Enzymatically Modified Low-Density Lipoprotein Is Recognized by C1q and Activates the Classical Complement Pathway

Several studies suggest that the complement system is involved in atherogenesis. To further investigate this question, we have studied the ability of native and modified forms of LDL to bind and activate C1, the complex protease that triggers the classical pathway of complement. Unlike native LDL, oxidized (oxLDL) and enzymatically modified (E-LDL) derivatives were both recognized by the C1q subunit of C1, but only E-LDL particles, obtained by sequential treatment with a protease and then with cholesterol esterase, had the ability to trigger C1 activation. Further investigations revealed that C1q recognizes a lipid component of E-LDL. Several approaches, including reconstitution of model lipid vesicles, cosedimentation, and electron microscopy analyses, provided evidence that C1 binding to E-LDL particles is mediated by the C1q globular domain, which senses unesterified fatty acids generated by cholesterol esterase. The potential implications of these findings in atherogenesis are discussed

Discriminative Speaker Representation via Contrastive Learning with Class-Aware Attention in Angular Space

The challenges in applying contrastive learning to speaker verification (SV) are that the softmax-based contrastive loss lacks discriminative power and that the hard negative pairs can easily influence learning. To overcome the first challenge, we propose a contrastive learning SV framework incorporating an additive angular margin into the supervised contrastive loss in which the margin improves the speaker representation's discrimination ability. For the second challenge, we introduce a class-aware attention mechanism through which hard negative samples contribute less significantly to the supervised contrastive loss. We also employed gradient-based multi-objective optimization to balance the classification and contrastive loss. Experimental results on CN-Celeb and Voxceleb1 show that this new learning objective can cause the encoder to find an embedding space that exhibits great speaker discrimination across languages.Comment: Accepted by ICASSP 2023, 5 pages, 2 figure

Job insecurity : cross-cultural comparison between Germany and China

Purpose – The recent economic crisis gave rise to job insecurity and had a seemingly greater effect on western than eastern countries. The purpose of this paper is to examine cross-cultural differences of the influence of job insecurity on employees’ wellbeing, innovative work behaviour (IWB) and safety outcomes in the form of attention-related cognitive errors (ARCES) in Germany as compared to mainland China. Design/methodology/approach – Samples from both Germany and China rate their job insecurity, work engagement, burnout, IWB and ARCES in a survey. Findings – For both German and Chinese employees there was an indirect relationship between job insecurity and ARCES through burnout. In the German sample, there was an indirect relationship between employees’ job insecurity and IWB through work engagement. In contrast, the Chinese sample only showed the direct relationship between quantitative job insecurity and IWB, but not a mediation effect. Practical implications – For organizations to be effective and their employees to work safely, it is essential to understand the nature and process of job insecurity in different national contexts. Originality/value – The present research is unique by relating job insecurity to employee’ innovation on the one hand and safety outcomes on the other. Furthermore, these relationships are examined in the cultural contexts of Germany and China, contributing to the gap of research carried out in eastern contexts

The Roles of H19 in Regulating Inflammation and Aging.

Accumulating evidence suggests that long non-coding RNA H19 correlates with several aging processes. However, the role of H19 in aging remains unclear. Many studies have elucidated a close connection between H19 and inflammatory genes. Chronic systemic inflammation is an established factor associated with various diseases during aging. Thus, H19 might participate in the development of age-related diseases by interplay with inflammation and therefore provide a protective function against age-related diseases. We investigated the inflammatory gene network of H19 to understand its regulatory mechanisms. H19 usually controls gene expression by acting as a microRNA sponge, or through mir-675, or by leading various protein complexes to genes at the chromosome level. The regulatory gene network has been intensively studied, whereas the biogenesis of H19 remains largely unknown. This literature review found that the epithelial-mesenchymal transition (EMT) and an imprinting gene network (IGN) might link H19 with inflammation. Evidence indicates that EMT and IGN are also tightly controlled by environmental stress. We propose that H19 is a stress-induced long non-coding RNA. Because environmental stress is a recognized age-related factor, inflammation and H19 might serve as a therapeutic axis to fight against age-related diseases

Dependence of Microstructure and Mechanical Properties on Heat Treat Cycles of Electron Beam Melted Ti-6Al-4V

The EBM Ti-6Al-4V alloy has generally superior mechanical properties, owing to finely spaced α−β laths which give a good combination of strength and ductility. The grain structures in the as-printed structures are long columnar which can give rise to anisotropic mechanical properties. Moreover the non-uniformity in microstructure can also arise from part geometry where the thin features have propensity to form martensite phase. Heat treatment provides a viable solution to modify the microstructure and to tailor to the properties as desired. A wide range of heat treatment experiments were performed, followed by microstructure and tensile property analyses. It was observed that the microstructure and the tensile properties significantly changed depending on the heat treat cycle performed. Tensile properties of solution treated air-cool plus aged samples yielded globular equiaxed grains with fine α−β lath structure, which were found to be the best among the different heat treated samples and better than ASTM F1472 specifications.Mechanical Engineerin

Multiphysics Structured Eddy Current and Thermography Defects Diagnostics System in Moving Mode

Eddy current testing (ET) and eddy current thermography (ECT) are both important non-destructive testing (NDT) methods that have been widely used in the field of conductive materials evaluation. Conventional ECT systems have often employed to test static specimens eventhough they are inefficient when the specimen is large. In addition, the requirement of high-power excitation sources tends to result in bulky detection systems. To mitigate these problems, a moving detection mode of multiphysics structured ET and ECT is proposed in which a novel L-shape ferrite magnetic yoke circumambulated with array coils is designed. The theoretical derivation model of the proposed method is developed which is shown to improve the detection efficiency without compromising the excitation current by ECT. The specimens can be speedily evaluated by scanning at a speed of 50-250 mm/s while reducing the power of the excitation current due to the supplement of ET. The unique design of the excitation-receiving structure has also enhanced the detectability of omnidirectional cracks. Moreover, it does not block the normal direction visual capture of the specimens. Both numerical simulations and experimental studies on different defects have been carried out and the obtained results have shown the reliability and detection efficiency of the proposed system

Extramammary Paget's Disease: 20 Years of Experience in Chinese Population

Background. To examine the results of treatment of Extramammary Paget's disease (EMPD) in ethnic Chinese. Method. Between 1990 and 2010, patients treated for EMPD were reviewed. Data were analyzed retrospectively. Results. Forty-eight patients were treated by surgical resection. Local recurrence rate was 14.6%. The postresection defects were repaired by primary closure (8.3%), partial thickness skin graft (72.9%), or local/regional flaps (18.8%). Dermal invasion was found in 9 patients (18.8%). Seven patients (14.6%) developed regional lymph node metastasis (concurrent with surgery, n = 1; subsequent to surgery, n = 6), and 3 patients (6.3%) had systemic metastasis after surgery. The presence of dermal invasion was associated with significantly higher incidence of regional lymph nodes and systemic metastasis. The incidence of associated internal malignancy was 8.3%. Conclusion. The mainstay of treatment for EMPD is surgery. Pathological dermal invasion increases the chance of regional lymph node as well as systemic metastasis. The association with internal malignancy warrants preoperative endoscopic examination in all patients

Deep Q‐network implementation for simulated autonomous vehicle control

Deep reinforcement learning is poised to be a revolutionised step towards newer possibilities in solving navigation and autonomous vehicle control tasks. Deep Q‐network (DQN) is one of the more popular methods of deep reinforcement learning that allows the agent that controls the vehicle to learn through its mistakes based on its actions and interactions with the environment. This paper presents the implementation of DQN to an autonomous self‐driving vehicle control in two different simulated environments; first environment is in Python which is a simple 2D environment and then advanced to Unity software separately which is a 3D environment. Based on the scores and pixel inputs, the agent in the vehicle learns and adapts to its surrounding. It develops the best solution strategy to direct itself in the environment where its task is to manoeuvre the vehicle from point to point on a simulated highway scenario. The implemented DQN technique approximates the action value function with convolutional neural network. This evaluates the Q‐function for the Q‐learning architecture and updates the action value function. This paper shows that DQN is an effective learning method for the agent of an autonomous vehicle. In both simulated environments, the autonomous vehicle gradually learnt the manoeuvre operations and progressively gained the ability to successfully navigate itself and avoid obstacles without prior information of the surrounding

Variable-heavy (VH) families influencing IgA1&2 engagement to the antigen, FcαRI and superantigen proteins G, A, and L

Interest in IgA as an alternative antibody format has increased over the years with much remaining to be investigated in relation to interactions with immune cells. Considering the recent whole antibody investigations showing significant distal effects between the variable (V) and constant (C)- regions that can be mitigated by the hinge regions of both human IgA subtypes A1 and A2, we performed an in-depth mechanistic investigation using a panel of 28 IgA1s and A2s of both Trastuzumab and Pertuzumab models. FcαRI binding were found to be mitigated by the differing glycosylation patterns in IgA1 and 2 with contributions from the CDRs. On their interactions with antigen-Her2 and superantigens PpL, SpG and SpA, PpL was found to sterically hinder Her2 antigen binding with unexpected findings of IgAs binding SpG at the CH2-3 region alongside SpA interacting with IgAs at the CH1. Although the VH3 framework (FWR) is commonly used in CDR grafting, we found the VH1 framework (FWR) to be a possible alternative when grafting IgA1 and 2 owing to its stronger binding to antigen Her2 and weaker interactions to superantigen Protein L and A. These findings lay the foundation to understanding the interactions between IgAs and microbial superantigens, and also guide the engineering of IgAs for future antibody applications and targeting of superantigen-producing microbes

Molecular insights of nickel binding to therapeutic antibodies as a possible new antibody superantigen

The binding of nickel by immune proteins can manifest as Type IV contact dermatitis (Ni-specific T cells mediated) and less frequently as Type I hypersensitivity with both mechanisms remaining unknown to date. Since there are reports of patients co-manifesting the two hypersensitivities, a common mechanism may underlie both the TCR and IgE nickel binding. Focusing on Trastuzumab and Pertuzumab IgE variants as serendipitous investigation models, we found Ni-NTA interactions independent of Her2 binding to be due to glutamine stretches. These stretches are both Ni-inducible and in fixed pockets at the antibody complementarity-determining regions (CDRs) and framework regions (FWRs) of both the antibody heavy and light chains with influence from the heavy chain constant region. Comparisons with TCRs structures revealed similar interactions, demonstrating the possible underlying mechanism in selecting for Ni-binding IgEs and TCRs respectively. With the elucidation of the interaction, future therapeutic antibodies could also be sagaciously engineered to utilize such nickel binding for biotechnological purposes