Zero-Shot Emotion Transfer For Cross-Lingual Speech Synthesis

Zero-shot emotion transfer in cross-lingual speech synthesis aims to transfer emotion from an arbitrary speech reference in the source language to the synthetic speech in the target language. Building such a system faces challenges of unnatural foreign accents and difficulty in modeling the shared emotional expressions of different languages. Building on the DelightfulTTS neural architecture, this paper addresses these challenges by introducing specifically-designed modules to model the language-specific prosody features and language-shared emotional expressions separately. Specifically, the language-specific speech prosody is learned by a non-autoregressive predictive coding (NPC) module to improve the naturalness of the synthetic cross-lingual speech. The shared emotional expression between different languages is extracted from a pre-trained self-supervised model HuBERT with strong generalization capabilities. We further use hierarchical emotion modeling to capture more comprehensive emotions across different languages. Experimental results demonstrate the proposed framework's effectiveness in synthesizing bi-lingual emotional speech for the monolingual target speaker without emotional training data.Comment: Accepted by ASRU202

Clearing Persistent Extracellular Antigen of Hepatitis B Virus: An Immunomodulatory Strategy To Reverse Tolerance for an Effective Therapeutic Vaccination

Development of therapeutic vaccines/strategies to control chronic hepatitis B virus (HBV) infection (CHB) has been challenging due to HBV-induced tolerance. In this study, we explored strategies for breaking tolerance and restoring the immune response to the HBV surface antigen in tolerant mice. We demonstrated that immune tolerance status is attributed to the level and duration of circulating HBsAg in HBV carrier models. Removal of circulating HBsAg by a monoclonal anti-HBsAg antibody in tolerant mice could gradually reduce tolerance and reestablish B cell and CD4+ T cell responses to subsequent Engerix-B vaccination, producing protective IgG. Furthermore, HBsAg-specific CD8+ T cells induced by the addition of a TLR agonist, resulted in clearance of HBV in both serum and liver. Thus, generation of protective immunity can be achieved by clearing extracellular viral antigen with neutralizing antibodies followed by vaccination

A mouse model for HBV immunotolerance and immunotherapy

Lack of an appropriate small animal model remains a major hurdle for studying the immunotolerance and immunopathogenesis induced by hepatitis B virus (HBV) infection. In this study, we report a mouse model with sustained HBV viremia after infection with a recombinant adeno-associated virus (AAV) carrying a replicable HBV genome (AAV/HBV). Similar to the clinical HBV carriers, the mice infected with AAV/HBV were sero-negative for antibodies against HBV surface antigen (HBsAg). Immunization with the conventional HBV vaccine in the presence of aluminum adjuvant failed to elicit an immune response against HBV in these mice. To identify a vaccine that can potentially circumvent this tolerance, the TLR9 agonist CpG was added to HBsAg as an adjuvant. Vaccination of mice with HBsAg/CpG induced not only clearance of viremia, but also strong antibody production and T-cell responses. Furthermore, both the DNA replication and protein expression of HBV were significantly reduced in the livers of AAV/HBV-infected mice. Accordingly, AAV/HBV-infected mice may be used as a robust model for investigating the underlying mechanism(s) of HBV immunotolerance and for developing novel immunotherapies to eradicate HBV infections

Vaccines targeting preS1 domain overcome immune tolerance in hepatitis B virus carrier mice

Strong tolerance to hepatitis B virus (HBV) surface antigens limits the therapeutic effect of the conventional hepatitis B surface antigen (HBsAg) vaccination in both preclinical animal models and patients with chronic hepatitis B (CHB) infection. In contrast, we observed that clinical CHB patients presented less immune tolerance to the preS1 domain of HBV large surface antigen. To study whether targeting the weak tolerance of the preS1 region could improve therapy gain, we explored vaccination with the long peptide of preS1 domain for HBV virions clearance. Our study showed that this preS1-polypeptide rather than HBsAg vaccination induced robust immune responses in HBV carrier mice. The anti-preS1 rapidly cleared HBV virions in vivo and blocked HBV infection to hepatocytes in vitro. Intriguingly, vaccination of preS1-polypeptide even reduced the tolerized status of HBsAg, opening a therapeutic window for the host to respond to the HBsAg vaccine. A sequential administration of antigenically distinct preS1-polypeptide and HBsAg vaccines in HBV carrier mice could finally induce HBsAg/hepatitis B surface antibody serological conversion and clear chronic HBV infection in carrier mice. Conclusion: These results suggest that preS1 can function as a therapeutic vaccine for the control of CHB. (Hepatology 2017;66:1067-1082)

An integrated Mg battery-powered iontophoresis patch for efficient and controllable transdermal drug delivery

Wearable transdermal iontophoresis eliminating the need for external power sources offers advantages for patient-comfort when deploying epidermal diseases treatments. However, current self-powered iontophoresis based on energy harvesters is limited to support efficient therapeutic administration over the long-term operation, owing to the low and inconsistent energy supply. Here we propose a simplified wearable iontophoresis patch with a built-in Mg battery for efficient and controllable transdermal delivery. This system decreases the system complexity and form factors by using viologen-based hydrogels as an integrated drug reservoir and cathode material, eliminating the conventional interface impedance between the electrode and drug reservoir. The redox-active polyelectrolyte hydrogel offers a high energy density of 3.57 mWh cm−2, and an optimal bioelectronic interface with ultra-soft nature and low tissue-interface impedance. The delivery dosage can be readily manipulated by tuning the viologen hydrogel and the iontophoresis stimulation mode. This iontophoresis patch demonstrates an effective treatment of an imiquimod-induced psoriasis mouse. Considering the advantages of being a reliable and efficient energy supply, simplified configuration, and optimal electrical skin-device interface, this battery-powered iontophoresis may provide a new non-invasive treatment for chronic epidermal diseases

An integrated Mg battery-powered iontophoresis patch for efficient and controllable transdermal drug delivery

Wearable transdermal iontophoresis offers advantages for patient-comfort when deploying epidermal diseases treatments but current self-powered iontophoresis based on energy harvesters is limited in the support of efficient long-term operation therapeutic administration. Here, the authors propose a simplified wearable iontophoresis patch with a built-in Mg battery for efficient and controllable transdermal delivery

Clearing Persistent Extracellular Antigen of Hepatitis B Virus: An Immunomodulatory Strategy To Reverse Tolerance for an Effective Therapeutic Vaccination

Development of therapeutic vaccines/strategies to control chronic hepatitis B virus (HBV) infection (CHB) has been challenging due to HBV-induced tolerance. In this study, we explored strategies for breaking tolerance and restoring the immune response to the HBV surface antigen in tolerant mice. We demonstrated that immune tolerance status is attributed to the level and duration of circulating HBsAg in HBV carrier models. Removal of circulating HBsAg by a monoclonal anti-HBsAg antibody in tolerant mice could gradually reduce tolerance and reestablish B cell and CD4+ T cell responses to subsequent Engerix-B vaccination, producing protective IgG. Furthermore, HBsAg-specific CD8+ T cells induced by the addition of a TLR agonist, resulted in clearance of HBV in both serum and liver. Thus, generation of protective immunity can be achieved by clearing extracellular viral antigen with neutralizing antibodies followed by vaccination