Revisiting the mechanism of coagulation factor XIII activation and regulation from a structure/functional perspective

The activation and regulation of coagulation Factor XIII (FXIII) protein has been the subject of active research for the past three decades. Although discrete evidence exists on various aspects of FXIII activation and regulation a combinatorial structure/functional view in this regard is lacking. In this study, we present results of a structure/function study of the functional chain of events for FXIII. Our study shows how subtle chronological submolecular changes within calcium binding sites can bring about the detailed transformation of the zymogenic FXIII to its activated form especially in the context of FXIIIA and FXIIIB subunit interactions. We demonstrate what aspects of FXIII are important for the stabilization (first calcium binding site) of its zymogenic form and the possible modes of deactivation (thrombin mediated secondary cleavage) of the activated form. Our study for the first time provides a structural outlook of the FXIIIA 2 B 2 heterotetramer assembly, its association and dissociation. The FXIIIB subunits regulatory role in the overall process has also been elaborated upon. In summary, this study provides detailed structural insight into the mechanisms of FXIII activation and regulation that can be used as a template for the development of future highly specific therapeutic inhibitors targeting FXIII in pathological conditions like thrombosis

Inertial and Liquefaction-Induced Kinematic Demands on a Pile-Supported Wharf: Physical Modeling

Results of a centrifuge test on a pile-supported wharf were used to investigate the time-, depth-, and row-dependent nature of kinematic and inertial loading on wharf piles in sloping rockfill. P-y models were calibrated against recorded bending moments in different piles and different depths. It was found that full kinematic demands and full superstructure inertia should be combined to estimate bending moments at pile head and shallow depths (less than 10 diameters below the ground surface). On the contrary, it was found that applying full kinematic demands alone was adequate to estimate pile bending moments at large depths (greater than 10 diameters deep)

Pile-Supported Wharves Subjected to Inertial Loads and Lateral Ground Deformations. II: Guidelines for Equivalent Static Analysis

An equivalent static analysis (ESA) procedure is proposed for the design of pile-supported wharves subjected to combined inertial and kinematic loads during earthquakes. The accuracy of the ESA procedure was evaluated against measurements from five large-scale centrifuge tests. The wharf structures in these tests were subjected to a suite of recorded ground motions and the associated superstructure inertia, as well as earthquake-induced slope deformations of varying magnitudes. It is shown that large bending moments at depths greater than 10 pile diameters were primarily induced by kinematic demands and can be estimated by applying soil displacements only (i.e., 100% kinematic). In contrast, the large bending moments at the pile head are primarily induced by wharf deck inertia and can be estimated by applying superstructure inertial loads at the pile head only (i.e., 100% inertial). Large bending moments at depths shallower than 10 pile diameters are affected by both inertial and kinematic loads; therefore, evaluation of pile performance should include soil displacements and a portion of the peak inertial load at the pile head that coincides with the peak kinematic loads. Ranges for inertial and kinematic load combinations in uncoupled analyses are provided for different soil profiles. The details on the back-calculated load combination factors are provided in the companion paper

Pile-Supported Wharves Subjected to Inertial Loads and Lateral Ground Deformations. I: Experimental Results from Centrifuge Tests

Five dynamic, large-scale centrifuge tests on pile-supported wharves were used to investigate the time- and depth-dependent nature of kinematic and inertial demands on the deep foundations during earthquake loading. The wharf structures in the physical experiments were subjected to a suite of recorded ground motions and imposed superstructure inertial demands on the piles. Partial to full liquefaction in loose sand resulted in slope deformations of varying magnitudes that imposed kinematic demands on the piles. It was found that the wharf inertia and soil displacements were always in phase during the critical cycle when bending moments were at their maximum values. The test results were analyzed to provide the relative contributions of peak inertial loads and peak soil displacements during critical cycles, and the data revealed the depth dependency of these factors. The results of this study are used in a companion paper to provide recommendations for the design of pile-supported wharves subjected to foundation deformations

Online teacher training in a context for forced immobility: the Case of Gaza, Palestine

This article discusses an action research study that involved the design and delivery of an online training course for teachers of Arabic to speakers of other languages in the Gaza Strip (Palestine). Grounded in Freirean pedagogy, the course aimed to respond to the employment needs of university graduates by creating opportunities for online language teaching. The action research study explored the dynamics at play within the online educational environment, to evidence elements that challenged and/or facilitated effective collaboration between trainers and trainees. This article retraces and discusses the processes through which the course moved from didacticism to engaged critical pedagogy

Cancer Grade Model: a multi-gene machine learning-based risk classification for improving prognosis in breast cancer

Background: Prognostic stratification of breast cancers remains a challenge to improve clinical decision making. We employ machine learning on breast cancer transcriptomics from multiple studies to link the expression of specific genes to histological grade and classify tumours into a more or less aggressive prognostic type. Materials and methods: Microarray data of 5031 untreated breast tumours spanning 33 published datasets and corresponding clinical data were integrated. A machine learning model based on gradient boosted trees was trained on histological grade-1 and grade-3 samples. The resulting predictive model (Cancer Grade Model, CGM) was applied on samples of grade-2 and unknown-grade (3029) for prognostic risk classification. Results: A 70-gene signature for assessing clinical risk was identified and was shown to be 90% accurate when tested on known histological-grade samples. The predictive framework was validated through survival analysis and showed robust prognostic performance. CGM was cross-referenced with existing genomic tests and demonstrated the competitive predictive power of tumour risk. Conclusions: CGM is able to classify tumours into better-defined prognostic categories without employing information on tumour size, stage, or subgroups. The model offers means to improve prognosis and support the clinical decision and precision treatments, thereby potentially contributing to preventing underdiagnosis of high-risk tumours and minimising over-treatment of low-risk disease.</p

Novel drug-target interactions via link prediction and network embedding

BACKGROUND: As many interactions between the chemical and genomic space remain undiscovered, computational methods able to identify potential drug-target interactions (DTIs) are employed to accelerate drug discovery and reduce the required cost. Predicting new DTIs can leverage drug repurposing by identifying new targets for approved drugs. However, developing an accurate computational framework that can efficiently incorporate chemical and genomic spaces remains extremely demanding. A key issue is that most DTI predictions suffer from the lack of experimentally validated negative interactions or limited availability of target 3D structures.RESULTS: We report DT2Vec, a pipeline for DTI prediction based on graph embedding and gradient boosted tree classification. It maps drug-drug and protein-protein similarity networks to low-dimensional features and the DTI prediction is formulated as binary classification based on a strategy of concatenating the drug and target embedding vectors as input features. DT2Vec was compared with three top-performing graph similarity-based algorithms on a standard benchmark dataset and achieved competitive results. In order to explore credible novel DTIs, the model was applied to data from the ChEMBL repository that contain experimentally validated positive and negative interactions which yield a strong predictive model. Then, the developed model was applied to all possible unknown DTIs to predict new interactions. The applicability of DT2Vec as an effective method for drug repurposing is discussed through case studies and evaluation of some novel DTI predictions is undertaken using molecular docking.CONCLUSIONS: The proposed method was able to integrate and map chemical and genomic space into low-dimensional dense vectors and showed promising results in predicting novel DTIs.</p

Evaluation of antioxidant activity of methanolic extracts and some fractions of Salvia verticillata L. using three different methods

Background: Bradykinin has effects on histaminic response,vessels seepage,cellular reproduction,causing fever, pain and coughs caused by ACE controllers (3,4,6). Noscapin has controlled Bradykinins contractional effects on guinea pigs trachea and rats vazodofran (5,6). noscapin stops the secondary effects of eskimi in brains edema, with antagonizing the responses caused by Bradykinin (3,4,8). Objective: considering that opium's alkaloids act as agonist of peptide systems like ankephalins and RAS, its interesting to know the effects of this alkaloids and among them Noscapine on B3 Bradykinin receptors on smooth muscle guinea pig trachea? Method: All variables are reported as mean and standard deviation. We have used pair test and the informations were processed by Excel, Statistical analysis with ANOVA (LSD) SPSS 9. Results: we took diagrams in to consideration and indicated that the contract ional effect of Bradykinin decreased dependent on density, in presence of three different amount of noscapines concentration. In this study we could demonstrate that noscapine interact with Bradykenin as a non competitive antagonist

Valvulotomy of the great saphenous vein in ex situ non-reversed and in situ setting: a multicenter post-market study to assess the safety and efficacy of the AndraValvulotome™”

Purpose To evaluate the safety and technical success of the AndraValvulotome™ device (Andramed GmbH, Reutlingen, Germany) in patients with peripheral arterial disease (PAD) requiring bypass surgery using the great saphenous vein (GSV) as graft. Methods This was a multicenter, post-market observational study conducted in 2021 in 11 German centers. Safety and efficacy data were prospectively collected and analyzed. Primary endpoints were the absence of device-related serious adverse events until 30 ± 7 days follow-up, the clinical efficacy of valvulotomy, which was defined as pulsatile blood flow in the bypass and the number of insufficiently destroyed vein valves. Secondary endpoints were the number of valvulotomy passages, the primary patency rate of the venous bypass (determined by a color-duplex sonography showing a normal blood flow through the bypass and absence of stenosis or occlusion), and the primary technical success defined as the absence of product-specific (serious) adverse events and clinical efficacy. Results Fifty-nine patients were enrolled. The mean age of the patients was 71 years (46–91), and 74.6% were males. The vein material used for bypass grafting had a median length of 47.5 cm (range 20–70 cm) with a median diameter of 5.0 mm (range 3–6 mm) and 4.0 mm (range 2–6 mm) in the proximal and distal segments, respectively. The technical success rate was 96.6%. The primary patency rate was 89.9% at 30 days follow-up. The clinical efficacy was rated as very good in 81% of patients, fair in 17%, and poor in 2%. Between 1 and 5 (average 2.9) valvulotome passages were performed. One product-related serious adverse event was recorded (bypass vein dissection). Conclusion The AndraValvulotome™ can be considered a safe and effective device to disrupt venous valves during in situ non-reversed bypass surgeries using GSV grafts in patients with PAD