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Large slow-moving deep-seated landslides are observed in two different regions of northern Canada with advanced Differential Synthetic Aperture Radar (DInSAR). Two-dimensional vertical and horizontal east-west deformation rates and time series are computed from ascending and descending Sentinel-1 imagery acquired during 2017–2022. The landslides' east-west deformation rate is significantly larger than the vertical deformation rate, so it is better suited for landslide characterization. The deformation rates remain nearly constant and unaffected by seasonal changes during the entire period, suggesting substantial landslide thickness. Two large landslides in Alberta and the largest landslide in the Northwest Territories are studied in detail to demonstrate various advanced value-added products produced from DInSAR results. From ascending and descending line-of-sight deformation rates, Surface-Parallel Flow (SPF) and Aspect-Parallel Flow (APF)-constrained three-dimensional (3D) deformation rates are computed. Landslides thicknesses are then estimated from the APF-constrained 3D deformation rates, and the limitations of these techniques are discussed. The estimated thickness of the Northwest Territories landslide reaches 100 m, suggesting that the entire permafrost block may be sliding above the non-permafrost ground. The described techniques allow for mapping slow-moving deep-seated landslides in harsh conditions in areas affected by seasonal land cover changes, as in northern Canada. The decomposition of landslide motion into two or three components in certain conditions allows us to derive landslide thickness and volume and improve the estimation of a potential hazard posed by landslides. • Performed DInSAR analysis of Sentinel-1 data over Alberta and Northwest Territories. • Identified two regions with large, slow-moving, deep-seated landslides. • Computed landslides' 2D deformation time series and constrained 3D deformation rates. • Estimated landslide thickness from constrained 3D deformation rates. [ABSTRACT FROM AUTHOR]

The anticancer agent ellipticine (ELP) functions as a DNA intercalating drug. Depending on the pH of the medium, it exists both in a neutral and a protonated form. In acidic extracellular microenvironment characteristic to malignant tissues, charged ELP molecules can also bind to glycosaminoglycans (GAGs), linear anionic periodic polysaccharides, which interact with various protein targets affecting diverse cellular events. Although a previous experimental work indicated specific GAG binding of protonated ELP, the underlying molecular mechanisms remain to be elucidated. From a computational point of view, analysis of molecular systems containing GAGs is challenging due to their high flexibility, variability in sulfation patterns and a key role of electrostatics and solvent-mediated interactions. In the present study, molecular dynamics-based approaches were employed to model ELP-GAG interactions in order to unveil the atomistic details of this biologically relevant molecular system. We characterized dynamic and energetic properties of three kinds of ELP-GAG complexes to rationalize and complement the available experimental data. The results reported herein provide insight into possible molecular pathways by which biological actions of ELP are mediated. [ABSTRACT FROM AUTHOR]

Procathepsins, inactive precursors of cathepsins are present in the extracellular matrix (ECM) and in lysosomes. Their active forms are involved in a number of biologically relevant processes, including bone resorption, intracellular proteolysis and regulation of programmed cell death. These processes might be mediated by glycosaminoglycans (GAGs), long unbranched periodic negatively charged polysaccharides. GAGs are also present in ECM and play important role in anticoagulation, angiogenesis and tissue regeneration. GAGs not only mediate the enzymatic activity of cathepsins but can also regulate the process of procathepsin maturation, as it was shown for procathepsin B and S. In this study, we propose the molecular mechanism underlying the biological role of GAGs in procathepsin S maturation and compare our findings with computational data obtained for procathepsin B. We rigorously analyse procathepsin S–GAG complexes in terms of their dynamics, free energy and potential allosteric regulation. We conclude that the GAG binding region might have an effect on the dynamics of procathepsin S structure and so affect its maturation by two different mechanisms. [Display omitted] • (Pro)cathepsin S-glycosaminoglycan complexes were analysed in silico. • The effect of glycosaminoglycan length, sulfation pattern and charge on zymogen-glycosaminoglycan complex stability was characterised. • Previously proposed mechanism for procathepsin B maturation was also suggested for procathepsin S. [ABSTRACT FROM AUTHOR]

An imbalance between tissue-degrading matrix metalloproteinases (MMPs) and their counterparts’ tissue inhibitors of metalloproteinases (TIMPs) causes pathologic extracellular matrix (ECM) degradation in chronic wounds and requires new adaptive biomaterials that interact with these regulators to re-establish their balance. Sulfated glycosaminoglycans (GAGs) and TIMP-3 are key modulators of tissue formation and remodeling. However, little is known about their molecular interplay. GAG/TIMP-3 interactions were characterized combining surface plasmon resonance, ELISA, molecular modeling and hydrogen/deuterium exchange mass spectrometry. We demonstrate the potential of solute and surface-bound sulfated hyaluronan (sHA) and chondroitin sulfate (sCS) derivatives to manipulate GAG/TIMP-3 interactions by varying GAG concentration, sulfation degree and chain length. Three GAG binding sites in the N - and C -terminal domains of TIMP-3 were identified. We reveal no overlap with the matrix metalloproteinases (MMP)-binding site, elucidating why GAGs did not change MMP-1/-2 inhibition by TIMP-3 in enzyme kinetics. Since we prove that GAGs alone have a low impact on MMP activity, sHA and sCS offer a promising strategy to possibly control ECM remodeling via stabilizing and accumulating TIMP-3 by maintaining its MMP inhibitory activity under GAG-bound conditions. Whether GAG-based functional biomaterials can be applied to foster chronic wound healing by shifting the MMP/TIMP balance to a healing promoting state needs to be evaluated in vivo . Statement of Significance Increased levels of tissue-degrading matrix metalloproteinases (MMPs) lead to pathologic matrix degradation in chronic wounds. Therefor functional biomaterials that restore the balance between MMPs and tissue inhibitors of metalloproteinases (TIMPs) are required to promote wound healing. Since sulfated glycosaminoglycan (GAG) derivatives demonstrated already to be e.g. anti-inflammatory and immunomodulatory, and native GAGs interact with TIMP-3 the former are promising candidates for functionalizing biomaterials. We identified the GAG binding sites of TIMP-3 by combining experimental and molecular modeling approaches and revealed that GAG derivatives have a higher capacity to sequester TIMP-3 than native GAGs without altering its inhibitory potential towards MMPs. Thus GAG derivative-containing biomaterials could protect tissue from excessive proteolytic degradation e.g. in chronic wounds by re-establishing the MMP/TIMP balance. [ABSTRACT FROM AUTHOR]

At the Aquistore CCS site, located in the southeastern Saskatchewan, Canada, carbon dioxide (CO 2 ) is to be injected at variable rates of up to 1500 tonne/day. The storage reservoir consists of a dominantly clastic, brine-filled interval (Deadwood and Winnipeg formations) which reside at 3150–3350 m depth. Ground deformation at this site is being monitored to track pressure-induced uplift and potential upward migration of CO 2 through faults and fractures. Deformation monitoring is conducted using space-borne Differential Interferometric Synthetic Aperture Radar (DInSAR), capable of achieving millimeter precision and meter spatial resolution over the entire monitored area. During June 2012–October 2014, prior to CO 2 injection, two ascending and two descending high-resolution RADARSAT-2 data sets were acquired and simultaneously processed with the advanced Multidimensional Small Baseline (MSBAS) DInSAR producing vertical and horizontal East-West deformation time series with six days temporal sampling, four times more frequent than the repeat cycle of each individual data set. Two years of monitoring prior to the onset of (CO 2 ) injection allowed measurement of the deformation field of the background natural and anthropogenic processes. Vertical and horizontal ground deformation was detected with the rates of ±1.0 and ±0.5 cm/year and with precision of 0.3 and 0.2 cm/year (2 σ ) correspondingly. Background motion (shape and magnitude) may resemble deformation signals due to potential upward migration of CO 2 through faults and fractures. Analytic elastic and poroelastic modeling was performed to estimate the ground deformation that will be produced when injection begins. For this purpose, rock properties determined from geophysical well logs and in situ temperature and pressure were used. For the elastic model it was determined that a maximum of vertical deformation of 1.6 cm/year will be located around the injection well, whereas the maximum of horizontal deformation of 0.6 cm/year will be located about 3 km away from the injection well. For a more realistic poroelastic model, it was determined that maximum vertical deformation will not exceed 1.6 cm and maximum horizontal deformation will not exceed 0.1 cm/year during the entire 25 year injection cycle. According to this model, the established monitoring network cannot detect predicted horizontal motion since it is below its sensitivity, whereas for detection of vertical motion ground-based monitoring sites need to be installed near and also at distance from the injection well. Six day temporal sampling allows determination of the transient uplift phase. A proposed MSBAS strategy overcomes limitations of the classical DInSAR, such as sparse temporal resolution and the lack of ability to extract individual deformation components from the line-of-sight retrievals, and can be implemented at other onshore CCS sites for operational monitoring, using readily available SAR data. [ABSTRACT FROM AUTHOR]

In order to improve bone defect regeneration, the development of new adaptive biomaterials and their functional and biological validation is warranted. Glycosaminoglycans (GAGs) are important extracellular matrix (ECM) components in bone and may display osteogenic properties that are potentially useful for biomaterial coatings. Using hyaluronan (HA), chondroitin sulfate (CS) and chemically modified highly sulfated HA and CS derivatives (sHA3 and sCS3; degree of sulfation ∼3), we evaluated how GAG sulfation modulates Wnt signaling, a major regulator of osteoblast, osteoclast and osteocyte biology. GAGs were tested for their capability to bind to sclerostin, an inhibitor of Wnt signaling, using surface plasmon resonance and molecular modeling to characterize their interactions. GAGs bound sclerostin in a concentration- and sulfate-dependent manner at a common binding region. These findings were confirmed in an LRP5/sclerostin interaction study and an in vitro model of Wnt activation. Here, pre-incubation of sclerostin with different GAGs led to a sulfate- and dose-dependent loss of its bioactivity. Using GAG-biotin derivatives in a competitive ELISA approach sclerostin was shown to be the preferred binding partner over Wnt3a. In conclusion, highly sulfated GAGs might control bone homeostasis via interference with sclerostin/LRP5/6 complex formation. Whether these properties can be utilized to improve bone regeneration needs to be validated in vivo . [ABSTRACT FROM AUTHOR]

Rapid determination of the location and extent of earthquake ruptures is helpful for disaster response, as it allows prediction of the likely area of major damage from the earthquake and can help with rescue and recovery planning. With the increasing availability of near real-time data from the Global Positioning System (GPS) and other global navigation satellite system receivers in active tectonic regions, and with the shorter repeat times of many recent and newly launched satellites, geodetic data can be obtained quickly after earthquakes or other disasters. We have been building a data system that can ingest, catalog, and process geodetic data and combine it with seismic analysis to estimate the fault rupture locations and slip distributions for large earthquakes. [ABSTRACT FROM AUTHOR]

Abstract: Rapidly accelerating ground subsidence in the south-western part of British Columbia, the third largest metropolitan area in Canada with over 2.3 million of inhabitants, is estimated using the Multidimensional Small Baseline Subset (MSBAS) advanced Differential Interferometric Synthetic Aperture Radar (DInSAR), an effective processing strategy for multi-mission, multi-temporal SAR data. The Synthetic Aperture Radar (SAR) data used in this study consists of seven independent data sets: one ascending and one descending ERS-1/2 and ENVISAT frames, together spanning July 1995–September 2010, and three RADARSAT-2 frames spanning February 2009–October 2012. During the July 1995–October 2012 period we observe fast ground subsidence with a maximum rate of about 2cm/year in the Greater Vancouver region that includes the Fraser River Delta and the cities of Burnaby, Richmond, Surrey, New Westminster and Vancouver. The rapidly accelerating subsidence is observed beneath the Vancouver International Airport, SkyTrain terminal as well as several agricultural and industrial locales. These time series suggest that the subsidence rate at the studied regions does not decrease with time, as suggested in previous studies, but remains steady or increases. These results also demonstrate the importance of acquiring and appropriately estimating longer time series, as previous studies on the same Greater Vancouver area may have misinterpreted the long term ground deformation rate and direction and underestimated the potential hazard. The long term impact of this subsidence on urban infrastructure can be significant and needs to be investigated further. [Copyright &y& Elsevier]

Highlights: [•] IdoA/IdoA(2S) ring conformations are studied in heparin–protein systems in silico. [•] The choice of a ring conformation in ligand significantly affects docking results. [•] Change of ring conformations is crucial for MD-based free energy calculations. [Copyright &y& Elsevier]

We present a novel methodology for integration of multiple InSAR data sets for computation of two dimensional time series of ground deformation. The proposed approach allows combination of SAR data acquired with different acquisition parameters, temporal and spatial sampling and resolution, wavelength and polarization. Produced time series have combined coverage, improved temporal resolution and lower noise level. We apply this methodology for mapping coal mining related ground subsidence and uplift in the Greater Region of Luxembourg along the French–German border. For this we processed 167 Synthetic Aperture Radar ERS-1/2 and ENVISAT images acquired between 1995 and 2009 from one ascending (track 29) and one descending (track 337) tracks and created over five hundred interferograms that were used for time series analysis. Derived vertical and east–west linear deformation rates show with remarkable precision a region of localized ground deformation located above and caused by mining and post-mining activities. Time series of ground deformation display temporal variability: reversal from subsidence to uplift and acceleration of subsidence in the vertical component, and horizontal motion toward the center of the subsidence on the east–west component. InSAR results are validated by leveling measurements collected by the French Geological Survey (BRGM) during 2006–2008. We determined that deformation rate changes are mainly caused by water level variations in the mines. Due to higher temporal and spatial resolution the proposed space-borne method detected a larger number of subsidence and uplift areas in comparison to leveling measurements restricted to annual monitoring of benchmark points along roads. We also identified one deformation region that is not precisely located above the mining sites. Comparison of InSAR measurements with the water levels measured in the mining pits suggest that part of the water that filled the galleries after termination of the dewatering systems may come from this region. Providing that enough SAR data is available, this method opens new opportunities for detecting and locating man-made and natural ground deformation signals with high temporal resolution and precision. [ABSTRACT FROM AUTHOR]

Abstract: Sulfated glycosaminoglycans are promising components for functional biomaterials since sulfate groups modulate the binding of growth factors and thereby influence wound healing. Here, we have investigated the influence of an artificial extracellular matrix (aECM) consisting of collagen I (coll) and hyaluronan (HA) or highly sulfated HA (hsHA) on dermal fibroblasts (dFb) with respect to their differentiation into myofibroblasts (MFb). Fibroblasts were cultured on aECM in the presence of aECM-adsorbed or soluble transforming growth factor β1 (TGFβ1). The synthesis of α-smooth muscle actin (αSMA), collagen and the ED-A splice variant of fibronectin (ED-A FN) were analyzed at the mRNA and protein levels. Furthermore, we investigated the bioactivity and signal transduction of TGFβ1 in the presence of aECM and finally made interaction studies of soluble HA or hsHA with TGFβ1. Artificial ECM composed of coll and hsHA prevents TGFβ1-stimulated αSMA, collagen and ED-A FN expression. Our data suggest an impaired TGFβ1 bioactivity and downstream signaling in the presence of aECM containing hsHA, shown by massively reduced Smad2/3 translocation to the nucleus. These data are explained by in silico docking experiments demonstrating the occupation of the TGFβ-receptor I binding site by hsHA. Possibly, HA sulfation has a strong impact on TGFβ1-driven differentiation of dFb and thus could be used to modulate the properties of biomaterials. [Copyright &y& Elsevier]

Abstract: We demonstrate here a computer code for calculation of time series and also mean and linear deformation rates from a set of coregistered unwrapped differential interferograms using a linear least-squares inversion technique based on the small baseline subset (SBAS) algorithm. The computer code is written in C and uses a singular value decomposition (SVD) routine from the LAPACK library and the fast Fourier transform for spatial filtering from the FFTW library. Various offset estimation and topographic correction algorithms are implemented, including simultaneous inversion for deformation rates and residual topographic error. This approach is particularly useful when applied to ALOS PALSAR interferograms that are coherent even at large perpendicular baselines and acquired with orbital parameters correlated with the time of acquisition. This methodology is applied to produce time series of ground deformation at Tauhara and Wairakei geothermal fields (Taupo Volcanic Zone, North Island, New Zealand) from 12 ALOS PALSAR images acquired between July 2007 and December 2009. We also present here a high-resolution deformation map of the ground subsidence caused by the extraction of geothermal groundwater for power generation, with maximum rates of subsidence of about 7cm/y. [Copyright &y& Elsevier]

Abstract: Mt Ruapehu is New Zealand''s most active onshore volcano. In 2007, the volcano produced a large lahar following a break-out from the summit Crater Lake. Here, satellite and airborne remote sensing and image processing is used to extract the path of the lahar using ASTER and SPOT5 visible and near infra-red imagery, ALOS-PALSAR L-band synthetic aperture RADAR data, and airborne LiDAR. The results obtained from each of these datasets were compared to the lahar deposit manually digitized from aerial photography. SPOT5 imagery produced the most accurate map of the lahar deposit (77% correct), even though these data were acquired a year after the event. This is attributed to the spatial resolution of the data. The ALOS-PALSAR coherence mapping calculated from images acquired 2 months before and nine months after the lahar was not as accurate as that obtained using the optical imagery (43% correct), but this was still considered an important tool for acquiring data during cloudy periods. LiDAR topographic data, collected to constrain geomorphic changes caused by the lahar, was the least accurate in terms of mapping the lahar path (28% correct). No single technique was deemed to be the most accurate under all circumstances, and a combination of data types would produce the best results. By combining the satellite and LiDAR data, it was possible to accurately classify 92% of the lahar path. [Copyright &y& Elsevier]

Modern remote sensing techniques, such as Synthetic Aperture Radar (SAR), can measure the direction and intensity of glacier flow. Yet the question remains as to what these measurements reveal about glaciers' adjustment to the warming climate. Here, we present a technique that addresses this question by linking the SAR-derived velocity measurements with the glacier elevation change and the specific mass balance (i.e. mass balance per unit area). The technique computes the speckle offset tracking results from the north, east and vertical flow displacement time series, with the vertical component further split into a Surface Parallel Flow (SPF) advection component due to the motion along a glacier surface slope and a non-Surface Parallel Flow (nSPF). The latter links the glacier surface elevation change with the specific mass balance and strain rates. We apply this technique to ascending and descending Sentinel-1 data to derive the four-dimensional flow displacement time series for glaciers in southeast Alaska during 2016–2019. Time series extracted for a few characteristic regions demonstrate remarkable temporal variability in flow velocities. The seasonal signal observed in the nSPF component is modeled using the Positive Degree Day model. This method can be used for computing either mass balance or glacier surface elevation change if one of these two parameters is known from external observations. • Developed novel technique for computing 3D/4D glacier flow displacement time series. • Computed flow displacement time series of glaciers in SE Alaska during 2016–2019. • Linked flow velocity, mass balance, strain rate and surface elevation change. [ABSTRACT FROM AUTHOR]

Siderophores are ferric ion-specific organic compounds that are used by bacteria and fungi to secure their iron supply when infecting target organisms. There are a few proteins in the human body, named siderocalins, which bind these important virulence factors and so starve microorganisms of iron. In this study, we analyzed in silico if serum α 1 -acid glycoprotein (AAG), the major acute phase lipocalin component of the human plasma, could functionally belong to this group. The real biological function of AAG is elusive and its concentration substantially increases in response to pathological stimuli, including bacterial infections. We computationally evaluated the potential binding of nine microbial siderophores into the β-barrel cavity of AAG and compared the results with the corresponding experimental data reported for siderophore-neutrophil gelatinase-associated lipocalin complexes. According to the results, petrobactin and Fe-BisHaCam are putative candidates to be recognized by this protein. It is proposed that AAG may function as a siderophore capturing component of the innate immune system being able to neutralize bacterial iron chelators not recognized by other siderocalins. [Display omitted] • Inclusion of microbial siderophores into the β-barrel of serum AAG was evaluated by molecular modeling methods. • In silico results suggest that AAG could potentially bind the stealth siderophore petrobactin and Fe-BisHaCam. • AAG may function as a siderophore capturing component neutralizing iron chelators not recognized by other siderocalins. [ABSTRACT FROM AUTHOR]

Milne Glacier is a marine-terminating glacier located on the northern coast of Ellesmere Island in the Canadian High Arctic, a region that has experienced extensive ice-mass loss over the last two decades. Milne Glacier flows into Milne Fiord where it transitions from grounded to floating at its grounding line. The glacier rests on a retrograde slope and is therefore potentially vulnerable to marine ice-sheet instability where enhanced basal melt and grounding-line retreat can trigger further deterioration of the glacier. Glacier changes that occur in the ice flexure zone, which spans from the hinge line, the inland limit of tidal flexure, past the grounding line to the landward limit of hydrostatic equilibrium, are critical for glacier dynamics. In this study, we quantify changes in the Milne Glacier grounding-line position from 1966 to 2023 using satellite, airborne, and ground radar observations. Double difference interferometric analysis of Synthetic Aperture Radar (DDInSAR) images acquired between 1992 and 2023 from European Remote Sensing (ERS-1/2) satellites, Sentinel-1 A/B, and RADARSAT Constellation Mission (RCM) was performed to delineate a timeseries of the hinge line. We used these hinge lines to quantify changes in the grounding-line position as their migration rates are directly correlated. RCM-derived results had the highest spatial resolution (10 m) and the best coherence between 4-day repeat acquisitions, which provided the most continuous and detailed hinge-line delineation across the glacier. We also used airborne and ground-based ice penetrating radar (IPR) data collected between 2014 and 2023 to calculate the normalized bed reflection (NBRP) and internal reflection power (NIRP) coefficients to distinguish between basal returns associated with water versus bed and assess signal attenuation within the ice column. Spatial patterns in NBRP and NIRP coefficients allowed us to reliably separate the floating and grounded parts of Milne Glacier. This alternate way of delineating the grounding line was in good agreement with our satellite-based DDInSAR results. Analysis of historical airborne radar surveys in 1966 and 1981 in conjunction with our more recent NBRP/NIRP analysis revealed a ∼3.1 km retreat (or ∼55 m yr−1) of the grounding line along the glacier centerline over the past 57 years. DDInSAR analysis provided additional details on this shift across the Milne Glacier. ERS and RCM images acquired in 3 and 4-day repeat cycles, respectively, revealed variability in hinge-line positions. This information allowed us to estimate the landward and seaward bounds, associated with the short-term hinge-line migration, that were used to quantify the grounding-line retreat over years. The grounding line retreat was highly asymmetric with the grounding-line retreating at over twice the average rate near the western margin (124 m yr−1) than at the center (53 m yr−1) of the glacier between 2011 and 2023. The calculated average retreat rates of grounding line showed a close association with changes in the ocean temperatures and subglacial discharge. Our study demonstrated that satellite-based monitoring of the hinge line at high spatiotemporal resolution is crucial to better assess the grounding line short-term positional variability and reliably quantify its long-term retreat. Airborne and ground-based radar observations can provide additional in-situ information to explain changes in the grounding line that affect glacier dynamics and viability. • The Milne Glacier grounding line retreated ∼3 km over the last 57 years. • The grounding line retreat was more pronounced on the western side of the glacier. • RCM provided the most detailed spatiotemporal information on hinge line variability. • Ground radar transects delineated grounded and floating glacier sections. • Satellite, airborne, and ground radar-derived grounding line positions agreed well. [ABSTRACT FROM AUTHOR]

Glycosaminoglycans (GAGs) is a particular class of linear anionic periodic polysaccharides, which play a key role in many cell signaling processes in the extracellular matrix by direct interactions with multiple proteins targets. Because of their periodic nature resulting in experimental challenges to study these molecules, computational approaches recently proved to be successful in complementing the experiments aimed to understand GAG interactions. However, the aspect of GAG binding of small, pharmacologically active molecules is still essentially understudied despite its significance. In this work, we apply computational approaches to rigorously characterize the interactions between GAGs and two trypanosoma active DNA targeting agents, berenil and pentamidine, which mainly differ in the structure of their intramolecular linkers connecting two benzamidine moieties. We thoroughly analyze their binding to heparin and chondroitin 6-sulfate in terms of dynamics, energetics and properties of π-stacked oligomeric structures of the drug molecules formed upon GAG association. Our work contributes to the general understanding of biologically relevant interactions between GAGs and small molecules which has potential impact in drug pharmacology and related therapeutic modalities. Image 1 • Glycosaminoglycan complexes of berenil and pentamidine were analyzed. • The differences in binding were described and explained at molecular level. • π-Stacked oligomers of drug molecules were characterized. • Rigorous computational approaches to analyze such π-stacks were proposed. [ABSTRACT FROM AUTHOR]

We present a benchmarking study for protein-glycosaminoglycan systems with eight docking programs: Dock, rDock, ClusPro, PLANTS, HADDOCK, Hex, SwissDock and ATTRACT. We used a non-redundant representative dataset of 28 protein-glycosaminoglycan complexes with experimentally available structures, where a glycosaminoglycan ligand was longer than a trimer. Overall, the ligand binding poses could be correctly predicted in many cases by the tested docking programs, however the ranks of the docking poses are often poorly assigned. Our results suggest that Dock program performs best in terms of the pose placement, has the most suitable scoring function, and its performance did not depend on the ligand size. This suggests that the implementation of the electrostatics as well as the shape complementarity procedure in Dock are the most suitable for docking glycosaminoglycan ligands. We also analyzed how free energy patterns of the benchmarking complexes affect the performance of the evaluated docking software. Image 1 • Performance of 8 docking programs for protein-glycosaminoglycan systems was analyzed. • Dock, ATTRACT and rDock revealed the best performance in general. • PLANTS demonstrated potentially the best scoring function. • Binding free energy patterns impact on docking performance was evaluated. • 14 docking programs were compared in terms of their utility for those systems. [ABSTRACT FROM AUTHOR]

This paper investigates the approximation properties of deep neural networks with piecewise-polynomial activation functions. We derive the required depth, width, and sparsity of a deep neural network to approximate any Hölder smooth function up to a given approximation error in Hölder norms in such a way that all weights of this neural network are bounded by 1. The latter feature is essential to control generalization errors in many statistical and machine learning applications. • Rates and complexity for smooth function approximation in Hölder norms by ReQU neural networks. • Explicit and uniform bounds for weights of the approximating neural network. • Exponential convergence rates for analytic functions. [ABSTRACT FROM AUTHOR]

Cysteine cathepsins constitute the largest cathepsin family, with 11 proteases in human that are present primarily within acidic endosomal and lysosomal compartments. They are involved in the turnover of intracellular and extracellular proteins. They are synthesized as inactive procathepsins that are converted to mature active forms. Cathepsins play important roles in physiological and pathological processes and, therefore, receive increasing attention as potential therapeutic targets. Their maturation and activity can be regulated by glycosaminoglycans (GAGs), long linear negatively charged polysaccharides composed of recurring dimeric units. In this review, we summarize recent computational progress in the field of (pro)cathepsin-GAG complexes analyses. [Display omitted] • Molecular modeling is crucial for better understanding GAG-mediated procathepsin maturation mechanisms at the atomic level. • In silico methods allow to study effect of length, charge and sulfation pattern on stability of cathepsin-GAG complexes. • Application of computational methods is essential in elucidating GAGs role in cathepsins enzymatic activity mediation. [ABSTRACT FROM AUTHOR]

Magma buoyancy is a mechanism usually neglected with respect to magma overpressure in eruption models constrained with geophysical data. In this study we provide evidence for a buoyancy-driven mechanism of magma ascent during the effusive phase of the 2008-2009 Chaitén rhyolitic eruption. We also constrain the volcano plumbing system with source models from InSAR and teleseismic data. InSAR data did not detect unambiguous evidence of pre-eruptive ground deformation up to 1 year before the eruption. Teleseismic data indicate that a dike opened twice during the first two days of the eruption, while InSAR data show that three sources deflated during the eruption. These include one dike and a sill during the onset of the eruption, and a spherical source halfway through it, all located at depths between 3 and 12 km. 75% of the total ground deformation of ∼0.5 m occurred during the first three weeks of the eruption. A Pléiades DEM show that the dome has a bulk volume of 1 km3, and was extruded with an exponential trend, but the lack of deformation during most of the effusive phase of the eruption implies that the dome extrusion did not result in depressurization of a magma reservoir. Instead, we show that the time series of extruded volume can be explained by magma ascending due its buoyancy instead of its overpressure. Further, the end of the first pulse of dome effusion in September 2008 can be explained by an increase in the dome surface load that equals the effect of the magma buoyancy. These results imply that in some cases ground deformation data alone cannot be used to forecast the temporal evolution of an eruption. They also call for the acquisition of denser time series of extruded volume, as a way to better constrain their evolution through time. • We present the first detailed analysis of the VEI 5 Chaitén rhyolitic eruption with geodetic and seismological data. • At least four magma sources were active during the extent of the eruption. • Lack of deformation during dome effusion indicates that magma buoyancy can drive the effusive phase of rhyolitic eruptions. [ABSTRACT FROM AUTHOR]

This paper describes an approach to analyze ground deformation data collected by InSAR (Interferometric Synthetic Aperture Radar) imaging the volcano feeding system (VFS) beneath a caldera. The approach is applied to the Campi Flegrei caldera in southern Italy, a densely populated area at high risk for volcanic eruption. The method is a 4D tomographic inversion that considers a combination of 3D pressure sources and dislocations (strike-slip, dip-slip and tensile) acting simultaneously. This is in contrast to traditional methods that assume a priori geometries and type for the volcanic source. Another novelty is that we carry out a time-series analysis of multifrequency InSAR displacement data. The analysis of these multiplatform and multifrequency InSAR data from 2011 to 2022 reveals an inflating source at a depth of 3–4 km that is interpreted as a pressurized magmatic intrusion. The source broadens and migrates laterally over time, with a possible new magmatic pulse arriving in 2018–2020. The model also identifies a shallow region (at 400 m depth) that may be feeding fumaroles in the area. The analysis also reveals a zone of weakness (dip-slip) that could influence the path of rising magma. This method provides a more detailed dynamic 4 - dimensional image of the VFS than previously possible and could be used to improve hazard assessments in active volcanic areas. • InSAR and state-of-the-art inversion technique to improve volcano monitoring. • Ground deformation of Campi Flegrei caldera from 2011 to 2022. • 4D geodetic tomography of the volcano feeding system below the caldera. • Identification of magmatic fluids paths and fractured regions below the caldera. [ABSTRACT FROM AUTHOR]

Glycosaminoglycans are long linear and complex polysaccharides that are fundamental components of the mammalian extracellular matrix. Therefore, it is crucial to appropriately characterize molecular structure, dynamics, and interactions of protein-glycosaminoglycans complexes for improving understanding of molecular mechanisms underlying GAG biological function. Nevertheless, this proved challenging experimentally, and theoretical techniques are beneficial to construct new hypotheses and aid the interpretation of experimental data. The scope of this mini-review is to summarize four specific aspects of the current theoretical approaches for investigating noncovalent protein-glycosaminoglycan complexes such as molecular docking, free binding energy calculations, modeling ion impact, and addressing the phenomena of multipose binding of glycosaminoglycans to proteins. • Dedicated molecular docking approaches are required for protein-glycosaminoglycan (GAG) systems. • Despite its limitations, molecular mechanics/Poisson-Boltzmann surface area remains the most useful free energy analysis tool. • The role of ions in protein-GAG interfaces should not be disregarded. • Multipose binding is an essential feature in protein-GAG modeling. [ABSTRACT FROM AUTHOR]

Abstract: Glycosaminoglycans (GAGs) of the extracellular matrix (ECM) contribute to the regulation of physiological processes by binding various immune-competent proteins. Due to their large structural diversity, the analysis of the binding properties and their functional consequences is challenging. The cytokine interleukin-8 (IL-8) is involved in the recruitment of neutrophils to inflammatory sites. Here, we investigated the interaction of heparin hexasaccharides and recombinant human IL-8, consisting of 77 amino acids using fluorescence and NMR spectroscopy. A dissociation constant of 2.0±0.4μM was determined for the heparin–IL-8 complex, which is slightly higher than what has been found for chondroitin-6-sulfate (K D =1.4±0.4μM) [Pichert, A.; Samsonov, S. A.; Theisgen, S.; Thomas, L.; Baumann, L.; Schiller, J.; Beck-Sickinger, A. G.; Huster, D.; Pisabarro, M. T. Glycobiology 2012, 22, 134–145], suggesting an important role of the sulfate group at position 6 of the second ring in the disaccharide unit of the GAGs in this interaction. In addition, the influence of long-chain hyaluronan, chondroitin sulfate, and heparin on IL-8-induced chemotaxis and oxidative activity of neutrophils was examined. Only the incubation of heparin with IL-8 affected the IL-8-mediated chemotaxis of neutrophils. However, all investigated GAGs enhanced the IL-8-induced formation of reactive oxygen species in neutrophils, which is an entirely new finding. This work provides a representative example of how protein functions can be regulated by different GAGs of the ECM. [Copyright &y& Elsevier]

Abstract: The α-helical coiled coil is a valuable folding motif for protein design and engineering. By means of phage display technology, we selected a capable binding partner for one strand of a coiled coil bearing a charged amino acid in a central hydrophobic core position. This procedure resulted in a novel coiled coil pair featuring an opposed Glu-Lys pair arranged staggered within the hydrophobic core of a coiled coil structure. Structural investigation of the selected coiled coil dimer by CD spectroscopy and MD simulations suggest that a buried salt bridge within the hydrophobic core enables the specific dimerization of two peptides. [Copyright &y& Elsevier]

Glycosaminoglycans (GAGs), anionic periodic linear polysaccharides, are involved in a manifold of key biochemical processes ongoing in the extracellular matrix via establishing direct intermolecular interactions with diverse classes of biopolymers as well as with bioactive small molecules. Due to their acidic nature, they are capable of binding positively charged ligands, which, in turn could affect their binding with protein and peptide targets, modulating a number of physiologically important signaling pathways. Therefore, it is of great significance to improve our understanding on the molecular basis underlying GAG-small molecule interactions. In this study, we applied in silico approaches (molecular dynamics and free energy calculations) complemented with circular dichroism and absorption spectroscopy to characterize the complex formation between heparin, one of the principal members of GAG family, and twenty different cationic ligands including therapeutic drugs, alkaloids and organic dyes. In particular, the oligomerization propensity of ligands prior to heparin binding, binding free energy parameters, effects of the ionic strength are rigorously described. Based on the performed analysis, the ligands are classified into three main groups depending on their heparin binding and oligomerization properties. The computational data agree and provide rationale for the corresponding experimental findings, contributing to the general knowledge of the physico-chemical nature of ligand-GAG intermolecular interactions. [Display omitted] • Heparin complexes of 20 small molecule ligands were in silico analyzed. • CD and absorption spectra of the complexes were measured. • The propensity of ligands to form oligomeric stacks was evaluated. • Ionic strength effect on the complex formation was characterized. • The ligands were classified into three groups depending on HP binding. [ABSTRACT FROM AUTHOR]

• New methodology constraining 3D volcanic sources using elementary sources aggregation. • It is effective in contexts where displacement is related to different sources. • No a-priori hypothesis about the causative sources is required. • The inversion process simultaneously inverts terrestrial and InSAR data. • It has been applied to the inversion of InSAR data for Mt. Etna during 2009-2013. Developments in Interferometric Synthetic Aperture Radar (InSAR) and GNSS (Global Navigation Satellite System) during the past decades have promoted significant advances in geosciences, providing high-resolution ground deformation data with dense spatio-temporal coverage. This large dataset can be exploited to produce accurate assessments of the primary processes occurring in geologically active areas. We present a new, original methodology to carry out a multi-source inversion of ground deformation data to better understand the subsurface causative processes. A nonlinear approach permits the determination of location, size and three-dimensional configuration, without any a priori assumption as to the number, nature or shape of the potential sources. The proposed method identifies a combination of pressure bodies and different types of dislocation sources (dip-slip, strike-slip and tensile) that represent magmatic sources and other processes such as earthquakes, landslides or groundwater-induced subsidence through the aggregation of elemental cells. This approach has the following features: (1) simultaneous inversion of the deformation components and/or line-of-sight (LOS) data; (2) simultaneous determination of diverse structures such as pressure bodies or dislocation sources, representing local and regional effects; (3) a fully 3D context; and (4) no initial hypothesis about the number, geometry or types of the causative sources is necessary. This methodology is applied to Mt. Etna (Southern Italy). We analyze the ground deformation field derived from a large InSAR dataset acquired during the January 2009 – June 2013 time period. The application of the inversion approach models several interesting buried structures as well as processes related to the volcano magmatic plumbing system, local subsidence within the Valle del Bove and seaward motion of eastern flank of the volcano. [ABSTRACT FROM AUTHOR]