Investigation on Data Adaptation Techniques for Neural Named Entity Recognition

Data processing is an important step in various natural language processing tasks. As the commonly used datasets in named entity recognition contain only a limited number of samples, it is important to obtain additional labeled data in an efficient and reliable manner. A common practice is to utilize large monolingual unlabeled corpora. Another popular technique is to create synthetic data from the original labeled data (data augmentation). In this work, we investigate the impact of these two methods on the performance of three different named entity recognition tasks.Comment: ACL SRW 2021 - camera read

Enhanced Phagocytic Activity of HIV-Specific Antibodies Correlates with Natural Production of Immunoglobulins with Skewed Affinity for FcγR2a and FcγR2b

While development of an HIV vaccine that can induce neutralizing antibodies remains a priority, decades of research have proven that this is a daunting task. However, accumulating evidence suggests that antibodies with the capacity to harness innate immunity may provide some protection. While significant research has focused on the cytolytic properties of antibodies in acquisition and control, less is known about the role of additional effector functions. In this study, we investigated antibody-dependent phagocytosis of HIV immune complexes, and we observed significant differences in the ability of antibodies from infected subjects to mediate this critical effector function. We observed both quantitative differences in the capacity of antibodies to drive phagocytosis and qualitative differences in their FcγR usage profile. We demonstrate that antibodies from controllers and untreated progressors exhibit increased phagocytic activity, altered Fc domain glycosylation, and skewed interactions with FcγR2a and FcγR2b in both bulk plasma and HIV-specific IgG. While increased phagocytic activity may directly influence immune activation via clearance of inflammatory immune complexes, it is also plausible that Fc receptor usage patterns may regulate the immune response by modulating downstream signals following phagocytosis—driving passive degradation of internalized virus, release of immune modulating cytokines and chemokines, or priming of a more effective adaptive immune response

N-acetylcysteine Facilitates Self-Imposed Abstinence After Escalation of Cocaine Intake.

BACKGROUND: N-acetylcysteine (NAC) has been suggested to prevent relapse to cocaine seeking. However, the psychological processes underlying its potential therapeutic benefit remain largely unknown. METHODS: We investigated the hallmark features of addiction that were influenced by chronic NAC treatment in rats given extended access to cocaine: escalation, motivation, self-imposed abstinence in the face of punishment, or propensity to relapse. For this, Sprague Dawley rats were given access either to 1 hour (short access) or 6 hours (long access [LgA]) self-administration (SA) sessions until LgA rats displayed a robust escalation. Rats then received daily saline or NAC (60 mg/kg, intraperitoneal) treatment and were tested under a progressive ratio and several consecutive sessions in which lever presses were punished by mild electric foot shocks. RESULTS: NAC increased the sensitivity to punishment in LgA rats only, thereby promoting abstinence. Following the cessation of punishment, NAC-treated LgA rats failed to recover fully their prepunishment cocaine intake levels and resumed cocaine SA at a lower rate than short access and vehicle-treated LgA rats. However, NAC altered neither the escalation of SA nor the motivation for cocaine. At the neurobiological level, NAC reversed cocaine-induced decreases in the glutamate type 1 transporter observed in both the nucleus accumbens and the dorsolateral striatum. NAC also increased the expression of Zif268 in the nucleus accumbens and dorsolateral striatum of LgA rats. CONCLUSIONS: Our results indicate that NAC contributes to the restoration of control over cocaine SA following adverse consequences, an effect associated with plasticity mechanisms in both the ventral and dorsolateral striatum.This research was supported by a French Institute of Health and Medical Research Avenir and an ANR12 SAMA00201 Grant (to DB) as well as a Newton Trust/Cambridge University Grant (to DB). BJE and JEM are supported by a Medical Research Council (G9536855, G0701500) Grant to BJE and by a joint award from the Medical Research Council and Wellcome Trust in support of the Behavioral and Clinical Neuroscience Institute at Cambridge University

Divergent Antibody Subclass and Specificity Profiles but Not Protective HLA-B Alleles Are Associated with Variable Antibody Effector Function among HIV-1 Controllers

Understanding the coordination between humoral and cellular immune responses may be the key to developing protective vaccines, and because genetic studies of long-term HIV-1 nonprogressors have associated specific HLA-B alleles with spontaneous control of viral replication, this subject group presents an opportunity to investigate relationships between arms of the adaptive immune system. Given evidence suggesting that cellular immunity may play a role in viral suppression, we sought to determine whether and how the humoral immune response might vary among controllers. Significantly, Fc-mediated antibody effector functions have likewise been associated with durable viral control. In this study, we compared the effector function and biophysical features of HIV-specific antibodies in a cohort of controllers with and without protective HLA-B alleles in order to investigate whether there was evidence for multiple paths to HIV-1 control, or whether cellular and humoral arms of immunity might exhibit coordinated profiles. However, with the exception of IgG2 antibodies to gp41, HLA status was not associated with divergent humoral responses. This finding did not result from uniform antibody responses across subjects, as controllers could be regrouped according to strong differences in their HIV-specific antibody subclass specificity profiles. These divergent antibody profiles were further associated with significant differences in nonneutralizing antibody effector function, with levels of HIV-specific IgG1 acting as the major distinguishing factor. Thus, while HLA background among controllers was associated with minimal differences in humoral function, antibody subclass and specificity profiles were associated with divergent effector function, suggesting that these features could be used to make functional predictions. Because these nonneutralizing antibody activities have been associated with spontaneous viral control, reduced viral load, and nonprogression in infected subjects and protection in vaccinated subjects, understanding the specific features of IgGs with potentiated effector function may be critical to vaccine and therapeutic antibody development

A robust, high-throughput assay to determine the phagocytic activity of clinical antibody samples

Phagocytosis can be induced via the engagement of Fcγ receptors by antibody-opsonized material. Furthermore, the efficiency of antibody-induced effector functions has been shown to be dramatically modulated by changes in antibody glycosylation. Because infection can modulate antibody glycans, which in turn modulate antibody functions, assays capable of determining the induction of effector functions rather than neutralization or titer provide a valuable opportunity to more fully characterize the quality of the adaptive immune response. Here we describe a robust and high-throughput flow cytometric assay to define the phagocytic activity of antigen-specific antibodies from clinical samples. This assay employs a monocytic cell line that expresses numerous Fc receptors: including inhibitory and activating, and high and low affinity receptors—allowing complex phenotypes to be studied. We demonstrate the adaptability of this high-throughput, flow-based assay to measure antigen-specific antibody-mediated phagocytosis against an array of viruses, including influenza, HIV, and dengue. The phagocytosis assay format further allows for simultaneous analysis of cytokine release, as well as determination of the role of specific Fcγ-receptor subtypes, making it a highly useful system for parsing differences in the ability of clinical and vaccine induced antibody samples to recruit this critical effector function.Neutralizing Antibody Consortium (International AIDS Vaccine Initiative)National Institute of Allergy and Infectious Diseases (U.S.)National Institutes of Health (U.S.) (AI055332)National Institutes of Health (U.S.) (AI080289)Ragon Institute of MGH, MIT and Harvar

Natural Variation in Fc Glycosylation of HIV-Specific Antibodies Impacts Antiviral Activity

While the induction of a neutralizing antibody response against HIV remains a daunting goal, data from both natural infection and vaccine-induced immune responses suggest that it may be possible to induce antibodies with enhanced Fc effector activity and improved antiviral control via vaccination. However, the specific features of naturally induced HIV-specific antibodies that allow for the potent recruitment of antiviral activity and the means by which these functions are regulated are poorly defined. Because antibody effector functions are critically dependent on antibody Fc domain glycosylation, we aimed to define the natural glycoforms associated with robust Fc-mediated antiviral activity. We demonstrate that spontaneous control of HIV and improved antiviral activity are associated with a dramatic shift in the global antibody-glycosylation profile toward agalactosylated glycoforms. HIV-specific antibodies exhibited an even greater frequency of agalactosylated, afucosylated, and asialylated glycans. These glycoforms were associated with enhanced Fc-mediated reduction of viral replication and enhanced Fc receptor binding and were consistent with transcriptional profiling of glycosyltransferases in peripheral B cells. These data suggest that B cell programs tune antibody glycosylation actively in an antigen-specific manner, potentially contributing to antiviral control during HIV infection

TRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKT.

Intrinsic and acquired resistance to chemotherapy is the fundamental reason for treatment failure for many cancer patients. The identification of molecular mechanisms involved in drug resistance or sensitization is imperative. Here we report that tribbles homologue 2 (TRIB2) ablates forkhead box O activation and disrupts the p53/MDM2 regulatory axis, conferring resistance to various chemotherapeutics. TRIB2 suppression is exerted via direct interaction with AKT a key signalling protein in cell proliferation, survival and metabolism pathways. Ectopic or intrinsic high expression of TRIB2 induces drug resistance by promoting phospho-AKT (at Ser473) via its COP1 domain. TRIB2 expression is significantly increased in tumour tissues from patients correlating with an increased phosphorylation of AKT, FOXO3a, MDM2 and an impaired therapeutic response. This culminates in an extremely poor clinical outcome. Our study reveals a novel regulatory mechanism underlying drug resistance and suggests that TRIB2 functions as a regulatory component of the PI3K network, activating AKT in cancer cells

Neutralizing anti-HIV antibodies develop in a humanized

From AIDS Vaccine 2012, Boston, MA, USA. 9-12 September 2012.Background: In BLT (bone marrow-liver-thymus) humanized mice, human thymocytes are educated by autologous human thymic tissue, resulting in functional human T cells capable of rapidly selecting for CTL escape mutations in HIV. In contrast, limitations to B cell maturation have been noted. But despite this, we show for the first time that HIV infected BLT mice can produce class-switched anti-HIV antibodies with neutralizing activities. Methods: Humanized BLT mice were generated by transplanting irradiated NOD-scid/IL2rgnull (NSG) mice with fetal thymus and liver fragments and then injecting them with autologous human CD34+ stem cells. BLT mice were then infected with HIVJRCSF and bled at various time-points. HIV neutralizing activity was measured using Tat-induced luciferase reporter TZM-bl cells. Results: Human transitional B cells were present in greater frequencies in BLT mice than adult humans. Most of these cells had a T1 phenotype in the blood and spleen. But despite this B cell maturation defect, class-switched IgG Abs against various HIV proteins were detected by Western Blot in HIV-infected BLT mice. Using ELISA to determine anti-p24 IgG Ab titers, Abs were present as early as 8 weeks post infection (p.i.), with peak Ab titers seen after 15 weeks. One infected mouse demonstrated a peak titer similar to that seen in a chronically infected human. Finally, plasma samples from infected BLT mice after 22 weeks p.i. demonstrated neutralizing activities against the challenge virus. Average IC50 neutralizing titers in these mice were similar to those from infected human samples. Conclusion: The ability of humanized BLT mice to generate functional humoral immune responses may be further improved by strategies to improve their B cell maturation, which will further improve the potential of these mice to become a model system to study candidate HIV vaccines and therapies

Lack of Protection following Passive Transfer of Polyclonal Highly Functional Low-Dose Non-Neutralizing Antibodies

Recent immune correlates analysis from the RV144 vaccine trial has renewed interest in the role of non-neutralizing antibodies in mediating protection from infection. While neutralizing antibodies have proven difficult to induce through vaccination, extra-neutralizing antibodies, such as those that mediate antibody-dependent cellular cytotoxicity (ADCC), are associated with long-term control of infection. However, while several non-neutralizing monoclonal antibodies have been tested for their protective efficacy in vivo, no studies to date have tested the protective activity of naturally produced polyclonal antibodies from individuals harboring potent ADCC activity. Because ADCC-inducing antibodies are highly enriched in elite controllers (EC), we passively transferred highly functional non-neutralizing polyclonal antibodies, purified from an EC, to assess the potential impact of polyclonal non-neutralizing antibodies on a stringent SHIV-SF162P3 challenge in rhesus monkeys. Passive transfer of a low-dose of ADCC inducing antibodies did not protect from infection following SHIV-SF162P3 challenge. Passively administered antibody titers and gp120-specific, but not gp41-specific, ADCC and antibody induced phagocytosis (ADCP) were detected in the majority of the monkeys, but did not correlate with post infection viral control. Thus these data raise the possibility that gp120-specific ADCC activity alone may not be sufficient to control viremia post infection but that other specificities or Fc-effector profiles, alone or in combination, may have an impact on viral control and should be tested in future passive transfer experiments