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Introduction:Arterial stiffening is a hallmark of vascular ageing, and unravelling its underlying mechanisms has become a central theme in the field of cardiovascular disease. While various techniques and experimental setups are accessible for investigating biomechanics of blood vessels both in vivo and ex vivo, comparing findings across diverse methodologies is challenging. Methods:Arterial stiffness in the aorta of adult (5 months) and aged (24 months) wild-type C57Bl/6J mice was measured in vivo, after which ex vivo biomechanical evaluation was performed using the Rodent Oscillatory Tension Setup to study Arterial Compliance (ROTSAC; University of Antwerp, Belgium) and the DynamX setup (Maastricht University, The Netherlands). Stiffness of aortic tissue was measured in both absence and presence of activated smooth muscle cells (i.e., contraction). Measurements in both setups were conducted in parallel with matched protocols and identical buffers and chemicals. Results:Overall, both methods revealed age-related increased aortic stiffness, although parameters of aortic mechanics showed different numerical values, suggesting that results are not directly interchangeable between methods. Surprisingly, smooth muscle cell contraction had opposing effects between the setups. Indeed, smooth muscle cell contraction increased arterial stiffness in the ROTSAC but decreased stiffness in the DynamX. These opposing effects could be attributed to how the two setups differentially load the collagen fibres in the arterial wall, ex vivo. Conclusion:Overall, this study provided critical insights into how different experimental setups can influence the interpretation of aortic biomechanics, emphasizing the need for careful consideration and contextualization of results based on the methodology used.

Yves Menheere. The Way and Its Powers. An Ethnographic Account of Taoist Practice and Religious Authority in Northern Taiwan. Abhan-dlungen fur die Kunde des Morgenlandes, Band 119. Wiesbaden: Harrassowitz Verlag, [...]

Laboratory diagnosis of immune-mediated thrombotic thrombocytopenic purpura (iTTP) remains challenging when ADAMTS-13 activity ranges between 10% and 20%. To prevent misdiagnosis, open ADAMTS-13 conformation gained clinical attention as a novel biomarker, especially to diagnose acute iTTP in patients with diagnostic undecisive ADAMTS-13 activity. Plasma ADAMTS-13 conformation analysis corrects for ADAMTS-13 antigen, with both parameters being characterized in enzyme-linked immunosorbent assay (ELISA)-based reference assays requiring expert technicians.

Barbara Witt. Die 'Nezha-Legende' im Roman Investitur der Gotter (Fengshen yanyi): Eine literaturwissenschaftliche Untersuchung und Kontextualisierung. Wiesbaden: Harrassowitz Verlag, 2020. viii, 207 pp. Hardcover [euro]38.00, ISBN 978-3-447-11398-4. Science, whether consciously [...]

ADAMTS-13 adopts an open conformation in patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) in acute phase while being closed in healthy donors. We reported that a substantial number of patients with iTTP in remission with restored ADAMTS-13 activity (>50%) still had an open ADAMTS-13 conformation, although a closed conformation is expected given the extent of remission.

Clathrin-mediated endocytosis is an essential cellular internalization pathway involving the dynamic assembly of clathrin and accessory proteins to form membrane-bound vesicles. The evolutionarily ancient TSET–TPLATE complex (TPC) plays an essential, but ill-defined role in endocytosis in plants. Here we show that two highly disordered TPC subunits, AtEH1 and AtEH2, function as scaffolds to drive biomolecular condensation of the complex. These condensates specifically nucleate on the plasma membrane through interactions with anionic phospholipids, and facilitate the dynamic recruitment and assembly of clathrin, as well as early- and late-stage endocytic accessory proteins. Importantly, condensation promotes ordered clathrin assemblies. TPC-driven biomolecular condensation thereby facilitates dynamic protein assemblies throughout clathrin-mediated endocytosis. Furthermore, we show that a disordered region of AtEH1 controls the material properties of endocytic condensates in vivo. Alteration of these material properties disturbs the recruitment of accessory proteins, influences endocytosis dynamics and impairs plant responsiveness. Our findings reveal how collective interactions shape endocytosis.

The interactions between gold nanoparticles, their surface ligands and the solvent critically influence the properties of these nanoparticles. Although spectroscopic and scattering techniques have been used to investigate their ensemble structure, a comprehensive understanding of these processes at the nanoscale remains challenging. Electron microscopy makes it possible to characterize the local structure and composition but is limited by insufficient contrast, electron beam sensitivity and the requirement for ultrahigh-vacuum conditions, which prevent the investigation of dynamic aspects. Here we show that, by exploiting high-quality graphene liquid cells, we can overcome these limitations and investigate the structure of the ligand shell around gold nanoparticles and at the ligand–gold interface in a liquid environment. Using this graphene liquid cell, we visualize the anisotropy, composition and dynamics of ligand distribution on gold nanorod surfaces. Our results indicate a micellar model for surfactant organization. This work provides a reliable and direct visualization of ligand distribution around colloidal nanoparticles.

Atherosclerosis is a progressive inflammatory disorder of the arterial vessel wall characterized by substantial infiltration of macrophages, which exert both favourable and detrimental functions. Early in atherogenesis, macrophages can clear cytotoxic lipoproteins and dead cells, preventing cytotoxicity. Efferocytosis — the efficient clearance of dead cells by macrophages — is crucial for preventing secondary necrosis and stimulating the release of anti-inflammatory cytokines. In addition, macrophages can promote tissue repair and proliferation of vascular smooth muscle cells, thereby increasing plaque stability. However, advanced atherosclerotic plaques contain large numbers of pro-inflammatory macrophages that secrete matrix-degrading enzymes, induce death in surrounding cells and contribute to plaque destabilization and rupture. Importantly, macrophages in the plaque can undergo apoptosis and several forms of regulated necrosis, including necroptosis, pyroptosis and ferroptosis. Regulated necrosis has an important role in the formation and expansion of the necrotic core during plaque progression, and several triggers for necrosis are present within atherosclerotic plaques. This Review focuses on the various forms of programmed macrophage death in atherosclerosis and the pharmacological interventions that target them as a potential means of stabilizing vulnerable plaques and improving the efficacy of currently available anti-atherosclerotic therapies.

The Mediterranean fruit fly (medfly), Ceratitis capitata, is a highly polyphagous pest that is economically important for fruit production in tropical, subtropical and temperate regions. It is considered a cosmopolitan pest due to its extreme invasiveness and has established populations in all continents except Antarctica. The medfly’s broad range of host plants and distinctive biological, behavioral, and genetic traits help it easily adapt to and colonize novel environments. This review provides an overview of the specific characteristics of this species and its current distribution and invasiveness. It also outlines future challenges for medfly bioecology and invasiveness.

Population monitoring and management of the Mediterranean fruit fly (medfly), Ceratitis capitata (Diptera: Tephritidae), are still challenging, and are tightly connected to a deep understanding of its biology and ecology. Within this framework, new innovative control approaches and tools are frequently proposed and developed to integrate the available techniques and to overcome the difficulties involved in designing effective Integrated Pest Management programs. Indeed, some biological, ecological, and genetic characteristics of C. capitata can limit the efficacy of classical pest management strategies. This article provides a comprehensive review of the currently available tools, devices and approaches used to monitor and control medfly populations worldwide.

Ceratitisis an economically important genus of fruit flies that originated in Africa, has a wide host range, and causes serious economic losses due to its invasive damage. As a result, it is critical to identify them accurately and quickly in the world. Loop-mediated isothermal amplification (LAMP), as one of the representatives of isothermal amplification technology, has been widely used in the rapid nucleic acid detection of human pathogens and has shown its advantages in the identification of insect agricultural pests. In this study, using the mitochondrial cox1and cobgenes as target genes, the rapid molecular identification of the CeratitisFARQ complex, C. cosyra,and C. capitatawas realized based on LAMP. The experimental conditions optimization results showed that F3/B3:FIP/BIP = 1:8 was the optimal primer concentration ratio and 63 °C was the optimal reaction temperature. The sensitivity of the primers obtained in this study can reach up to 0.01 ng/μl DNA. A loop-mediated isothermal amplification identification technology system was established based on rapid, rough DNA extraction and visual detection of Ceratitiseconomically important fruit flies. The positive reaction system changed from pink to khaki by visual detection. The identification flow can be completed within 1 hour, including sample processing, DNA extraction, and LAMP visual detection.

The chemical absorption of CO2and H2S in aqueous tertiary amines is a well-known acid–base reaction. Kinetic and vapor–liquid equilibrium experiments show that the addition of an amide such as HMPA, which is known to be a strong liquid structure maker, significantly inhibits the acid–base reactions. The impact is more pronounced for CO2than for H2S absorption. Despite the presence of water in the solvent, the absorption becomes almost physical. Due to hydrogen bonding and the hydrophobic effect, each amide molecule is involved in a cluster containing several water molecules, thus rendering the water molecules less available to participate in the reaction and to solvate HS–and HCO3–ions. This effect is absent when ethylene glycol, a weak structure maker, is added, even in large quantities. This study demonstrates the importance of solvent structure in the study of chemical reactions. State-of-the-art molecular dynamics simulations of the water–HMPA system could not reproduce the strongly negative excess volume of the mixture. This illustrates the need for more accurate force fields to simulate the structuring effect and their impact on chemical reactions.

This review aims to provide a comprehensive guideline for authors to encourage more consistent calculations in plasma-based CO2 conversion and stimulate the further development of this technology.

In the treatment of many fuel gases such as biogas, natural gas, syngas, and so on, tertiary alkanolamines play an important role in the selective removal of H2S with respect to CO2. The selectivity might be required for various reasons: to respect more stringent H2S specifications, to optimize the performance of the Claus unit, to lower the cost of CO2capture, and so on. The H2S/CO2selectivity is mainly kinetic and, to a lesser extent, thermodynamic. A novel experimental setup has been put in place to measure the time evolution of the simultaneous absorption of H2S and CO2. The results of an extensive experimental campaign with 18 different aqueous tertiary alkanolamine solvents (13 mol % amine, 87 mol % H2O) are presented. Although the absorption of H2S is expected to be a very fast proton transfer, a significant variation in H2S absorption rates and thus in selectivity is observed. This could not only be explained by the pKaor the viscosity of the amines. Therefore, an accurate quantitative molecular simulations-based kinetic model is developed and validated. The study allowed us to better understand the molecular origin of selectivity, as well as to identify amines with a higher selectivity than aqueous MDEA (MethylDiEthanolAmine), the standard industrial selective solvent.

He is a participant and mentor in the boundary-breaking Brown in the South collective of chefs who are challenging the norms of Indian food, Southern food, and even American food. In 2009, he opened the first location of Chai Pani, his Indian street food restaurant that brought a bold, uncompromising vision of Indian food to life, in Asheville, North Carolina. BY MAHIRA RIVERS After moving to America from India for grad school, chef Meherwan Irani quickly grew frustrated with the generic buffets that seemed to be the status quo in South Asian restaurants. I photography by i GREG DUPREE REEM ASSIL The chef is turning her restaurant into an employee-owned co-op, hoping it will serve as a model for others. [Extracted from the article]

Tephritidae is one of the largest families of Diptera, with high diversity and a wide global distribution, and includes numerous important agricultural pests. However, the origin, phylogeny, and evolutionary history remain poorly understood. We undertook the first comprehensive mitogenomic study covering phylogenetic reconstruction, divergence time estimation, and historical biogeography analyses by analyzing 147 mitochondrial genomes representing three subfamilies, seven tribes, 11 genera, and 82 species. Within the Dacini subfamily, our phylogeny strongly supported the sister group relationship of (Zeugodacus + Dacus) + Bactrocera, which further supported to the elevation of Zeugodacus to the generic level of Dacini. On the other hand, our molecular phylogenetic analyses did not align well with the currently recognized subgeneric designations within Ceratitis, Dacus, and Zeugodacus. Some subgenera were recovered as polyphyletic or paraphyletic, implying the incongruence between morphological characters and mitogenomic data. Neither the taxa within the Ceratitis FARQ complex (formerly FAR complex) nor those within the Bactrocera dorsalis complex could be clearly distinguished by mitochondrial phylogenetic trees as distinct species corresponding to the morphospecies. Divergence time estimation and historical biogeography analyses indicated that the earliest common ancestor of Tephritidae, originated in the Palaearctic realm at 138.92-71.44 Ma (million years ago), with the subsequent divergence into Dacinae + Trypetinae and Tephritinae at 115.19-67.45 Ma equally in the Palaearctic realm. Dacini might have originated in Laurasia rather than Gondwana, and diverged into Bactrocera and Dacus + Zeugodacus at 48.43-28.70 Ma after the India plate docked with Laurasia.

We developed an open-source chemical reaction equilibrium solver in Python (CASpy, https://github.com/omoultosEthTuDelft/CASpy) to compute the concentration of species in any reactive liquid-phase absorption system. We derived an expression for a mole fraction-based equilibrium constant as a function of excess chemical potential, standard ideal gas chemical potential, temperature, and volume. As a case study, we computed the CO2absorption isotherm and speciation in a 23 wt % N-methyldiethanolamine (MDEA)/water solution at 313.15 K, and compared the results with available data from the literature. The results show that the computed CO2isotherms and speciations are in excellent agreement with experimental data, demonstrating the accuracy and the precision of our solver. The binary absorptions of CO2and H2S in 50 wt % MDEA/water solutions at 323.15 K were computed and compared with available data from the literature. The computed CO2isotherms showed good agreement with other modeling studies from the literature while the computed H2S isotherms did not agree well with experimental data. The experimental equilibrium constants used as an input were not adjusted for H2S/CO2/MDEA/water systems and need to be adjusted for this system. Using free energy calculations with two different force fields (GAFF and OPLS-AA) and quantum chemistry calculations, we computed the equilibrium constant (K) of the protonated MDEA dissociation reaction. Despite the good agreement of the OPLS-AA force field (ln[K] = −24.91) with the experiments (ln[K] = −23.04), the computed CO2pressures were significantly underestimated. We systematically investigated the limitations of computing CO2absorption isotherms using free energy and quantum chemistry calculations and showed that the computed values of μiexare very sensitive to the point charges used in the simulations, which limits the predictive power of this method.

Congenital thrombotic thrombocytopenic purpura (cTTP) is caused by a severe deficiency in the plasma metalloprotease ADAMTS-13. The current management of cTTP is dependent on the prophylactic administration of ADAMTS-13 via plasma infusion. This is a demanding therapy for patients because transfusions are lifelong and time-consuming and allergic reactions frequently occur. Although current management of cTTP controls acute episodes, it does not provide a long-lasting cure for this disease. The endogenous expression of ADAMTS-13 after gene transfer would provide a curative therapy and ongoing research explores various preclinical gene therapeutic approaches for cTTP. This review focuses on the current state of the literature regarding preclinical gene therapy studies for cTTP and on the challenges of developing a gene therapy medicinal product for cTTP.

Congenital thrombotic thrombocytopenic purpura is caused by defects in the ADAMTS13gene. ADAMTS13 is normally preactivated by conformational changes of the Metalloprotease (M) domain. Studying a novel congenital thrombotic thrombocytopenic purpura p.R102S mutation in the M domain, which results in undetectable ADAMTS13 activity in the patient, could help to explain the patients’ phenotype and to elucidate the currently unclear mechanism of allosteric preactivation.

The removal of CO2and H2S from a gas by absorption with an aqueous alkanolamine solution is an energy-intensive process. The addition of a physical cosolvent might lower the regeneration energy but also affects the thermodynamics and kinetics of acid gas absorption. In this work, we study the impact on the thermodynamics and kinetics of CO2and H2S absorption of the addition of 1,3-dimethyl-2-imidazolidinone (DMI) to the aqueous 2-(2-diethylaminoethoxy)ethanol (DEAE-EO) solvent. A comparison is made with the impact of DMI on an aqueous methyldiethanolamine (MDEA) solvent. In all cases, DMI reduced the solubility and the absorption rate of the acid gases. DMI also reduced the initial kinetic H2S/CO2selectivity, although this effect seems much more pronounced in aqueous MDEA than in aqueous DEAE-EO. The equilibrium thermodynamic H2S/CO2selectivity is higher in the presence of DMI.

1.Spacer-CUB interactions maintain the ADAMTS13 global latency to structurally constrain its proteolytic function.2.An opening anti-ADAMTS13 CUB1 mAb uncouples the spacer-CUB domain interaction indirectly to disrupt the ADAMTS13 global latency.

Following the industrial revolution and the modernization of chemistry, purple became one of the most popular colors in the palettes of late 19th- to 20th-century painters. Among them, Robert Delaunay (1885–1941) was one of the key artists of the avant-garde movement in France in the early 20th century. Although widely used in modern and contemporary paintings, inorganic purple pigments of the cobalt phosphate and cobalt arsenate families have been little studied chemically until now. The diversity of emerging chemical syntheses resulted in a wide range of products, characterized by a high diversity of hues, function of their respective composition, and crystal structures. The present work combines structural and optical analyses to probe the purple pigments used by Delaunay. Reference materials synthesized in the laboratory were characterized via synchrotron radiation-based high-angular-resolution X-ray powder diffraction and UV–vis–NIR spectroscopy. Structure–color relationships were established for the first time for several inorganic compounds of the Co–P/As family. Two of Robert Delaunay’s earliest masterpieces conserved at the Centre Pompidou in Paris were probed in situ via X-ray powder diffraction in imaging mode and fiber optic UV–vis–NIR reflectance spectroscopy. The results highlight the decisive effect of their structural chemistry on the palettes of modern and contemporary painters.

This article reports on the discovery of pararealgar and semi-amorphous pararealgar in Rembrandt's masterpiece The Night Watch. A large-scale research project named Operation Night Watchwas started in 2019.A variety of non-invasive analytical imaging techniques, together with paint sample research, has provided new information about Rembrandt's pigments, materials, and techniques as well as the current condition of the painting. Macroscopic X-ray fluorescence, macroscopic X-ray powder diffraction and reflectance imaging spectroscopy identified the presence of arsenic sulfide pigments and degradation products of these pigments in the doublet sleeves and embroidered buff coat worn by Lieutenant Willem van Ruytenburch (central figure to the right of Captain Frans Banninck Cocq). Examination by light microscopy of two paint samples taken from this area shows a mixture of large sharp-edged tabular yellow and orange to red pigment particles, and scanning electron microscopy-energy dispersive X-ray analysis identified these particles as containing arsenic and sulfur. Using micro-Raman spectroscopy, the yellow particles were identified as pararealgar, and the orange to red particles as semi-amorphous pararealgar. Synchrotron-based X-ray diffraction allowed visualization of the presence of multiple degradation products associated with arsenic sulfides throughout the paint layer. The discovery of pararealgar and semi-amorphous pararealgar is a new addition to Rembrandt's pigment palette. To contextualize our findings and to hypothesize why, how, and where Rembrandt obtained the pigments, we studied related historical sources. A comprehensive review of historical sources gives insight into the types of artificial arsenic sulfides that were available and suggests that a broader range of arsenic pigments could have been available in Amsterdam in the seventeenth century than previously thought. This is supported by the use of a very similar mixture of pigments by Willem Kalf (1619–1693), a contemporary artist based in Amsterdam. Together with the condition of the particles in the paint cross sections, this brings us to the conclusion that Rembrandt intentionally used pararealgar and semi-amorphous pararealgar, together with lead–tin yellow and vermilion, to create an orange paint.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is an ultrarare thrombotic disease caused by autoantibody-induced ADAMTS13 deficiency. Open ADAMST13 conformation, induced by autoantibodies, was identified as a novel biomarker for iTTP. Determining immunoprofiles in patients with iTTP has been shown to guide the development of novel targeted therapies. However, these studies were done in mainly Caucasian iTTP cohorts. To validate those findings across other ethnic cohorts, we investigated 195 acute TTP plasma samples from the Japanese iTTP registry. Seventy-six of the 195 samples had detectable ADAMTS13 antigen levels, of which 94.7% were shown to have an open ADAMTS13 conformation. A positive correlation was observed between ADAMTS13 inhibitor titers (a diagnostic parameter in Japan) and anti-ADAMTS13 immunoglobulin G autoantibody titers. Studying anti-M, anti-DT, anti-CS, anti-T2-T5, anti-T6-T8, anti–CUB1-2 autoantibodies and the corresponding immunoprofile showed that 73% of the patients had anti-CS autoantibodies and 25.8% had anti-M autoantibodies, with the latter being higher than in Caucasians. Stratifying patients according to their immunoprofiles revealed that the profile with only anti-CS autoantibodies was the most common immunoprofile similar to that in Caucasians (28.9%). Although this profile did not affect the 1-year TTP-related mortality rate, patients with autoantibodies against all 6 ADAMTS13 fragments had a higher risk for TTP-related death than other patients (P = .02). We here validated open ADAMTS13 as a novel biomarker for acute iTTP and determined the dominant immunoprofiling in the Japanese cohort, contributing to setting up the diagnosis and managing guidelines across different ethnic cohorts and developing ADAMTS13 variants that do not bind to the anti-CS autoantibodies.

In rural areas, parcel deliveries are characterized by a lack of drop density and high-mileage delivery. As a result, rural areas are difficult to make profitable for each individual carrier company. The VIL project “Rural Parcel Delivery” investigates the effect of 2 cooperation strategies: (1) Parcel delivery outsourced to a neutral third party from a common distribution hub and (2) Setting up a shared network of collection points between carriers. MooV has developed a model of the parcel delivery chain to assess the impact of these cooperation strategies on the efficiency of parcel deliveries as well as the location of the common hub. Given the obtained input data for the Walloon region, joint delivery in rural areas results in a reduction in costs (-35%) and CO2emissions (-60%). Large differences exist between carriers based on the type of their delivery network and parcel volume.

Separate logistics of building materials to construction sites generate many truck movements, increased mileage and increased on-site storage costs and damage risks due to the ill planned deliveries. With the Construction Hubs-project the impact of a hub for centralising construction materials at the edge of the city is investigated.

Introduction: Cotrimoxazole (CTX) 800/160 mg daily or thrice-weekly is recommended as prophylaxis of Pneumocystis jiroveciipneumonia in kidney transplant recipients. Cotrimoxazole 800/160 daily elevates plasma creatinine and potassium levels but whether the thrice-weekly regimen does so is unknown. Methods: Medical records of 225 kidney transplant recipients at Cliniques Universitaires Saint-Luc were analyzed retrospectively. All received thrice-weekly CTX 800/160 for 6 months after transplantation. Monthly laboratory results, co-medications, and tacrolimus trough levels were compared. Standard statistical tests were used. Results: One month after CTX stop, creatinine level decreased by 0.11 mg/dl (8%, p = 0.029). This contrasts with its stability in previous and subsequent months. No co-medication change accounted for this decrease. The decrease averaged 0.17 mg/dl (p < 0.01) in the highest initial creatinine tertile. The higher the initial creatinine level, the greater the decrease after CTX stop (p < 0.001), and urea levels remained stable after CTX stop. Potassium levels decreased by 0.09 mmol/L (p = 0.021) one month after CTX stop, and decreased by 0.23 mmol/L (p < 0.01) in the highest initial potassium level tertile. Conclusions: Our study pinpoints the impact of CTX 800/160 thrice-weekly on creatinine and potassium levels in kidney transplant recipients. This should be considered when interpreting the evolution of plasma creatinine over time, especially in patients with graft dysfunction. Thus, creatinine levels of cohorts with 6 months versus lifelong CTX require different interpretations. Graphical abstract:

Dengue is a major health threat and the number of symptomatic infections caused by the four dengue serotypes is estimated to be 96 million1with annually around 10,000 deaths2. However, no antiviral drugs are available for the treatment or prophylaxis of dengue. We recently described the interaction between non-structural proteins NS3 and NS4B as a promising target for the development of pan-serotype dengue virus (DENV) inhibitors3. Here we present JNJ-1802—a highly potent DENV inhibitor that blocks the NS3–NS4B interaction within the viral replication complex. JNJ-1802 exerts picomolar to low nanomolar in vitro antiviral activity, a high barrier to resistance and potent in vivo efficacy in mice against infection with any of the four DENV serotypes. Finally, we demonstrate that the small-molecule inhibitor JNJ-1802 is highly effective against viral infection with DENV-1 or DENV-2 in non-human primates. JNJ-1802 has successfully completed a phase I first-in-human clinical study in healthy volunteers and was found to be safe and well tolerated4. These findings support the further clinical development of JNJ-1802, a first-in-class antiviral agent against dengue, which is now progressing in clinical studies for the prevention and treatment of dengue.

Acquired von Willebrand syndrome (aVWS) is common in patients with mechanical circulatory support (MCS) devices. In these patients, the high shear stress in the device leads to increased shear‐induced proteolysis of von Willebrand factor (VWF) by A Disintegrin And Metalloprotease with Thrombospondin type 1 repeats, number 13 (ADAMTS13). As a result, the high molecular weight (HMW) VWF multimers are lost, leading to a decreased VWF function and impaired hemostasis that could explain the bleeding complications that are frequently observed in these patients. To counteract this abnormal VWF degradation by ADAMTS13, we developed a novel targeted therapy, using an anti‐ADAMTS13 monoclonal antibody (mAb) that inhibits the shear‐induced proteolysis of VWF by ADAMTS13. Human or bovine blood was circulated through in vitroMCS device systems with either inhibitory anti‐ADAMTS13 mAb 3H9 or 17C7 (20 μg/ml) or control anti‐ADAMTS13 mAb 5C11 or phosphate buffered saline (PBS). VWF multimers and function (collagen binding activity) were determined at different time points. Next, Impella pumps were implanted in calves and the calves were injected with PBS and subsequently treated with mAb 17C7. VWF, ADAMTS13, and blood parameters were determined. We demonstrated that blocking ADAMTS13 could prevent the loss of HMW VWF multimers in in vitroMCS device systems. Importantly, our antibody could reverse aVWS in a preclinical Impella‐induced aVWS calf model. Hence, inhibition of ADAMTS13 could become a novel therapeutic strategy to manage aVWS in MCS device patients.

Acquired von Willebrand syndrome (aVWS) is common in patients with mechanical circulatory support (MCS) devices. In these patients, the high shear stress in the device leads to increased shear‐induced proteolysis of von Willebrand factor (VWF) by A Disintegrin And Metalloprotease with Thrombospondin type 1 repeats, number 13 (ADAMTS13). As a result, the high molecular weight (HMW) VWF multimers are lost, leading to a decreased VWF function and impaired hemostasis that could explain the bleeding complications that are frequently observed in these patients. To counteract this abnormal VWF degradation by ADAMTS13, we developed a novel targeted therapy, using an anti‐ADAMTS13 monoclonal antibody (mAb) that inhibits the shear‐induced proteolysis of VWF by ADAMTS13.

Endocytosis controls the perception of stimuli by modulating protein abundance at the plasma membrane. In plants, clathrin-mediated endocytosis is the most prominent internalization pathway and relies on two multimeric adaptor complexes, the AP-2 and the TPLATE complex (TPC). Ubiquitination is a well-established modification triggering endocytosis of cargo proteins, but how this modification is recognized to initiate the endocytic event remains elusive. Here we show that TASH3, one of the large subunits of TPC, recognizes ubiquitinated cargo at the plasma membrane via its SH3 domain-containing appendage. TASH3 lacking this evolutionary specific appendage modification allows TPC formation but the plants show severely reduced endocytic densities, which correlates with reduced endocytic flux. Moreover, comparative plasma membrane proteomics identified differential accumulation of multiple ubiquitinated cargo proteins for which we confirm altered trafficking. Our findings position TPC as a key player for ubiquitinated cargo internalization, allowing future identification of target proteins under specific stress conditions.

During atherosclerosis, lipid-rich plaques are formed in large- and medium-sized arteries, which can reduce blood flow to tissues. This situation becomes particularly precarious when a plaque develops an unstable phenotype and becomes prone to rupture. Despite advances in identifying and treating vulnerable plaques, the mortality rate and disability caused by such lesions remains the number one health threat in developed countries. Vulnerable, unstable plaques are characterized by a large necrotic core, implying a prominent role for necrotic cell death in atherosclerosis and plaque destabilization. Necrosis can occur accidentally or can be induced by tightly regulated pathways. Over the past decades, different forms of regulated necrosis, including necroptosis, ferroptosis, pyroptosis, and secondary necrosis, have been identified, and these may play an important role during atherogenesis. In this review, we describe several forms of necrosis that may occur in atherosclerosis and how pharmacological modulation of these pathways can stabilize vulnerable plaques. Moreover, some challenges of targeting necrosis in atherosclerosis such as the presence of multiple death-inducing stimuli in plaques and extensive cross-talk between necrosis pathways are discussed. A better understanding of the role of (regulated) necrosis in atherosclerosis and the mechanisms contributing to plaque destabilization may open doors to novel pharmacological strategies and will enable clinicians to tackle the residual cardiovascular risk that remains in many atherosclerosis patients.

AbstractBackgroundPostoperative cardio-surgical haemostatic management is centre-specific and experience-based, which leads to a variability in patient care. This study aimed to identify which postoperative haemostatic interventions may reduce the need for reoperation after cardiac surgery in adults.MethodsA retrospective case-control study in a tertiary centre. Adult, elective, primary cardiac surgical patients were selected (n = 2098); cases (n = 42) were patients who underwent reoperation within 72 h after the initial surgery. Interventions administered to control surgical bleeding were compared for the need to re-operate using multiple logistic regression.ResultsRate of cardiac surgical reoperation was 2% in the study population. Three variables were found to be associated with cardiac reoperation: preoperative administration of fresh frozen plasma (OR 5.45, CI 2.34-12.35), cumulative volume of chest tube drainage and cumulative count of packed red blood cells transfusion on ICU (OR 1.98, CI 1.56-2.51).ConclusionNo significant difference among specific types of postoperative haemostatic interventions was found between patients who needed reoperation and those who did not. Perioperative transfusion of fresh frozen plasma, postoperative transfusion of packed cells and cumulative volume of chest tube drainage were associated with reoperation after cardiac surgery. These variables could help predict the need for reoperation.

Intra‐device thrombosis remains one of the most common complications during extracorporeal membrane oxygenation (ECMO). Despite anticoagulation, approximately 35% of patients develop thrombi in the membrane oxygenator, pump heads, or tubing. The aim of this study was to describe the molecular and cellular features of ECMO thrombi and to study the main drivers of thrombus formation at different sites in the ECMO circuits. Thrombi (n= 85) were collected immediately after veno‐arterial‐(VA)‐ECMO circuit removal from 25 patients: 23 thrombi from the pump, 25 from the oxygenator, and 37 from the tubing. Quantitative histological analysis was performed for the amount of red blood cells (RBCs), platelets, fibrin, von Willebrand factor (VWF), leukocytes, and citrullinated histone H3 (H3Cit). ECMO thrombi consist of a heterogenous composition with fibrin and VWF being the major thrombus components. A clustering analysis of the four major histological parameters identified two typical thrombus types: RBC‐rich and RBC‐poor/fibrin‐rich thrombi with no significant differences in VWF and platelet content. Thrombus composition was not associated with the thrombus location, except for higher amounts of H3Cit that were found in pump and oxygenator thrombi compared to tubing samples. We observed higher blood leukocyte count and lactate dehydrogenase levels in patients with fibrin‐rich thrombi. We found that thrombus composition is heterogenous, independent of their location, consisting of two types: RBC‐rich and a fibrin‐rich types. We also found that NETs play a minor role. These findings are important to improve current anticoagulation strategies in ECMO.

Bleeding and thrombosis are major clinical problems with high morbidity and mortality. Treatment modalities for these diseases have improved in recent years, but there are many clinical questions remaining and a need to advance diagnosis, management, and therapeutic options. Basic research plays a fundamental role in understanding normal and disease processes, yet this sector has observed a steady decline in funding prospects thereby hindering support for studies of mechanisms of disease and therapeutic development opportunities. With the financial constraints faced by basic scientists, the ISTH organized a basic science task force (BSTF), comprising Scientific and Standardization Committee subcommittee chairs and co‐chairs, to identify research opportunities for basic science in hemostasis and thrombosis. The goal of the BSTF was to develop a set of recommended priorities to build support in the thrombosis and hemostasis community and to inform ISTH basic science programs and policy making. The BSTF identified three principal opportunity areas that were of significant overarching relevance: mechanisms causing bleeding, innate immunity and thrombosis, and venous thrombosis. Within these, five fundamental research areas were highlighted: blood rheology, platelet biogenesis, cellular contributions to thrombosis and hemostasis, structure–function protein analyses, and visualization of hemostasis. This position paper discusses the importance and relevance of these opportunities and research areas, and the rationale for their inclusion. These findings have implications for the future of fundamental research in thrombosis and hemostasis to make transformative scientific discoveries and tackle key clinical questions. This will permit better understanding, prevention, diagnosis, and treatment of hemostatic and thrombotic conditions.

Despite decades of promising preclinical validation and clinical translation, ischemic stroke still remains as one of the leading causes of death and disability worldwide. Within its complex pathophysiological signatures, thrombosis and inflammation, that is, thromboinflammation, are highly interconnected processes leading to cerebral vessel occlusion, inflammatory responses, and severe neuronal damage following the ischemic event. Hence, we here review the most recent updates on thromboinflammatory-dependent mediators relevant after stroke focusing on recent discoveries on platelet modulation, a potential regulation of the innate and adaptive immune system in thromboinflammation, utterly providing a thorough up-to-date overview of all therapeutic approaches currently undergoing clinical trial.

Partnerships are important to small, fledgling organizations yet many such ventures fail because they have been forged for the wrong reasons or managed badly. A study on the creation and development of start-up, high-technology firms sought to determine when and under what conditions a strategic alliance is required by these firms, what form it ought to take, and what observation can be made about the successful management of these partnerships.

Florian C. Reiter. The Beginning of the Subtle School of Taoism: An Official Perception of Taoism in the Early T'ang Period. Abhandlungen fur die Kunde des Morgenlandes, Band 94. Wiesbaden: [...]

BackgroundRelationships between occlusive clot histopathology, baseline characteristics, imaging findings, revascularization rates, and clinical outcomes of stroke patients with large vessel occlusion (LVO) are not well understood. This study will assess the real-world experience on the efficacy and safety of using the EmboTrap device as the first approach in LVO patients and explore the associations between clot histological characteristics, imaging and clinical findings, revascularization rates, and clinical outcomes.MethodsProspective, global, multicenter, single-arm, imaging core laboratory, and clot analysis central laboratory observational registry. Adult patients (>18 years) with LVO, treated with EmboTrap as the first attempted device, will be eligible for study participation.ResultsUp to 1000 subjects at 50 international sites may be enrolled. Occlusive clots will be collected from at least 500 subjects. Independent central and imaging core laboratories will perform clot analysis and image adjudication. Statistical analysis will assess the association between imaging and clinical findings, clot characteristics, subject comorbidities, revascularization, and clinical outcomes. Study endpoints are functional independence (modified Rankin Scale score ≤2 at 90 days), expanded Thrombolysis In Cerebral Infarction (eTICI) score ≥2b50 rate, first-pass effect, number of passes, embolization into new territory, symptomatic intracranial hemorrhage, and 90-day mortality.ConclusionsThe EXCELLENT registry will provide reproducible effectiveness and safety data of EmboTrap for its use for mechanical thrombectomy. Additionally, the study will characterize the blood clots retrieved during mechanical thrombectomy with respect to their composition and histopathological analysis and potential correlations with clinical and imaging findings.Trial registration numberNCT03685578.