Viperin inhibits interferon-γ production to promote Mycobacterium tuberculosis survival by disrupting TBK1-IKKε-IRF3-axis and JAK-STAT signaling.

OBJECTIVES AND DESIGN: As an interferon-inducible protein, Viperin has broad-spectrum antiviral effects and regulation of host immune responses. We aim to investigate how Viperin regulates interferon-γ (IFN-γ) production in macrophages to control Mycobacterium tuberculosis (Mtb) infection. METHODS: We use Viperin deficient bone-marrow-derived macrophage (BMDM) to investigate the effects and machines of Viperin on Mtb infection. RESULTS: Viperin inhibited IFN-γ production in macrophages and in the lung of mice to promote Mtb survival. Further insight into the mechanisms of Viperin-mediated regulation of IFN-γ production revealed the role of TANK-binding kinase 1 (TBK1), the TAK1-dependent inhibition of NF-kappa B kinase-epsilon (IKKε), and interferon regulatory factor 3 (IRF3). Inhibition of the TBK1-IKKε-IRF3 axis restored IFN-γ production reduced by Viperin knockout in BMDM and suppressed intracellular Mtb survival. Moreover, Viperin deficiency activated the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway, which promoted IFN-γ production and inhibited Mtb infection in BMDM. Additionally, a combination of the anti-TB drug INH treatment in the absence of Viperin resulted in further IFN-γ production and anti-TB effect. CONCLUSIONS: This study highlights the involvement of TBK1-IKKε-IRF3 axis and JAK-STAT signaling pathways in Viperin-suppressed IFN-γ production in Mtb infected macrophages, and identifies a novel mechanism of Viperin on negatively regulating host immune response to Mtb infection.

Improved 3D-2D Perovskite for Efficient Perovskite Photovoltaics with Low-Temperature Carbon Electrodes.

Surface passivation and interface modification are effective strategies to acquire outstanding performances for perovskite solar cells (PeSCs). To suppress charge recombination and enhance the stability of the perovskite device, a hydrophobic two-dimensional (2D) perovskite is presented to construct a 3D-2D composite perovskite, passivating the perovskite surface/interfacial imperfection. Herein, a 3D-2D heterojunction perovskite is in situ synthesized on a 3D surface to maximize the charge transport and environmental stability. Through optimizing the annealing procedure systematically, the champion 3D-2D carbon-based PeSC achieves a power conversion efficiency of 17.95% and has wonderful long-term stability. Especially, an improved 3D-2D (3D-2D+) PeSC from restrict annealing even maintains 96.2% of the initial efficiency in air over 800 h and 90% efficiency under continuous 70 °C heating for 10 h owing to the passivation of the surface and thorough crystal boundary for the 3D-2D+ perovskite. The strong environmental stability of 3D-2D PeSCs has provided a wider avenue for fully low-temperature carbon-based PeSCs.

Targeting neoantigens for cancer immunotherapy.

Neoantigens, a type of tumor-specific antigens derived from non-synonymous mutations, have recently been characterized as attractive targets for cancer immunotherapy. Owing to the development of next-generation sequencing and utilization of machine-learning algorithms, it has become feasible to computationally predict neoantigens by depicting genetic alterations, aberrant post-transcriptional mRNA processing and abnormal mRNA translation events within tumor tissues. Consequently, neoantigen-based therapies such as cancer vaccines have been widely tested in clinical trials and have demonstrated promising safety and efficacy, opening a new era for cancer immunotherapy. We systematically summarize recent advances in the identification of both personalized and public neoantigens, neoantigen formulations and neoantigen-based clinical trials in this review. Moreover, we discuss future techniques and strategies for neoantigen-based cancer treatment either as a monotherapy or as a combination therapy with radiotherapy, chemotherapy or immune checkpoint inhibitors.

Automatic Recognition of Auditory Brainstem Response Characteristic Waveform Based on Bidirectional Long Short-Term Memory.

Background: Auditory brainstem response (ABR) testing is an invasive electrophysiological auditory function test. Its waveforms and threshold can reflect auditory functional changes in the auditory centers in the brainstem and are widely used in the clinic to diagnose dysfunction in hearing. However, identifying its waveforms and threshold is mainly dependent on manual recognition by experimental persons, which could be primarily influenced by individual experiences. This is also a heavy job in clinical practice. Methods: In this work, human ABR was recorded. First, binarization is created to mark 1,024 sampling points accordingly. The selected characteristic area of ABR data is 0-8 ms. The marking area is enlarged to expand feature information and reduce marking error. Second, a bidirectional long short-term memory (BiLSTM) network structure is established to improve relevance of sampling points, and an ABR sampling point classifier is obtained by training. Finally, mark points are obtained through thresholding. Results: The specific structure, related parameters, recognition effect, and noise resistance of the network were explored in 614 sets of ABR clinical data. The results show that the average detection time for each data was 0.05 s, and recognition accuracy reached 92.91%. Discussion: The study proposed an automatic recognition of ABR waveforms by using the BiLSTM-based machine learning technique. The results demonstrated that the proposed methods could reduce recording time and help doctors in making diagnosis, suggesting that the proposed method has the potential to be used in the clinic in the future.

Incoherent feed-forward regulatory loops control segregation of C-mechanoreceptors, nociceptors, and pruriceptors.

Mammalian skin is innervated by diverse, unmyelinated C fibers that are associated with senses of pain, itch, temperature, or touch. A key developmental question is how this neuronal cell diversity is generated during development. We reported previously that the runt domain transcription factor Runx1 is required to coordinate the development of these unmyelinated cutaneous sensory neurons, including VGLUT3(+) low-threshold c-mechanoreceptors (CLTMs), MrgprD(+) polymodal nociceptors, MrgprA3(+) pruriceptors, MrgprB4(+) c-mechanoreceptors, and others. However, how these Runx1-dependent cutaneous sensory neurons are further segregated is poorly illustrated. Here, we find that the Runx1-dependent transcription factor gene Zfp521 is expressed in, and required for establishing molecular features that define, VGLUT3(+) CLTMs. Furthermore, Runx1 and Zfp521 form a classic incoherent feedforward loop (I-FFL) in controlling molecular identities that normally belong to MrgprD(+) neurons, with Runx1 and Zfp51 playing activator and repressor roles, respectively (in genetic terms). A knock-out of Zfp521 allows prospective VGLUT3 lineage neurons to acquire MrgprD(+) neuron identities. Furthermore, Runx1 might form other I-FFLs to regulate the expression of MrgprA3 and MrgprB4, a mechanism preventing these genes from being expressed in Runx1-persistent VGLUT3(+) and MrgprD(+) neurons. The evolvement of these I-FFLs provides an explanation for how modality-selective sensory subtypes are formed during development and may also have intriguing implications for sensory neuron evolution and sensory coding.