Background
Milvexian (BMS‐986177/JNJ‐70033093) is an orally bioavailable factor XIa (FXIa) inhibitor currently in phase 2 clinical trials.
Objectives
To evaluate in vitro properties and in vivo ...characteristics of milvexian.
Methods
In vitro properties of milvexian were evaluated with coagulation and enzyme assays, and in vivo profiles were characterized with rabbit models of electrolytic‐induced carotid arterial thrombosis and cuticle bleeding time (BT).
Results
Milvexian is an active‐site, reversible inhibitor of human and rabbit FXIa (Ki 0.11 and 0.38 nM, respectively). Milvexian increased activated partial thromboplastin time (APTT) without changing prothrombin time and potently prolonged plasma APTT in humans and rabbits. Milvexian did not alter platelet aggregation to ADP, arachidonic acid, or collagen. Milvexian was evaluated for in vivo prevention and treatment of thrombosis. For prevention, milvexian 0.063 + 0.04, 0.25 + 0.17, and 1 + 0.67 mg/kg+mg/kg/h preserved 32 ± 6*, 54 ± 10*, and 76 ± 5%* of carotid blood flow (CBF) and reduced thrombus weight by 15 ± 10*, 45 ± 2*, and 70 ± 4%*, respectively (*p < .05; n = 6/dose). For treatment, thrombosis was initiated for 15 min and CBF decreased to 40% of control. Seventy‐five minutes after milvexian administration, CBF averaged 1 ± 0.3, 39 ± 10, and 66 ± 2%* in groups treated with vehicle and milvexian 0.25 + 0.17 and 1 + 0.67 mg/kg+mg/kg/h, respectively (*p < .05 vs. vehicle; n = 6/group). The combination of milvexian 1 + 0.67 mg/kg+mg/kg/h and aspirin 4 mg/kg/h intravenous did not increase BT versus aspirin monotherapy.
Conclusions
Milvexian is an effective antithrombotic agent with limited impact on hemostasis, even when combined with aspirin in rabbits. This study supports inhibition of FXIa with milvexian as a promising antithrombotic therapy with a wide therapeutic window.
Inorganic solid electrolytes are the most important component for realizing all-solid-state batteries with lithium metal anodes and enable safe battery cells with high energy densities. Their ...synthesis and processing are the subject of current research, especially the NASICON-type Li
1+x
AlxTi
2-x
(PO
4
)
3
(LATP). Herein, the ability of sintering with electro-magnetic irradiation is investigated and correlated with different properties of prepared LATP pellets. First of all, an infrared camera records the temperature of the surface during the treatment. Second, the effect of the pulse fluence is investigated in terms of the topology and morphology of the pellets. Here, the arithmetic surface roughness Ra is the main parameter. Then, the depth of the radiation interaction in the pellet is measured. The focus of this paper is on the different pulse widths of the laser sources, and therefore, similar pulse and hatch overlap ensure equivalent areal energy input in both cases. As a summarized result, treatment with a shorter pulse width generates high peak pulse powers, resulting in higher temperatures, rougher surfaces and affecting deeper layers of the pellets compared to treatment with longer pulse width. On the contrary, excessive power leads to the ablation of the material up to destruction.
A generic activation mode for asymmetric LUMO-lowering catalysis has been developed using the long-established principles of oxy-allyl cation chemistry. Here, the enantioselective conversion of ...racemic α-tosyloxy ketones to optically enriched α-indolic carbonyls has been accomplished using a new amino alcohol catalyst in the presence of electron-rich indole nucleophiles. Kinetic studies reveal that the rate-determining step in this SN1 pathway is the catalyst-mediated α-tosyloxy ketone deprotonation step to form an enantiodiscriminant oxy-allyl cation prior to the stereodefining nucleophilic addition event.
The application of carbon fiber reinforced plastics (CFRP) has increased in recent years. Besides aerospace applications, automotive industry relies on those materials as they offer the possibility ...to reduce component weight significantly. A main challenge is the joining of those materials. Due to several advantages, adhesive bonding has been established as the preferred joining method for CFRP. The adhesive bonding process is challenging as the surfaces of CFRP are not suited for adhesive bonding. On one hand, the resulting CFRP-parts have smooth surfaces preventing mechanical interlocking with the adhesive and on the other hand, the release agent is transferred from the mold to the surface of the CFRP contaminating the surface. The resulting surfaces are generally inappropriate to achieve structural and durable bonds, making a surface pre-treatment inevitable.
As an alternative approach, this study focuses on the manufacturing method for CFRP with surfaces suitable for adhesive bonding without an additional surface pre-treatment. Therefore, the amount of release agent is varied to achieve a low degree of contamination and laser-structured molds are used resulting in CFRP with varying surface topographies. The surfaces of the CFRP-plates are analyzed. Then the influence of the varied parameters on the bonding strength is investigated by lap-shear tests.
In the recent aerospace generations, composite materials have shown that they can fulfil the increasing demand for structural efficiency. In this context adhesive bonding could be used to max out the ...material properties of carbon fibre reinforced polymers (CFRP). However, investigations have shown that residues of release agents on the CFRP surface can cause adhesion problems. Thus, a reliable surface cleaning procedure for removing residues prior to bonding is necessary.
Analytical surface investigations of an Aerospace CFRP material revealed the thickness and morphology of the predominant adhesion-weakening contamination. The optical absorptions of the epoxy material and the release agent characterised by UV–vis measurements were considered to develop a cleaning model based on a ns-pulsed ultra-violet laser with 266nm wavelength. This removal mechanism leads to chipping and peeling of the release agent layer and could be supported with light microscopy, scanning electron microscopy (SEM) and x-ray photoelectron spectroscopy (XPS) investigations. Single lap shear tests of the CFRP samples in the pristine and contaminated state, pre-treated with UV-laser as well as with the reference process (grinding) show that the laser pre-treated samples lead to the highest joint strength in the study. The failure mode changed from adhesion failure in the pristine state to a failure in the fibre-resin interface after laser treatment. Comparing a laser parameter with the focus on a smooth cleaning process and a laser parameter that lead to a surface with exposed carbon fibres, the surfaces treated with the smooth laser parameter showed the higher joint strength. The measured joint strength was 100% higher than with grinding, which underlines the high potential of laser technology for CFRP surface pre-treatment.
A significant influence on the strength of adhesively bonded fibre-reinforces plastics is the local ply orientation of the adherend, especially in a hybrid or multi-material joint. In this paper, the ...joint strength and failure behaviour is investigated for different ply orientations using single lap shear tests. The tests are performed with quasi static loading and also under high strain rates. Digital image correlation is used to monitor the specimen deformation and separation. Analysing the cracking process, a distinction between the appearance of a cohesive failure pattern and an actual cohesively progressing failure can be made. This provides an insight to the fracture mechanics and allows a comparison between high and low strain rates. A correlation between the cracking behaviour and the maximum load and displacement is observed.
The investigations of this article are showing the bonding performance after aging of hybrid fusion bonds in combination with a laser pre-treatment. The investigated materials are a galvanized steel ...(HX340 LAD Z100MB) and two glass fiber reinforced Polyamide 6 materials. In order to achieve a structural strength of the fusion bond a laser pre-treatment is used. The investigation is focusing on the changes from the laser pre-treatment to the galvanized surface by analyzing the steel surface with a scanning electron microscope, energy disperse X-ray spectroscopy, micro sections and surface roughness measurements. The composition of the applied thermoplastic materials is not in the focus of the article which is why different manufacturers for the fiber reinforced thermoplastic material have been chosen. The aging of the samples is done by a climate change (PV1200) and a salt spray (PV1210) test in order to evaluate different aging mechanisms. Furthermore the investigation is providing a crucial finding by showing the impact of a batch change on the achievable lap-shear strength by comparing two batches from the same manufacturer. The results of the laser surface pre-treatment show that the zinc coating of the steel adherend is reduced significantly and does not provide a closed coating. The climate change test after 100 cycles showed no decrease of lap-shear strength compared to the reference when the highest investigated pre-treatment intensity is applied to the surface. The salt spray test showed a corrosion of the pre-treated area for laser pre-treatment settings which generate a low amount of oxygen on the surface. The pre-treatment settings generating a more oxidized surface (medium and high intensity) showed only a minor influence on the achievable lap-shear strength after 90 cycles.
A fundamental feature of the mammalian visual system is the presence of separate channels that work in parallel to efficiently extract and analyze specific elements of a visual scene. Despite the ...extensive use of the mouse as a model system, it is not clear whether such parallel organization extends beyond the retina to subcortical structures, such as the dorsal lateral geniculate (dLGN) of thalamus. To begin to address this, we examined the morphology of biocytin-filled relay cells recorded in dLGN of mice. Based on a quantitative assessment of their dendritic architecture, we found that even at early postnatal ages relay cells could be readily classified as X-like (biconical), Y-like (symmetrical), or W-like (hemispheric) and that each cell type was regionally specified in dLGN. X-like cells were confined primarily to the monocular ventral region of dLGN. Y-like cells occupied a central core that also contained ipsilateral eye projections, whereas W-like cells were found along the perimeter of dLGN. Similar to cat, Y-like cells were more prevalent than X- and W-like cells, and X-like cells tended to be smaller than other cell types. However, the dendritic fields of X- and W-like cells did not exhibit an orientation bias with respect to optic tract or boundaries of dLGN. Although we found clear morphological differences among relay cells, an analysis of their electrophysiological properties did not reveal any additional distinguishing characteristics. Overall, these data coupled with recent observations in the retina suggest that the mouse has many of the hallmark features of a system-wide parallel organization.
Abstract
In the production of modern electric drives for battery electric vehicles, hairpin technology is used to increase the copper fill factor in the stator of a permanently excited synchronous ...machine. A central process in the production of these stators is the contacting of the hairpin ends by means of laser beam welding. This welding process is characterized by geometric and process-related deviations from previous process steps, which influence the result of the welded joint. It is desirable to find an in-process method for monitoring. As part of the process monitoring of welded joints, high-speed camera images are often used to detect weld spatter. These can be detected by a program based on a static algorithm. For this reason, a feasibility analysis is performed regarding the application of AI for the detection of spatters, in which the methods of semantic segmentation and single-image classification prove to be useful. In a preliminary experiment, three base networks for each of the two methods are evaluated with respect to the best training results. The single-image classification method will then be extended by a subsequent static algorithm, so that a hybrid use of AI and static algorithm will be investigated. The evaluation and final comparison of all evaluation methods is performed using data from a welding experiment. It turns out that the hybrid approach of single-image classification and static algorithm has numerous advantages in the detection of spatter compared to semantic segmentation and the static algorithm.
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