Inhibition of the NLRP3 inflammasome attenuates spiral ganglion neuron degeneration in aminoglycoside-induced hearing loss

Aminoglycosides are a widely used class of antibacterials renowned for their effectiveness and broad antimicrobial spectrum.However,their use leads to irreversible hearing damage by causing apoptosis of hair cells as their direct target.In addition,the hearing damage caused by aminoglycosides involves damage of spiral ganglion neurons upon exposure.To investigate the mechanisms underlying spiral ganglion neuron degeneration induced by aminoglycosides,we used a C57BL/6J mouse model treated with kanamycin.We found that the mice exhibited auditory deficits following the acute loss of outer hair cells.Spiral ganglion neurons displayed hallmarks of pyroptosis and exhibited progressive degeneration over time.Transcriptomic profiling of these neurons showed significant upregulation of genes associated with inflammation and immune response,particularly those related to the NLRP3 inflammasome.Activation of the canonical pyroptotic pathway in spiral ganglion neurons was observed,accompanied by infiltration of macrophages and the release of proinflammatory cytokines.Pharmacological intervention targeting NLRP3 using Mcc950 and genetic intervention using NLRP3 knockout ameliorated spiral ganglion neuron degeneration in the injury model.These findings suggest that NLRP3 inflammasome-mediated pyroptosis plays a role in aminoglycoside-induced spiral ganglion neuron degeneration.Inhibition of this pathway may offer a potential therapeutic strategy for treating sensorineural hearing loss by reducing spiral ganglion neuron degeneration.

Evaluating foot reflexology as a proposed treatment for sensorineural hearing loss:A critical review

This editorial critically evaluates the application of foot reflexology as a treatment for sensorineural hearing loss(SNHL)in infants,as proposed in a case report published in the World of Clinical Cases.SNHL is a condition characterized by damage to the cochlea or the neural pathways that transmit auditory information to the brain.The etiology of SNHL is often complex,involving genetic mutations,prenatal factors,or perinatal insults.Reflexology,an alternative therapy involving the application of pressure to specific points on the feet,is based on the hypothesis that these points correspond to different organs and systems in the body,including the auditory system.However,the biological plausibility and clinical efficacy of foot reflexology in addressing SNHL lack empirical support.This editorial examines the pathophysiology of SNHL,assesses the clinical claims of reflexology practitioners,and emphasizes the necessity of evidence-based approaches in treating infant hearing loss.While complementary therapies may provide ancillary benefits,they should not supplant validated medical treatments in managing SNHL in infants.Further research is needed to evaluate the safety and efficacy of foot reflexology and other alternative therapies in pediatric audiology.

Acquired sensorineural hearing loss,oxidative stress,and microRNAs

Hearing loss is the third leading cause of human disability.Age-related hearing loss,one type of acquired sensorineural hearing loss,is largely responsible for this escalating global health burden.Noise-induced,ototoxic,and idiopathic sudden sensorineural are other less common types of acquired hearing loss.The etiology of these conditions is complex and multi-fa ctorial involving an interplay of genetic and environmental factors.Oxidative stress has recently been proposed as a likely linking cause in most types of acquired sensorineural hearing loss.Short non-coding RNA sequences known as microRNAs(miRNAs)have increasingly been shown to play a role in cellular hypoxia and oxidative stress responses including promoting an apoptotic response.Sensory hair cell death is a central histopathological finding in sensorineural hearing loss.As these cells do not regenerate in humans,it underlies the irreversibility of human age-related hearing loss.Ovid EMBASE,Ovid MEDLINE,Web of Science Core Collection,and ClinicalTrials.gov databases over the period August 1,2018 to July 31,2023 were searched with"hearing loss,""hypoxamiRs,""hypoxia,""microRNAs,""ischemia,"and"oxidative stress"text words for English language primary study publications or registered clinical trials.Registe red clinical trials known to the senior author we re also assessed.A total of 222studies were thus identified.After excluding duplicates,editorials,retra ctions,secondary research studies,and non-English language articles,39 primary studies and clinical trials underwent full-text screening.This resulted in 11 animal,in vitro,and/or human subject journal articles and 8 registered clinical trial database entries which form the basis of this narrative review.MiRNAs miR-34a and miR-29b levels increase with age in mice.These miRNAs were demonstrated in human neuroblastoma and murine cochlear cell lines to target Sirtuin 1/peroxisome proliferato r-activated receptor gamma coactivator-1-alpha(SIRT1/P GC-1α),SIRT1p53,and SIRT1/hypoxia-inducible factor 1-alpha signaling pathways resulting in increased apoptosis.Furthermore,hypoxia and oxidative stress had a similar adve rse apoptotic effect,which was inhibited by resve ratrol and a myocardial inhibitorassociated transcript,a miR-29b competing endogenous mRNA.Gentamicin reduced miR-182-5p levels and increased cochlear oxidative stress and cell death in mice-an effect that was corrected by inner ear stem cell-derived exosomes.There is ongoing work seeking to determine if these findings can be effectively translated to humans.

Induced neural stem cells regulate microglial activation through Akt-mediated upregulation of CXCR4 and Crry in a mouse model of closed head injury

Microglial activation that occurs rapidly after closed head injury may play important and complex roles in neuroinflammation-associated neuronal damage and repair.We previously reported that induced neural stem cells can modulate the behavior of activated microglia via CXCL12/CXCR4 signaling,influencing their activation such that they can promote neurological recovery.However,the mechanism of CXCR4 upregulation in induced neural stem cells remains unclear.In this study,we found that nuclear factor-κB activation induced by closed head injury mouse serum in microglia promoted CXCL12 and tumor necrosis factor-αexpression but suppressed insulin-like growth factor-1 expression.However,recombinant complement receptor 2-conjugated Crry(CR2-Crry)reduced the effects of closed head injury mouse serum-induced nuclear factor-κB activation in microglia and the levels of activated microglia,CXCL12,and tumor necrosis factor-α.Additionally,we observed that,in response to stimulation(including stimulation by CXCL12 secreted by activated microglia),CXCR4 and Crry levels can be upregulated in induced neural stem cells via the interplay among CXCL12/CXCR4,Crry,and Akt signaling to modulate microglial activation.In agreement with these in vitro experimental results,we found that Akt activation enhanced the immunoregulatory effects of induced neural stem cell grafts on microglial activation,leading to the promotion of neurological recovery via insulin-like growth factor-1 secretion and the neuroprotective effects of induced neural stem cell grafts through CXCR4 and Crry upregulation in the injured cortices of closed head injury mice.Notably,these beneficial effects of Akt activation in induced neural stem cells were positively correlated with the therapeutic effects of induced neural stem cells on neuronal injury,cerebral edema,and neurological disorders post–closed head injury.In conclusion,our findings reveal that Akt activation may enhance the immunoregulatory effects of induced neural stem cells on microglial activation via upregulation of CXCR4 and Crry,thereby promoting induced neural stem cell–mediated improvement of neuronal injury,cerebral edema,and neurological disorders following closed head injury.

Is it possible to foot reflexology for infants with sensorineural hearing loss?

Foot reflexology is a non-invasive and safe complementary therapy that works by massaging the reflex zones of the feet and exerts systemic or whole-body regulation through meridian nerve conduction.This therapy is commonly used in the treatment of various conditions such as autism and Parkinson's disease.However,there is limited reporting on the use of foot reflexology therapy for infants with sensorineural hearing loss(SNHL).Currently,there is no definitive conclusion on how foot reflexology therapy can influence hearing.This editorial holds some guiding significance regarding this clinical issue.The aim is to present physiological evidence of how foot reflexology therapy can impact infants with SNHL,thereby enhancing clinician’s awareness of foot reflexology in treating infants with SNHL.

Restless head syndrome:A retrospective study

BACKGROUND Restless legs syndrome(RLS)is characterized by an urge to move with an unpleasant sensation in the lower limbs.RLS typically affects the legs.However,it can also affect several other body regions,such as the arms,abdomen,face,neck,head,and genital area.There are only a few reports of the RLS variant affecting the head.AIM To assess the epidemiological,clinical,and other aspects of the RLS variant affecting the head.METHODS We conducted a retrospective study of 17 adult patients(>18 years)who met the RLS criteria and simultaneously experienced RLS-like symptoms in the head.RESULTS The median age at which symptoms appeared was 41.6 years.Males and females were equally affected(1.1:1).All 17 patients had uncomfortable sensations in the lower legs.Insomnia or disturbed sleep was the most common comorbidity(n=16,88.2%).However,headache was the most common presenting or primary symptom(n=10,70.5%).Dizziness or an abnormal sensation in the head was the second most common presenting symptom(5 patients,29.4%).Other presenting features were leg pain,backache,and generalized body pain.All patients responded favorably to dopaminergic medications.CONCLUSION If RLS-related unpleasant sensations and pain are felt in the head,they may be misinterpreted as headache,dizziness,or psychosomatic symptoms.RLS and headaches in a subset of patients may be two phenotypic manifestations of the same disorder.

Tranylcypromine upregulates Sestrin 2 expression to ameliorate NLRP3-related noise-induced hearing loss

Noise-induced hearing loss is the primary non-genetic factor contributing to auditory dysfunction.However,there are currently no effective pharmacological interventions for patients with noise-induced hearing loss.Here,we present evidence suggesting that the lysine-specific demethylase 1 inhibitor–tranylcypromine is an otoprotective agent that could be used to treat noise-induced hearing loss,and elucidate its underlying regulatory mechanisms.We established a mouse model of permanent threshold shift hearing loss by exposing the mice to white broadband noise at a sound pressure level of 120 d B for 4 hours.We found that tranylcypromine treatment led to the upregulation of Sestrin2(SESN2)and activation of the autophagy markers light chain 3B and lysosome-associated membrane glycoprotein 1 in the cochleae of mice treated with tranylcypromine.The noise exposure group treated with tranylcypromine showed significantly lower average auditory brainstem response hearing thresholds at click,4,8,and 16 k Hz frequencies compared with the noise exposure group treated with saline.These findings indicate that tranylcypromine treatment resulted in increased SESN2,light chain 3B,and lysosome-associated membrane glycoprotein 1 expression after noise exposure,leading to a reduction in levels of 4-hydroxynonenal and cleaved caspase-3,thereby reducing noise-induced hair cell loss.Additionally,immunoblot analysis demonstrated that treatment with tranylcypromine upregulated SESN2 expression via the autophagy pathway.Tranylcypromine treatment also reduced the production of NOD-like receptor family pyrin domaincontaining 3(NLRP3)production.In conclusion,our results showed that tranylcypromine treatment ameliorated cochlear inflammation by promoting the expression of SESN2,which induced autophagy,thereby restricting NLRP3-related inflammasome signaling,alleviating cochlear hair cell loss,and protecting hearing function.These findings suggest that inhibiting lysine-specific demethylase 1 is a potential therapeutic strategy for preventing hair cell loss and noise-induced hearing loss.

基于Focal Loss改进LightGBM的供水管网毛刺数据检测

针对数据不平衡导致的管网毛刺数据检测召回率偏低问题,提出一种Focal Loss改进LightGBM的管网毛刺数据检测方法。首先,结合管网毛刺数据的特点,针对性构造邻域相关特征。其次,将Focal Loss函数引入LightGBM,提高模型对难以检测的毛刺样本的权重,并对Focal Loss不同的参数取值进行实验,以平衡精确率与召回率。最后,选择不同参数的Focal Loss进行模型融合,进一步提升模型对不平衡毛刺数据的检测性能。在某市供水管网的真实数据上进行实验,结果表明,对比基于交叉熵损失函数的单一模型,本文提出的Focal Loss改进后的融合模型在毛刺数据上召回率和F1值的提升幅度达33.3和18个百分点,但毛刺数据的精确率还有待进一步提升。本文所提方法从损失函数入手,动态调整难易样本的权重,有效地提升了不平衡数据下的毛刺数据的检测性能。

Cross influence of discharge and circulation on head loss of conduit of pump system with low head

The relationship between the head loss and the discharge and circulation of the conduit of a pump system with low head is an important problem with an obvious influence on the improvement of its hydraulic performance. The velocity circulation from the pump guide vane makes the relationship more complicated, which has to be understood comprehensively. The results indicate that, under the condition of zero circulation, the head loss of the inlet and outlet conduits is in proportion to the square of discharge. Under the condition that the Reynolds number is satisfied with the resistant square area, the conduit loss is in proportion to the square of discharge for the similar working points with different speeds in a certain rotational speed range, indicating that the pump system efficiency is constant. The outlet conduit loss of design discharge for a pump system with low head depends on the velocity circulation from the guide vane exit, and the relationship between the loss and the circulation is an open curve with an upward direction, meaning that there is an optimal circulation for the loss. Under the condition of various working points for a pump system with low head, the head loss of the outlet conduit is under the cross influence of both the discharge and the circulation. As a result, the relationship between the head loss and the discharge is almost linear, and the mechanism needs to be further studied.

Evaluation of “C” Values to Head Loss and Water Pressure Due to Pipe Aging: Case Study of Uni-Central Sarawak

Samarahan has transformed from a small village into education hub for the past 2 decades. Rapid development and population growth had led to speedy growth in water demand. The situation is getting worse as the pipes are deteriorating due to pipe aging. Therefore, there is a need to study the adequacy of water supply and relationships among roughness coefficient (C) values in Hazen Williams’ Equation with head loss and water pressure due to pipe aging at Uni-Central, a residential area located at Samarahan Sarawak. Investigations were carried out with Ductile Iron, Abestos Cement and Cast Iron pipes at age categories of 0 - 10 years, 10 - 30 years, 30 - 50 years, 50 - 70 years and >70 years. Six critical nodes named as A, B, C, D, E and F were identified to study the water pressure and head loss. Model was developed with InfoWorks Water Supply (WS) Pro software. The impact of pipe aging and materials to water pressure and head loss was not significant at Nodes A, B, C and F. However, max water pressure at Nodes D and F were only reaching 6.30 m and 7.30 m, respectively for all investigations. Therefore, some improvement works are required. Results also show that Asbestos Cement pipe has the least impact on the head loss and water pressure, followed by Ductile Iron pipe and lastly Cast Iron pipe. Simulation results also revealed that older pipes have higher roughness coefficients, indicated with lower “C” values, thus increase the head loss and reduce the water pressure. In contrast, as “C” values increased, head loss will be reduced and water pressure will be increased.

Experimental and numerical investigation of groundwater head losses on and nearby short intersections between disc-shaped fractures

Discrete fracture models are used for investigating precise processes of groundwater flow in fractured rocks,while a disc-shaped parallel-plates model for a single fracture is more reasonable and efficient for computational treatments.The flow velocity has a large spatial differentiation which is more likely to produce non-linear flow and additional head losses on and nearby intersections in such shaped fractures,therefore it is necessary to understand and quantify them.In this study,both laboratory experiments and numerical simulations were performed to investigate the total head loss on and nearby the intersections as well as the local head loss exactly on the intersections,which were not usually paid sufficient attention or even ignored.The investigation results show that these two losses account for 29.17%-84.97%and 0-73.57%of the entire total head loss in a fracture,respectively.As a result,they should be necessarily considered for groundwater modeling in fractured rocks.Furthermore,both head losses become larger when aperture and flow rate increase and intersection length decreases.Particularly,the ratios of these two head losses to the entire total head loss in a fracture could be well statistically explained by power regression equations with variables of aperture,intersection length,and flow rates,both of which achieved high coefficients of determination.It could be feasible through this type of study to provide a way on how to adjust the groundwater head from those obtained by numerical simulations based on the traditional linear flow model.Finally,it is practicable and effective to implement the investigation approach combining laboratory experiments with numerical simulations for quantifying the head losses on and nearby the intersections between disc-shaped fractures.

Thermodynamic Head Loss in a Channel with Combined Radiation and Convection Heat Transfer

Losses in channel flows are usually determined using a frictional head loss parameter. Fluid friction is however not the only source of loss in channel flows with heat transfer. For such flow problems, thermal energy degradation, in addition to mechanical energy degradation, add to the total loss in thermodynamic head. To assess the total loss in a channel with combined convection and radiation heat transfer, the conventional frictional head loss parameter is extended in this study. The analysis is applied to a 3D turbulent channel flow and identifies the critical locations in the flow domain where the losses are concentrated. The influence of Boltzmann number is discussed, and the best channel geometry for flows with combined heat transfer modes is also determined.

A Value Engineering Analysis of Head Loss in Pumping Mains

With net zero carbon emissions targets approaching over the next 20 to 30 years, the water industry must act now to develop energy efficient techniques and designs to reduce emissions and reduce the carbon footprint of water utility providers. There is also the potential for significant energy and therefore financial savings to be realised from the adoption of more energy efficient designs approaches. Water utility providers account for a significant proportion of national electricity consumption. The purpose of this research is to determine if, over the long term, opting for a larger diameter pipe at design stage can lead to significant financial and emissions savings for water utility providers when considering pumping mains. Pumping mains are widely used throughout the water and wastewater industry where a gravity solution is not possible. 72 hypothetical water main design scenarios were analysed and the long term financial and environmental impact of each hypothetical water main was assessed. It was found across all design scenarios that larger diameter water mains were capable of delivering the same rate of flow of smaller diameter pipes at a much reduced velocity and requiring reduced pumping power. It was concluded that pumped mains of larger diameters can ultimately be more energy efficient and cost effective over the long term when selected in favour of smaller diameter pumped mains in otherwise identical design scenarios.

A Practical Speed Loss Prediction Model at Arbitrary Wave Heading for Ship Voyage Optimization

This paper proposes a semi-empirical model to predict a ship’s speed loss at arbitrary wave heading.In the model,the formulas that estimate a ship’s added resistance due to waves attacking from different heading angles have been further developed.A correction factor is proposed to consider the nonlinear effect due to large waves in power estimation.The formulas are developed and verified by model tests of 5 ships in regular waves with various heading angles.The full-scale measurements from three different types of ships,i.e.,a PCTC,a container ship,and a chemical tanker,are used to validate the proposed model for speed loss prediction in irregular waves.The effect of the improved model for speed loss prediction on a ship’s voyage optimization is also investigated.The results indicate that a ship’s voyage optimization solutions can be significantly affected by the prediction accuracy of speed loss caused by waves.

Loss of Resistance to <i>Nilaparvata lugens</i>May Be Due to the Low-Level Expression of <i>BPH32 </i>in Rice Panicles at the Heading Stage

The brown planthopper (BPH), Nilaparvata lugens (St&#229;l), is the most important insect pest of rice in Asia. Host plant resistance is one of the strategies currently used to control BPH. The resistant rice cultivar Rathu Heenati (RH) carrying the BPH3 gene (recently renamed as “BPH32”) remains effective despite more than 30 years of deployment. RH has been determined to be resistant against BPH at all growth stages. However, we observed that BPH could feed on panicles but not on the leaf sheaths of RH. The resistance gene BPH32 was introduced into KDML105 through marker-assisted selection, and the introgression line UBN03078 was developed. This rice line was used to observe the patterns of target gene’s regulation. A low-level expression of BPH32 on panicles has been hypothesized to cause susceptibility in UBN03078 at the heading stage. Findings from our gene expression analysis support the hypothesis that the resistance gene was down regulated in the uppermost internodes compared with the leaf sheaths of the heading rice plant. This phenomenon may allow BPH to feed on the panicles of the resistant plants, but this requires further investigation.

融合MacBERT和Talking⁃Heads Attention实体关系联合抽取模型

针对现有的医学文本关系抽取任务模型在训练过程中存在语义理解能力不足,可能导致关系抽取的效果不尽人意的问题,文中提出一种融合MacBERT和Talking⁃Heads Attention的实体关系联合抽取模型。该模型首先利用MacBERT语言模型来获取动态字向量表达,MacBERT作为改进的BERT模型,能够减少预训练和微调阶段之间的差异,从而提高模型的泛化能力;然后,将这些动态字向量表达输入到双向门控循环单元(BiGRU)中,以便提取文本的上下文特征。BiGRU是一种改进的循环神经网络(RNN),具有更好的长期依赖捕获能力。在获取文本上下文特征之后,使用Talking⁃Heads Attention来获取全局特征。Talking⁃Heads Attention是一种自注意力机制,可以捕获文本中不同位置之间的关系,从而提高关系抽取的准确性。实验结果表明,与实体关系联合抽取模型GRTE相比,该模型F1值提升1%,precision值提升0.4%,recall值提升1.5%。

Effect of foot reflexology on an infant with sensorineural hearing loss:A case report

BACKGROUND Our study contributes to the further understanding of the mechanism of foot reflexology.Foot reflexology has been reported to affect hearing recovery,but no physiological evidence has been provided.This lack of evidence hampers the acceptance of the technique in clinical practice.CASE SUMMARY A girl was taken to North Sichuan Medical University Affiliated Hospital for a hearing screen by her parents.Her parents reported that her hearing level was the same as when she was born.The girl was diagnosed with sensorineural hearing loss(SNHL)by a doctor in the otolaryngology department.After we introduced the foot reflexology project,the parents agreed to participate in the experiment.After 6 months of foot reflexology treatment,the hearing threshold of the girl recovered to a normal level,below 30 dB.CONCLUSION Foot reflexology should be encouraged in clinical practice and for families of infants with SNHL.

Long non-coding RNA H19 regulates neurogenesis of induced neural stem cells in a mouse model of closed head injury

Stem cell-based therapies have been proposed as a potential treatment for neural regeneration following closed head injury.We previously reported that induced neural stem cells exert beneficial effects on neural regeneration via cell replacement.However,the neural regeneration efficiency of induced neural stem cells remains limited.In this study,we explored differentially expressed genes and long non-coding RNAs to clarify the mechanism underlying the neurogenesis of induced neural stem cells.We found that H19 was the most downregulated neurogenesis-associated lnc RNA in induced neural stem cells compared with induced pluripotent stem cells.Additionally,we demonstrated that H19 levels in induced neural stem cells were markedly lower than those in induced pluripotent stem cells and were substantially higher than those in induced neural stem cell-derived neurons.We predicted the target genes of H19 and discovered that H19 directly interacts with mi R-325-3p,which directly interacts with Ctbp2 in induced pluripotent stem cells and induced neural stem cells.Silencing H19 or Ctbp2 impaired induced neural stem cell proliferation,and mi R-325-3p suppression restored the effect of H19 inhibition but not the effect of Ctbp2 inhibition.Furthermore,H19 silencing substantially promoted the neural differentiation of induced neural stem cells and did not induce apoptosis of induced neural stem cells.Notably,silencing H19 in induced neural stem cell grafts markedly accelerated the neurological recovery of closed head injury mice.Our results reveal that H19 regulates the neurogenesis of induced neural stem cells.H19 inhibition may promote the neural differentiation of induced neural stem cells,which is closely associated with neurological recovery following closed head injury.

A crosstalk-free dual-mode sweat sensing system for naked-eye sweat loss quantification via changes in structural reflectance

Sweat loss monitoring is important for understanding the body’s thermoregulation and hydration status,as well as for comprehensive sweat analysis.Despite recent advances,developing a low-cost,scalable,and universal method for the fabrication of colorimetric microfluidics designed for sweat loss monitoring remains challenging.In this study,we propose a novel laserengraved surface roughening strategy for various flexible substrates.This process permits the construction of microchannels that show distinct structural reflectance changes before and after sweat filling.By leveraging these unique optical properties,we have developed a fully laser-engraved microfluidic device for the quantification of naked-eye sweat loss.This sweat loss sensor is capable of a volume resolution of 0.5µL and a total volume capacity of 11µL,and can be customized to meet different performance requirements.Moreover,we report the development of a crosstalk-free dual-mode sweat microfluidic system that integrates an Ag/AgCl chloride sensor and a matching wireless measurement flexible printed circuit board.This integrated system enables the real-time monitoring of colorimetric sweat loss signals and potential ion concentration signals without crosstalk.Finally,we demonstrate the potential practical use of this microfluidic sweat loss sensor and its integrated system for sports medicine via on-body studies.

Genetically modified pigs:Emerging animal models for hereditary hearing loss

Hereditary hearing loss(HHL),a genetic disorder that impairs auditory function,significantly affects quality of life and incurs substantial economic losses for society.To investigate the underlying causes of HHL and evaluate therapeutic outcomes,appropriate animal models are necessary.Pigs have been extensively used as valuable large animal models in biomedical research.In this review,we highlight the advantages of pig models in terms of ear anatomy,inner ear morphology,and electrophysiological characteristics,as well as recent advancements in the development of distinct genetically modified porcine models of hearing loss.Additionally,we discuss the prospects,challenges,and recommendations regarding the use pig models in HHL research.Overall,this review provides insights and perspectives for future studies on HHL using porcine models.