Hyperdimensional Brain-Inspired Learning for Phoneme Recognition With Large-Scale Inferior Colliculus Neural Activities.

OBJECTIVE: Develop a novel and highly efficient framework that decodes Inferior Colliculus (IC) neural activities for phoneme recognition. METHODS: We propose using Hyperdimensional Computing (HDC) to support an efficient phoneme recognition algorithm, in contrast to widely applied Deep Neural Networks (DNN). The high-dimensional representation and operations in HDC are rooted in human brain functionalities and naturally parallelizable, showing the potential for efficient neural activity analysis. Our proposed method includes a spatial and temporal-aware HDC encoder that effectively captures global and local patterns. As part of our framework, we deploy the lightweight HDC-based algorithm on a highly customizable and flexible hardware platform, i.e., Field Programmable Gate Arrays (FPGA), for optimal algorithm speedup. To evaluate our method, we record IC neural activities on gerbils while playing the sound of different phonemes. RESULTS: We compare our proposed method with multiple baseline machine learning algorithms in recognition quality and learning efficiency, across different hardware platforms. The results show that our method generally achieves better classification quality than the best-performing baseline. Compared to the Deep Residual Neural Network (i.e., ResNet), our method shows a speedup up to 74×, 67×, 210× on CPU, GPU, and FPGA respectively. We achieve up to 15% (10%) higher accuracy in consonant (vowel) classification than ResNet. CONCLUSION: By leveraging brain-inspired HDC for IC neural activity encoding and phoneme classification, we achieve orders of magnitude runtime speedup while improving accuracy in various challenging task settings. SIGNIFICANCE: Decoding IC neural activities is an important step to enhance understanding about human auditory system. However, these responses from the central auditory system are noisy and contain high variance, demanding large-scale datasets and iterative model fine-tuning. The proposed HDC-based framework is more scalable and viable for future real-world deployment thanks to its fast training and overall better quality.

Trichostatin A Promotes Cytotoxicity of Cisplatin, as Evidenced by Enhanced Apoptosis/Cell Death Markers.

Trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, promotes the cytotoxicity of the genotoxic anticancer drug cisplatin, yet the underlying mechanism remains poorly understood. Herein, we revealed that TSA at a low concentration (1 µM) promoted the cisplatin-induced activation of caspase-3/6, which, in turn, increased the level of cleaved PARP1 and degraded lamin A&C, leading to more cisplatin-induced apoptosis and G2/M phase arrest of A549 cancer cells. Both ICP-MS and ToF-SIMS measurements demonstrated a significant increase in DNA-bound platinum in A549 cells in the presence of TSA, which was attributable to TSA-induced increase in the accessibility of genomic DNA to cisplatin attacking. The global quantitative proteomics results further showed that in the presence of TSA, cisplatin activated INF signaling to upregulate STAT1 and SAMHD1 to increase cisplatin sensitivity and downregulated ICAM1 and CD44 to reduce cell migration, synergistically promoting cisplatin cytotoxicity. Furthermore, in the presence of TSA, cisplatin downregulated TFAM and SLC3A2 to enhance cisplatin-induced ferroptosis, also contributing to the promotion of cisplatin cytotoxicity. Importantly, our posttranslational modification data indicated that acetylation at H4K8 played a dominant role in promoting cisplatin cytotoxicity. These findings provide novel insights into better understanding the principle of combining chemotherapy of genotoxic drugs and HDAC inhibitors for the treatment of cancers.

Attention-Modulated Cortical Responses as a Biomarker for Tinnitus.

Attention plays an important role in not only the awareness and perception of tinnitus but also its interactions with external sounds. Recent evidence suggests that attention is heightened in the tinnitus brain, likely as a result of relatively local cortical changes specific to deafferentation sites or global changes that help maintain normal cognitive capabilities in individuals with hearing loss. However, most electrophysiological studies have used passive listening paradigms to probe the tinnitus brain and produced mixed results in terms of finding a distinctive biomarker for tinnitus. Here, we designed a selective attention task, in which human adults attended to one of two interleaved tonal (500 Hz and 5 kHz) sequences. In total, 16 tinnitus (5 females) and 13 age- and hearing-matched control (8 females) subjects participated in the study, with the tinnitus subjects matching the tinnitus pitch to 5.4 kHz (range = 1.9-10.8 kHz). Cortical responses were recorded in both passive and attentive listening conditions, producing no differences in P1, N1, and P2 between the tinnitus and control subjects under any conditions. However, a different pattern of results emerged when the difference was examined between the attended and unattended responses. This attention-modulated cortical response was significantly greater in the tinnitus than control subjects: 3.9-times greater for N1 at 5 kHz (95% CI: 2.9 to 5.0, p = 0.007, ηp2 = 0.24) and 3.0 for P2 at 500 Hz (95% CI: 1.9 to 4.5, p = 0.026, ηp2 = 0.17). We interpreted the greater N1 modulation as local neural changes specific to the tinnitus frequency and the greater P2 as global changes to hearing loss. These two cortical measures were used to differentiate between the tinnitus and control subjects, producing 83.3% sensitivity and 76.9% specificity (AUC = 0.81, p = 0.006). These results suggest that the tinnitus brain is more plastic than that of the matched non-tinnitus controls and that the attention-modulated cortical response can be developed as a clinically meaningful biomarker for tinnitus.

Strophanthidin Induces Apoptosis of Human Lung Adenocarcinoma Cells by Promoting TRAIL-DR5 Signaling.

Strophanthidin (SPTD), one of the cardiac glycosides, is refined from traditional Chinese medicines such as Semen Lepidii and Antiaris toxicaria, and was initially used for the treatment of heart failure disease in clinic. Recently, SPTD has been shown to be a potential anticancer agent, but the underlying mechanism of action is poorly understood. Herein, we explored the molecular mechanism by which SPTD exerts anticancer effects in A549 human lung adenocarcinoma cells by means of mass spectrometry-based quantitative proteomics in combination with bioinformatics analysis. We revealed that SPTD promoted the expression of tumor necrosis factor (TNF)-related apoptosis-inducing ligand receptor 2 (TRAIL-R2, or DR5) in A549 cells to activate caspase 3/6/8, in particular caspase 3. Consequently, the activated caspases elevated the expression level of apoptotic chromatin condensation inducer in the nucleus (ACIN1) and prelamin-A/C (LMNA), ultimately inducing apoptosis via cooperation with the SPTD-induced overexpressed barrier-to-autointegration factor 1 (Banf1). Moreover, the SPTD-induced DEPs interacted with each other to downregulate the p38 MAPK/ERK signaling, contributing to the SPTD inhibition of the growth of A549 cells. Additionally, the downregulation of collagen COL1A5 by SPTD was another anticancer benefit of SPTD through the modulation of the cell microenvironment.

Syllable-rate-adjusted-modulation (SRAM) predicts clear and conversational speech intelligibility.

Introduction: Objectively predicting speech intelligibility is important in both telecommunication and human-machine interaction systems. The classic method relies on signal-to-noise ratios (SNR) to successfully predict speech intelligibility. One exception is clear speech, in which a talker intentionally articulates as if speaking to someone who has hearing loss or is from a different language background. As a result, at the same SNR, clear speech produces higher intelligibility than conversational speech. Despite numerous efforts, no objective metric can successfully predict the clear speech benefit at the sentence level. Methods: We proposed a Syllable-Rate-Adjusted-Modulation (SRAM) index to predict the intelligibility of clear and conversational speech. The SRAM used as short as 1 s speech and estimated its modulation power above the syllable rate. We compared SRAM with three reference metrics: envelope-regression-based speech transmission index (ER-STI), hearing-aid speech perception index version 2 (HASPI-v2) and short-time objective intelligibility (STOI), and five automatic speech recognition systems: Amazon Transcribe, Microsoft Azure Speech-To-Text, Google Speech-To-Text, wav2vec2 and Whisper. Results: SRAM outperformed the three reference metrics (ER-STI, HASPI-v2 and STOI) and the five automatic speech recognition systems. Additionally, we demonstrated the important role of syllable rate in predicting speech intelligibility by comparing SRAM with the total modulation power (TMP) that was not adjusted by the syllable rate. Discussion: SRAM can potentially help understand the characteristics of clear speech, screen speech materials with high intelligibility, and convert conversational speech into clear speech.

Predictive coding and stochastic resonance as fundamental principles of auditory phantom perception.

Mechanistic insight is achieved only when experiments are employed to test formal or computational models. Furthermore, in analogy to lesion studies, phantom perception may serve as a vehicle to understand the fundamental processing principles underlying healthy auditory perception. With a special focus on tinnitus-as the prime example of auditory phantom perception-we review recent work at the intersection of artificial intelligence, psychology and neuroscience. In particular, we discuss why everyone with tinnitus suffers from (at least hidden) hearing loss, but not everyone with hearing loss suffers from tinnitus. We argue that intrinsic neural noise is generated and amplified along the auditory pathway as a compensatory mechanism to restore normal hearing based on adaptive stochastic resonance. The neural noise increase can then be misinterpreted as auditory input and perceived as tinnitus. This mechanism can be formalized in the Bayesian brain framework, where the percept (posterior) assimilates a prior prediction (brain's expectations) and likelihood (bottom-up neural signal). A higher mean and lower variance (i.e. enhanced precision) of the likelihood shifts the posterior, evincing a misinterpretation of sensory evidence, which may be further confounded by plastic changes in the brain that underwrite prior predictions. Hence, two fundamental processing principles provide the most explanatory power for the emergence of auditory phantom perceptions: predictive coding as a top-down and adaptive stochastic resonance as a complementary bottom-up mechanism. We conclude that both principles also play a crucial role in healthy auditory perception. Finally, in the context of neuroscience-inspired artificial intelligence, both processing principles may serve to improve contemporary machine learning techniques.

Audiometric Validation of a Smart Watch Decibel Meter.

This diagnostic study assesses the performance of the Apple Watch Noise application in comparison with a class 1 sound level meter.

Celebrating the one millionth cochlear implant.

Cochlear implants have been the most successful neural prosthesis, with one million users globally. Researchers used the source-filter model and speech vocoder to design the modern multi-channel implants, allowing implantees to achieve 70%-80% correct sentence recognition in quiet, on average. Researchers also used the cochlear implant to help understand basic mechanisms underlying loudness, pitch, and cortical plasticity. While front-end processing advances improved speech recognition in noise, the unilateral implant speech recognition in quiet has plateaued since the early 1990s. This lack of progress calls for action on re-designing the cochlear stimulating interface and collaboration with the general neurotechnology community.

Adopting Change and Incorporating Technological Advancements in Audiology Education, Research, and Clinical Practice.

PURPOSE: With the rapid development of new technologies and resources, many avenues exist to adapt and grow as a profession. Embracing change can lead to growth, evolution, and new opportunities. Audiologists have the potential to harness many of these technological advancements to improve patient health care. Adoption and incorporation of these new technologies will likely benefit educational experiences, research methods, clinical practice, and clinical outcomes. METHOD: This commentary highlights some historical perspectives and accepted practices while illustrating opportunities to embrace new ideas and technologies. We also provide examples of how such adoption may yield positive outcomes. Specifically, we address embracing technology in audiology education, how artificial intelligence may influence patient performance in realistic listening scenarios, the convergence between hearing aids and consumer electronics, and the emergence of audiology telehealth services and their inclusion in clinical practice. Models of change are also discussed and related to audiology. CONCLUSION: This commentary aims to be a call to action for the entire profession of audiology to consider conscientiously the adoption of useful, evidence-based technological advancements in education, research, and clinical practice.

Astragaloside IV promotes pharmacological effect of Descurainia sophia seeds on isoproterenol-induced cardiomyopathy in rats by synergistically modulating the myosin motor.

Descurainia sophia seeds (DS), Astragalus mongholicus (AM), and their formulas are widely used to treat heart failure caused by various cardiac diseases in traditional Chinese medicine practice. However, the molecular mechanism of action of DS and AM has not been completely understood. Herein, we first used mass spectrometry coupled to UPLC to characterize the chemical components of DS and AM decoctions, then applied MS-based quantitative proteomic analysis to profile protein expression in the heart of rats with isoproterenol-induced cardiomyopathy (ISO-iCM) before and after treated with DS alone or combined with AM, astragaloside IV (AS4), calycosin-7-glucoside (C7G), and Astragalus polysaccharides (APS) from AM. We demonstrated for the first time that DS decoction alone could reverse the most of differentially expressed proteins in the heart of the rats with ISO-iCM, including the commonly recognized biomarkers natriuretic peptides (NPPA) of cardiomyopathy and sarcomeric myosin light chain 4 (MYL4), relieving ISO-iCM in rats, but AM did not pronouncedly improve the pharmacological efficiency of DS. Significantly, we revealed that AS4 remarkably promoted the pharmacological potency of DS by complementarily reversing myosin motor MYH6/7, and further downregulating NPPA and MYL4. In contrast, APS reduced the efficiency of DS due to upregulating NPPA and MYL4. These findings not only provide novel insights to better understanding in the combination principle of traditional Chinese medicine but also highlight the power of mass spectrometric proteomics strategy combined with conventional pathological approaches for the traditional medicine research.

Regulating the electronic structure of Fe-based metal organic frameworks by electrodeposition of Au nanoparticles for electrochemical overall water splitting.

Reasonable regulating the electronic structure is one of the effective strategies for improving the conductivity of metal-organic frameworks (MOFs) based electrocatalysts. Herein, a series of Fe-MOF/Au composites grown in situ on Fe Foam (FF) were prepared through a hydrothermal and the controlled electrodeposition time strategy, in which the Fe Foam acts both as the conductive substrate and a self-sacrificing template. The electronic structure of the Fe-MOF/Au/FF composites can be finely adjusted by tailoring the electrodeposition time. Therefore, the Fe-MOF/Au/FF composites possess enhanced conductivity, accompanied by increased electrochemical activity of specific areas and oxygen evolution (OER), hydrogen evolution (HER) and overall water splitting properties. In particular, the optimized Fe-MOF/Au-8/FF composites used as bifunctional electrocatalysts for overall water splitting require only small voltage of 1.61 V to achieve a current density of 10 mA cm-2. This strategy will provide new inspiration and creativity to enhance the electrocatalytic performance of MOF-based electrocatalysts for hydrogen conversion and application.

Ligand Evolution in the Photoactivatable Platinum(IV) Anticancer Prodrugs.

Photoactivatable Pt(IV) anticancer prodrugs with the structure of [PtIV(N1)(N2)(L1)(L2)(A1)(A2)], where N1 and N2 are non-leaving nitrogen donor ligands, L1 and L2 are leaving ligands, and A1 and A2 are axial ligands, have attracted increasing attention due to their promising photo-cytotoxicity even to cisplatin-resistant cancer cells. These photochemotherapeutic prodrugs have high dark-stability under physiological conditions, while they can be activated by visible light restrained at the disease areas, as a consequence showing higher spatial and temporal controllability and much more safety than conventional chemotherapy. The coordinated ligands to the Pt center have been proved to be pivotal in determining the function and activity of the photoactivatable Pt(IV) prodrugs. In this review, we will focus on the development of the coordinated ligands in such Pt(IV) prodrugs and discuss the effects of diverse ligands on their photochemistry and photoactivity as well as the future evolution directions of the ligands. We hope this review can help to facilitate the design and development of novel photoactivatable Pt(IV) anticancer prodrugs.

Harnessing the Power of Artificial Intelligence in Otolaryngology and the Communication Sciences.

Use of artificial intelligence (AI) is a burgeoning field in otolaryngology and the communication sciences. A virtual symposium on the topic was convened from Duke University on October 26, 2020, and was attended by more than 170 participants worldwide. This review presents summaries of all but one of the talks presented during the symposium; recordings of all the talks, along with the discussions for the talks, are available at https://www.youtube.com/watch?v=ktfewrXvEFg and https://www.youtube.com/watch?v=-gQ5qX2v3rg . Each of the summaries is about 2500 words in length and each summary includes two figures. This level of detail far exceeds the brief summaries presented in traditional reviews and thus provides a more-informed glimpse into the power and diversity of current AI applications in otolaryngology and the communication sciences and how to harness that power for future applications.

Auditory Brainstem Response Wave I Amplitude Has Limited Clinical Utility in Diagnosing Tinnitus in Humans.

Animal studies have discovered that noise, even at levels that produce no permanent threshold shift, may cause cochlear damage and selective nerve degeneration. A hallmark of such damage, or synaptopathy, is recovered threshold but reduced suprathreshold amplitude for the auditory brainstem response (ABR) wave I. The objective of the present study is to evaluate whether the ABR wave I amplitude or slope can be used to diagnose tinnitus in humans. A total of 43 human subjects, consisting of 21 with tinnitus and 22 without tinnitus, participated in the study. The subjects were on average 44 ± 24 (standard deviation) years old and 16 were female; a subgroup of 19 were young adults with normal audiograms from 125 to 8000 Hz. The ABR was measured using ear canal recording tiptrodes for clicks, 1000, 4000 and 8000 Hz tone bursts at 30, 50, and 70 dB nHL. Compared with control subjects, tinnitus subjects did not show reduced ABR wave I amplitude or slope in either the entire group of 21 tinnitus subjects or a subset of tinnitus subjects with normal audiograms. Despite the small sample size and diverse tinnitus population, the present result suggests that low signal-to-noise ratios in non-invasive measurement of the ABR limit its clinical utility in diagnosing tinnitus in humans.

Electric hearing and tinnitus suppression by noninvasive ear stimulation.

While noninvasive brain stimulation is convenient and cost effective, its utility is limited by the substantial distance between scalp electrodes and their intended neural targets in the head. The tympanic membrane, or eardrum, is a thin flap of skin deep in an orifice of the head that may serve as a port for improved efficiency of noninvasive stimulation. Here we chose the cochlea as a target because it resides in the densest bone of the skull and is adjacent to many deep-brain-stimulation structures. We also tested the hypothesis that noninvasive electric stimulation of the cochlea may restore neural activities that are missing in acoustic stimulation. We placed an electrode in the ear canal or on the tympanic membrane in 25 human adults (10 females) and compared their stimulation efficiency by characterizing the electrically-evoked auditory sensation. Relative to ear canal stimulation, tympanic membrane stimulation was four times more likely to produce an auditory percept, required eight times lower electric current to reach the threshold and produced two-to-four times more linear suprathreshold responses. We further measured tinnitus suppression in 14 of the 25 subjects who had chronic tinnitus. Compared with ear canal stimulation, tympanic membrane stimulation doubled both the probability (22% vs. 55%) and the amount (-15% vs. -34%) of tinnitus suppression. These findings extended previous work comparing evoked perception and tinnitus suppression between electrodes placed in the ear canal and on the scalp. Together, the previous and present results suggest that the efficiency of conventional scalp-based noninvasive electric stimulation can be improved by at least one order of magnitude via tympanic membrane stimulation. This increased efficiency is most likely due to the shortened distance between the electrode placed on the tympanic membrane and the targeted cochlea. The present findings have implications for the management of tinnitus by offering a potential alternative to interventions using invasive electrical stimulation such as cochlear implantation, or other non-invasive transcranial electrical stimulation methods.

Atorvastatin Enhances Inhibitory Effects of Irradiation on Tumor Growth by Reducing MSH2 Expression Both in Prostate Cancer Cells and Xenograft Tumor Models.

BACKGROUND: Prostate cancer (PCa) is the fourth most common tumor in males. OBJECTIVE: This study aimed to investigate effects of atorvastatin (AS) on PCa cells proliferation and clarify the associated mechanisms. METHODS: PCa cell lines were cultured and treated with irradiation (IR) (4 Gy), AS (6 µg/ml), transfected with Bcl-2 siRNA, and then divided into different groups. Xenograft tumor mouse model was established. Bcl-2 and MSH2 gene transcription and protein expression were evaluated using RT-PCR assay and western blot assay. Plate clone formation assay was employed to examine colony formation. MTT assay was used to detect cell viabilities. Flow cytometry analysis was utilized to verify apoptosis. Co-immunoprecipitation and immuno-fluorescence assay were used to identify interaction between Bcl-2 and MSH2. RESULTS: IR significantly reduced colony formation, enhanced Bcl-2 and reduced MSH2 gene transcription in PCa cells compared to un-treated cells (p<0.05). AS significantly strengthened radio-therapeutic effects of IR on colony formation, decreased cell apoptosis and increased Bcl-2 gene transcription/protein expression in PCa cells compared to single IR treatment cells (p<0.05). AS combining IR down-regulated MSH2 gene transcription/protein expression in PCa cells compared to single IR treatment cells (p<0.05). Bcl-2 interacted with MSH2 both in PCa cells and tumor tissues administrating with AS. AS enhanced reductive effects of IR on tumor size of Xenograft tumor mice. CONCLUSION: Atorvastatin administration enhanced inhibitory effects of IR either on PCa cells or tumor size of Xenograft tumor mice. The inhibitory effects of atorvastatin were mediated by reducing MSH2 expression and triggering interaction between Bcl-2 and MSH2, both in vitro and in vivo levels.

Tinnitus Is Associated With Improved Cognitive Performance in Non-hispanic Elderly With Hearing Loss.

Because hearing loss is a high-risk factor for cognitive decline, tinnitus, a comorbid condition of hearing loss, is often presumed to impair cognition. The present cross-sectional study aimed to delineate the interaction of tinnitus and cognition in the elderly with and without hearing loss after adjusting for covariates in race, age, sex, education, pure tone average, hearing aids, and physical well-being. Participants included 643 adults (60-69 years old; 51.3% females) from the National Health and Nutrition Examination Survey (NHANES, 2011-2012), and 1,716 (60-69 years old; 60.4% females) from the Hispanic Community Health Study (HCHS, 2008-2011). Multivariable linear and binary logistic regression was used to assess the association between tinnitus and cognition in the two sub-cohorts of normal hearing (NHANES, n = 508; HCHS, n = 1264) and hearing loss (NHANES, n = 135; HCHS, n = 453). Cognitive performance was measured as a composite z-score from four cognitive tests: The Consortium to Establish a Registry for Alzheimer's Disease (CERAD)-word learning, CERAD-animal fluency, CERAD-word list recall, and the digit symbol substitution test (DSST) in NHANES, and a comparable Hispanic version of these four tests in HCHS. Multivariable linear regression revealed no association between tinnitus and cognition, except for the NHANES (non-Hispanic) participants with hearing loss, where the presence of tinnitus was associated with improved cognitive performance (Mean = 0.3; 95% CI, 0.1-0.5; p, 0.018). Using the 25th percentile score of the control (i.e., normal hearing and no tinnitus) as a threshold for poor cognitive performance, the absence of tinnitus increased the risk for poor cognitive performance (OR = 5.6, 95% CI, 1.9-17.2; p, 0.002). Sensitivity analysis found a positive correlation between tinnitus duration and cognitive performance in the NHANES cohort [F(4,140), 2.6; p, 0.037]. The present study finds no evidence for the assumption that tinnitus impairs cognitive performance in the elderly. On the contrary, tinnitus is associated with improved cognitive performance in the non-Hispanic elderly with hearing loss. The present result suggests that race be considered as an important and relevant factor in the experimental design of tinnitus research. Future longitudinal and imaging studies are needed to validate the present findings and understand their mechanisms.

Task-dependent effects of nicotine treatment on auditory performance in young-adult and elderly human nonsmokers.

Electrophysiological studies show that nicotine enhances neural responses to characteristic frequency stimuli. Previous behavioral studies partially corroborate these findings in young adults, showing that nicotine selectively enhances auditory processing in difficult listening conditions. The present work extended previous work to include both young and older adults and assessed the nicotine effect on sound frequency and intensity discrimination. Hypotheses were that nicotine improves auditory performance and that the degree of improvement is inversely proportional to baseline performance. Young (19-23 years old) normal-hearing nonsmokers and elderly (61-80) nonsmokers with normal hearing between 500 and 2000 Hz received nicotine gum (6 mg) or placebo gum in a single-blind, randomized crossover design. Participants performed three experiments (frequency discrimination, frequency modulation identification, and intensity discrimination) before and after treatment. The perceptual differences were analyzed between pre- and post-treatment, as well as between post-treatment nicotine and placebo conditions as a function of pre-treatment baseline performance. Compared to pre-treatment performance, nicotine significantly improved frequency discrimination. Compared to placebo, nicotine significantly improved performance for intensity discrimination, and the improvement was more pronounced in the elderly with lower baseline performance. Nicotine had no effect on frequency modulation identification. Nicotine effects are task-dependent, reflecting possible interplays of subjects, tasks and neural mechanisms.

Achieving global mortality reduction targets and universal health coverage: The impact of COVID-19.

Wenhui Mao and coauthors discuss possible implications of the COVID-19 pandemic for health aspirations in low- and middle-income countries.