between running in different organism modes, and for expanding it by introducing more reactions either related to one of the current organisms included in the model, or to a new organism.

The Asian summer monsoon affects the lives of billions of people. With the aim of identifying geochemical tracers for the monsoon-related freshwater input from the major rivers draining into the Bay of Bengal (BoB) and the Andaman Sea (AnS), we have analyzed the yttrium and rare earth element (YREE) concentration of surface seawater samples from various locations spanning the Andaman Islands in 2011 to 2013. In some locations, samples have been taken in March, July, and November 2011, thus spanning the seasonal cycle and including different monsoon phases. Generally, the YREE patterns are similar to those reported for offshore samples from the BoB and AnS in January 1997, with seawater-normalized patterns of most samples characterized by middle REE enrichments. An enhancement of these middle REE bulges accompanies large increases in dissolved REE concentrations from streams and sediment-rich areas such as mangrove environments. Conversely, some samples, in particular those taken 1–2 days after heavy rainfall in March 2011, show pronounced REE scavenging accompanied by the preferential removal of dissolved light REEs (LREEs) and by higher Y/Ho ratios. The Nd isotope signature of the remaining dissolved REE phase of these low YREE samples is more radiogenic than local rocks and sediments. The time series at a location away from local input sources show remarkably similar REE patterns and concentrations in March and July. Then in October–November, following the peak in monsoon-induced river discharge, the dissolved REE concentrations increase by almost a factor of two, whereas Nd isotopes become less radiogenic by 1.5 εNd units. These unradiogenic values are found at the same site in the winter dry season of the following year, demonstrating the decoupling of sea surface salinity (SSS) and Nd. The large sub-annual variability of YREE concentrations and Nd isotopes encountered was likely caused by the conversion of YREE from the dissolved (probably colloidal) pool to the labile particulate fraction. The comparison of unfiltered and filtered sample concentrations reveals the existence of a large labile particulate pool in the BoB and AnS that most likely originates from the massive river sediment fluxes and is instrumental in the seasonal changes observed.

The chloroplast is a promising platform for biotechnological innovation due to its compact translation machinery. Nucleotide modifications within a minimal set of tRNAs modulate codon–anticodon interactions that are crucial for translation efficiency. However, a comprehensive assessment of these modifications does not presently exist in chloroplasts. Here, we synthesize all available information concerning tRNA modifications in the chloroplast and assign translation efficiency for each modified anticodon–codon pair. In addition, we perform a bioinformatics analysis that links enzymes to tRNA modifications and aminoacylation in the chloroplast of Chlamydomonas reinhardtii. This work provides the first comprehensive analysis of codon and anticodon interactions of chloroplasts and its implication for translation efficiency.

Abstract Background Rare diseases are, by definition, very serious and chronic diseases with a high negative impact on quality of life. Approximately 350 million people worldwide live with rare diseases. The resulting high disease burden triggers health information search, but helpful, high-quality, and up-to-date information is often hard to find. Therefore, the improvement of health information provision has been integrated in many national plans for rare diseases, discussing the telephone as one access option. In this context, this study examines the need for a telephone service offering information for people affected by rare diseases, their relatives, and physicians. Methods In total, 107 individuals participated in a qualitative interview study conducted in Germany. Sixty-eight individuals suffering from a rare disease or related to somebody with rare diseases and 39 health care professionals took part. Individual interviews were conducted using a standardized semi-structured questionnaire. Interviews were analysed using the qualitative content analysis, triangulating patients, relatives, and health care professionals. The fulfilment of qualitative data processing standards has been controlled for. Results Out of 68 patients and relatives and 39 physicians, 52 and 18, respectively, advocated for the establishment of a rare diseases telephone service. Interviewees expected a helpline to include expert staffing, personal contact, good availability, low technical barriers, medical and psychosocial topics of counselling, guidance in reducing information chaos, and referrals. Health care professionals highlighted the importance of medical topics of counselling—in particular, differential diagnostics—and referrals. Conclusions Therefore, the need for a national rare diseases helpline was confirmed in this study. Due to limited financial resources, existing offers should be adapted in a stepwise procedure in accordance with the identified attributes.

Abstract Background Synechococcus sp. PCC 7002 (henceforth Synechococcus) is developing into a powerful synthetic biology chassis. In order to streamline the integration of genes into the Synechococcus chromosome, validation of neutral integration sites with optimization of the DNA transformation protocol parameters is necessary. Availability of BioBrick-compatible integration modules is desirable to further simplifying chromosomal integrations. Results We designed three BioBrick-compatible genetic modules, each targeting a separate neutral integration site, A2842, A0935, and A0159, with varying length of homologous region, spanning from 100 to 800 nt. The performance of the different modules for achieving DNA integration were tested. Our results demonstrate that 100 nt homologous regions are sufficient for inserting a 1 kb DNA fragment into the Synechococcus chromosome. By adapting a transformation protocol from a related cyanobacterium, we shortened the transformation procedure for Synechococcus significantly. Conclusions The optimized transformation protocol reported in this study provides an efficient way to perform genetic engineering in Synechococcus. We demonstrated that homologous regions of 100 nt are sufficient for inserting a 1 kb DNA fragment into the three tested neutral integration sites. Integration at A2842, A0935 and A0159 results in only a minimal fitness cost for the chassis. This study contributes to developing Synechococcus as the prominent chassis for future synthetic biology applications.

The heat transfer performance of a solar external receiver tube with guide vanes was numerically studied under non-uniform heat flux conditions. Models of the smooth tube and the tube with guide vanes were built. The distributions of the temperature, velocity, turbulence intensity, and Nu predicted by these two models were compared to investigate the heat transfer enhancement and the mixing effect of the guide vanes. The effect of the Re and the α on the heat transfer enhancement was also studied. The results show that the guide vanes form spiraling flows, reduce the maximum tube and molten salt temperatures, and improve the heat transfer. In addition, a more uniform temperature distribution is achieved compared to the smooth tube, allowing the molten salt to work safely under higher heat flux conditions in the receiver tube with guide vanes. It was observed that a larger Re enhances the heat transfer on the tube wall and achieves a longer effective distance of enhanced heat transfer in the downstream region, while the spiraling flow, the heat transfer enhancement, and the mixing are stronger for a larger α.

Enveloped viruses hijack not only the host translation processes, but also its glycosylation machinery, and to a variable extent cover viral surface proteins with tolerogenic host-like structures. SARS-CoV-2 surface protein S presents as a trimer on the viral surface and is covered by a dense shield of N-linked glycans, and a few O-glycosites have been reported. The location of O-glycans is controlled by a large family of initiating enzymes with variable expression in cells and tissues and hence is difficult to predict. Here, we used our well-established O-glycoproteomic workflows to map the precise positions of O-linked glycosylation sites on three different entities of protein S—insect cell or human cell-produced ectodomains, or insect cell derived receptor binding domain (RBD). In total 25 O-glycosites were identified, with similar patterns in the two ectodomains of different cell origin, and a distinct pattern of the monomeric RBD. Strikingly, 16 out of 25 O-glycosites were located within three amino acids from known N-glycosites. However, O-glycosylation was primarily found on peptides that were unoccupied by N-glycans, and otherwise had low overall occupancy. This suggests possible complementary functions of O-glycans in immune shielding and negligible effects of O-glycosylation on subunit vaccine design for SARS-CoV-2.

Cyanobacteria have high iron requirements due to iron-rich photosynthetic machineries. Despite the high concentrations of iron in the Earth’s crust, iron is limiting in many marine environments due to iron’s low solubility. Oxic conditions leave a large portion of the ocean’s iron pool unavailable for biotic uptake, and so the physiochemical properties of iron are hugely important for iron’s bioavailability. Our study is the first to investigate the effect of iron source on iron internalization and extracellular reduction by Synechococcus sp. PCC 7002. The results indicated that the amorphous iron hydrolysis species produced by FeCl3 better support growth in Synechococcus through more efficient iron internalization and a larger degree of extracellular reduction of iron than the crystalline FeO(OH). An analysis of dissolved iron (II) indicated that biogenic reduction took place in cultures of Synechococcus grown on both FeCl3 and FeO(OH).

Iron is an essential, yet scarce, nutrient in marine environments. Phytoplankton, and especially cyanobacteria, have developed a wide range of mechanisms to acquire iron and maintain their iron-rich photosynthetic machinery. Iron limitation studies often utilize either oceanographic methods to understand large scale processes, or laboratory-based, molecular experiments to identify underlying molecular mechanisms on a cellular level. Here, we aim to highlight the benefits of both approaches to encourage interdisciplinary understanding of the effects of iron limitation on cyanobacteria with a focus on avoiding pitfalls in the initial phases of collaboration. In particular, we discuss the use of trace metal clean methods in combination with sterile techniques, and the challenges faced when a new collaboration is set up to combine interdisciplinary techniques. Methods necessary for producing reliable data, such as High Resolution Inductively Coupled Plasma Mass Spectrometry (HR-ICP-MS), Flow Injection Analysis Chemiluminescence (FIA-CL), and 77K fluorescence emission spectroscopy are discussed and evaluated and a technical manual, including the preparation of the artificial seawater medium Aquil, cleaning procedures, and a sampling scheme for an iron limitation experiment is included. This paper provides a reference point for researchers to implement different techniques into interdisciplinary iron studies that span cyanobacteria physiology, molecular biology, and biogeochemistry.

Zhang et al [...]

The Rare Earth Elements (REEs) have been widely used to investigate marine biogeochemical processes as well as the sources and mixing of water masses. However, there are still important uncertainties about the global aqueous REE cycle with respect to the contributions of highly reactive basaltic minerals originating from volcanic islands and the role of Submarine Groundwater Discharge (SGD). Here we present dissolved REE concentrations obtained from waters at the island-ocean interface (including SGD, river, lagoon and coastal waters) from the island of Tahiti and from three detailed open ocean profiles on the Manihiki Plateau (including neodymium (Nd) isotope compositions), which are located in ocean currents downstream of Tahiti. Tahitian fresh waters have highly variable REE concentrations that likely result from variable water–rock interaction and removal by secondary minerals. In contrast to studies on other islands, the SGD samples do not exhibit elevated REE concentrations but have distinctive REE distributions and Y/Ho ratios. The basaltic Tahitian rocks impart a REE pattern to the waters characterized by a middle REE enrichment, with a peak at europium similar to groundwaters and coastal waters of other volcanic islands in the Pacific. However, the basaltic island REE characteristics (with the exception of elevated Y/Ho ratios) are lost during transport to the Manihiki Plateau within surface waters that also exhibit highly radiogenic Nd isotope signatures. Our new data demonstrate that REE concentrations are enriched in Tahitian coastal water, but without multidimensional sampling, basaltic island Nd flux estimates range over orders of magnitude from relatively small to globally significant. Antarctic Intermediate Water (AAIW) loses its characteristic Nd isotopic signature (−6 to −9) around the Manihiki Plateau as a consequence of mixing with South Equatorial Pacific Intermediate Water (SEqPIW), which shows more positive values (−1 to −2). However, an additional Nd input/exchange along the pathway of AAIW, eventually originating from the volcanic Society, Tuamotu and Tubuai Islands (including Tahiti), is indicated by an offset from the mixing array of AAIW and SEqPIW to more radiogenic Nd isotope compositions.

Oligosaccharide structures derived from the lipooligosaccharide of M. catarrhalis show that the highly branched glucose-rich inner core of the oligosaccharide has an altered conformation compared to the most truncated tetra-glucose-Kdo lgt1/4Δ oligosaccharide structure. Addition of one residue each to the (1-4) and (1-6) chains to give the lgt2Δ oligosaccharide is the minimum requirement for this conformational change to occur. Extensive molecular modeling and NMR investigations have shown that the (1-3), (1-4), and (1-6) glycosidic linkages from the central α-D-Glcp have significantly altered conformational preferences between the two structures. For the lgt1/4Δ oligosaccharide the (1-3) and (1-4) linkage populates predominantly the syn minimum on the conformational free energy map and for the (1-6) linkage conformational flexibility is observed, which is supported by 1H-NMR T1 measurements. For the lgt2Δ oligosaccharide the unusual “(1-4)anti-ψ(1-6)gg” conformation, which could be confirmed by long-range NOE signals, is a dominant conformation in which the oligosaccharide is very compact with the terminal α-D-GlcNAc residue folding back towards the center of the molecule leading to an extensive intra-molecular hydrophobic interaction between the terminal residues. Comparing effective H-H distances, which were calculated for conformational sub-ensembles, with the NOE distances revealed that typically multiple conformations could be present without significantly violating the measured NOE restraints. For lgt2Δ the presence of more than one conformation is supported by the NOE data.

The lipid-producing model alga Nannochloropsis oceanica has a distinct photosynthetic machinery. This organism possesses chlorophyll a as its only chlorophyll species, and has a high ratio of PSI to PSII. This high ratio of PSI to PSII may affect the redox state of the plastoquinone pool during exposure to light, and consequently may play a role in activating photoprotection mechanisms. We utilized pulse-amplitude modulated fluorometry to investigate the redox state of the plastoquinone pool during and after bright light pulses. Our data indicate that even very intense (5910 μmol photons s-1m-2 of blue light having a wavelength of 440 nm) light pulses of 0.8 second duration are not sufficient to completely reduce the plastoquinone pool in Nannochloropsis. In order to achieve extensive reduction of the plastoquinone pool by bright light pulses, anaerobic conditions or an inhibitor of the photosynthetic electron transport chain has to be utilized. The implication of this finding for the application of the widely used saturating pulse method in algae is discussed.

La correspondance entre le mathématicien Guidobaldo dal Monte et Filippo Pigafetta concerne la traduction du Mechanicorum liber, un important traité de mécanique publié en 1577 par Guidobaldo. Conservés à la Bibliothèque Ambrosienne de Milan et en grande partie inédits, ces documents exceptionnels témoignent du travail de traduction qui, entre 1580 et 1581, précéda la publication des Mechaniche. Connu des historiens des sciences pour ses aspects scientifiques, ce témoignage se révèle particulièrement important pour les historiens de la langue. L’analyse de cette correspondance montre que Guidobaldo contrôla la langue de la traduction ainsi que les annotations que Pigafetta publia en son nom, mais qui furent en réalité dictées par l’auteur. Au fil de ces lettres, auteur et traducteur définissent empiriquement une langue scientifique nouvelle, exacte et univoque, proche de la langue des traités scientifiques classiques.Il presente articolo è dedicato all’analisi della corrispondenza inedita tra Guidobaldo dal Monte, matematico di primo livello del tardo Cinquecento, e Filippo Pigafetta. Risalente agli anni 1580-1581, lo scambio epi­stolare riguarda la traduzione del Mechanicorum Liber, un importante trattato di meccanica pubblicato da Guidobaldo qualche anno prima.

Oligosaccharides aberrantly expressed on tumor cells influence processes such as cell adhesion and modulation of the cell’s microenvironment resulting in an increased malignancy. Schmidt’s imidate strategy offers an effective method to synthesize libraries of various oligosaccharide mimetics. With the aim to perturb interactions of tumor cells with extracellular matrix proteins and host cells, molecules with 3,4-bis(hydroxymethyl)furan as core structure were synthesized and screened in biological assays for their abilities to interfere in cell adhesion and other steps of the metastatic cascade, such as tumor-induced angiogenesis.The most active compound, (4-{[(β-D-galactopyranosyl)oxy]methyl}furan-3-yl)methyl hydrogen sulfate (GSF), inhibited the activation of matrix-metalloproteinase-2 (MMP-2) as well as migration of the human melanoma cells of the lines WM-115 and WM-266-4 in a two-dimensional migration assay. GSF inhibited completely the adhesion of WM-115 cells to the extracellular matrix (ECM) proteins, fibrinogen and fibronectin.In an in vitro angiogenesis assay with human endothelial cells, GSF very effectively inhibited endothelial tubule formation and sprouting of blood vessels, as well as the adhesion of endothelial cells to ECM proteins. GSF was not cytotoxic at biologically active concentrations; neither were 3,4-bis{[(β-D-galactopyranosyl)oxy]methyl}furan (BGF) nor methyl β-D-galactopyranoside nor 3,4-bis(hydroxymethyl)furan, which were used as controls, eliciting comparable biological activity. In silico modeling experiments, in which binding of GSF to the extracellular domain of the integrin αvβ3 was determined, revealed specific docking of GSF to the same binding site as the natural peptidic ligands of this integrin. The sulfate in the molecule coordinated with one manganese ion in the binding site.These studies show that this chemically easily accessible molecule GSF, synthesized in three steps from 3,4-bis(hydroxymethyl)furan and benzoylated galactose imidate, is nontoxic and antagonizes cell physiological processes in vitro that are important for the dissemination and growth of tumor cells in vivo.

Several species in the oomycete genus Peronosclerospora cause downy mildew on maize and can result in significant yield losses in Asia. Bio-surveillance of these pathogens is a high priority to prevent epidemics on maize in the United States and consequent damage to the US economy. The unresolved taxonomy and dearth of molecular resources for Peronosclerospora spp. hinder these efforts. P. sorghi is a pathogen of sorghum and maize with a global distribution, for which limited diversity has been detected in the southern USA. We characterized the genome, transcriptome, and mitogenome of an isolate, representing the US pathotype 6. The highly homozygous genome was assembled using 10× Genomics linked reads and scaffolded using Hi-C into 13 chromosomes. The total assembled length was 303.2 Mb, larger than any other oomycete previously assembled. The mitogenome was 38 kb, similar in size to other oomycetes, although it had a unique gene order. Nearly 20,000 genes were annotated in the nuclear genome, more than described for other downy mildew causing oomycetes. The 13 chromosomes of P. sorghi were highly syntenic with the 17 chromosomes of Peronospora effusa with conserved centromeric regions and distinct chromosomal fusions. The increased assembly size and gene count of P. sorghi is due to extensive retrotransposition, resulting in putative pseudogenization. Ancestral genes had higher transcript abundance and were enriched for differential expression. This study provides foundational resources for analysis of Peronosclerospora and comparisons to other oomycete genera. Further genomic studies of global Peronosclerospora spp. will determine the suitability of the mitogenome, ancestral genes, and putative pseudogenes for marker development and taxonomic relationships.

The picornaviruses coxsackievirus A24 variant (CVA24v) and enterovirus 70 (EV70) cause continued outbreaks and pandemics of acute hemorrhagic conjunctivitis (AHC), a highly contagious eye disease against which neither vaccines nor antiviral drugs are currently available. Moreover, these viruses can cause symptoms in the cornea, upper respiratory tract, and neurological impairments such as acute flaccid paralysis. EV70 and CVA24v are both known to use 5-N-acetylneuraminic acid (Neu5Ac) for cell attachment, thus providing a putative link between the glycan receptor specificity and cell tropism and disease. We report the structures of an intact human picornavirus in complex with a range of glycans terminating in Neu5Ac. We determined the structure of the CVA24v to 1.40 Å resolution, screened different glycans bearing Neu5Ac for CVA24v binding, and structurally characterized interactions with candidate glycan receptors. Biochemical studies verified the relevance of the binding site and demonstrated a preference of CVA24v for α2,6-linked glycans. This preference can be rationalized by molecular dynamics simulations that show that α2,6-linked glycans can establish more contacts with the viral capsid. Our results form an excellent platform for the design of antiviral compounds to prevent AHC.

The termination of the African Humid Period in northeastern Africa during the early Holocene was marked by the southward migration of the rain belt and the disappearance of the Green Sahara. This interval of drastic environmental changes was also marked by the initiation of food production by North African hunter-gatherer populations and thus provides critical information on human-environment relationships. However, existing records of regional climatic and environmental changes exhibit large differences in timing and modes of the wet/dry transition at the end of the African Humid Period. Here we present independent records of changes in river runoff, vegetation and erosion in the Nile River watershed during the Holocene obtained from a unique sedimentary sequence on the Nile River fan using organic and inorganic proxy data. This high-resolution reconstruction allows to examine the phase relationship between the changes of these three parameters and provides a detailed picture of the environmental conditions during the Paleolithic/Neolithic transition. The data show that river runoff decreased gradually during the wet/arid transition at the end of the AHP whereas rapid shifts of vegetation and erosion occurred earlier between 8.7 and ∼6 ka BP. These asynchronous changes are compared to other regional records and provide new insights into the threshold responses of the environment to climatic changes. Our record demonstrates that the degradation of the environment in northeastern Africa was more abrupt and occurred earlier than previously thought and may have accelerated the process of domestication in order to secure sustainable food resources for the Neolithic African populations.

Human Galectin-8 (Gal-8) is a member of the galectin family which shares an affinity for β-galactosides. The tandem-repeat Gal-8 consists of a N- and a C-terminal carbohydrate recognition domain (N- and C-CRD) joined by a linker peptide of various length. Despite their structural similarity both CRDs recognize different oligosaccharides. While the molecular requirements of the N-CRD for high binding affinity to sulfated and sialylated glycans have recently been elucidated by crystallographic studies of complexes with several oligosaccharides, the binding specificities of the C-CRD for a different set of oligosaccharides, as derived from experimental data, has only been explained in terms of the three-dimensional structure for the complex C-CRD with lactose. In this study we performed molecular dynamics (MD) simulations using the recently released crystal structure of the Gal-8C-CRD to analyse the three-dimensional conditions for its specific binding to a variety of oligosaccharides as previously defined by glycan-microarray analysis. The terminal β-galactose of disaccharides (LacNAc, lacto-N-biose and lactose) and the internal β-galactose moiety of blood group antigens A and B (BGA, BGB) as well as of longer linear oligosaccharide chains (di-LacNAc and lacto-N-neotetraose) are interacting favorably with conserved amino acids (H53, R57, N66, W73, E76). Lacto-N-neotetraose and di-LacNAc as well as BGA and BGB are well accommodated. BGA and BGB showed higher affinity than LacNAc and lactose due to generally stronger hydrogen bond interactions and water mediated hydrogen bonds with α1-2 fucose respectively. Our results derived from molecular dynamics simulations are able to explain the glycan binding specificities of the Gal-8C-CRD in comparison to those of the Gal-8N -CRD.

Viruses within a family often vary in their cellular tropism and pathogenicity. In many cases, these variations are due to viruses switching their specificity from one cell surface receptor to another. The structural requirements that underlie such receptor switching are not well understood especially for carbohydrate-binding viruses, as methods capable of structure-specificity studies are only relatively recently being developed for carbohydrates. We have characterized the receptor specificity, structure and infectivity of the human polyomavirus BKPyV, the causative agent of polyomavirus-associated nephropathy, and uncover a molecular switch for binding different carbohydrate receptors. We show that the b-series gangliosides GD3, GD2, GD1b and GT1b all can serve as receptors for BKPyV. The crystal structure of the BKPyV capsid protein VP1 in complex with GD3 reveals contacts with two sialic acid moieties in the receptor, providing a basis for the observed specificity. Comparison with the structure of simian virus 40 (SV40) VP1 bound to ganglioside GM1 identifies the amino acid at position 68 as a determinant of specificity. Mutation of this residue from lysine in BKPyV to serine in SV40 switches the receptor specificity of BKPyV from GD3 to GM1 both in vitro and in cell culture. Our findings highlight the plasticity of viral receptor binding sites and form a template to retarget viruses to different receptors and cell types.