Neural delays shape selectivity to interaural intensity differences in the lateral superior olive

Neurons in the lateral superior olive (LSO) respond selectively to interaural intensity differences (IIDs), one of the chief cues used to localize sounds in space. LSO cells are innervated in a characteristic pattern: they receive an excitatory input from the ipsilateral ear and an inhibitory input from the contralateral ear. Consistent with this pattern, LSO cells generally are excited by sounds that are more intense at the ipsilateral ear and inhibited by sounds that are more intense at the contralateral ear. Despite their relatively homogeneous pattern of innervation, IID selectivity varies substantially from cell to cell, such that selectivities are distributed over the range of IIDs that would be encountered in nature. For some time, researchers have speculated that the relative timing of the excitatory and inhibitory inputs to an LSO cell might shape IID selectivity. To test this hypothesis, we recorded from 50 LSO cells in the free-tailed bat while presenting stimuli that varied in interaural intensity and in interaural time of arrival. The results suggest that, for more than half of the cells, the latency of inhibition was several hundred microseconds longer than the latency of excitation. Increasing the intensity to the inhibitory ear shortened the latency of inhibition and brought the timing of the inputs from the two ears into register. Thus, a neural delay of the inhibition helped to define the IID selectivity of these cells, accounting for a significant part of the variation in selectivity among LSO cells

Inhibiting the inhibition

The precedence effect describes the phenomenon whereby echoes are spatially fused to the location of an initial sound by selectively suppressing the directional information of lagging sounds (echo suppression). Echo suppression is a prerequisite for faithful sound localization in natural environments but can break down depending on the behavioral context. To date, the neural mechanisms that suppress echo directional information without suppressing the perception of echoes themselves are not understood. We performed in vivo recordings in Mongolian gerbils of neurons of the dorsal nucleus of the lateral lemniscus (DNLL), a GABAergic brainstem nucleus that targets the auditory midbrain, and show that these DNLL neurons exhibit inhibition that persists tens of milliseconds beyond the stimulus offset, so-called persistent inhibition (PI). Using in vitro recordings, we demonstrate that PI stems from GABAergic projections from the opposite DNLL. Furthermore, these recordings show that PI is attributable to intrinsic features of this GABAergic innervation. Implementation of these physiological findings into a neuronal model of the auditory brainstem demonstrates that, on a circuit level, PI creates an enhancement of responsiveness to lagging sounds in auditory midbrain cells. Moreover, the model revealed that such response enhancement is a sufficient cue for an ideal observer to identify echoes and to exhibit echo suppression, which agrees closely with the percepts of human subjects

Tissue-engineered vascular graft remodeling in a growing lamb model: expression of matrix metalloproteinases

OBJECTIVES We have previously demonstrated the functionality and growth of autologous, living, tissue-engineered vascular grafts (TEVGs) in long-term animal studies. These grafts showed substantial in vivo tissue remodeling and approximation to native arterial wall characteristics. Based on this, in vitro and in vivo matrix metalloproteinase (MMP) activity of TEVGs is investigated as a key marker of matrix remodeling. METHODS TEVGs fabricated from biodegradable scaffolds (polyglycolic-acid/poly-4-hydroxybutyrate, PGA/P4HB) seeded with autologous vascular cells were cultured in static and dynamic in vitro conditions. Thereafter, TEVGs were implanted as pulmonary artery replacements in lambs and followed up for 2 years. Gelatin gel zymography to detect MMP-2 and -9 was performed and collagen content quantified (n=5). Latent (pro) and active MMP-2 and -9 were detected. RESULTS Comparable levels of active MMP-9 and pro-MMP-2 were detected in static and dynamic culture. Higher levels of active MMP-2 were detected in dynamic cultures. Expression of MMP-2 and -9 was minimal in native grafts but was increased in implanted TEVG. Pro-MMP-9 was expressed 20 weeks post implantation and persisted up to 80 weeks post implantation. Collagen content in vitro was increased in dynamically conditioned TEVG as compared with static constructs and was increased in vivo compared with the corresponding native pulmonary artery. CONCLUSIONS MMPs are up-regulated in vitro by dynamic culture conditions and could contribute to increased matrix remodeling, native analogous tissue formation and functional growth of TEVGs in vivo. Monitoring of MMP activity, for example, by molecular imaging techniques, may enable the non-invasive assessment of functional tissue quality in future clinical tissue-engineering application

A Cloud-Based Collaboration Platform for Model-Based Design of Cyber-Physical Systems

Businesses, particularly small and medium-sized enterprises, aiming to start up in Model-Based Design (MBD) face difficult choices from a wide range of methods, notations and tools before making the significant investments in planning, procurement and training necessary to deploy new approaches successfully. In the development of Cyber-Physical Systems (CPSs) this is exacerbated by the diversity of formalisms covering computation, physical and human processes. In this paper, we propose the use of a cloud-enabled and open collaboration platform that allows businesses to offer models, tools and other assets, and permits others to access these on a pay-per-use basis as a means of lowering barriers to the adoption of MBD technology, and to promote experimentation in a sandbox environment

Coronavirus Pseudotypes for All Circulating Human Coronaviruses for Quantification of Cross-Neutralizing Antibody Responses.

The novel coronavirus SARS-CoV-2 is the seventh identified human coronavirus. Understanding the extent of pre-existing immunity induced by seropositivity to endemic seasonal coronaviruses and the impact of cross-reactivity on COVID-19 disease progression remains a key research question in immunity to SARS-CoV-2 and the immunopathology of COVID-2019 disease. This paper describes a panel of lentiviral pseudotypes bearing the spike (S) proteins for each of the seven human coronaviruses (HCoVs), generated under similar conditions optimized for high titre production allowing a high-throughput investigation of antibody neutralization breadth. Optimal production conditions and most readily available permissive target cell lines were determined for spike-mediated entry by each HCoV pseudotype: SARS-CoV-1, SARS-CoV-2 and HCoV-NL63 best transduced HEK293T/17 cells transfected with ACE2 and TMPRSS2, HCoV-229E and MERS-CoV preferentially entered HUH7 cells, and CHO cells were most permissive for the seasonal betacoronavirus HCoV-HKU1. Entry of ACE2 using pseudotypes was enhanced by ACE2 and TMPRSS2 expression in target cells, whilst TMPRSS2 transfection rendered HEK293T/17 cells permissive for HCoV-HKU1 and HCoV-OC43 entry. Additionally, pseudotype viruses were produced bearing additional coronavirus surface proteins, including the SARS-CoV-2 Envelope (E) and Membrane (M) proteins and HCoV-OC43/HCoV-HKU1 Haemagglutinin-Esterase (HE) proteins. This panel of lentiviral pseudotypes provides a safe, rapidly quantifiable and high-throughput tool for serological comparison of pan-coronavirus neutralizing responses; this can be used to elucidate antibody dynamics against individual coronaviruses and the effects of antibody cross-reactivity on clinical outcome following natural infection or vaccination