Steroidal alkaloids are the main active components in many medicinal plants and exhibit diverse biological activities.Axillaridine A(AA)is a newly discovered steroidal alkaloid.However,whether AA could suppress osteoc...Steroidal alkaloids are the main active components in many medicinal plants and exhibit diverse biological activities.Axillaridine A(AA)is a newly discovered steroidal alkaloid.However,whether AA could suppress osteoclastogenesis and alleviate ovariectomy-induced bone loss in mice remains unknown.In vitro,AA significantly suppressed the receptor activator of nuclear factor-κB(NF-κB)ligand(RANKL)-induced osteoclast differentiation via downregulating the expression of osteoclastogenesis-related marker genes,proteins,and transcriptional regulators,including tartrate-resistant acid phosphatase(TRAP),c-Src,matrix metallopeptidase-9(MMP-9),cathepsin K,nuclear factor of activated T cells,cytoplasmic 1(NFATc1),and c-Fos.This was achieved by blocking RANKL-RANK interaction and inhibiting RANKL-mediated RANK signaling pathways,including NF-κB,AKT,and mitogen-activated protein kinases(MAPKs)in osteoclast precursors.In vivo,AA significantly inhibited the ovariectomized(OVX)-induced body weight gain and blood glucose increase in mice.AA did not adversely affect the histomorphologies,weights,and indices of the kidney and liver in OVX mice.AA effectively ameliorated bone loss in OVX mice by inhibiting osteoclastogenesis.AA significantly inhibited the serum levels of tartrate-resistant acid phosphatase 5b(TRACP-5b)and C-telopeptide of type I collagen(CTX-I).AA significantly inhibited the OVX-induced expression of osteoclastogenesis-related marker genes and proteins in the femur.In summary,AA alleviates ovariectomy-induced bone loss in mice by suppressing osteoclastogenesis via inhibition of RANKL-mediated RANK signaling pathways and could be potentially used for the prevention and treatment of osteoclastrelated diseases such as osteoporosis.展开更多
Tinnitus:the hearing of a sound that has not been produced by any external or internal source,is a rather heterogeneous hearing disorder.Background/Objectives:Hearing loss has been shown to be the main risk factor for...Tinnitus:the hearing of a sound that has not been produced by any external or internal source,is a rather heterogeneous hearing disorder.Background/Objectives:Hearing loss has been shown to be the main risk factor for tinnitus while emotional disorders are risk factors for developing intrusive or bothersome tinnitus.Moreover,aging has also been identified as another risk factor.The aim of this paper was to analyse the correlation between hearing loss,age and tinnitus severity in a cohort of 610 tinnitus sufferers.Methods:Age,audiometric(hearing condition)and tinnitus(time duration and severity)data were assessed and analysed for all subjects just after recruiting(baseline).Furthermore,the average hearing loss(HL)curves of the participants for age groups were compared to these with the corresponding Age Related HL(ARHL).Results:For most of the age groups,the measured HL curves exceeded in 10-20 dB those of the ARHL.The average age of tinnitus onset(age minus tinnitus duration)was found to be 44-46 years in both men and women.Weak correlation between audiometric feature and tinnitus distress was observed.Conclusions:Hearing loss has been shown to be a clear risk factor for triggering tinnitus(86%of participants were hearing impaired).In this cohort,average measures of hearing loss showed,at most,weak associations with tinnitus-related distress,suggesting that non-audiological factors may play a predominant role.展开更多
Background:Brucellosis is a zoonotic infection common in Mediterranean countries and the Middle East.Neurological involvement,although rare,can lead to severe complications,including sensorineural hearing loss(SNHL).T...Background:Brucellosis is a zoonotic infection common in Mediterranean countries and the Middle East.Neurological involvement,although rare,can lead to severe complications,including sensorineural hearing loss(SNHL).This case is particularly noteworthy as it highlights irreversible auditory nerve damage in brucellosis,emphasizing the importance of early diagnosis and treatment to prevent permanent neurological consequences.The novelty of this case lies in the severity of auditory involvement despite timely treatment.Case Presentation:A 43-year-old male farmer of Maghrebi origin presented with neurobrucellosis complicated by severe,irreversible bilateral sensorineural hearing loss.The patient initially reported symptoms of hearing loss and dizziness,which were confirmed to be associated with auditory nerve involvement.Wright's serology and polymerase chain reaction(PCR)testing confirmed brucellosis.Despite appropriate and prolonged antibiotic therapy,including drugs that penetrate the meningeal barrier and act intracellularly,the patient's auditory impairment remained permanent.The patient is currently a candidate for cochlear implantation to manage his severe hearing loss.Neurological symptoms did not improve with treatment,but cochlear implantation may offer a potential solution to his hearing deficit.Conclusions:This case highlights the importance of early recognition and intervention in brucellosis cases,particularly those with neurological involvement.Delayed diagnosis and treatment can result in irreversible neurological damage.It also underscores the potential for cochlear implantation in patients with severe,irreversible sensorineural hearing loss caused by neurobrucellosis.Cochlear implantation offers an important solution for patients with brucellosis-related hearing deficits,improving their quality of life despite the neurological damage caused by the infection.展开更多
Objective:To investigate the potential link between chromosomal polymorphisms in couples who had a medical history of idiopathic recurrent pregnancy loss.Methods:Cytogenetic investigation was conducted with mitogen(Ph...Objective:To investigate the potential link between chromosomal polymorphisms in couples who had a medical history of idiopathic recurrent pregnancy loss.Methods:Cytogenetic investigation was conducted with mitogen(Phytohemagglutinin-M,Gibco)stimulated blood T lymphocytes by Giemsa trypsin Giemsa banding and Ag-NOR banding on 580 couples with a history of idiopathic recurrent pregnancy loss and 240 couples from the general population.Thirty good chromosomal spreads were captured,karyotyped,and analyzed.The karyotypes were designated using the International System for Human Cytogenomic Nomenclature 2024.Pearson Chi-square test was used to compare the frequency of chromosomal polymorphism variations in the idiopathic recurrent pregnancy loss group with the general population group.Results:A conventional cytogenetic investigation revealed that 45.43%of couples experiencing idiopathic recurrent pregnancy loss presented with various types of chromosomal polymorphic variants,compared to 11.88%in the general population.The overall frequency of these chromosomal polymorphic variants was significantly higher in the idiopathic recurrent pregnancy loss group compared to the general population group(OR 9.97,95%CI 6.99-14.21;P<0.05).Additionally,the prevalence of polymorphic variants was higher among males(49.14%)than females(41.72%)(P=0.01).Conclusions:Chromosomal polymorphic analysis may play a crucial role in the assessment and careful clinical management of cases with idiopathic recurrent pregnancy loss,especially when no other conclusive reasons are identified during the initial evaluation.Therefore,heteromorphism should not be overlooked while investigating the causes of idiopathic recurrent pregnancy loss.展开更多
The micro-riblet structures have been demonstrated effective in controlling the Total Pressure Loss(TPL)of aero-engine blades.However,due to the considerable scale gap between micro-texture and an actual aero-engine b...The micro-riblet structures have been demonstrated effective in controlling the Total Pressure Loss(TPL)of aero-engine blades.However,due to the considerable scale gap between micro-texture and an actual aero-engine blade,wind tunnel tests and numerical simulations with massive grids directly describing the global flow field are costly for aerodynamic evaluation.Furthermore,the fine micro surface structure brings unavoidable manufacturing errors,and the probability prediction contributes to gaining the confidence interval of the results.Therefore,a novel relay-based probabilistic model for multi-fidelity scenarios in the TPL prediction of a compressor cascade with micro-riblet surfaces is proposed to trade off accuracy and efficiency.Combined with the low-fidelity flow data generated by an aerodynamic solution strategy using the boundary surrogate model and the high-fidelity flow data from the experiment,the relay-based modeling has been achieved through knowledge transferring,and the confidence interval can be provided by the Gaussian Process Regression(GPR)model.The TPL of compressor cascades with micro-riblet surfaces under different surface structures at March number Ma=0.64,0.74,0.84 have been evaluated using the Relay-Based Probabilistic(RBP)model.The results illustrate that the RBP model could provide higher accuracy than the Single-Fidelity-Data-Driven(SFDD)prediction model,which show the promising potential of multi-fidelity scenarios data fusion in the aerodynamic evaluation of multi-scale configurations.展开更多
The lateral transport of labile organic carbon represents a critical pathway for soil organic carbon(SOC) loss,reducing organic carbon sequestration and increasing the risk of waterbody pollution.Livestock manure appl...The lateral transport of labile organic carbon represents a critical pathway for soil organic carbon(SOC) loss,reducing organic carbon sequestration and increasing the risk of waterbody pollution.Livestock manure application on croplands serves as a common fertilizer reduction practice to sustain crop yields,enhance SOC sequestration,and reduce water erosion.However,limited quantitative assessments have examined the effects of livestock manure substitution on labile organic carbon lateral loss and fluxes in long-term experiments.This study conducted a three-year field investigation on subtropical sloping croplands to assess the impact of livestock manure substitution on dissolved organic carbon(DOC) and particulate organic carbon(POC) loss via surface runoff,interflow and eroded sediments.There are four treatments:no fertilization(CK);chemical nitrogen fertilizer(SF),40% nitrogen substitution with pig manure(PMF),and 100% nitrogen substitution from pig manure(PM).Compared to SF treatment,long-term livestock manure substitution in PMF and PM treatments significantly(P<0.05) reduced annual cumulative surface runoff fluxes by 13.5 and 21.6%,respectively.Manure applications decreased annual sediment fluxes by 12.9 and 19.1%,respectively.Soil water stable aggregates for mean weight diameter(MWD) increased significantly by 37.7 and 73.6%.Annual cumulative POC loss flux via eroded sediment under PMF and PM treatments increased significantly(P<0.05) by 61.1 and 47.9%,respectively.The labile organic carbon loss fluxes,including DOC and POC losses,under PMF and PM treatments increased significantly(P<0.05) by 11.9 and 31.4%,respectively.These results demonstrate that while water erosion intensity decreases due to enhanced soil aggregate stability,the risk of labile organic carbon loss increases after long-term livestock manure substitution in subtropical sloping croplands.Future research should examine labile organic carbon lateral migration under various soil types and slope gradients for livestock manure application in subtropical agricultural ecosystem croplands to better understand extreme rainfall effects.展开更多
Highlights OsCAX2 is localized to tonoplast,and cadmium induces its expression.OsCAX2 overexpression reduces cadmium concentration in indica rice grains by 49.1%.Cadmium(Cd)exposure poses significant health risks to h...Highlights OsCAX2 is localized to tonoplast,and cadmium induces its expression.OsCAX2 overexpression reduces cadmium concentration in indica rice grains by 49.1%.Cadmium(Cd)exposure poses significant health risks to humans,and the International Agency for Research on Cancer has classified it as a Group I carcinogen.Cadmium undergoes minimal metabolism in the human body;consequently,prolonged Cd^(2+)exposure can cause severe damage to multiple organs including the liver,kidneys,lungs,bones,and immune system(Shao et al.2024).Rice,one of the three global staple crops,and Cd exposure in humans primarily occurs the consumption of contaminated rice grains.The contribution of rice to the total dietary Cd intake is over 50% for non-smoking Asian populations(Chen et al.2018;Shi et al.2020).展开更多
Amphibious vehicles are more prone to attitude instability compared to ships,making it crucial to develop effective methods for monitoring instability risks.However,large inclination events,which can lead to instabili...Amphibious vehicles are more prone to attitude instability compared to ships,making it crucial to develop effective methods for monitoring instability risks.However,large inclination events,which can lead to instability,occur frequently in both experimental and operational data.This infrequency causes events to be overlooked by existing prediction models,which lack the precision to accurately predict inclination attitudes in amphibious vehicles.To address this gap in predicting attitudes near extreme inclination points,this study introduces a novel loss function,termed generalized extreme value loss.Subsequently,a deep learning model for improved waterborne attitude prediction,termed iInformer,was developed using a Transformer-based approach.During the embedding phase,a text prototype is created based on the vehicle’s operation log data is constructed to help the model better understand the vehicle’s operating environment.Data segmentation techniques are used to highlight local data variation features.Furthermore,to mitigate issues related to poor convergence and slow training speeds caused by the extreme value loss function,a teacher forcing mechanism is integrated into the model,enhancing its convergence capabilities.Experimental results validate the effectiveness of the proposed method,demonstrating its ability to handle data imbalance challenges.Specifically,the model achieves over a 60%improvement in root mean square error under extreme value conditions,with significant improvements observed across additional metrics.展开更多
Guanting Reservoir, one of the drinking water supply sources of Beijing, suffers from water eutrophication. It is mainly supplied by Guishui River. Thus, to investigate the reasons of phosphorus （P） loss and improve...Guanting Reservoir, one of the drinking water supply sources of Beijing, suffers from water eutrophication. It is mainly supplied by Guishui River. Thus, to investigate the reasons of phosphorus （P） loss and improve the P management strategies in Guishui River watershed are important for the safety of drinking water in this region. In this study, a Revised Field P Ranking Scheme （PRS） was developed to reflect the field vulnerability of P loss at the field scale based on the Field PRS. In this new scheme, six factors are included, and each one was assigned a relative weight and a determination method. The affecting factors were classified into transport factors and source factors, and, the standards of environmental quality on surface water and soil erosion classification and degradation of the China were used in this scheme. By the new scheme, thirty-four fields in the Guishui River were categorized as ＂low＂, ＂medium＂ or ＂high＂ potential for P loss into the runoff. The results showed that the P loss risks of orchard and vegetable fields were higher than that of corn and soybean fields. The source factors were the main factors to affect P loss from the study area. In the study area, controlling P input and improving P usage efficiency are critical to decrease P loss. Based on the results, it was suggested that more attention should be paid on the fields of vegetable and orchard since they have extremely high usage rate of P and high soil test of P. Compared with P surplus by field measurements, the Revised Field PRS was more suitable for reflecting the characteristics of fields, and had higher potential capacity to identify critical source areas of P loss than PRS.展开更多
Coping with extreme climate events and its related climatic disasters caused by climate change has become a global issue and drew wide attention from scientists, policy-makers and public. This paper calculated the exp...Coping with extreme climate events and its related climatic disasters caused by climate change has become a global issue and drew wide attention from scientists, policy-makers and public. This paper calculated the expected annual multiple climatic hazards intensity index based on the results of nine climatic hazards including tropical cyclone, flood, landslide, storm surge, sand-dust storm, drought, heat wave, cold wave and wildfire. Then a vulnerability model involving the coping capacity indicator with mortality rate, affected population rate and GDP loss rate, was developed to estimate the expected annual affected population, mortality and GDP loss risks. The results showed that： countries with the highest risks are also the countries with large population or GDP. To substantially reduce the global total climatic hazards risks, these countries should reduce the exposure and improving the governance of integrated climatic risk; Without considering the total exposure, countries with the high mortality rate, affected population rate or GDP loss rate, which also have higher or lower coping capacity, such as the Philippines, Bangladesh and Vietnam, are the hotspots of the planning and strategy making for the climatic disaster risk reduction and should focus on promoting the coping capacity.展开更多
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 ...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.展开更多
Developing effective strategies to regulate graphene’s conduction loss and polarization has become a key to expanding its application in the electromagnetic wave absorption(EMWA)field.Based on the unique energy band ...Developing effective strategies to regulate graphene’s conduction loss and polarization has become a key to expanding its application in the electromagnetic wave absorption(EMWA)field.Based on the unique energy band structure of graphene,regulating its bandgap and electrical properties by introducing heteroatoms is considered a feasible solution.Herein,metal-nitrogen doping reduced graphene oxide(M–N-RGO)was prepared by embedding a series of single metal atoms M–N_(4) sites(M=Mn,Fe,Co,Ni,Cu,Zn,Nb,Cd,and Sn)in RGO using an N-coordination atom-assisted strategy.These composites had adjustable conductivity and polarization to optimize dielectric loss and impedance matching for efficient EMWA performance.The results showed that the minimum reflection loss(RL_(min))of Fe–N-RGO reaches−74.05 dB(2.0 mm)and the maximum effective absorption bandwidth(EAB_(max))is 7.05 GHz(1.89 mm)even with a low filler loading of only 1 wt%.Combined with X-ray absorption spectra(XAFS),atomic force microscopy,and density functional theory calculation analysis,the Fe–N_(4) can be used as the polarization center to increase dipole polarization,interface polarization and defect-induced polarization due to d-p orbital hybridization and structural distortion.Moreover,electron migration within the Fe further leads to conduction loss,thereby synergistically promoting energy attenuation.This study demonstrates the effectiveness of metal-nitrogen doping in regulating the graphene′s dielectric properties,which provides an important basis for further investigation of the loss mechanism.展开更多
The application of organic fertilizers has become an increasingly popular practice in maize production to reduce thegaseous nitrogen(N) loss and soil degradation caused by inorganic fertilizers. Organic fertilizer pla...The application of organic fertilizers has become an increasingly popular practice in maize production to reduce thegaseous nitrogen(N) loss and soil degradation caused by inorganic fertilizers. Organic fertilizer plays a key rolein improving soil quality and stabilizing maize yields, but few studies have compared different substitution rates. Afield study was carried out in 2021 and 2022, based on a long-term trial initiated in 2016, which included five organicfertilizer N substitution rates with equal inputs of 200 kg N ha^(–1): 0% organic fertilizer(T1, 100% inorganic fertilizer),50.0% organic+50.0% inorganic fertilizer(T2), 37.5% organic+62.5% inorganic fertilizer(T3), 25.0% organic+75.0%inorganic fertilizer(T4), and 12.5% organic+87.5% inorganic fertilizer(T5), as well as a no fertilizer control(T6). Theresults of the two years showed that T3 and T1 had the highest grain yield and biomass, respectively, and there wasno significant difference between T1 and T3. Compared with T1, the 12.5, 25.0, 37.5, and 50.0% substitution rates in T5, T4, T3, and T2 significantly reduced total nitrogen losses(NH_(3), N_(2)O) by 8.3, 16.1, 18.7, and 27.0%, respectively.Nitrogen use efficiency(NUE) was higher in T5, T3, and T1, and there were no significant differences among them.Organic fertilizer substitution directly reduced NH_(3)volatilization and N_(2)O emission from farmland by lowering theammonium nitrogen and alkali-dissolved N contents and by increasing soil moisture. These substitution treatmentsreduced N_(2)O emissions indirectly by regulating the abundances of AOB and nirK-harboring genes by promotingsoil moisture. Specifically, the 37.5% organic fertilizer substitution reduces NH_(3)volatilization and N_(2)O emission from farmland by reducing the ammonium nitrogen and alkali-dissolved N contents and increasing moisture, which negatively regulate the abundance of AOB and nir K-harboring genes to reduce N_(2)O emissions indirectly in rainfed maize fields on the Loess Plateau of China.展开更多
Activity cliffs(ACs)are generally defined as pairs of similar compounds that only differ by a minor structural modification but exhibit a large difference in their binding affinity for a given target.ACs offer crucial...Activity cliffs(ACs)are generally defined as pairs of similar compounds that only differ by a minor structural modification but exhibit a large difference in their binding affinity for a given target.ACs offer crucial insights that aid medicinal chemists in optimizing molecular structures.Nonetheless,they also form a major source of prediction error in structure-activity relationship(SAR)models.To date,several studies have demonstrated that deep neural networks based on molecular images or graphs might need to be improved further in predicting the potency of ACs.In this paper,we integrated the triplet loss in face recognition with pre-training strategy to develop a prediction model ACtriplet,tailored for ACs.Through extensive comparison with multiple baseline models on 30 benchmark datasets,the results showed that ACtriplet was significantly better than those deep learning(DL)models without pretraining.In addition,we explored the effect of pre-training on data representation.Finally,the case study demonstrated that our model's interpretability module could explain the prediction results reasonably.In the dilemma that the amount of data could not be increased rapidly,this innovative framework would better make use of the existing data,which would propel the potential of DL in the early stage of drug discovery and optimization.展开更多
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 con...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.展开更多
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,ototox...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.展开更多
基金supported by the grants from the National Natural Science Foundation of China(82404638)the Xingdian Talent Plan of Yunnan Province(XDYC-QNRC-2023-0427 and XDYC-YLXZ2022-0025)the Natural Science Foundation of Yunnan Province(202101BD070001-034,202101BD070001-049,202201AT070267,and 202201AU070183)。
文摘Steroidal alkaloids are the main active components in many medicinal plants and exhibit diverse biological activities.Axillaridine A(AA)is a newly discovered steroidal alkaloid.However,whether AA could suppress osteoclastogenesis and alleviate ovariectomy-induced bone loss in mice remains unknown.In vitro,AA significantly suppressed the receptor activator of nuclear factor-κB(NF-κB)ligand(RANKL)-induced osteoclast differentiation via downregulating the expression of osteoclastogenesis-related marker genes,proteins,and transcriptional regulators,including tartrate-resistant acid phosphatase(TRAP),c-Src,matrix metallopeptidase-9(MMP-9),cathepsin K,nuclear factor of activated T cells,cytoplasmic 1(NFATc1),and c-Fos.This was achieved by blocking RANKL-RANK interaction and inhibiting RANKL-mediated RANK signaling pathways,including NF-κB,AKT,and mitogen-activated protein kinases(MAPKs)in osteoclast precursors.In vivo,AA significantly inhibited the ovariectomized(OVX)-induced body weight gain and blood glucose increase in mice.AA did not adversely affect the histomorphologies,weights,and indices of the kidney and liver in OVX mice.AA effectively ameliorated bone loss in OVX mice by inhibiting osteoclastogenesis.AA significantly inhibited the serum levels of tartrate-resistant acid phosphatase 5b(TRACP-5b)and C-telopeptide of type I collagen(CTX-I).AA significantly inhibited the OVX-induced expression of osteoclastogenesis-related marker genes and proteins in the femur.In summary,AA alleviates ovariectomy-induced bone loss in mice by suppressing osteoclastogenesis via inhibition of RANKL-mediated RANK signaling pathways and could be potentially used for the prevention and treatment of osteoclastrelated diseases such as osteoporosis.
文摘Tinnitus:the hearing of a sound that has not been produced by any external or internal source,is a rather heterogeneous hearing disorder.Background/Objectives:Hearing loss has been shown to be the main risk factor for tinnitus while emotional disorders are risk factors for developing intrusive or bothersome tinnitus.Moreover,aging has also been identified as another risk factor.The aim of this paper was to analyse the correlation between hearing loss,age and tinnitus severity in a cohort of 610 tinnitus sufferers.Methods:Age,audiometric(hearing condition)and tinnitus(time duration and severity)data were assessed and analysed for all subjects just after recruiting(baseline).Furthermore,the average hearing loss(HL)curves of the participants for age groups were compared to these with the corresponding Age Related HL(ARHL).Results:For most of the age groups,the measured HL curves exceeded in 10-20 dB those of the ARHL.The average age of tinnitus onset(age minus tinnitus duration)was found to be 44-46 years in both men and women.Weak correlation between audiometric feature and tinnitus distress was observed.Conclusions:Hearing loss has been shown to be a clear risk factor for triggering tinnitus(86%of participants were hearing impaired).In this cohort,average measures of hearing loss showed,at most,weak associations with tinnitus-related distress,suggesting that non-audiological factors may play a predominant role.
文摘Background:Brucellosis is a zoonotic infection common in Mediterranean countries and the Middle East.Neurological involvement,although rare,can lead to severe complications,including sensorineural hearing loss(SNHL).This case is particularly noteworthy as it highlights irreversible auditory nerve damage in brucellosis,emphasizing the importance of early diagnosis and treatment to prevent permanent neurological consequences.The novelty of this case lies in the severity of auditory involvement despite timely treatment.Case Presentation:A 43-year-old male farmer of Maghrebi origin presented with neurobrucellosis complicated by severe,irreversible bilateral sensorineural hearing loss.The patient initially reported symptoms of hearing loss and dizziness,which were confirmed to be associated with auditory nerve involvement.Wright's serology and polymerase chain reaction(PCR)testing confirmed brucellosis.Despite appropriate and prolonged antibiotic therapy,including drugs that penetrate the meningeal barrier and act intracellularly,the patient's auditory impairment remained permanent.The patient is currently a candidate for cochlear implantation to manage his severe hearing loss.Neurological symptoms did not improve with treatment,but cochlear implantation may offer a potential solution to his hearing deficit.Conclusions:This case highlights the importance of early recognition and intervention in brucellosis cases,particularly those with neurological involvement.Delayed diagnosis and treatment can result in irreversible neurological damage.It also underscores the potential for cochlear implantation in patients with severe,irreversible sensorineural hearing loss caused by neurobrucellosis.Cochlear implantation offers an important solution for patients with brucellosis-related hearing deficits,improving their quality of life despite the neurological damage caused by the infection.
基金funded by the Technology Development Board(TDB)of India's Ministry of Science and Technology(TDB/M-25/2018-19).
文摘Objective:To investigate the potential link between chromosomal polymorphisms in couples who had a medical history of idiopathic recurrent pregnancy loss.Methods:Cytogenetic investigation was conducted with mitogen(Phytohemagglutinin-M,Gibco)stimulated blood T lymphocytes by Giemsa trypsin Giemsa banding and Ag-NOR banding on 580 couples with a history of idiopathic recurrent pregnancy loss and 240 couples from the general population.Thirty good chromosomal spreads were captured,karyotyped,and analyzed.The karyotypes were designated using the International System for Human Cytogenomic Nomenclature 2024.Pearson Chi-square test was used to compare the frequency of chromosomal polymorphism variations in the idiopathic recurrent pregnancy loss group with the general population group.Results:A conventional cytogenetic investigation revealed that 45.43%of couples experiencing idiopathic recurrent pregnancy loss presented with various types of chromosomal polymorphic variants,compared to 11.88%in the general population.The overall frequency of these chromosomal polymorphic variants was significantly higher in the idiopathic recurrent pregnancy loss group compared to the general population group(OR 9.97,95%CI 6.99-14.21;P<0.05).Additionally,the prevalence of polymorphic variants was higher among males(49.14%)than females(41.72%)(P=0.01).Conclusions:Chromosomal polymorphic analysis may play a crucial role in the assessment and careful clinical management of cases with idiopathic recurrent pregnancy loss,especially when no other conclusive reasons are identified during the initial evaluation.Therefore,heteromorphism should not be overlooked while investigating the causes of idiopathic recurrent pregnancy loss.
基金supported by the National Natural Science Foundation of China(No.12301672)the Shanghai Science and Technology Innovation Action Plan(Yangfan Special Project),China(No.23YF1401300)。
文摘The micro-riblet structures have been demonstrated effective in controlling the Total Pressure Loss(TPL)of aero-engine blades.However,due to the considerable scale gap between micro-texture and an actual aero-engine blade,wind tunnel tests and numerical simulations with massive grids directly describing the global flow field are costly for aerodynamic evaluation.Furthermore,the fine micro surface structure brings unavoidable manufacturing errors,and the probability prediction contributes to gaining the confidence interval of the results.Therefore,a novel relay-based probabilistic model for multi-fidelity scenarios in the TPL prediction of a compressor cascade with micro-riblet surfaces is proposed to trade off accuracy and efficiency.Combined with the low-fidelity flow data generated by an aerodynamic solution strategy using the boundary surrogate model and the high-fidelity flow data from the experiment,the relay-based modeling has been achieved through knowledge transferring,and the confidence interval can be provided by the Gaussian Process Regression(GPR)model.The TPL of compressor cascades with micro-riblet surfaces under different surface structures at March number Ma=0.64,0.74,0.84 have been evaluated using the Relay-Based Probabilistic(RBP)model.The results illustrate that the RBP model could provide higher accuracy than the Single-Fidelity-Data-Driven(SFDD)prediction model,which show the promising potential of multi-fidelity scenarios data fusion in the aerodynamic evaluation of multi-scale configurations.
基金funded by the Joint Funds of the National Natural Science Foundation of China (U20A20107 and U22A20562)the National Key Research and Development Program of China (2023YFD1900201-3)the International Cooperation Project,Ministry of Science and Technology of China (G2023019005L)。
文摘The lateral transport of labile organic carbon represents a critical pathway for soil organic carbon(SOC) loss,reducing organic carbon sequestration and increasing the risk of waterbody pollution.Livestock manure application on croplands serves as a common fertilizer reduction practice to sustain crop yields,enhance SOC sequestration,and reduce water erosion.However,limited quantitative assessments have examined the effects of livestock manure substitution on labile organic carbon lateral loss and fluxes in long-term experiments.This study conducted a three-year field investigation on subtropical sloping croplands to assess the impact of livestock manure substitution on dissolved organic carbon(DOC) and particulate organic carbon(POC) loss via surface runoff,interflow and eroded sediments.There are four treatments:no fertilization(CK);chemical nitrogen fertilizer(SF),40% nitrogen substitution with pig manure(PMF),and 100% nitrogen substitution from pig manure(PM).Compared to SF treatment,long-term livestock manure substitution in PMF and PM treatments significantly(P<0.05) reduced annual cumulative surface runoff fluxes by 13.5 and 21.6%,respectively.Manure applications decreased annual sediment fluxes by 12.9 and 19.1%,respectively.Soil water stable aggregates for mean weight diameter(MWD) increased significantly by 37.7 and 73.6%.Annual cumulative POC loss flux via eroded sediment under PMF and PM treatments increased significantly(P<0.05) by 61.1 and 47.9%,respectively.The labile organic carbon loss fluxes,including DOC and POC losses,under PMF and PM treatments increased significantly(P<0.05) by 11.9 and 31.4%,respectively.These results demonstrate that while water erosion intensity decreases due to enhanced soil aggregate stability,the risk of labile organic carbon loss increases after long-term livestock manure substitution in subtropical sloping croplands.Future research should examine labile organic carbon lateral migration under various soil types and slope gradients for livestock manure application in subtropical agricultural ecosystem croplands to better understand extreme rainfall effects.
基金financially supported by the National Key R&D Program of China(2024YFD1200800)the Guangdong Basic and Applied Basic Research Foundation,China(2024A1515030094)。
文摘Highlights OsCAX2 is localized to tonoplast,and cadmium induces its expression.OsCAX2 overexpression reduces cadmium concentration in indica rice grains by 49.1%.Cadmium(Cd)exposure poses significant health risks to humans,and the International Agency for Research on Cancer has classified it as a Group I carcinogen.Cadmium undergoes minimal metabolism in the human body;consequently,prolonged Cd^(2+)exposure can cause severe damage to multiple organs including the liver,kidneys,lungs,bones,and immune system(Shao et al.2024).Rice,one of the three global staple crops,and Cd exposure in humans primarily occurs the consumption of contaminated rice grains.The contribution of rice to the total dietary Cd intake is over 50% for non-smoking Asian populations(Chen et al.2018;Shi et al.2020).
基金Supported by the National Defense Basic Scientific Research Program of China.
文摘Amphibious vehicles are more prone to attitude instability compared to ships,making it crucial to develop effective methods for monitoring instability risks.However,large inclination events,which can lead to instability,occur frequently in both experimental and operational data.This infrequency causes events to be overlooked by existing prediction models,which lack the precision to accurately predict inclination attitudes in amphibious vehicles.To address this gap in predicting attitudes near extreme inclination points,this study introduces a novel loss function,termed generalized extreme value loss.Subsequently,a deep learning model for improved waterborne attitude prediction,termed iInformer,was developed using a Transformer-based approach.During the embedding phase,a text prototype is created based on the vehicle’s operation log data is constructed to help the model better understand the vehicle’s operating environment.Data segmentation techniques are used to highlight local data variation features.Furthermore,to mitigate issues related to poor convergence and slow training speeds caused by the extreme value loss function,a teacher forcing mechanism is integrated into the model,enhancing its convergence capabilities.Experimental results validate the effectiveness of the proposed method,demonstrating its ability to handle data imbalance challenges.Specifically,the model achieves over a 60%improvement in root mean square error under extreme value conditions,with significant improvements observed across additional metrics.
基金Project supported by the National Basic Research Program of China(No.2005CB121107)the Innovation Research Group of National Basic Research Program of China(No.2005).
文摘Guanting Reservoir, one of the drinking water supply sources of Beijing, suffers from water eutrophication. It is mainly supplied by Guishui River. Thus, to investigate the reasons of phosphorus （P） loss and improve the P management strategies in Guishui River watershed are important for the safety of drinking water in this region. In this study, a Revised Field P Ranking Scheme （PRS） was developed to reflect the field vulnerability of P loss at the field scale based on the Field PRS. In this new scheme, six factors are included, and each one was assigned a relative weight and a determination method. The affecting factors were classified into transport factors and source factors, and, the standards of environmental quality on surface water and soil erosion classification and degradation of the China were used in this scheme. By the new scheme, thirty-four fields in the Guishui River were categorized as ＂low＂, ＂medium＂ or ＂high＂ potential for P loss into the runoff. The results showed that the P loss risks of orchard and vegetable fields were higher than that of corn and soybean fields. The source factors were the main factors to affect P loss from the study area. In the study area, controlling P input and improving P usage efficiency are critical to decrease P loss. Based on the results, it was suggested that more attention should be paid on the fields of vegetable and orchard since they have extremely high usage rate of P and high soil test of P. Compared with P surplus by field measurements, the Revised Field PRS was more suitable for reflecting the characteristics of fields, and had higher potential capacity to identify critical source areas of P loss than PRS.
基金The Innovative Research Group Project of National Natural Science Foundation of China,No.41321001The National Basic Research Program(973 Program),No.2012CB955404The Program for Introducing Talents of Disciplines to Universities funded by the Ministry of Education and State Administration of Foreign Experts Affairs,China,No.B08008
文摘Coping with extreme climate events and its related climatic disasters caused by climate change has become a global issue and drew wide attention from scientists, policy-makers and public. This paper calculated the expected annual multiple climatic hazards intensity index based on the results of nine climatic hazards including tropical cyclone, flood, landslide, storm surge, sand-dust storm, drought, heat wave, cold wave and wildfire. Then a vulnerability model involving the coping capacity indicator with mortality rate, affected population rate and GDP loss rate, was developed to estimate the expected annual affected population, mortality and GDP loss risks. The results showed that： countries with the highest risks are also the countries with large population or GDP. To substantially reduce the global total climatic hazards risks, these countries should reduce the exposure and improving the governance of integrated climatic risk; Without considering the total exposure, countries with the high mortality rate, affected population rate or GDP loss rate, which also have higher or lower coping capacity, such as the Philippines, Bangladesh and Vietnam, are the hotspots of the planning and strategy making for the climatic disaster risk reduction and should focus on promoting the coping capacity.
基金supported by the National Natural Science Foundation of China,Nos.81800919(to YX),82171140(to PW)the International Cooperation and Exchange of the National Natural Science Foundation of China,Nos.82020108008(to HS),81720108010(to SY).
文摘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.
基金supported by National Natural Science Foundation of China(NSFC 52432002,52372041,52302087)Heilongjiang Touyan Team Program,the Fundamental Research Funds for the Central Universities(Grant No.HIT.OCEF.2021003)the Shanghai Aerospace Science and Technology Innovation Fund(SAST2022-60).
文摘Developing effective strategies to regulate graphene’s conduction loss and polarization has become a key to expanding its application in the electromagnetic wave absorption(EMWA)field.Based on the unique energy band structure of graphene,regulating its bandgap and electrical properties by introducing heteroatoms is considered a feasible solution.Herein,metal-nitrogen doping reduced graphene oxide(M–N-RGO)was prepared by embedding a series of single metal atoms M–N_(4) sites(M=Mn,Fe,Co,Ni,Cu,Zn,Nb,Cd,and Sn)in RGO using an N-coordination atom-assisted strategy.These composites had adjustable conductivity and polarization to optimize dielectric loss and impedance matching for efficient EMWA performance.The results showed that the minimum reflection loss(RL_(min))of Fe–N-RGO reaches−74.05 dB(2.0 mm)and the maximum effective absorption bandwidth(EAB_(max))is 7.05 GHz(1.89 mm)even with a low filler loading of only 1 wt%.Combined with X-ray absorption spectra(XAFS),atomic force microscopy,and density functional theory calculation analysis,the Fe–N_(4) can be used as the polarization center to increase dipole polarization,interface polarization and defect-induced polarization due to d-p orbital hybridization and structural distortion.Moreover,electron migration within the Fe further leads to conduction loss,thereby synergistically promoting energy attenuation.This study demonstrates the effectiveness of metal-nitrogen doping in regulating the graphene′s dielectric properties,which provides an important basis for further investigation of the loss mechanism.
基金supported by the State Key Laboratory of Arid Land Crop Science, Gansu Agricultural University,China (GSCS-2022-Z02)the National Key R&D Program of China (2022YFD1900300)+2 种基金the National Natural Science Foundation of China (32260549)the Innovation Group of Basic Research in Gansu Province, China (25JRRA807)the Major Special Research Projects in Gansu Province, China (22ZD6NA009)。
文摘The application of organic fertilizers has become an increasingly popular practice in maize production to reduce thegaseous nitrogen(N) loss and soil degradation caused by inorganic fertilizers. Organic fertilizer plays a key rolein improving soil quality and stabilizing maize yields, but few studies have compared different substitution rates. Afield study was carried out in 2021 and 2022, based on a long-term trial initiated in 2016, which included five organicfertilizer N substitution rates with equal inputs of 200 kg N ha^(–1): 0% organic fertilizer(T1, 100% inorganic fertilizer),50.0% organic+50.0% inorganic fertilizer(T2), 37.5% organic+62.5% inorganic fertilizer(T3), 25.0% organic+75.0%inorganic fertilizer(T4), and 12.5% organic+87.5% inorganic fertilizer(T5), as well as a no fertilizer control(T6). Theresults of the two years showed that T3 and T1 had the highest grain yield and biomass, respectively, and there wasno significant difference between T1 and T3. Compared with T1, the 12.5, 25.0, 37.5, and 50.0% substitution rates in T5, T4, T3, and T2 significantly reduced total nitrogen losses(NH_(3), N_(2)O) by 8.3, 16.1, 18.7, and 27.0%, respectively.Nitrogen use efficiency(NUE) was higher in T5, T3, and T1, and there were no significant differences among them.Organic fertilizer substitution directly reduced NH_(3)volatilization and N_(2)O emission from farmland by lowering theammonium nitrogen and alkali-dissolved N contents and by increasing soil moisture. These substitution treatmentsreduced N_(2)O emissions indirectly by regulating the abundances of AOB and nirK-harboring genes by promotingsoil moisture. Specifically, the 37.5% organic fertilizer substitution reduces NH_(3)volatilization and N_(2)O emission from farmland by reducing the ammonium nitrogen and alkali-dissolved N contents and increasing moisture, which negatively regulate the abundance of AOB and nir K-harboring genes to reduce N_(2)O emissions indirectly in rainfed maize fields on the Loess Plateau of China.
基金supported by the National Natural Science Foundation of China(Grant Nos.:U23A20530,82273858,and 82173746)the National Key Research and Development Programof China(Grant No.:2023YFF1204904)Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism(Shanghai Municipal Education Commission,China).
文摘Activity cliffs(ACs)are generally defined as pairs of similar compounds that only differ by a minor structural modification but exhibit a large difference in their binding affinity for a given target.ACs offer crucial insights that aid medicinal chemists in optimizing molecular structures.Nonetheless,they also form a major source of prediction error in structure-activity relationship(SAR)models.To date,several studies have demonstrated that deep neural networks based on molecular images or graphs might need to be improved further in predicting the potency of ACs.In this paper,we integrated the triplet loss in face recognition with pre-training strategy to develop a prediction model ACtriplet,tailored for ACs.Through extensive comparison with multiple baseline models on 30 benchmark datasets,the results showed that ACtriplet was significantly better than those deep learning(DL)models without pretraining.In addition,we explored the effect of pre-training on data representation.Finally,the case study demonstrated that our model's interpretability module could explain the prediction results reasonably.In the dilemma that the amount of data could not be increased rapidly,this innovative framework would better make use of the existing data,which would propel the potential of DL in the early stage of drug discovery and optimization.
文摘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.
文摘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.
