Blocking interaction between SHP2 and PD‐1 denotes a novel opportunity for developing PD‐1 inhibitors

Small molecular PD‐1 inhibitors are lacking in current immuno‐oncology clinic. PD‐1/PD‐L1 antibody inhibitors currently approved for clinical usage block interaction between PD‐L1 and PD‐1 to enhance cytotoxicity of CD8+ cytotoxic T lymphocyte (CTL). Whether other steps along the PD‐1 signaling pathway can be targeted remains to be determined. Here, we report that methylene blue (MB), an FDA‐approved chemical for treating methemoglobinemia, potently inhibits PD‐1 signaling. MB enhances the cytotoxicity, activation, cell proliferation, and cytokine‐secreting activity of CTL inhibited by PD‐1. Mechanistically, MB blocks interaction between Y248‐phosphorylated immunoreceptor tyrosine‐based switch motif (ITSM) of human PD‐1 and SHP2. MB enables activated CTL to shrink PD‐L1 expressing tumor allografts and autochthonous lung cancers in a transgenic mouse model. MB also effectively counteracts the PD‐1 signaling on human T cells isolated from peripheral blood of healthy donors. Thus, we identify an FDA‐approved chemical capable of potently inhibiting the function of PD‐1. Equally important, our work sheds light on a novel strategy to develop inhibitors targeting PD‐1 signaling axis

Reduced cortical thickness in right Heschl’s gyrus associated with auditory verbal hallucinations severity in first-episode schizophrenia

BACKGROUND: Auditory verbal hallucinations (AVHs) represent one of the most intriguing phenomena in schizophrenia, however, brain abnormalities underlying AVHs remain unclear. The present study examined the association between cortical thickness and AVHs in first-episode schizophrenia. METHOD: High-resolution MR images were obtained in 49 first-episode schizophrenia (FES) patients and 50 well-matched healthy controls (HCs). Among the FES patients, 18 suffered persistent AVHs (“auditory hallucination” AH group), and 31 never experienced AVHs (“no hallucination” NH group). The severity of AVHs was rated by the Auditory Hallucinations Rating Scale (AHRS). Cortical thickness differences among the three groups and their association with AVHs severity were examined. RESULTS: Compared to both HCs and NH patients, AH patients showed lower cortical thickness in the right Heschl’s gyrus. The degree of reduction in the cortical thickness was correlated with AVH severity in the AH patients. CONCLUSIONS: Abnormalities of cortical thickness in the Heschl’s gyrus may be a physiological factor underlying auditory verbal hallucinations in schizophrenia. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12888-015-0546-2) contains supplementary material, which is available to authorized users

Tunable Dirac Fermion Dynamics in Topological Insulators

Three-dimensional topological insulators are characterized by insulating bulk state and metallic surface state involving Dirac fermions that behave as massless relativistic particles. These Dirac fermions are responsible for achieving a number of novel and exotic quantum phenomena in the topological insulators and for their potential applications in spintronics and quantum computations. It is thus essential to understand the electron dynamics of the Dirac fermions, i.e., how they interact with other electrons, phonons and disorders. Here we report super-high resolution angle-resolved photoemission studies on the Dirac fermion dynamics in the prototypical Bi2(Te,Se)3 topological insulators. We have directly revealed signatures of the electron-phonon coupling in these topological insulators and found that the electron-disorder interaction is the dominant factor in the scattering process. The Dirac fermion dynamics in Bi2(Te3-xSex) topological insulators can be tuned by varying the composition, x, or by controlling the charge carriers. Our findings provide crucial information in understanding the electron dynamics of the Dirac fermions in topological insulators and in engineering their surface state for fundamental studies and potential applications.Comment: 14 Pages, 4 Figure

A unified fused Lasso approach for sparse and blocky feature selection in regression and classification

In many applications, sparse and blocky coefficients often occur in regression and classification problems. The fused Lasso was designed to recover these sparse structured features especially when the design matrix encounters the situation of ultrahigh dimension. Quantile loss is well known as a robust loss function in regression and classification. In this paper, we combine quantile loss and fused Lasso penalty together to produce quantile fused Lasso which can achieve sparse and blocky feature selection in both regression and classification. Interestingly, our proposed model has the unified optimization formula for regression and classification. For ultrahigh dimensional collected data, we derive multi-block linearized alternating direction method of multipliers (LADMM) to deal with it. Moreover, we prove convergence and derive convergence rates of the proposed LADMM algorithm through an elegant method. Note that the algorithm can be easily extended to solve many existing fused Lasso models. Finally, we present some numerical results for several synthetic and real world examples, which illustrate the robustness, scalability, and accuracy of the proposed method