IL-10 inhibition during immunization improves vaccine-induced protection against Staphylococcus aureus infection.

Staphylococcus aureus is a major human pathogen. An effective anti-S. aureus vaccine remains elusive as the correlates of protection are ill-defined. Targeting specific T cell populations is an important strategy for improving anti-S. aureus vaccine efficacy. Potential bottlenecks that remain are S. aureus-induced immunosuppression and the impact this might have on vaccine-induced immunity. S. aureus induces IL-10, which impedes effector T cell responses, facilitating persistence during both colonization and infection. Thus, it was hypothesized that transient targeting of IL-10 might represent an innovative way to improve vaccine efficacy. In this study, IL-10 expression was elevated in the nares of persistent carriers of S. aureus, and this was associated with reduced systemic S. aureus-specific Th1 responses. This suggests that systemic responses are remodeled because of commensal exposure to S. aureus, which negatively implicates vaccine function. To provide proof of concept that targeting immunosuppressive responses during immunization may be a useful approach to improve vaccine efficacy, we immunized mice with T cell-activating vaccines in combination with IL-10-neutralizing antibodies. Blocking IL-10 during vaccination enhanced effector T cell responses and improved bacterial clearance during subsequent systemic and subcutaneous infection. Taken together, these results reveal a potentially novel strategy for improving anti-S. aureus vaccine efficacy.

PYHIN protein IFI207 regulates cytokine transcription and IRF7 and contributes to the establishment of K. pneumoniae infection.

PYHIN proteins AIM2 and IFI204 sense pathogen DNA, while other PYHINs have been shown to regulate host gene expression through as-yet unclear mechanisms. We characterize mouse PYHIN IFI207, which we find is not involved in DNA sensing but rather is required for cytokine promoter induction in macrophages. IFI207 co-localizes with both active RNA polymerase II (RNA Pol II) and IRF7 in the nucleus and enhances IRF7-dependent gene promoter induction. Generation of Ifi207-/- mice shows no role for IFI207 in autoimmunity. Rather, IFI207 is required for the establishment of a Klebsiella pneumoniae lung infection and for Klebsiella macrophage phagocytosis. These insights into IFI207 function illustrate that PYHINs can have distinct roles in innate immunity independent of DNA sensing and highlight the need to better characterize the whole mouse locus, one gene at a time.

Targeted control of pneumolysin production by a mobile genetic element in Streptococcus pneumoniae.

Streptococcus pneumoniae is a major human pathogen that can cause severe invasive diseases such as pneumonia, septicaemia and meningitis. Young children are at a particularly high risk, with an estimated 3-4 million cases of severe disease and between 300 000 and 500 000 deaths attributable to pneumococcal disease each year. The haemolytic toxin pneumolysin (Ply) is a primary virulence factor for this bacterium, yet despite its key role in pathogenesis, immune evasion and transmission, the regulation of Ply production is not well defined. Using a genome-wide association approach, we identified a large number of potential affectors of Ply activity, including a gene acquired horizontally on the antibiotic resistance-conferring Integrative and Conjugative Element (ICE) ICESp23FST81. This gene encodes a novel modular protein, ZomB, which has an N-terminal UvrD-like helicase domain followed by two Cas4-like domains with potent ATP-dependent nuclease activity. We found the regulatory effect of ZomB to be specific for the ply operon, potentially mediated by its high affinity for the BOX repeats encoded therein. Using a murine model of pneumococcal colonization, we further demonstrate that a ZomB mutant strain colonizes both the upper respiratory tract and lungs at higher levels when compared to the wild-type strain. While the antibiotic resistance-conferring aspects of ICESp23FST81 are often credited with contributing to the success of the S. pneumoniae lineages that acquire it, its ability to control the expression of a major virulence factor implicated in bacterial transmission is also likely to have played an important role.

The Impact of Lung Proteases on Snake-Derived Antimicrobial Peptides.

Respiratory infections are a leading cause of global morbidity and mortality and are of significant concern for individuals with chronic inflammatory lung diseases. There is an urgent need for novel antimicrobials. Antimicrobial peptides (AMPs) are naturally occurring innate immune response peptides with therapeutic potential. However, therapeutic development has been hindered by issues with stability and cytotoxicity. Availing of direct drug delivery to the affected site, for example the lung, can reduce unwanted systemic side effects and lower the required dose. As cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) lungs typically exhibit elevated protease levels, the aim of this study was to assess their impact on snake-derived AMPs. Peptide cleavage was determined using SDS-PAGE and antimicrobial and anti-inflammatory activities of neutrophil elastase (NE)-incubated peptides were assessed using a radial diffusion assay (RDA) and an in vitro LPS-induced inflammation model, respectively. Although the snake-derived AMPs were found to be susceptible to cleavage by lung proteases including NE, several retained their function following NE-incubation. This facilitated the design of novel truncated derivatives that retained functionality following NE incubation. Snake-derived AMPs are tractable candidate treatments for use in environments that feature elevated NE levels, such as the CF airways.

The Quest for Ecological Validity in Hearing Science: What It Is, Why It Matters, and How to Advance It.

Ecological validity is a relatively new concept in hearing science. It has been cited as relevant with increasing frequency in publications over the past 20 years, but without any formal conceptual basis or clear motive. The sixth Eriksholm Workshop was convened to develop a deeper understanding of the concept for the purpose of applying it in hearing research in a consistent and productive manner. Inspired by relevant debate within the field of psychology, and taking into account the World Health Organization's International Classification of Functioning, Disability, and Health framework, the attendees at the workshop reached a consensus on the following definition: "In hearing science, ecological validity refers to the degree to which research findings reflect real-life hearing-related function, activity, or participation." Four broad purposes for striving for greater ecological validity in hearing research were determined: A (Understanding) better understanding the role of hearing in everyday life; B (Development) supporting the development of improved procedures and interventions; C (Assessment) facilitating improved methods for assessing and predicting ability to accomplish real-world tasks; and D (Integration and Individualization) enabling more integrated and individualized care. Discussions considered the effects of variables and phenomena commonly present in hearing-related research on the level of ecological validity of outcomes, supported by examples from a few selected outcome domains and for different types of studies. Illustrated with examples, potential strategies were offered for promoting a high level of ecological validity in a study and for how to evaluate the level of ecological validity of a study. Areas in particular that could benefit from more research to advance ecological validity in hearing science include: (1) understanding the processes of hearing and communication in everyday listening situations, and specifically the factors that make listening difficult in everyday situations; (2) developing new test paradigms that include more than one person (e.g., to encompass the interactive nature of everyday communication) and that are integrative of other factors that interact with hearing in real-life function; (3) integrating new and emerging technologies (e.g., virtual reality) with established test methods; and (4) identifying the key variables and phenomena affecting the level of ecological validity to develop verifiable ways to increase ecological validity and derive a set of benchmarks to strive for.

Conversational Interaction Is the Brain in Action: Implications for the Evaluation of Hearing and Hearing Interventions.

Humans have evolved the unique capacity to efficiently communicate using the spoken word. Hearing plays a key role as a receiver in this process and dysfunction leads to difficulties in listening and communication. It is widely accepted that effective communication is not adequately captured with current behavioral speech tests that principally focus on passive sound detection and speech recognition with idealized stimuli. To address the question of what it will take to obtain more ecologically valid outcomes from behavioral speech tests, recent approaches, and test paradigms devised to address some of the acknowledged shortcomings of current speech tests were reviewed. Additionally, some recent work which has focused on understanding brain function in social and dynamic interaction scenarios, so-called second person neuroscience, was reviewed. These reviews revealed that, while recent efforts in bridging the gap between behavioral speech tests and everyday communication situations represent important steps in the right direction, they are unlikely to provide a complete account of everyday communication situations. Further, brain imaging studies, together with our growing understanding of "mirror" neurons and the development of theories around embodied cognition, have demonstrated that the brain networks recruited during emotionally engaged interaction between interlocutors are far more complex when compared to that of a passive listener. Speech and nonspeech (e.g., gaze direction, body posture, etc.) interactions between the interlocutors give rise to the perception of effective interaction (sense of "agency") and activate neural networks important in decision-making and subsequent communication interaction. Successful conversational interaction represents the negotiation of a dynamic context and the emergence of a state of shared understanding between participants. In conclusion, to achieve highly ecologically valid outcomes related to communication, future testing will most likely require an interactive or conversational paradigm to elicit the brain states that are present in everyday social interactions.

The monaural spectral cues identified by a reverse correlation analysis of free-field auditory localization data.

The outer-ear's location-dependent pattern of spectral filtering generates cues used to determine a sound source's elevation as well as front-back location. The authors aim to identify these features using a reverse correlation analysis (RCA), combining free-field localization behaviour with the associated head-related transfer functions' (HRTFs) magnitude spectrum from a sample of 73 participants. Localization responses were collected before and immediately after introducing a pair of outer-ear inserts which modified the listener's HRTFs to varying extent. The RCA identified several different features responsible for eliciting localization responses. The efficacy of these was examined using two models of monaural localization. In general, the predicted performance was closely aligned with the free-field localization error for the bare-ear condition; however, both models tended to grossly over-estimate the localization error based on HRTFs modified by the outer-ear inserts. The RCA's feature selection notably had the effect of better aligning the predicted performance of both models to the actual localization performance. This suggests that the RCA revealed sufficient detail for both models to correctly predict localization performance and also limited the influence of filtered-out elements in the distorted HRTFs that contributed to the degraded accuracy of both models.

The Effects of Switching Non-Spatial Attention During Conversational Turn Taking.

This study examined the effect of a change in target voice on word recall during a multi-talker conversation. Two experiments were conducted using matrix sentences to assess the cost of a single endogenous switch in non-spatial attention. Performance in a yes-no recognition task was significantly worse when a target voice changed compared to when it remained the same after a turn-taking gap. We observed a decrease in target hit rate and sensitivity, and an increase in masker confusion errors following a change in voice. These results highlight the cognitive demands of not only engaging attention on a new talker, but also of disengaging attention from a previous target voice. This shows that exposure to a voice can have a biasing effect on attention that persists well after a turn-taking gap. A second experiment showed that there was no change in switching performance using different talker combinations. This demonstrates that switching costs were consistent and did not depend on the degree of acoustic differences in target voice characteristics.

Sea snake cathelicidin (Hc-cath) exerts a protective effect in mouse models of lung inflammation and infection.

We investigated the anti-inflammatory and antibacterial activities of Hc-cath, a cathelicidin peptide derived from the venom of the sea snake, Hydrophis cyanocyntus, using in vivo models of inflammation and infection. Hc-cath function was evaluated in in vitro, in vivo in the wax moth, Galleria mellonella, and in mouse models of intraperitoneal and respiratory Pseudomonas aeruginosa infection. Hc-Cath downregulated LPS-induced pro-inflammatory responses in macrophages and significantly improved the survival of P. aeruginosa infected G. mellonella over a 5-day period. We also demonstrated, for the first time, that Hc-cath can modulate inflammation in a mouse model of LPS-induced lung inflammation by significantly reducing the release of the pro-inflammatory cytokine and neutrophil chemoattractant, KC, resulting in reduced cellular infiltration into the lungs. Moreover, Hc-cath treatment significantly reduced the bacterial load and inflammation in mouse models of P. aeruginosa intraperitoneal and respiratory infection. The effect of Hc-cath in our studies highlights the potential to develop this peptide as a candidate for therapeutic development.

Tracking the dynamic representation of consonants from auditory periphery to cortex.

In order to perceive meaningful speech, the auditory system must recognize different phonemes amidst a noisy and variable acoustic signal. To better understand the processing mechanisms underlying this ability, evoked cortical responses to different spoken consonants were measured with electroencephalography (EEG). Using multivariate pattern analysis (MVPA), binary classifiers attempted to discriminate between the EEG activity evoked by two given consonants at each peri-stimulus time sample, providing a dynamic measure of their cortical dissimilarity. To examine the relationship between representations at the auditory periphery and cortex, MVPA was also applied to modelled auditory-nerve (AN) responses of consonants, and time-evolving AN-based and EEG-based dissimilarities were compared with one another. Cortical dissimilarities between consonants were commensurate with their articulatory distinctions, particularly their manner of articulation, and to a lesser extent, their voicing. Furthermore, cortical distinctions between consonants in two periods of activity, centered at 130 and 400 ms after onset, aligned with their peripheral dissimilarities in distinct onset and post-onset periods, respectively. In relating speech representations across articulatory, peripheral, and cortical domains, the understanding of crucial transformations in the auditory pathway underlying the ability to perceive speech is advanced.

A Review of the Possible Perceptual and Physiological Effects of Wind Turbine Noise.

This review considers the nature of the sound generated by wind turbines focusing on the low-frequency sound (LF) and infrasound (IS) to understand the usefulness of the sound measures where people work and sleep. A second focus concerns the evidence for mechanisms of physiological transduction of LF/IS or the evidence for somatic effects of LF/IS. While the current evidence does not conclusively demonstrate transduction, it does present a strong prima facia case. There are substantial outstanding questions relating to the measurement and propagation of LF and IS and its encoding by the central nervous system relevant to possible perceptual and physiological effects. A range of possible research areas are identified.

Listening Into 2030 Workshop: An Experiment in Envisioning the Future of Hearing and Communication Science.

Here we report the methods and output of a workshop examining possible futures of speech and hearing science out to 2030. Using a design thinking approach, a range of human-centered problems in communication were identified that could provide the motivation for a wide range of research. Nine main research programs were distilled and are summarized: (a) measuring brain and other physiological parameters, (b) auditory and multimodal displays of information, (c) auditory scene analysis, (d) enabling and understanding shared auditory virtual spaces, (e) holistic approaches to health management and hearing impairment, (f) universal access to evolving and individualized technologies, (g) biological intervention for hearing dysfunction, (h) understanding the psychosocial interactions with technology and other humans as mediated by technology, and (i) the impact of changing models of security and privacy. The design thinking approach attempted to link the judged level of importance of different research areas to the "end in mind" through empathy for the real-life problems embodied in the personas created during the workshop.

The Generalization of Auditory Accommodation to Altered Spectral Cues.

The capacity of healthy adult listeners to accommodate to altered spectral cues to the source locations of broadband sounds has now been well documented. In recent years we have demonstrated that the degree and speed of accommodation are improved by using an integrated sensory-motor training protocol under anechoic conditions. Here we demonstrate that the learning which underpins the localization performance gains during the accommodation process using anechoic broadband training stimuli generalize to environmentally relevant scenarios. As previously, alterations to monaural spectral cues were produced by fitting participants with custom-made outer ear molds, worn during waking hours. Following acute degradations in localization performance, participants then underwent daily sensory-motor training to improve localization accuracy using broadband noise stimuli over ten days. Participants not only demonstrated post-training improvements in localization accuracy for broadband noises presented in the same set of positions used during training, but also for stimuli presented in untrained locations, for monosyllabic speech sounds, and for stimuli presented in reverberant conditions. These findings shed further light on the neuroplastic capacity of healthy listeners, and represent the next step in the development of training programs for users of assistive listening devices which degrade localization acuity by distorting or bypassing monaural cues.

Characterisation of eppin function: expression and activity in the lung.

Eppin is a serine protease inhibitor expressed in male reproductive tissues.The aim of this study was to investigate the localisation and regulation of eppin expression in myeloid and epithelial cell lines, and explore its potential role as a multifunctional host defence protein.Using immunohistochemistry and Western blotting, eppin was detected in the lungs of patients with acute respiratory distress syndrome and cystic fibrosis lung disease. Expression of eppin in monocytic cells was unaffected by stimulation with Toll-like receptor agonists, cytokines and hormone receptor agonists. However, upregulated expression and secretion of eppin was observed following treatment of monocytes with epidermal growth factor. Incubation of recombinant eppin with monocytic cells resulted in significant inhibition of lipopolysaccharide-induced chemokine production. Furthermore, eppin inhibited lipopolysaccharide-induced NF-κB activation by a mechanism which involved accumulation of phosphorylated IκBα. In an in vivo model of lung inflammation induced by lipopolysaccharide, eppin administration resulted in decreased recruitment of neutrophils to the lung with a concomitant reduction in the levels of the neutrophil chemokine macrophage inflammatory protein-2.Overall, these results suggest a role for eppin outside of the reproductive tract and that eppin may have a role in the innate immune response in the lung.

Development and evaluation of a mixed gender, multi-talker matrix sentence test in Australian English.

OBJECTIVE: To develop, in Australian English, the first mixed-gender, multi-talker matrix sentence test. DESIGN: Speech material consisted of a 50-word base matrix whose elements can be combined to form sentences of identical syntax but unpredictable content. Ten voices (five female and five male) were recorded for editing and preliminary level equalization. Elements were presented as single-talker sentences-in-noise during two perceptual tests: an optimization phase that provided the basis for further level correction, and an evaluation phase that perceptually validated those changes. STUDY SAMPLE: Ten listeners participated in the optimization phase; these and an additional 32 naïve listeners completed the evaluation test. All were fluent in English and all but one had lived in Australia for >2 years. RESULTS: Optimization reduced the standard deviation (SD) and speech reception threshold (SRT) range across all speech material (grand mean SRT = -10.6 dB signal-to-noise ratio, median = -10.8, SD =1.4, range =13.7, slope =19.3%/dB), yielding data consistent with cross-validated matrix tests in other languages. Intelligibility differences between experienced and naïve listeners were minimal. CONCLUSIONS: The Australian matrix corpus provides a robust set of test materials suitable for both clinical assessment and research into the dynamics of active listening in multi-talker environments.

Sensitivity to Auditory Velocity Contrast.

A natural auditory scene often contains sound moving at varying velocities. Using a velocity contrast paradigm, we compared sensitivity to velocity changes between continuous and discontinuous trajectories. Subjects compared the velocities of two stimulus intervals that moved along a single trajectory, with and without a 1 second inter stimulus interval (ISI). We found thresholds were threefold larger for velocity increases in the instantaneous velocity change condition, as compared to instantaneous velocity decreases or thresholds for the delayed velocity transition condition. This result cannot be explained by the current static "snapshot" model of auditory motion perception and suggest a continuous process where the percept of velocity is influenced by previous history of stimulation.

Six Degrees of Auditory Spatial Separation.

The location of a sound is derived computationally from acoustical cues rather than being inherent in the topography of the input signal, as in vision. Since Lord Rayleigh, the descriptions of that representation have swung between "labeled line" and "opponent process" models. Employing a simple variant of a two-point separation judgment using concurrent speech sounds, we found that spatial discrimination thresholds changed nonmonotonically as a function of the overall separation. Rather than increasing with separation, spatial discrimination thresholds first declined as two-point separation increased before reaching a turning point and increasing thereafter with further separation. This "dipper" function, with a minimum at 6 ° of separation, was seen for regions around the midline as well as for more lateral regions (30 and 45 °). The discrimination thresholds for the binaural localization cues were linear over the same range, so these cannot explain the shape of these functions. These data and a simple computational model indicate that the perception of auditory space involves a local code or multichannel mapping emerging subsequent to the binaural cue coding.

The Perception of Auditory Motion.

The growing availability of efficient and relatively inexpensive virtual auditory display technology has provided new research platforms to explore the perception of auditory motion. At the same time, deployment of these technologies in command and control as well as in entertainment roles is generating an increasing need to better understand the complex processes underlying auditory motion perception. This is a particularly challenging processing feat because it involves the rapid deconvolution of the relative change in the locations of sound sources produced by rotational and translations of the head in space (self-motion) to enable the perception of actual source motion. The fact that we perceive our auditory world to be stable despite almost continual movement of the head demonstrates the efficiency and effectiveness of this process. This review examines the acoustical basis of auditory motion perception and a wide range of psychophysical, electrophysiological, and cortical imaging studies that have probed the limits and possible mechanisms underlying this perception.

Auditory Perception: Attentive Solution to the Cocktail Party Problem.

A recent study has demonstrated how the focus of auditory attention can rapidly shift to follow spectrally dynamic speech-like sounds in the presence of a similar interferer. This requires multidimensional variation in sound features and a minimum spacing in spectral feature space.