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Abstract In surgical medicine, suturing is the standard treatment for large incisions, yet traditional sutures are limited in functionality. Electrical stimulation is a non-pharmacological therapy that promotes wound healing. In this context, we designed a passive and biodegradable mechanoelectric suture. The suture consists of multi-layer coaxial structure composed of (poly(lactic-co-glycolic acid), polycaprolactone) and magnesium to allow safe degradation. In addition to the excellent mechanical properties, the mechanoelectrical nature of the suture grants the generation of electric fields in response to movement and stretching. This is shown to speed up wound healing by 50% and reduce the risk of infection. This work presents an evolution of the conventional wound closure procedures, using a safe and degradable device ready to be translated into clinical practice.

Abstract Otitis media (OM), a condition stemming from the proliferation of various bacteria within the tympanic cavity (TC), is commonly addressed through the administration of ofloxacin (OFL), a fluoroquinolone antibiotic. Nevertheless, the escalating issue of antibiotic resistance and the challenge of drug leakage underscore the exploration of an alternative, more effective treatment modality in clinical practice. Here, we introduce a simple and easily implementable fluid-regulated strategy aimed at delivering immunomodulatory hydrogels into the TC, ensuring conformal contact with the irregular anatomical surfaces of the middle ear cavity to more effectively eliminate bacteria and treat OM. This innovative strategy exhibits expedited therapeutic process of antibiotic-resistant, acute and chronic OM rats, and significant reductions in the severity of tympanic membrane (TM) inflammation, residual bacteria within the TC (0.12 *105 CFU), and the thickness of TM/TC mucosa (17.63/32.43 μm), as compared to conventional OFL treatment (3.6, 0.76 *105 CFU, 48.70/151.26 μm). The broad-spectrum antibacterial and antibiofilm properties of this strategy against a spectrum of OM pathogens are demonstrated. The strategy is validated to bolster the host’s innate immune response through the stimulation of antibacterial protein synthesis, macrophage proliferation and activation, thereby accelerating bacterial eradication and inflammation resolution within the TC. This facile, cost-effective and in vivo degradable technology exhibits promising prospects for future clinical implementation.

The activation of spinal astrocytes accounts for opioid-induced hyperalgesia (OIH), but the underlying mechanisms remain elusive. The presence of astrocyte-neuron lactate shuttle (ANLS) makes astrocytes necessary for some neural function and communication. The aim of this study was to explore the role of ANLS in the occurrence and maintenance of OIH. After 7 days consecutive morphine injection, a mice OIH model was established and astrocytic pyruvate dehydrogenase kinase 4 (PDK4), phosphorylated pyruvate dehydrogenase (p-PDH) and accumulation of L-lactate was elevated in the spinal dorsal horn. Intrathecally administration of inhibitors of PDK, lactate dehydrogenase 5 and monocarboxylate transporters to decrease the supply of L-lactate on neurons was observed to attenuate hypersensitivity behaviors induced by repeated morphine administration and downregulate the expression of markers of central sensitization in the spinal dorsal horns. The astrocyte line and the neuronal line were co-cultured to investigate the mechanisms in vitro. In this study, we demonstrated that morphine-induced hyperalgesia was sustained by lactate overload consequent upon aberrant function of spinal ANLS. In this process, PDK-p-PDH-lactate axis serves a pivotal role, which might therefore be a new target to improve long-term opioid treatment strategy in clinical practice.

Abstract Background Renal calculi are one of the most frequent diseases in urology, and percutaneous nephrolithotomy (PCNL) being the gold standard for treating renal calculi larger than 2 cm. However, traditional rigid nephroscope cannot bend, presents significant limitations during PCNL. This study aims to develop a novel digital flexible nephroscope for PCNL and verify its safety and efficacy using 3D printed models and ex vivo porcine kidney models, providing new equipment for PCNL. Methods Based on the determined technical parameters, the novel digital flexible nephroscope was manufactured. First, 3D-printed model and ex vivo porcine kidney models were utilized to simulate the PCNL procedures. Then, the traditional rigid nephroscope and the novel digital flexible nephroscope were utilized to simulate the PCNL procedures on 10 ex vivo porcine kidneys for comparison. We observed and recorded the renal calyces visualized and accessed by both the traditional rigid nephroscope and the novel digital flexible nephroscope. Results In both the 3D printing and ex vivo porcine kidney models, the novel percutaneous digital flexible nephroscope smoothly entered the renal collecting system through the percutaneous renal tract. It freely changed angles to reach most target calyces, demonstrating significant advantages over the traditional rigid nephroscope. Conclusion The successful development of the novel percutaneous digital flexible nephroscope allows it to be used either independently or as an adjunct in complex stone cases, providing more effective and safer surgical equipment for percutaneous nephrolithotomy.

Abstract Background Extracellular matrix (ECM) protein malfunction or defect may lead to temporomandibular joint osteoarthritis (TMJ OA). Dentin sialophophoprotein (DSPP) is a mandibular condylar cartilage ECM protein, and its deletion impacted cell proliferation and other extracellular matrix alterations of postnatal condylar cartilage. However, it remains unclear if long-term loss of function of DSPP leads to TMJ OA. The study aimed to test the hypothesis that long-term haploinsufficiency of DSPP causes TMJ OA. Materials and methods To determine whether Dspp +/– mice exhibit TMJ OA but no severe tooth defects, mandibles of wild-type (WT), Dspp +/–, and Dspp homozygous (Dspp −/− ) mice were analyzed by Micro-computed tomography (micro-CT). To characterize the progression and possible mechanisms of osteoarthritic degeneration over time in Dspp +/– mice over time, condyles of Dspp +/– and WT mice were analyzed radiologically, histologically, and immunohistochemically. Results Micro-CT and histomorphometric analyses revealed that Dspp +/– and Dspp −/− mice had significantly lower subchondral bone mass, bone volume fraction, bone mineral density, and trabecular thickness compared to WT mice at 12 months. Interestingly, in contrast to Dspp −/− mice which exhibited tooth loss, Dspp +/– mice had minor tooth defects. RNA sequencing data showed that haplodeficency of DSPP affects the biological process of ossification and osteoclast differentiation. Additionally, histological analysis showed that Dspp +/– mice had condylar cartilage fissures, reduced cartilage thickness, decreased articular cell numbers and severe subchondral bone cavities, and with signs that were exaggerated with age. Radiographic data showed an increase in subchondral osteoporosis up to 18 months and osteophyte formation at 21 months. Moreover, Dspp +/– mice showed increased distribution of osteoclasts in the subchondral bone and increased expression of MMP2, IL-6, FN-1, and TLR4 in the mandibular condylar cartilage. Conclusions Dspp +/– mice exhibit TMJ OA in a time-dependent manner, with lesions in the mandibular condyle attributed to hypomineralization of subchondral bone and breakdown of the mandibular condylar cartilage, accompanied by upregulation of inflammatory markers.

Abstract The neural basis of fear of heights remains largely unknown. In this study, we investigated the fear response to heights in male mice and observed characteristic aversive behaviors resembling human height vertigo. We identified visual input as a critical factor in mouse reactions to heights, while peripheral vestibular input was found to be nonessential for fear of heights. Unexpectedly, we found that fear of heights in naïve mice does not rely on image-forming visual processing by the primary visual cortex. Instead, a subset of neurons in the ventral lateral geniculate nucleus (vLGN), which connects to the lateral/ventrolateral periaqueductal gray (l/vlPAG), drives the expression of fear associated with heights. Additionally, we observed that a subcortical visual pathway linking the superior colliculus to the lateral posterior thalamic nucleus inhibits the defensive response to height threats. These findings highlight a rapid fear response to height threats through a subcortical visual and defensive pathway from the vLGN to the l/vlPAG.

BackgroundThe psychological status of Chinese postgraduate students majoring in stomatology after the COVID-19 restrictions still remains unclear. The objective of this study is to evaluate the mental status through a cross-sectional survey and gather related theoretical evidence for psychological intervention on postgraduate students majoring in stomatology.MethodsAn online survey was administered, and subjective well-being, anxiety, stress and depression symptoms were assessed using the 5-item World Health Organization Well-Being Index (WHO-5), item Generalized Anxiety Disorder Scale (GAD-7), 10-item Perceived Stress Scale (PSS-10), and Patient Health Questionnaire-9 (PHQ-9), respectively, wherein suicidal ideation and sleep-related problems were measured with PHQ-9 and Insomnia Severity Index (ISI).ResultsA total of 208 participants who completed one questionnaire were considered as valid. It was found that female respondents generally exhibited significantly higher levels of PSS-10, PHQ-9, and GAD-7 scores and shorter physical activity hours than male students. Students from rural areas demonstrated significantly higher levels of PHQ-9, suicidal ideation, and less portion of good or fair family economic support. Additionally, individuals from only-child families reported increased levels of activity hours (1.78 ± 2.07, p = 0.045) and a higher portion (55.10%, p = 0.007) of having clear future plan as compared with multiple-child families. The risk factors for anxiety symptoms (GAD-7 score) were higher scores of PSS-10 (OR = 1.15, 95% CI = 1.09–1.22), PHQ-9 (OR = 1.35, 95% CI = 1.22–1.49), and ISI-7 (OR = 1.14, 95% CI = 1.06–1.23), while owning a clear graduation plan was the protective factor (OR = 0.55, 95% CI = 0.31–0.98). Moreover, the risk factors for depressive symptoms (PHQ-9) included PSS-10 (OR = 1.10, 95% CI = 1.04–1.16), GAD-7 (OR = 1.38, 95% CI = 1.25–1.52), suicidal ideation (OR = 5.66, 95% CI = 3.37–9.51), and ISI-7 (OR = 1.17, 95% CI = 1.09–1.25). Approximately 98.08% of Chinese postgraduates studying stomatology reported experiencing at least moderate stress after the COVID-19 restrictions.ConclusionWithin the limitations of this study, senior students were more inclined to stress, while anxiety symptoms were related to severer levels of stress, depression, and insomnia. Depressive symptoms were associated with higher levels of stress, anxiety, insomnia, suicidal ideation, and lower levels of self-reported well-being. Thus, psychological interventions for postgraduates should be timely and appropriately implemented by strengthening well-being, reasonably planning for the future, and good physique, thereby mitigating the psychological issues after COVID-19 restrictions.

Abstract Background Age-related hearing loss (ARHL) signifies the bilateral, symmetrical, sensorineural hearing loss that commonly occurs in elderly individuals. Several studies have suggested a higher risk of dementia among patients diagnosed with ARHL. Although the precise causal association between ARHL and cognitive decline remains unclear, ARHL has been recognized as one of the most significant factors that can be modified to reduce the risk of developing dementia potentially. Mild cognitive impairment (MCI) typically serves as the initial stage in the transition from normal cognitive function to dementia. Consequently, the objective of our randomized controlled trial (RCT) is to further investigate whether the use of hearing aids can enhance cognitive function in older adults diagnosed with ARHL and MCI. Methods and design This study is a parallel-arm, randomized controlled trial conducted at multiple centers in Shanghai, China. We aim to enlist a total of 688 older adults (age ≥ 60) diagnosed with moderate-to-severe ARHL and MCI from our four research centers. Participants will be assigned randomly to either the hearing aid fitting group or the health education group using block randomization with varying block sizes. Audiometry, cognitive function assessments, and other relevant data will be collected at baseline, as well as at 6, 12, and 24 months post-intervention by audiologists and trained researchers. The primary outcome of our study is the rate of progression to dementia among the two groups of participants. Additionally, various evaluations will be conducted to measure hearing improvement and changes in cognitive function. Apart from the final study results, we also plan to conduct an interim analysis using data from 12-month follow-up. Discussion In recent years, there has been a notable lack of randomized controlled trials (RCTs) investigating the possible causal relationship between hearing fitting and the improvement of cognitive function. Our findings may demonstrate that hearing rehabilitation can be a valuable tool in managing ARHL and preventing cognitive decline, which will contribute to the development of a comprehensive framework for the prevention and control of cognitive decline. Trial registration Chinese Clinical Trial Registry chictr.org.cn ChiCTR2000036139. Registered on 21 August 2020.

As the third-largest maize-producing province in China and a typical arid and semi-arid region, quantitatively evaluating the carbon and nitrogen footprints of maize production and their dominant factors is of great significance in guiding the high-yield, low-carbon, and sustainable development of maize production in the Inner Mongolia Autonomous Region. This study quantitatively evaluated the interannual evolution characteristics of the carbon and nitrogen footprints in maize production and their dominant factors in Inner Mongolia from 2003 to 2022 based on statistical yearbook data and emission parameter models. The results showed that from 2003 to 2022, the maize planting area, yield, and total yield in Inner Mongolia all increased, with an average annual increase of 97 kg ha−1 in yield and 1.23 × 106 Mg in total yield. The carbon and nitrogen footprints of Inner Mongolia maize production over the past 20 years had overall decreasing trends, while the nitrogen fertilizer bias productivity, net ecosystem carbon balance, and sustainability index had increasing trends. Carbon footprint reduced by an average of 5.2 kg CO2 eq Mg−1 per year, and nitrogen footprint reduced by an average of 0.21 g N eq kg−1 per year. Currently, the transportation and production of fertilizer and field application of N fertilizer are the main controlling factors of GHG emissions from maize production. NO3−-N, NH4+-N leaching, and NH3 volatilization from field application of N fertilizer are the main sources of reactive N losses. The application of simplified processes, such as phased regulation of nitrogen and controlled-release fertilizers, as well as conservation tillage, have broad prospects for emission reduction in maize production in Inner Mongolia.

Abstract Background Phosphatidylserine is translocated to the inner leaflet of the phospholipid bilayer membrane by the flippase function of type IV P-tape ATPase (P4-ATPase), which is critical to maintain cellular stability and homeostasis. Transmembrane protein 30A (TMEM30A) is the β-subunit of P4-ATPase. Loss of P4-ATPase function causes sensorineural hearing loss and visual dysfunction in human. However, the function of TMEM30A in the auditory system is unclear. Methods P4-ATPase subtype expression in the cochlea was detected by immunofluorescence staining and quantitative real-time polymerase chain reaction (qRT-PCR) at different developmental stages. Hair cell specific TMEM30A knockout mice and wild-type littermates were used for the following functional and morphological analysis. Auditory function was evaluated by auditory brainstem response. We investigated hair cell and stereocilia morphological changes by immunofluorescence staining. Scanning electron microscopy was applied to observe the stereocilia ultrastructure. Differentially expressed transcriptomes were analyzed based on RNA-sequencing data from knockout and wild-type mouse cochleae. Differentially expressed genes were verified by qRT-PCR. Results TMEM30A and subtypes of P4-ATPase are expressed in the mouse cochlea in a temporal-dependent pattern. Deletion of TMEM30A in hair cells impaired hearing onset due to progressive hair cell loss. The disrupted kinocilia placement and irregular distribution of spectrin-α in cuticular plate indicated the hair cell planar polarity disruption in TMEM30A deletion hair cells. Hair cell degeneration begins at P7 and finishes around P14. Transcriptional analysis indicates that the focal adhesion pathway and stereocilium tip-related genes changed dramatically. Without the TMEM30A chaperone, excessive ATP8A2 accumulated in the cytoplasm, leading to overwhelming endoplasmic reticulum stress, which eventually contributed to hair cell death. Conclusions Deletion of TMEM30A led to disrupted planar polarity and stereocilia bundles, and finally led to hair cell loss and auditory dysfunction. TMEM30A is essential for hair cell polarity maintenance and membrane homeostasis. Our study highlights a pivotal role of TMEM30A in the postnatal development of hair cells and reveals the possible mechanisms underlying P4-ATPase-related genetic hearing loss.

The aim of this article is to reduce the environmental harm caused by industrial solid waste, specifically tannery sludge, and enable its reutilization. This study prepared an alkali-activated tannery sludge–slag solidification product (ATSSP) with high mechanical properties using blast furnace slag and tannery sludge as raw materials. The response surface methodology (RSM) was used to optimize the product mix ratio. The hydration mechanism and solidification method of ATSSP for Cr in tannery sludge were studied using X-ray diffraction (XRD), scanning electron microscope-energy dispersive spectrometer (SEM-EDS), and Fourier transform infrared reflection (FT-IR). The results indicate that the compressive strength regression model established through RSM has high accuracy and credibility. When the ratio of activator to binder is 0.2174, the alkali activation modulus is 1.02, and the water-to-cement ratio is 0.37; the 28 d compressive strength of ATSSP can reach 71.3 MPa. The sulfate in tannery sludge can promote the secondary hydration reaction of slag, and the generated hydrated calcium silicate and calcite greatly improve the strength of the ATSSP. The reducing substances contained in slag can reduce Cr (VI) in tannery sludge to Cr (III) in the form of uvarovite. The total Cr and Cr (VI) precipitation concentrations of the product are far less than the specification requirements.

Astrocytes are highly heterogeneous and involved in different aspects of fundamental functions in the central nervous system (CNS). However, whether and how this heterogeneous population of cells reacts to the pathophysiological challenge is not well understood. To investigate the response status of astrocytes in the medial vestibular nucleus (MVN) after vestibular loss, we examined the subtypes of astrocytes in MVN using single-cell sequencing technology in a unilateral labyrinthectomy mouse model. We discovered four subtypes of astrocytes in the MVN with each displaying unique gene expression profiles. After unilateral labyrinthectomy, the proportion of the astrocytic subtypes and their transcriptional features on the ipsilateral side of the MVN differ significantly from those on the contralateral side. With new markers to detect and classify the subtypes of astrocytes in the MVN, our findings implicate potential roles of the adaptive changes of astrocyte subtypes in the early vestibular compensation following peripheral vestibular damage to reverse behavioral deficits.

Bilirubin, an open chain tetrapyrrole, has powerful antioxidant, anti-inflammatory, immuno-suppressive, metabolic-modulating and anti-proliferative activities. Bilirubin is a natural molecule that is produced and metabolized within the human body, making it highly biocompatible and well suited for clinical use. However, the use of bilirubin has been hampered by its poor water solubility and instability. With advanced construction strategies, bilirubin-derived nanoparticles (BRNPs) have not only overcome the disadvantages of bilirubin but also enhanced its therapeutic effects by targeting damaged tissues, passing through physiological barriers, and ensuring controlled sustained release. We review the mechanisms underlying the biological activities of bilirubin, BRNP preparation strategies and BRNP applications in various disease models. Based on their superior performance, BRNPs require further exploration of their efficacy, biodistribution and long-term biosafety in nonhuman primate models that recapitulate human disease to promote their clinical translation.

Abstract To study the growth rate of different Arthrospira strains, three species of Arthrospira from Ordos alkaline lake, labeled as sp.DD, sp.ER, sp.FB, one species of Arthrospira from Hasu Sea in Hohhot, labeled as sp.HS, another purified strain labeled as sp.QD donated by the Ocean University of China had been collected. The first four need to be further isolated and purified in culture. The growth curves of all strains were plotted. Subsequently, 16S rRNA sequences were amplified and sequenced in an attempt to study taxonomic relationships. The results showed that the growth rate was increased in the first 9 days, and sp.DD had the highest growth rate. Analysis of the sequencing results revealed that sp.HS had 99.79% homology with Arthrospira platensis strain Sp-2, sp.DD had 99.69% homology with Arthrospira platensis FACHB834, sp.QD had 99.54% homology with Arthrospira platensis F3S, sp.ER had 99.79% homology with Arthrospira erdosensis ‘Inner Mongolia’, sp.FB had 99.74% homology with Arthrospira erdosensis ‘Inner Mongolia’. Phylogenetic analysis indicated that sp.HS was closely related to Arthrospira platensis strain Sp-2; sp.DD and sp.QD had a close genetic relationship; sp.ER and sp.FB had a close genetic relationship. In conclusion, these findings provide a theoretical basis for the further development and reproduction of dominant algae species in Inner Mongolia through biological analysis of Arthrospira.

Abstract. The vestibular system involves high-level sensory and cognitive processes, such as spatial perception, balance control, visual stability, and emotional control. Vestibular dysfunction can induce vertigo, blurred vision, postural imbalance, walking instability, and spatial discomfort, which causes serious damage to health. It has long been known that after peripheral vestibular lesion, vestibular dysfunction may spontaneously recover. This is known as vestibular compensation. However, at least 20% to 30% of patients with vestibular disorders cannot yield vestibular compensation and remain with vestibular dysfunction for the rest of their lives. The exploration of the biological characteristics and regulatory factors of the loss and reestablishment of vestibular function will establish a new understanding of the mechanism of vestibular compensation and provide new tools and strategies for promoting vestibular rehabilitation. We aim to comprehensively review the mechanism of vestibular compensation and discuss future directions in this field.

Hepatic encephalopathy (HE)–a major complication of liver disease–has been found to increase the risk of olfactory dysfunction, which may be attributed to elevated levels of ammonia/ammonium in the blood and cerebrospinal fluid. However, the cellular mechanisms underlying hyperammonemia-induced olfactory dysfunction remain unclear. By performing patch-clamp recordings of mitral cells (MCs) in the mouse olfactory bulb (OB), we found that 3 mM ammonium (NH4+) increased the spontaneous firing frequency and attenuated the amplitude, but synaptic blockers could prevent the changes, suggesting the important role of glutamate receptors in NH4+-induced hyperexcitability of MCs. We also found NH4+ reduced the currents of voltage-gated K+ channel (Kv), which may lead to the attenuation of spontaneous firing amplitude by NH4+. Further studies demonstrated NH4+ enhanced the amplitude and integral area of long-lasting spontaneous excitatory post-synaptic currents (sEPSCs) in acute OB slices. This enhancement of excitatory neurotransmission in MCs occurred independently of pre-synaptic glutamate release and re-uptake, and was prevented by the exocytosis inhibitor TAT-NSF700. In addition, an NH4+-induced increasement in expression of NR1 and GluR1 was detected on cytoplasmic membrane, indicating that increased trafficking of glutamate receptors on membrane surface in MCs is the core mechanism. Moreover, NH4+-induced enhanced activity of glutamate receptors in acute OB slices caused cell death, which was prevented by antagonizing glutamate receptors or chelating intracellular calcium levels. Our study demonstrates that the enhancement of the activity and recruitment of glutamate receptor directly induces neuronal excitotoxicity, and contributes to the vulnerability of OB to acute hyperammonemia, thus providing a potential pathological mechanism of olfactory defects in patients with hyperammonemia and HE.

Fatty acid profile, protein and fatty acid oxidation and flavor profile of pan-fried chicken patties formulated with various levels of Perilla frutescens seed meal (PSM) as a fat substitute was investigated in this study. The formation of heterocyclic amines (HCAs) in the chicken patties was also evaluated. The results showed that pan-fried patties formulated with 20% PSM (PSM4) had the highest ranges of oleic acid and ΣMUFA content and ΣPUFA/ΣSFA ratio. Low to medium levels of PSM (PSM1, 2, and 3 corresponding to 5, 10, and 15% of PSM, respectively) reduced the content of lipid peroxidation products, while high level (PSM4) increased it. All levels of PSM were also found to be effective against elevation in carbonyl content relative to the control. Moreover, the PSM effectively inhibited HCA formation in the chicken patties. The total contents of HCAs in PSM1, PSM2, PSM3, and PSM4 samples were significantly (P < 0.05) lower than that of the control sample, corresponding to 31.9, 46.1, 57.2, and 44.8% inhibition, respectively. PSM4, however, had no or very little effect on the formation of PhIP, 4,8-DiMeIQx and AαC, despite a strong inhibitory effect on MeIQx formation. These findings not only support the promising potential of PSM for application as a fat substitute to improve the fatty acid profile and reduce the content of harmful by-products in heat-processed chicken, but also highlight that appropriate addition level is a critical factor in optimizing the functional capacity of this natural agent.

Computer Assisted Diagnosis (CAD) based on brain Magnetic Resonance Imaging (MRI) is a popular research field for the computer science and medical engineering. Traditional machine learning and deep learning methods were employed in the classification of brain MRI images in the previous studies. However, the current algorithms rarely take into consideration the influence of multi-scale brain connectivity disorders on some mental diseases. To improve this defect, a deep learning structure was proposed based on MRI images, which was designed to consider the brain's connections at different sizes and the attention of connections. In this work, a Multiscale View (MV) module was proposed, which was designed to detect multi-scale brain network disorders. On the basis of the MV module, the path attention module was also proposed to simulate the attention selection of the parallel paths in the MV module. Based on the two modules, we proposed a 3D Multiscale View Convolutional Neural Network with Attention (3D MVA-CNN) for classification of MRI images for mental disease. The proposed method outperformed the previous 3D CNN structures in the structural MRI data of ADHD-200 and the functional MRI data of schizophrenia. Finally, we also proposed a preliminary framework for clinical application using 3D CNN, and discussed its limitations on data accessing and reliability. This work promoted the assisted diagnosis of mental diseases based on deep learning and provided a novel 3D CNN method based on MRI data.

Abstract Developing efficient and promising tenderising techniques for postmortem meat is a heavily researched topic among meat scientists as consumers are willing to pay more for guaranteed tender meat. However, emerging tenderising techniques are not broadly used in the meat industry and, to some degree, are controversial due to lack of theoretical support. Thus, understanding the mechanisms involved in postmortem tenderisation is essential. This article first provides an overview of the relationship of ageing tenderisation and calpain system, as well as proteomics applied to identify protein biomarkers characterizing tenderness. In general, the ageing tenderisation is mediated by multiple biochemical activities, and it can exhibit better palatability and commercial benefit by combining other interventions. The calpain system plays a key role in ageing tenderisation functions by rupturing myofibrils and regulating proteolysis, glycolysis, apoptosis and metabolic modification. Additionally, tenderising techniques from different aspects including exogenous enzymes, chemistry, physics and the combined methods are discussed in depth. Particularly, innovation of home cooking could be recommended to prepare relatively tender meat due to its convenience and ease of operation by consumers. Furthermore, the combined interventions provide better performance in controlled tenderness. Finally, future trends in developing new tenderising techniques, and applied consideration in the meat processing industry are proposed in order to improve meat quality with higher economical value. Graphical abstract

Background: Nicotinamide adenine dinucleotide (NAD+), a coenzyme that plays crucial roles in many cellular processes, is a potential therapeutic target for various diseases. Dihydronicotinamide riboside (NRH), a novel reduced form of nicotinamide riboside, has emerged as a potent NAD+ precursor. Here, we studied the protective effects and underlying mechanism of NRH on aminoglycoside-induced ototoxicity. Methods: Auditory function and hair-cell (HC) morphology were examined to assess the effects of NRH on kanamycin-induced hearing loss. The pharmacokinetic parameters of NRH were measured in plasma and the cochlea using liquid chromatography tandem mass spectrometry. NAD+ levels in organ explant cultures were assessed to compare NRH with known NAD+ precursors. Immunofluorescence analysis was performed to detect reactive oxygen species (ROS) and apoptosis. We analyzed SIRT1 and 14–3–3 protein expression. EX527 and resveratrol were used to investigate the role of SIRT1 in the protective effect of NRH against kanamycin-induced ototoxicity. Results: NRH alleviated kanamycin-induced HC damage and attenuated hearing loss in mice. NRH reduced gentamicin-induced vestibular HC loss. Compared with NAD and NR, NRH produced more NAD+ in cochlear HCs and significantly ameliorated kanamycin-induced oxidative stress and apoptosis. NRH rescued the aminoglycoside-induced decreases in SIRT1 and 14–3–3 protein expression. Moreover, EX527 antagonized the protective effect of NRH on kanamycin-induced HC loss by inhibition of SIRT1, while resveratrol alleviated HC damage caused by EX527. Conclusions: NRH ameliorates aminoglycoside-induced ototoxicity by inhibiting HC apoptosis by activating SIRT1 and decreasing ROS. NRH is an effective therapeutic option for aminoglycoside-induced ototoxicity.

Symptoms of vertigo are frequently reported and are usually accompanied by eye-movements called nystagmus. In this article, we designed a three-dimensional nystagmus recognition model and a benign paroxysmal positional vertigo automatic diagnosis system based on deep neural network architectures (Chinese Clinical Trials Registry ChiCTR-IOR-17010506). An object detection model was constructed to track the movement of the pupil centre. Convolutional neural network-based models were trained to detect nystagmus patterns in three dimensions. Our nystagmus detection models obtained high areas under the curve; 0.982 in horizontal tests, 0.893 in vertical tests, and 0.957 in torsional tests. Moreover, our automatic benign paroxysmal positional vertigo diagnosis system achieved a sensitivity of 0.8848, specificity of 0.8841, accuracy of 0.8845, and an F1 score of 0.8914. Compared with previous studies, our system provides a clinical reference, facilitates nystagmus detection and diagnosis, and it can be applied in real-world medical practices.

Traditionally, process planning and scheduling were performed sequentially, where scheduling depended on the result of process planning. Considering their complementarity, the two functions are more tightly integrated to improve the performance of job shop flexible manufacturing environment. This study proposes an adaptive multi-strategy artificial bee colony (AMSABC) algorithm to solve integrated process planning and scheduling (IPPS) problem. In AMSABC, two search strategies with different characteristics are introduced into employed bees and onlooker bees to take on the responsibility of both exploration and exploitation. The selection probability of each search strategy is dynamically adjusted according to previous experiences. To further improve the exploitation performance of the approach, a problem-specific multi-objective local search has been embedded in the proposed algorithm. Furthermore, AMSABC algorithm presents a unique solution representation where a food source is represented by three discrete vectors, and a well-designed decoding scheme is developed. Next, the corresponding neighborhood structure is adopted that it can directly generate feasible solutions in the search space. The proposed algorithm is tested on the well-known benchmark instances and compared with the state-of-the-art algorithms. Through detail analysis of experimental results, AMSABC algorithm is more beneficial in the quality and efficiency of solution.

Otosclerosis is caused by abnormal bone remodeling in the middle ear, resulting in progressive hearing loss, dizziness, balance problems, and tinnitus. Previous infection, stress fractures of the bony tissue surrounding the inner ear, immune disorders, and genetic factors are believed to contribute to this disease. Currently, no effective drug treatment for otosclerosis is known. Herein, we generated an induced pluripotent stem cell line from the peripheral blood mononuclear cells of an otosclerosis patient. The cell line exhibited normal morphology, karyotype, and pluripotency marker expression. A teratoma assay revealed successful differentiation into all three germ layers.

ObjectiveCisplatin is a broad-spectrum anti-tumour drug commonly used in clinical practice. However, its ototoxicity greatly limits its clinical application, and no effective method is available to prevent this effect. Endoplasmic reticulum stress (ERS) is reportedly involved in cisplatin ototoxicity, but the exact mechanism remains unclear. Therefore, this study aimed to investigate the role of eukaryotic translation initiation factor 2α (eIF2α) signalling and its dephosphorylation inhibitor salubrinal in cisplatin ototoxicity.MethodsWe evaluated whether salubrinal could protect against cisplatin-induced damage in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells and mouse cochlear explants. By knocking down eIF2α, we elucidated the vital role of eIF2α in cisplatin-induced damage in HEI-OC1 cells. Whole-mount immunofluorescent staining and confocal microscopy of mouse cochlear explants and HEI-OC1 cells were performed to analyse cisplatin-induced damage in cochlear hair cells and the auditory cell line.ResultsData suggested salubrinal attenuated cisplatin-induced hair cell injury by inhibiting apoptosis. In addition, salubrinal significantly reduced ERS levels in hair cells via eIF2α signalling, while eIF2α knockdown inhibited the protective effect of salubrinal.SignificanceSalubrinal and eIF2α signalling play a role in protecting against cisplatin-induced ototoxicity, and pharmacological inhibition of eIF2α-mediated ERS is a potential treatment for cisplatin-induced damage in the cochlea and HEI-OC1 cells.

This paper aimed to evaluate the effects of ultrasound-assisted L-histidine marination (UMH) on meat quality and actomyosin properties of beef M. semitendinosus. Our results found that UMH treatment effectively avoided excessive liquid withdrawal, and disrupted myofibril integrity by modifying the water distribution and weakening connection of actin-myosin with increased muscle pH. The ultrasound-treated sample provided more opportunity for the filtration of L-histidine to intervene the isoelectric point and conformation of muscle protein. The activated caspase-3 and changes of ATPase activity in UMH-treated meat accelerated the postmortem ageing, and L-histidine might competitively inhibit the actin-myosin binding by the imidazole group. UMH decreased the surface hydrophobicity by shielding hydrophobic area and unfolding the actomyosin structure. In addition, the increased actomyosin solubility with smaller particle size enhanced the SH content for better cross-linking of myosin tail, and formation of heat-set gelling protein structure. Therefore, UMH treatment manifested the potential to improve beef quality.

Abstract Background Due to economic development and an increase in the aging population, the demand for medical resources is increasing. A good doctor-patient relationship (DPR) can optimize patients’ medical experience and improve treatment efficiency. The DPR, however, is currently in crisis in China. To explore ways to improve DPR, this study assessed the views on the status of the DPR, medical services, and the general situation of medical work among medical personnel (MP) and the general population (GP). Methods This cross-sectional study, conducted between December 2019 and March 2020, targeted the MP and the GP in Nanjing City, Jiangsu Province, and Zhengzhou City, Henan Province. A total of 154 MP and 329 GP answered a self-administered questionnaire through Questionnaire Star and WeChat apps. Wilcoxon’s Sign Rank Test, Chi-square test, and frequency distributions and percentages were used to process the data. Results Only 11.04% of the MP and 14.89% of the GP believed that the current DPR was harmonious. Moreover, 54.55% of the MP and 71.12% of the GP believed that the medical industry was a service industry. While 14.29% of the MP and 64.44% of the GP thought medical staff earned high salaries, 19.48% of the MP and 47.11% of the GP wanted their children to be in the medical industry. The recognition of the current status of the DPR did not affect the GP’s preference for their children’s practice (p

The imbalance of reactive oxygen species and antioxidants is considered to be an important factor in the cellular injury of the inner ear. At present, great attention has been placed on oxidative stress. However, little is known about fighting oxidative stress. In the current study, we evaluated antioxidant-induced cochlear damage by applying several different additional antioxidants. To determine whether excessive antioxidants can cause damage to cochlear cells, we treated cochlear explants with 50 μM M40403, a superoxide dismutase mimetic, 50 μM coenzyme Q-10, a vitamin-like antioxidant, or 50 μM d-methionine, an essential amino acid and the important antioxidant glutathione for 48 h. Control cochlear explants without the antioxidant treatment maintained their normal structures after incubation in the standard serum-free medium for 48 h, indicating the maintenance of the inherent oxidative and antioxidant balance in these cochlear explants. In contrast, M40403 and coenzyme Q-10-treated cochlear explants displayed significant hair cell damage together with slight damage to the auditory nerve fibers. Moreover, d-methiodine-treated explants exhibited severe damage to the surface structure of hair cells and the complete loss of the spiral ganglion neurons and their peripheral fibers. These results indicate that excessive antioxidants are detrimental to cochlear cells, suggesting that inappropriate dosages of antioxidant treatments can interrupt the balance of the inherent oxidative and antioxidant capacity in the cell. Keywords: Antioxidative stress, Cochlea, M40403, Coenzyme Q-10, D-methiodine

Neuronal oscillatory phase and phase synchronization are two main aspects of neuronal oscillation. Neurophysiological and computational studies have demonstrated that oscillatory phase for individual neurons has quantifiable relationships with neuronal excitation and input stimulus. In order to investigate the issue for neuronal groups, we constructed orientation columns by means of a spiking neural network and introduced six network activity states, pre-stimulus and stimulus periods for comparison. We proposed a new method of spike-LFP (Local Field Potential) phase based on vector addition of point spike-LFP phases to represent oscillatory phase. We also proposed a PPCG (Pairwise Phase Consistency for Group) method to quantify phase synchronization for neuronal groups. As illustrated in the simulation, the characteristics of oscillatory phase and phase synchronization for neuronal groups were consistent with the ones for individual neurons. Preferred orientations and stronger external inputs tended to result in smaller and more concentrated oscillatory phases. No matter individual neurons or neuronal groups, the oscillatory phase decreased monotonically as a function of neuronal excitation and input strength. More importantly, neuronal groups had a competitive advantage over individual neurons, because they can achieve reliable relationship quantification of oscillatory phase for all network activity states, even in weak oscillatory or non-oscillatory states.

Ferroptosis is associated with the pathology of myocardial ischemia/reperfusion (MI/R) injury following myocardial infarction, which is a leading cause of death worldwide. Although long noncoding RNAs (lncRNAs) are known to regulate gene expression, their roles in MI/R-induced ferroptosis remain unclear. In this study, we explored the lncRNA expression profiles in a rat model of MI/R injury and found that the novel lncRNA, lncAABR07025387.1, was highly expressed in MI/R-injured myocardial tissues and hypoxia/reoxygenation (H/R)-challenged myocardial cells. Silencing lncAABR07025387.1 improved MI/R injury in vivo and inhibited myocardial cell ferroptosis under H/R conditions. Bioinformatics analyses and luciferase, pull-down, and RNA-binding immunoprecipitation assays further revealed that lncAABR07025387.1 interacted with miR-205, which directly targeted ACSL4, a known contributor to ferroptosis. Furthermore, downregulating miR-205 reversed the ACSL4 inhibition induced by silencing lncAABR07025387.1. These findings suggest that, mechanistically, lncAABR07025387.1 negatively regulates miR-205 expression and subsequently upregulates ACSL4-mediated ferroptosis. In conclusion, this study demonstrates that lncAABR07025387.1 acts as a competing endogenous RNA during MI/R injury and highlights the therapeutic potential of lncRNAs for treating myocardial injury.

BackgroundThe clinical efficacy of triple semicircular canal occlusion (TSCO) and vestibular nerve resection (VNS) for patients with Ménière's disease has been unclear.ObjectiveTo explore changes in vestibular symptoms after TSCO and its advantages compared to the classical operation of VNS in patients with Menière's disease.MethodsIn total, 36 patients with Menière's disease performed TSCO or VNS at Shanghai Jiao Tong University Affiliated Sixth People's Hospital, China from May 2005 to July 2021, and all of them were enrolled in our study. Twelve of them underwent TSCO, 23 underwent VNS, and 1 had both treatments. We compared the demographic parameters, clinical symptoms, and selected test results between the two surgical methods. Ten patients each who underwent TSCO and VNS completed the follow-up. We collected and compared data pertaining to changes in vestibular symptoms.ResultsNo significant difference in demographic parameters, clinical symptoms, or auditory or vestibular test results was detected between the two groups preoperatively. The TSCO group with vertigo as the main complaint experienced less residual paroxysmal dizziness after surgery than the VNS group (P = 0.020). Also, 57% of the patients in the VNS group had unsteadiness after surgery, while no such problems were reported in the TSCO group (P = 0.025).ConclusionsOur study shows that TSCO controls vertigo in most Menière's disease patients, and also has the advantage of lower rates of postoperative paroxysmal dizziness and unsteadiness than VNS. Thus, TSCO may be an effective surgery for refractory Menière's disease.

The governing equations of nonlinear dynamic systems is of great significance for understanding the internal physical characteristics. In order to learn the governing equations of nonlinear systems from noisy observed data, we propose a novel method named governing equation discovery based on causal graph that combines spatio-temporal graph convolution network with governing equation modeling. The essence of our method is to first devise the causal graph encoding based on transfer entropy to obtain the adjacency matrix with causal significance between variables. Then, the spatio-temporal graph convolutional network is used to obtain approximate solutions for the system variables. On this basis, automatic differentiation is applied to obtain basic derivatives and form a dictionary of candidate algebraic terms. Finally, sparse regression is used to obtain the coefficient matrix and determine the explicit formulation of the governing equations. We also design a novel cross-combinatorial optimization strategy to learn the heterogeneous parameters that include neural network parameters and control equation coefficients. We conduct extensive experiments on seven datasets from different physical fields. The experimental results demonstrate the proposed method can automatically discover the underlying governing equation of the systems, and has great robustness.

Background: At present, there are a variety of treatment strategies for percutaneous coronary intervention. The role of drug-coated balloon (DCB) in the treatment of side branch for de novo coronary bifurcated lesions (CBL) is unclear.Objective: To examine the effect of DCB in side branch protection for de novo CBL.Methods: Electronic databases, including Pubmed, Embase, the Web of science, Cochrance library, CNKI, CBM, WanFang Data and VIP were searched for studies that compared DCB with non-drug-coated balloon (NDCB) in side branch protection for de novo CBL from inception through July 7th, 2021. The primary outcome was target lesion revascularization (TLR). Secondary clinical outcomes included myocardial infarction (MI), cardiac death (CD). The angiographic outcomes included side branch late lumen loss (LLL), minimum lumen diameter (MLD), diameter stenosis (DS) and binary restenosis (BR). The target lesion failure (TLF) was also analyzed.Results: A total of 10 studies, including 5 randomized controlled trials and 5 non-randomized observational studies, with 934 patients were included. Meta-analysis results of angiographic outcomes suggested that DCB group had the less LLL, DS and BR and the higher MLD compared with NDCB group at follow-up (P < 0.05). Meta-analysis results of clinical outcomes suggested that the significant difference in the TLR, MI and CD between DCB group and NDCB group has not been found yet (P > 0.05). However, the MACE of DCB group was significantly less than that of NDCB group at 9-month follow-up [OR = 0.21, 95%CI (0.05, 0.84), P = 0.03] and 12-month follow-up [OR = 0.45, 95%CI (0.22, 0.90), P = 0.02]. In addition, there was no significant difference in TLF between DCB group and NDCB group (P > 0.05).Conclusions: DCB had great effect in side branch protection for de novo CBL at short and medium-term follow-up with no reduction in the procedural success rate.Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=267426, PROSPERO [Identifier: CRD42021267426].

Glycosylated hemoglobin A1c (HbA1c) level has strong relevance to microvascular disorders, which are also thought to be the current main aspect of sudden sensorineural hearing loss (SSNHL), so we aim to elucidate the association of the HbA1c level with the severity, types, and prognosis of SSNHL. In this study, comparative analyses based on propensity score matching of the severity, types, and prognosis of SSNHL with the HbA1c level in 116 patients diagnosed as SSNHL were conducted, where they were divided into diabetes mellitus (DM) group and non-DM group. We finally found that, among patients with SSNHL, diabetic patients had a higher HbA1c level, more severe hearing loss, and poorer prognosis than non-diabetic patients. The HbA1c level was found to be significantly correlated with the severity and types of SSNHL, while no strong relevance was found between the higher HbA1c level and the poorer prognosis of SSNHL.

Objectives: As a common otology emergency, sudden sensorineural hearing loss (SSNHL) has a great impact on quality of life. The diagnosis and treatment of SSNHL remain challenging. This study aims to identify and investigate the association of liver functions with SSNHL.Methods: A total of 135 SSNHL patients and 135 sex- and age-matched controls were prospectively enrolled. The baseline and clinical characteristics, along with liver function levels of participators, were collected. Linear correlation, logistic regression, and receiving operator characteristic curve analysis tests were applied to examine the association between liver function levels and SSNHL.Results: There were no differences in baseline characteristics between SSNHL and control groups. The albumin (ALB) level of the SSNHL group was significantly lower than that in the control group (p < 0.001). The logistic regression showed that the low ALB level may be a predictive factor of SSNHL with an adjusted OR of 0.809 (95% CI, 0.742–0.882, p < 0.001). By comparing the indicators of different prognosis groups, we found that the effective group had a significantly lower hearing impair onset and higher ALB (p = 0.001) and AGR (p = 0.003) levels than the ineffective group. Logistic regression revealed that the hearing level onset (OR, 0.976; 95% CI, 0.956–0.997; p = 0.026) and ALB level (OR, 1.181; 95% CI, 1.071–1.301; p = 0.001) showed strong associations with treatment outcome.Conclusions: Lower ALB levels, within the normal ranges, were associated with the occurrence and unfavorable outcome of SSNHL. However, further research on the underlying mechanisms needs to be conducted.

Objectives: Sudden sensorineural hearing loss (SSNHL) is a common otological emergency, causing a measure of hearing loss and affecting the quality of life. This study aims to investigate the association of thyroid-related hormone levels with moderately severe-to-profound SSNHL.Methods: The study included 70 patients with moderately severe-to-profound SSNHL and 100 age- and sex-matched healthy controls. Peripheral venous blood samples were taken from the participants, and their thyroid-related hormone levels were measured at admission and 1 week after treatment.Results: In moderately severe-to-profound SSNaHL patients, the concentrations of total triiodothyronine (TT3), total thyroxine (TT4), free triiodothyronine (FT3), and thyroid-stimulating hormone (TSH) (all P < 0.05) were significantly lower than in the control group. The TT3, TT4, FT3, and TSH levels were significantly higher in the effective group than in the ineffective group (all P < 0.05). Linear correlation analysis revealed that TSH level (R = 0.707, P < 0.05) elevation after treatment successfully predicted a favorable outcome of hearing recovery. Logistic regression analyses suggested low FT3 and TSH levels to be independent occurrence predictors, while the increase of TSH level may be an independent favorable outcome predictor.Conclusions: The results suggest that low FT3 and TSH levels are risk factors for moderately severe-to-profound SSNHL. By discovering the positive association between TSH elevation and hearing recovery, along with the potential novel predictors of FT3 and TSH, our study may contribute valuable insights to the research and treatment of moderately severe-to-profound SSNHL.

Ferroptosis is a form of cell death induced by excess iron and accumulation of reactive oxygen species in cells. Recently, ferroptosis has been reported to be associated with cancer and ischemia/reperfusion (I/R) injury in multiple organs. However, the regulatory effects and underlying mechanisms of myocardial I/R injury are not well-understood. The role of miR-135b-3p as an oncogene that accelerates tumor development has been confirmed; however, its role in myocardial I/R is not fully understood. In this study, we established an in vivo myocardial I/R rat model and an in vitro hypoxia/reoxygenation (H/R)-induced H9C2 cardiomyocyte injury model and observed that ferroptosis occurred in tissues and cells during I/R myocardial injury. We used database analysis to find miR-135b-3p and validated its inhibitory effect on the ferroptosis-related gene glutathione peroxidase 4 (Gpx4), using a luciferase reporter assay. Furthermore, miR-135b-3p was found to promote the myocardial I/R injury by downregulating GPX4 expression. The results of this study elucidate a novel function of miR-135b-3p in exacerbating cardiomyocyte ferroptosis, providing a new therapeutic target for improving I/R injury.

Neuroinflammation is a key pathological factor in numerous neurological disorders. Cumulating evidence has indicated critical roles of NAD+/NADH metabolism in multiple major diseases, while the role of malate-aspartate shuttle (MAS) - a major NADH shuttle - in inflammation has remained unclear. In this study we investigated the roles of MAS in LPS-induced neuroinflammation both in vivo and in vitro. Immunofluorescence staining, Western blot assay and Real-time PCR assays were conducted to determine the activation of Iba-1, the protein levels of iNOS and COX2 and the mRNA levels of IL-1β, IL-6, and TNF-α in vivo, showing that both pre-treatment and post-treatment of aminooxyacetic acid (AOAA) - an MAS inhibitor - profoundly decreased the LPS-induced neuroinflammation in mice. BV2 microglia was also used as a cellular model to investigate the mechanisms of this finding, in which such assays as Western blot assay and nitrite assay. Our study further indicated that AOAA produced its effects on LPS-induced microglial activation by its effects on MAS: Pyruvate treatment reversed the effects of AOAA on the cytosolic NAD+/NADH ratio, which also restored the LPS-induced activation of the AOAA-treated microglia. Moreover, the lactate dehydrogenase (LDH) inhibitor GSK2837808A blocked the effects of pyruvate on the AOAA-produced decreases in both the cytosolic NAD+/NADH ratio and LPS-induced microglial activation. Our study has further suggested that AOAA produced inhibition of LPS-induced microglial activation at least partially by decreasing STAT3 phosphorylation. Collectively, our findings have indicated AOAA as a new and effective drug for inhibiting LPS-induced neuroinflammation. Our study has also indicated that MAS is a novel mediator of LPS-induced neuroinflammation due to its capacity to modulate LPS-induced STAT3 phosphorylation, which has further highlighted a critical role of NAD+/NADH metabolism in inflammation.

Aiming at solving the problems of limited training data, single input information, and limited diagnostic accuracy under the influence of strong background noise in fault diagnosis of rotating machinery, this paper proposes a fault diagnosis method based on the combination of discriminant correlation analysis (DCA) and convolutional neural network (CNN). Firstly, the original vibration signal is divided into several segments in the time domain, and the training data is directly processed by one CNN branch to extract multi-scale time domain features. Simultaneously, the divided data is subjected to discrete wavelet transform (DWT), and processed by another branch of CNN to extract multi-scale time-frequency features. Then, the DCA feature fusion mechanism is adopted to fuse the two-domain features extracted in the parallel branches to improve the model' detection ability. Finally, the fused features are input into the deep CNN for training and learning to extract new features and output the classification results. Through the experimental analysis of two different types of data, the results show that the proposed method can be used for fault diagnosis of rotating machinery effectively. Compared with the single CNN network, the proposed method combines the multi-domain multi-scale feature extraction module with the DCA feature fusion module to enrich the feature information extraction ability. At the same time, the network performance is improved to get higher fault classification accuracy higher. [ABSTRACT FROM AUTHOR]

Abstract. Zebrafish have the potential to regrow injured organs and tissues, but their use as a model for hearing regeneration following blast injury has never been reported. In this study, zebrafish were exposed to a blast wave produced by an underwater blast wave generator. The first peak sound pressures produced by this generator were up to 224 dB and 160kPa, measured at 25 cm away from the machine. Zebrafish hearing sensitivity was examined by analyzing auditory evoked potentials from 1 to 35 days post blast wave exposure. Cell death and cell proliferation in inner ear organs, including the saccule, lagena, and utricle, were investigated using a terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assay, and cell proliferation assay using 5-ethynyl-2′-deoxyuridine, respectively. Significant differences in auditory evoked potential thresholds were observed between exposed and control groups, demonstrating both blast wave-induced hearing loss and recovery of hearing sensitivity. An apoptosis assay revealed significantly increased numbers of terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling-positive cells in the inner ear sensory epithelia of exposed groups compared with the control group. However, numbers of 5-ethynyl-2′-deoxyuridine-positive cells in the inner ear of exposed groups recovered to a normal level within 10 post blast wave exposure. Furthermore, blast wave exposure caused brain injury with increased cell apoptosis and decreased neurogenesis. Compared with drug or noise-induced zebrafish models, our blast wave-induced model elicited more serious hearing loss phenotypes, which required more time to return to a normal level. Overall, this zebrafish model can provide a reliable animal model for both hearing loss and regeneration research. The study was approved by the Shanghai 6th Hospital Animal Care and Use Committee, China (approval No. 2017-0196) on February 28, 2017.

It has been evidenced that the neural motor control exploits the hierarchical and intermittent representation. In this paper, we propose a hierarchical deep reinforcement learning (DRL) method to learn the continuous control policy across multiple levels, by unifying the neuroscience principle of the minimum transition hypothesis. The control policies in the two levels of the hierarchy operate at different time scales. The high-level controller produces the intermittent actions to set a sequence of goals for the low-level controller, which in turn conducts the basic skills with the modulation of goals. The goal planning and the basic motor skills are trained jointly with the proposed algorithm: hierarchical intermittent deep deterministic policy gradient (HI-DDPG). The performance of the method is validated in two continuous control problems. The results show that the method successfully learns to temporally decompose compound tasks into sequences of basic motions with sparse transitions and outperforms the previous DRL methods that lack a hierarchical continuous representation.

Cisplatin, a widely used anticancer drug, damages hair cells in cochlear organotypic cultures at low doses, but paradoxically causes little damage at high doses resulting in a U-shaped dose-response function. To determine if the cisplatin dose-response function for vestibular hair cells follows a similar pattern, we treated vestibular organotypic cultures with doses of cisplatin ranging from 10 to 1000 μM. Vestibular hair cell lesions progressively increased as the dose of cisplatin increased with maximum damage occurring around 50–100 μM, but the lesions progressively decreased at higher doses resulting in little hair cell loss at 1000 μM. The U-shaped dose-response function for cisplatin-treated vestibular hair cells in culture appears to be regulated by copper transporters, Ctr1, ATP7A and ATP7B, that dose-dependently regulate the uptake, sequestration and extrusion of cisplatin. Keywords: Cisplatin, Ototoxicity, Copper transporters, Vestibular organotypic cultures

Dentin dysplasia (DD) and dentinogenesis imperfecta (DGI) patients have abnormal structure, morphology, and function of dentin. DD-II, DGI-II, and DGI-III are caused by heterozygous mutations in the dentin sialophosphoprotein (DSPP) gene in humans. Evidences have shown that loss of function of DSPP in Dspp knockout mice leads to phenotypes similar to DGI-III, and that the abnormal dentinogenesis is associated with decreased levels of DSPP, indicating that DSPP haploinsufficiency may play a role in dentinogenesis. Thus, to testify the haploinsufficiency of Dspp, we used a Dspp heterozygous mouse model to observe the phenotypes in the teeth and the surrounding tissues. We found that Dspp heterozygous mice displayed dentin phenotypes similar to DD-II at the ages of 12 and 18 months, which was characterized by excessive attrition of the enamel at the occlusal surfaces, thicker floor dentin of the pulp chamber, decreased pulp volume, and compromised mineralization of the dentin. In addition, the periodontium was also affected, exhibiting apical proliferation of the junctional epithelium, decreased height and width of the alveolar bone, and infiltration of the inflammatory cells, leading to the destruction of the periodontium. Both the dental and periodontal phenotypes were age-dependent, which were more severe at 18 months old than those at 12 months old. Our report is the first to claim the haploinsufficiency of Dspp gene and a DD-II mouse model, which can be further used to study the molecular mechanisms of DD-II.