Reverberation impairs brainstem temporal representations of voiced vowel sounds: challenging "periodicity-tagged" segregation of competing speech in rooms.

The auditory system typically processes information from concurrently active sound sources (e.g., two voices speaking at once), in the presence of multiple delayed, attenuated and distorted sound-wave reflections (reverberation). Brainstem circuits help segregate these complex acoustic mixtures into "auditory objects." Psychophysical studies demonstrate a strong interaction between reverberation and fundamental-frequency (F0) modulation, leading to impaired segregation of competing vowels when segregation is on the basis of F0 differences. Neurophysiological studies of complex-sound segregation have concentrated on sounds with steady F0s, in anechoic environments. However, F0 modulation and reverberation are quasi-ubiquitous. We examine the ability of 129 single units in the ventral cochlear nucleus (VCN) of the anesthetized guinea pig to segregate the concurrent synthetic vowel sounds /a/ and /i/, based on temporal discharge patterns under closed-field conditions. We address the effects of added real-room reverberation, F0 modulation, and the interaction of these two factors, on brainstem neural segregation of voiced speech sounds. A firing-rate representation of single-vowels' spectral envelopes is robust to the combination of F0 modulation and reverberation: local firing-rate maxima and minima across the tonotopic array code vowel-formant structure. However, single-vowel F0-related periodicity information in shuffled inter-spike interval distributions is significantly degraded in the combined presence of reverberation and F0 modulation. Hence, segregation of double-vowels' spectral energy into two streams (corresponding to the two vowels), on the basis of temporal discharge patterns, is impaired by reverberation; specifically when F0 is modulated. All unit types (primary-like, chopper, onset) are similarly affected. These results offer neurophysiological insights to perceptual organization of complex acoustic scenes under realistically challenging listening conditions.This work was supported by a grant from the BBSRC to Ian M. Winter. Mark Sayles received a University of Cambridge MB/PhD studentship. Tony Watkins (University of Reading, UK) provided the real-room impulse responses. Portions of the data analysis and manuscript preparation were performed by Mark Sayles during the course of an Action on Hearing Loss funded UK–US Fulbright Commission professional scholarship held in the Auditory Neurophysiology and Modeling Laboratory at Purdue University, USA. Mark Sayles is currently supported by a post-doctoral fellowship from Fonds Wetenschappelijk Onderzoek—Vlaanderen, held in the Laboratory of Auditory Neurophysiology at KU Leuven, Belgium.This paper was originally published in Frontiers in Systems Neuroscience (Sayles M, Stasiak A, Winter IM, Frontiers in Systems Neuroscience 2015, 8, 248, doi:10.3389/fnsys.2014.00248)

Enhancement of forward suppression begins in the ventral cochlear nucleus.

A neuron׳s response to a sound can be suppressed by the presentation of a preceding sound. It has been suggested that this suppression is a direct correlate of the psychophysical phenomenon of forward masking, however, forward suppression, as measured in the responses of the auditory nerve, was insufficient to account for behavioural performance. In contrast the neural suppression seen in the inferior colliculus and auditory cortex was much closer to psychophysical performance. In anaesthetised guinea-pigs, using a physiological two-interval forced-choice threshold tracking algorithm to estimate suppressed (masked) thresholds, we examine whether the enhancement of suppression can occur at an earlier stage of the auditory pathway, the ventral cochlear nucleus (VCN). We also compare these responses with the responses from the central nucleus of the inferior colliculus (ICc) using the same preparation. In both nuclei, onset-type neurons showed the greatest amounts of suppression (16.9-33.5dB) and, in the VCN, these recovered with the fastest time constants (14.1-19.9ms). Neurons with sustained discharge demonstrated reduced masking (8.9-12.1dB) and recovery time constants of 27.2-55.6ms. In the VCN the decrease in growth of suppression with increasing suppressor level was largest for chopper units and smallest for onset-type units. The threshold elevations recorded for most unit types are insufficient to account for the magnitude of forward masking as measured behaviourally, however, onset responders, in both the cochlear nucleus and inferior colliculus demonstrate a wide dynamic range of suppression, similar to that observed in human psychophysics.This work was supported by Wellcome Trust and BBSRC Project Grants to IMW and first presented in preliminary form by Ingham et al. (2006b). We thank Elinor Gunning and Catherine Slattery for their help and input during pilot experiments and Mark Sayles for help in data collection in later experiments.This is the final version of the article. It first appeared from Elsevier via https://doi.org/10.1016/j.brainres.2016.02.04

Dual Coding of Frequency Modulation in the Ventral Cochlear Nucleus.

Frequency modulation (FM) is a common acoustic feature of natural sounds and is known to play a role in robust sound source recognition. Auditory neurons show precise stimulus-synchronized discharge patterns that may be used for the representation of low-rate FM. However, it remains unclear whether this representation is based on synchronization to slow temporal envelope (ENV) cues resulting from cochlear filtering or phase locking to faster temporal fine structure (TFS) cues. To investigate the plausibility of those encoding schemes, single units of the ventral cochlear nucleus of guinea pigs of either sex were recorded in response to sine FM tones centered at the unit's best frequency (BF). The results show that, in contrast to high-BF units, for modulation depths within the receptive field, low-BF units (<4 kHz) demonstrate good phase locking to TFS. For modulation depths extending beyond the receptive field, the discharge patterns follow the ENV and fluctuate at the modulation rate. The receptive field proved to be a good predictor of the ENV responses for most primary-like and chopper units. The current in vivo data also reveal a high level of diversity in responses across unit types. TFS cues are mainly conveyed by low-frequency and primary-like units and ENV cues by chopper and onset units. The diversity of responses exhibited by cochlear nucleus neurons provides a neural basis for a dual-coding scheme of FM in the brainstem based on both ENV and TFS cues.SIGNIFICANCE STATEMENT Natural sounds, including speech, convey informative temporal modulations in frequency. Understanding how the auditory system represents those frequency modulations (FM) has important implications as robust sound source recognition depends crucially on the reception of low-rate FM cues. Here, we recorded 115 single-unit responses from the ventral cochlear nucleus in response to FM and provide the first physiological evidence of a dual-coding mechanism of FM via synchronization to temporal envelope cues and phase locking to temporal fine structure cues. We also demonstrate a diversity of neural responses with different coding specializations. These results support the dual-coding scheme proposed by psychophysicists to account for FM sensitivity in humans and provide new insights on how this might be implemented in the early stages of the auditory pathway

Muscle recruitment and stone tool use ergonomics across three million years of Palaeolithic technological transitions

Ergonomic relationships that minimize muscle activity relative to the creation of cutting stress underpin the design of modern knives, saws, and axes. The Palaeolithic archaeological record, and the > 3 million years of technological behavior that it represents, is predominantly characterized by sharp stone implements used for cutting. To date, we do not know whether Palaeolithic hominins adhered to ergonomic principles when designing stone tools, if lithic technological transitions were linked to ease-of-use advances, or even how muscularly demanding different Palaeolithic tools are on an empirically defined relative basis. Here, we report the results of an experimental program that examines how four key stone tool types, produced between ∼ 3.3 million and ∼ 40 thousand years ago, influence muscle activation in the hominin upper limb. Using standardized laboratory-based tests designed to imitate Pleistocene cutting behaviors, surface electromyography recorded electrical activity (amplitude) in nine muscles across the hand, forearm and shoulder of modern humans during the use of replica Lomekwian, Oldowan, Acheulean and Mousterian stone tools. Results confirm digit flexors and abductors, particularly the first dorsal interosseous and flexor pollicis longus, to be the most heavily recruited muscles during the use of all tool types. Significant differences in muscle activation are, however, identified dependent on the type of stone tool used. Notably, the abductor digiti minimi, flexor pollicis longus, and biceps brachii were highly activated during handaxe use, particularly when compared to the use of Oldowan and Levallois flakes. Results are discussed in light of current understanding on the origin of Lower and Middle Palaeolithic technologies, why specific tool types were produced over others during these periods, and the extent to which early hominins produced ergonomically designed tools

Field demonstration of a cost-optimized solar powered electrodialysis reversal desalination system in rural India

This study provides experimental validation of a previously published optimal design theory for photovoltaic (PV)-powered electrodialysis reversal (EDR) desalination systems. The prior work describes the co-optimization of PV and EDR subsystems, and flexible operation to accommodate daily and annual solar irradiance variability, significantly reducing water cost. This study presents the fabrication of a PV-EDR pilot system designed using the co-optimization theory and field testing results from the rural village of Chelluru, India. Testing in the field enabled observation and evaluation of real-world factors on system performance, resulting in updates to the previous theory to include unaccounted factors that affect costs, including: filling and draining of water tanks, salt and water accumulation in tanks from prior batches, unexpected energy losses due to locally purchased converters, and scaling in the ED stack. Therefore, water cost in the PV-EDR pilot system was updated from previous estimates based on field performance. The estimated capital cost and lifetime cost of the Chelluru system are 34% and 45% lower, respectively, than the corresponding costs if the PV-EDR system was designed using conventional design practice. The theory and experimental insights presented in this paper will enable desalination engineers to better design and optimize PV-EDR systems

Clinically actionable mutation profiles in patients with cancer identified by whole-genome sequencing

Next-generation sequencing (NGS) efforts have established catalogs of mutations relevant to cancer development. However, the clinical utility of this information remains largely unexplored. Here, we present the results of the first eight patients recruited into a clinical whole-genome sequencing (WGS) program in the United Kingdom. We performed PCR-free WGS of fresh frozen tumors and germline DNA at 75× and 30×, respectively, using the HiSeq2500 HTv4. Subtracted tumor VCFs and paired germlines were subjected to comprehensive analysis of coding and noncoding regions, integration of germline with somatically acquired variants, and global mutation signatures and pathway analyses. Results were classified into tiers and presented to a multidisciplinary tumor board. WGS results helped to clarify an uncertain histopathological diagnosis in one case, led to informed or supported prognosis in two cases, leading to de-escalation of therapy in one, and indicated potential treatments in all eight. Overall 26 different tier 1 potentially clinically actionable findings were identified using WGS compared with six SNVs/indels using routine targeted NGS. These initial results demonstrate the potential of WGS to inform future diagnosis, prognosis, and treatment choice in cancer and justify the systematic evaluation of the clinical utility of WGS in larger cohorts of patients with cancer

A living biobank of ovarian cancer ex vivo models reveals profound mitotic heterogeneity

High-grade serous ovarian carcinoma is characterised by TP53 mutation and extensive chromosome instability (CIN). Because our understanding of CIN mechanisms is based largely on analysing established cell lines, we developed a workflow for generating ex vivo cultures from patient biopsies to provide models that support interrogation of CIN mechanisms in cells not extensively cultured in vitro. Here, we describe a “living biobank” of ovarian cancer models with extensive replicative capacity, derived from both ascites and solid biopsies. Fifteen models are characterised by p53 profiling, exome sequencing and transcriptomics, and karyotyped using single-cell whole-genome sequencing. Time-lapse microscopy reveals catastrophic and highly heterogeneous mitoses, suggesting that analysis of established cell lines probably underestimates mitotic dysfunction in advanced human cancers. Drug profiling reveals cisplatin sensitivities consistent with patient responses, demonstrating that this workflow has potential to generate personalized avatars with advantages over current pre-clinical models and the potential to guide clinical decision making

A mitotic recombination map proximal to the APC locus on chromosome 5q and assessment of influences on colorectal cancer risk

Mitotic recombination is important for inactivating tumour suppressor genes by copy-neutral loss of heterozygosity (LOH). Although meiotic recombination maps are plentiful, little is known about mitotic recombination. The APC gene (chr5q21) is mutated in most colorectal tumours and its usual mode of LOH is mitotic recombination.

Surgical Management of Crohn Disease in Children: Guidelines From the Paediatric IBD Porto Group of ESPGHAN

The incidence of Crohn disease (CD) has been increasing and surgery needs to be contemplated in a substantial number of cases. The relevant advent of biological treatment has changed but not eliminated the need for surgery in many patients. Despite previous publications on the indications for surgery in CD, there was a need for a comprehensive review of existing evidence on the role of elective surgery and options in pediatric patients affected with CD. We present an expert opinion and critical review of the literature to provide evidence-based guidance to manage these patients. Indications, surgical options, risk factors, and medications in pre-and perioperative period are reviewed in the light of available evidence. Risks and benefits of surgical options are addressed. An algorithm is proposed for the management of postsurgery monitoring, timing for follow-up endoscopy, and treatment options