Induced Aggregation
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2021 ◽  
pp. 2108255
Author(s):  
Zhongli Wang ◽  
Mengyuan Gao ◽  
Chunyong He ◽  
Weichao Shi ◽  
Yunfeng Deng ◽  
...  

Membranes ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 950
Author(s):  
Jasleen Kaur Daljit Singh ◽  
Minh Tri Luu ◽  
Jonathan F. Berengut ◽  
Ali Abbas ◽  
Shelley F. J. Wickham ◽  
...  

DNA nanotechnology provides methods for building custom membrane-interacting nanostructures with diverse functions, such as shaping membranes, tethering defined numbers of membrane proteins, and transmembrane nanopores. The modification of DNA nanostructures with hydrophobic groups, such as cholesterol, is required to facilitate membrane interactions. However, cholesterol-induced aggregation of DNA origami nanostructures remains a challenge. Aggregation can result in reduced assembly yield, defective structures, and the inhibition of membrane interaction. Here, we quantify the assembly yield of two cholesterol-modified DNA origami nanostructures: a 2D DNA origami tile (DOT) and a 3D DNA origami barrel (DOB), by gel electrophoresis. We found that the DOT assembly yield (relative to the no cholesterol control) could be maximised by reducing the number of cholesterols from 6 to 1 (2 ± 0.2% to 100 ± 2%), optimising the separation between adjacent cholesterols (64 ± 26% to 78 ± 30%), decreasing spacer length (38 ± 20% to 95 ± 5%), and using protective ssDNA 10T overhangs (38 ± 20% to 87 ± 6%). Two-step folding protocols for the DOB, where cholesterol strands are added in a second step, did not improve the yield. Detergent improved the yield of distal cholesterol configurations (26 ± 22% to 92 ± 12%), but samples re-aggregated after detergent removal (74 ± 3%). Finally, we confirmed functional membrane binding of the cholesterol-modified nanostructures. These findings provide fundamental guidelines to reducing the cholesterol-induced aggregation of membrane-interacting 2D and 3D DNA origami nanostructures, improving the yield of well-formed structures to facilitate future applications in nanomedicine and biophysics.


Haematologica ◽  
2021 ◽  
Author(s):  
Katarina D. Kovacevic ◽  
Jürgen Grafeneder ◽  
Christian Schörgenhofer ◽  
Georg Gelbenegger ◽  
Gloria Gager ◽  
...  

Von Willebrand Factor (VWF) and Factor VIII (FVIII) circulate in a noncovalent complex in blood and promote primary haemostasis and clotting respectively. A new VWF A1-domain binding aptamer, BT200, demonstrated good subcutaneous bioavailability and a long half-life in non-human primates. This first-in-human, randomised, placebo-controlled, double-blind trial tested the hypothesis that BT200 is well tolerated and has favourable pharmacokinetic and pharmacodynamic effects in 112 volunteers. Participants received one of the following: Single ascending dose of BT200 (0.18-48mg) subcutaneously, an intravenous dose, BT200 with concomitant desmopressin or multiple doses. Pharmacokinetics were characterised, and the pharmacodynamic effects were measured by VWF levels, FVIII clotting activity, ristocetin induced aggregation, platelet function under high shear rates, and thrombin generation. Mean half-lives ranged from 7-12 days and subcutaneous bioavailability increased dosedependently exceeding 55% for doses of 6-48 mg. By blocking free A1 domains, BT200 dose-dependently decreased ristocetin-induced aggregation, and prolonged collagenadenosine diphosphate and shear-induced platelet plug formation times. However, BT200 also increased VWF antigen and FVIII levels 4-fold (p


Author(s):  
Huaxin Tan ◽  
Sisi Liu ◽  
Yaolin He ◽  
Guofeng Cheng ◽  
Yu Zhang ◽  
...  

Goldnanoclusters (GNCs) have become a promising nanomaterial for bioimaging because of their unique optical properties and biocompatibility. In this study, lycosin-I peptide, which possesses a highly selective anticancer activity by affecting the permeability of cancer cell membrane, was firstly modified for constructing fluorescent GNCs (LGNCs) for bioimaging of tumor cells. The obtained LGNCs exhibited strong near-infrared (NIR) fluorescence, which can be further enhanced by the peptide-induced aggregation and selectively stained three cancerous cell lines over normal cell lines with low intrinsic toxicity. After uptake by tumor cells, LGNC aggregates can be depolymerized into ultrasmall nanoclusters by high-level glutathione (GSH) and realize the nuclear targeting translocation. Collectively, our work suggests the potential of natural active biomolecules in designing NIR fluorescent GNCs for bioimaging.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4203-4203
Author(s):  
Chuanbin Shen ◽  
Daniel Mackeigan ◽  
Guangheng Zhu ◽  
Miguel A. D. Neves ◽  
Wenjing Ma ◽  
...  

Abstract Abstract Introduction:Snake venom-derived botrocetin facilitates von Willebrand factor (VWF) binding to GPIbα, and has been used clinically for the detection of von Willebrand disease (VWD) and GPIb-related disorders. Botrocetin has also been widely used experimentally for the development and characterization of potential antithrombotic drugs targeting the GPIb-VWF axis. Although compelling evidence suggests GPIb is responsible for botrocetin-induced VWF binding and platelet aggregation, some reports suggest that botrocetin could induce platelet aggregation in some Bernard-Soulier syndrome (BSS) patients who lack a functional GPIb complex. However, the alternative mechanism for botrocetin-induced BSS platelet aggregation and the receptor(s) mediating this action are unclear. Methods: Botrocetin was purified from the lyophilized venom of Bothrops jararaca using ion-exchange column chromatography. Light transmission aggregometry assay was performed using platelet-rich plasma (PRP) from human, wild type (WT) mice, GPIbα-deficient mice, αIIbβ3-deficient mice and VWF-deficient mice, or CHO cells stably transfected with αIIbβ3 integrin. O-sialoglycoprotein endopeptidase (OSGE) was used to cleave the N-terminal extracellular domain of GPIbα. The binding of botrocetin, VWF and fibrinogen to platelets from WT or the gene-deficient mice were measured by flow cytometry. Antibodies against GPIbα (SZ2, NIT A) and integrin αIIbβ3 (abciximab, JON/A, M1, PSI E1) were used to investigate the binding site of botrocetin. Perfusion chamber assay was used to measure thrombus formation under different shear stresses. Results: We discovered that botrocetin induced aggregation of human platelets lacking the N-terminal extracellular domain of GPIbα and platelets from GPIbα-deficient mice in the presence of VWF. This VWF-dependent, GPIbα-independent platelet aggregation induced by botrocetin was inhibited by αIIbβ3 antagonists. Botrocetin also induced aggregation of CHO cells stably transfected with αIIbβ3 in VWF-dependent manner. Further experiments with gel-filtered platelets showed that botrocetin competitively bound to the ligand-binding area exposed on αIIbβ3 and blocked fibrinogen and other ligands from binding to the active state of αIIbβ3 in the absence of VWF. Botrocetin inhibited platelet aggregation and thrombus formation in VWF-deficient mice. Conclusion: Integrin αIIbβ3 is the alternative receptor that mediates VWF-dependent, GPIb-independent platelet aggregation induced by botrocetin. However, via targeting αIIbβ3, botrocetin itself inhibits platelet aggregation in the absence of VWF. These results demonstrate versatility in the mechanism of botrocetin, which may provide snakes containing this toxin the adaptability necessary to aggregate platelets/thrombocytes of different prey or predators. Our data reveals a previously unknown role of botrocetin in the integrin-VWF interaction and also provides insight into developing new antithrombotic drugs that target the active conformation of integrin αIIbβ3. The target switching of botrocetin between GPIb-VWF and αIIbβ3-VWF may explain the possible misdiagnosis of the GPIb-related congenital disorders evaluated by botrocetin. Disclosures No relevant conflicts of interest to declare.


2021 ◽  
Vol 12 ◽  
Author(s):  
Dongheng Zhou ◽  
Huanhuan Yan ◽  
Shuying Yang ◽  
Yuhong Zhang ◽  
Xiaoyan Xu ◽  
...  

Abnormal accumulation of TDP43-related mutant proteins in the cytoplasm causes amyotrophic lateral sclerosis (ALS). Herein, unbiased drug screening approaches showed that SC75741, a multi-target inhibitor, inhibited inflammation-induced aggregation by inhibiting NF-κB and also degraded already aggregated proteins by inhibiting c-Abl mediated autophagy-lysosomal pathway. We delineate the mechanism that SC75741 could markedly enhance TFEB nuclear translocation by an mTORC1-independent TFEB regulatory pathway. In addition, SC75741 enhanced the interaction between p62 with TDP25 and LC3C, thus promoting TDP25 degradation. Taken together, these findings show that SC75741 has beneficial neuroprotective effects in ALS. Our study elucidates that dual-targeted inhibition of c-Abl and NF-κB may be a potential treatment for TDP43 proteinopathies and ALS.


Talanta ◽  
2021 ◽  
pp. 123003
Author(s):  
Xiangheng Niu ◽  
Mengzhu Wang ◽  
Hengjia Zhu ◽  
Peng Liu ◽  
Jianming Pan ◽  
...  
Keyword(s):  

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
V Netiazhenko ◽  
A V Liakhotska

Abstract   Mutation C807 in the ITGA2 gene is associated with the risk of early myocardial infarction, ischemic stroke, embolism, thrombosis after angioplasty and stenting of coronary arteries. Aim To study the relationship between ITGA2 gene polymorphism and increased risk of CAD in patients with hypertension and hypercholesterolemia Materials and methods 72 patients were included. Study involved patients with ACS, which developed on the background of hypertension, 32 patients also had coronary angiography and stenting. We used analysis of spontaneous and induced platelet aggregation, polymorphism of C807T of the ITGA2 gene was determined by polymerase chain reaction. Results At 82.5% of patients with ACS genotype ITGA 2 C/T was prevalent – 40.3%, T/T – 31.9%. Aggregation capability research in the studied groups has shown that patients of all groups had their degree of spontaneous aggregation significantly exceeding limits of control. Wherein, the highest indices were recorded in the T/T genotype group, which exceeded reference values by 3,02 times. AA-induced aggregation in the group of patients with T/T genotype exceeded indexes of the C/C group by 17.3%, while C/T group's rates-by 16.5% (p<0.05 in both cases). Studying the degree of collagen-induced aggregation, it was noted that the highest rates were recorded in T/T genotype group – 1.68 times higher than control group. Conclusion It is found that T allele of ITGA2 carrier is typical for 72.1% of patients with acute coronary syndrome and combined with spontaneous acceleration of platelet aggregation and increases sensitivity of platelets to ADP and collagen. Results allow us to consider the carrier of the T-allele as a marker of predisposition to thrombophilia. FUNDunding Acknowledgement Type of funding sources: None.


Author(s):  
Amelia Staats ◽  
Peter W. Burback ◽  
Mostafa Eltobgy ◽  
Dana M. Parker ◽  
Amal O. Amer ◽  
...  

Bacterial infections of hip and knee implants are rare but devastating complications of orthopedic surgery. Despite a widespread appreciation of the considerable financial, physical, and emotional burden associated with the development of a prosthetic joint infection, the establishment of bacteria in the synovial joint remains poorly understood.


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