G. Meng

Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma

Natural killer/T-cell lymphoma (NKTCL) is a malignant proliferation of CD56+ and cytoCD3+ lymphocytes with aggressive clinical course, which is prevalent in Asian and South American populations. The molecular pathogenesis of NKTCL has largely remained elusive. We identified somatic gene mutations in 25 people with NKTCL by whole-exome sequencing and confirmed them in an extended validation group of 80 people by targeted sequencing. Recurrent mutations were most frequently located in the RNA helicase gene DDX3X (21/105 subjects, 20.0%), tumor suppressors (TP53 and MGA), JAK-STAT-pathway molecules (STAT3 and STAT5B) and epigenetic modifiers (MLL2, ARID1A, EP300 and ASXL3). As compared to wild-type protein, DDX3X mutants exhibited decreased RNA-unwinding activity, loss of suppressive effects on cell-cycle progression in NK cells and transcriptional activation of NF-κB and MAPK pathways. Clinically, patients with DDX3X mutations presented a poor prognosis. Our work thus contributes to the understanding of the disease mechanism of NKTCL.

Spline-Kernelled Chirplet Transform for the Analysis of Signals With Time-Varying Frequency and Its Application

The conventional time-frequency analysis (TFA) methods, including continuous wavelet transform, short-time Fourier transform, and Wigner-Ville distribution, have played important roles in analyzing nonstationary signals. However, they often show less capability in dealing with nonstationary signals with time-varying frequency due to the bad energy concentration in the time-frequency plane. On the other hand, by introducing an extra transform kernel that matches the instantaneous frequency of the signal, parameterized TFA methods show powerful ability in characterizing time-frequency patterns of nonstationary signals with time-varying frequency. In this paper, a novel time-frequency transform, called spline-kernelled chirplet transform (SCT), is proposed. By introducing a frequency-rotate operator and a frequency-shift operator constructed with spline kernel function, the SCT is particularly powerful for the strongly nonlinear frequency-modulated signals. In addition, an effective algorithm is developed to estimate the parameters of transform kernel in the SCT. The capabilities of the SCT and parameter estimation algorithm are validated by their applications for numerical signals and a set of vibration signal collected from a rotor test rig.

Structural framework of c-Src activation by integrin β3

The integrin β3-mediated c-Src priming and activation, via the SH3 domain, is consistently associated with diseases, such as the formation of thrombosis and the migration of tumor cells. Conventionally, activation of c-Src is often induced by the binding of proline-rich sequences to its SH3 domain. Instead, integrin β3 uses R(760)GT(762) for priming and activation. Because of the lack of structural information, it is not clear where RGT will bind to SH3, and under what mechanism this interaction can prime/activate c-Src. In this study, we present a 2.0-Å x-ray crystal structure in which SH3 is complexed with the RGT peptide. The binding site lies in the N-Src loop of the SH3 domain. Structure-based site-directed mutagenesis showed that perturbation on the N-Src loop disrupts the interaction between the SH3 domain and the RGT peptide. Furthermore, the simulated c-Src:β3 complex based on the crystal structure of SH3:RGT suggests that the binding of the RGT peptide might disrupt the intramolecular interaction between the SH3 and linker domains, leading to the disengagement of Trp260:C-helix and further activation of c-Src.

Functional and molecular features of the calmodulin-interacting protein IQCG required for haematopoiesis in zebrafish

We previously reported a fusion protein NUP98-IQCG in an acute leukaemia, which functions as an aberrant regulator of transcriptional expression, yet the structure and function of IQCG have not been characterized. Here we use zebrafish to investigate the role of iqcg in haematopoietic development, and find that the numbers of haematopoietic stem cells and multilineage-differentiated cells are reduced in iqcg-deficient embryos. Mechanistically, IQCG binds to calmodulin (CaM) and acts as a molecule upstream of CaM-dependent kinase IV (CaMKIV). Crystal structures of complexes between CaM and IQ domain of IQCG reveal dual CaM-binding footprints in this motif, and provide a structural basis for a higher CaM-IQCG affinity when deprived of calcium. The results collectively allow us to understand IQCG-mediated calcium signalling in haematopoiesis, and propose a model in which IQCG stores CaM at low cytoplasmic calcium concentrations, and releases CaM to activate CaMKIV when calcium level rises.

Experimental study on electrode displacement fluctuation characteristics during resistance spot welding

Abstract Electrode displacement has been used to monitor resistance spot weld quality for long, but the fluctuation of the electrode displacement has not been well studied. This paper analysed the mechanism of the displacement fluctuation by collecting the welding current and electrode displacement during welding process and extracted the incremental pulse expansion of the electrode displacement, which was named as the displacement fluctuation peak. Through metallurgical experiments, the relationship of the displacement fluctuation peak with the weld nugget growth during resistance spot welding process was analysed. The whole process can be divided into four successive stages, and five characteristic points of the displacement fluctuation peak curve were selected to online predict the weld quality. The variation in the displacement fluctuation peak curve under different welding currents was studied, and the results showed that the displacement fluctuation characteristics can be used to effectively evaluate the weld quality.

RING tetramerization is required for nuclear body biogenesis and PML sumoylation

ProMyelocyticLeukemia nuclear bodies (PML NBs) are stress-regulated domains directly implicated in acute promyelocytic leukemia eradication. Most TRIM family members bind ubiquitin E2s and manyxa0acquire ligase activity upon RING dimerization. In contrast, PML binds UBC9, the SUMO E2 enzyme. Here, using X-ray crystallography and SAXS characterization, we demonstrate that PML RING tetramerizes through highly conserved PML-specific sequences, which are required for NB assembly and PML sumoylation. Conserved residues implicated in RING dimerization of other TRIMs also contribute to PML tetramer stability. Wild-type PML rescues the ability of some RING mutants to form NBs as well as their sumoylation. Impaired RING tetramerization abolishes PML/RARA-driven leukemogenesis in vivo and arsenic-induced differentiation ex vivo. Our studies thus identify RING tetramerization as a key step in the NB macro-molecular scaffolding. They suggest that higher order RING interactions allow efficient UBC9 recruitment and thus change the biochemical nature of TRIM-facilitated post-translational modifications.Promyelocytic leukemia protein (PML) is a scaffolding protein that organizes PML nuclear bodies. Here the authors present the tetrameric crystal structure of the PML RING domain and show that RING tetramerization is functionally important for nuclear body formation and PML sumoylation.

Response of a strongly non-linear oscillator to narrowband random excitations

Abstract The principal resonance of a van der Pol–Duffing oscillator subject to narrowband random excitations has been studied. By introducing a new expansion parameter e=e( e ,u 0 ) the method of multiple scales is adapted for the strongly non-linear system. The behavior of steady state responses, together with their stability, and the effects of system damping and the detuning, and magnitude of the random excitation on steady state responses are analyzed in detail. Theoretical analyses are verified by some numerical results. It is found that when the random noise intensity increases, the steady state solution may change form a limit cycle to a diffused limit cycle, and the system may have two different stable steady state solutions for the same excitation under certain conditions. The results obtained for the strongly non-linear oscillator complement previous results in the literature for weakly non-linear systems.

Local variation detection in MDOF system using wavelet based transmissibility and its application in cracked beam

Since the local stiffness or damping variation happens when damage occurs in engineer structures, it is useful to detect the local variation as a way for structural damage inspection. As a vibration based approach, transmissibility has attracted considerable interest because of its convenience and effectiveness in damage detection. However, using the traditional Fourier transform, it should be very careful to select the frequency bands in transmissibility calculation. Inappropriate choice of frequency band could cause a complete inaccurate result. For unknown damage detection, it is difficult to select the frequency band which eigen-frequency should be included. This paper proposes a novel method using wavelet based transmissibility for local variation detection. Benefiting from the ability in subtle information acquisition of wavelet transform, it is useful in reducing the influence of frequency bands to the indicators. Analytical derivation using wavelet balance method and numerical studies of a multiple degree of freedom (MDOF) system are carried out to verify the effectiveness of the proposed method. In the last section, the method is applied for detecting crack position in cantilever beam with analysis of its sensitivity to frequency bands and measurement inaccuracies.

Analysis of Locally Nonlinear Two Dimensional Periodic Structures Using NOFRFs

The analysis of locally nonlinear two dimensional (2D) periodic structures is studied using the concept of nonlinear output frequency response functions (NOFRFs). NOFRFs are a series of one-dimensional functions of frequency, which allow the analysis of nonlinear systems to be implemented in a manner similar to the analysis of linear system in the frequency domain. By inspecting the relationships between the NOFRFs of unit cell in the locally nonlinear two dimensional periodic structures, a series of properties about the NOFRFs of the nonlinear system are derived. The correctness of these properties is demonstrated by numerical studies. These properties obtained in this paper are of significance to the frequency response analysis for nonlinear 2D periodic structures. One important potential application of these properties is the location of damage in 2D periodic structures, which make system behave locally nonlinearity.

Publisher Correction: RING tetramerization is required for nuclear body biogenesis and PML sumoylation

In the originally published version of this Article, the authors Sai-Juan Chen and Zhu Chen were incorrectly listed as being affiliated with ‘University Paris Diderot, Sorbonne Paris Cité, INSERM U944, CNRS UMR7212, Equipe labellisée LNCC, Hôpital St. Louis 1, Paris 75475, France’, and the affiliation ‘Institute of Health Sciences, Shanghai Institutes for Biological Sciences and Graduate School, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China’ was inadvertently omitted. These errors have now been corrected in both the PDF and HTML versions of the Article.