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Abstract Over 700 syndromes associated with hearing loss (HL) have been identified. Labyrinthine aplasia, microtia, and microdontia (LAMM syndrome, OMIM: 610706) is a rare HL syndrome characterized by congenital sensorineural HL, labyrinthine aplasia, type I microtia and microdontia, which is caused by biallelic variants in the FGF3 gene. Using Whole-exome sequencing (WES), we identified a novel missense FGF3 variant (c.137G > C, p. Arg46Pro (NM_005247.4) in three unrelated Uyghur ethnic families. This variant is classified as a variant of uncertain significance according to ACMG guidelines, with the applied criteria of PM3, PM2_Supporting, PP3 and PP4. Patients from the three families revealed variable clinical features. We found a novel phenotype, sparse hair, in one of the proband. Our findings expanded the variant and phenotype spectrum of LAMM syndrome and provided new insights to the diagnose and pathogenesis investigation of the disease.

Abstract Magnetic frustration is a route for novel ground states, including spin liquids and spin ices. Such frustration can be introduced through either lattice geometry or incompatible exchange interactions. Here, we find that epitaxial strain is an effective tool for tuning antiferromagnetic exchange interactions in a square-lattice system. By studying the magnon excitations in La2NiO4 films using resonant inelastic x-ray scattering, we show that the magnon displays substantial dispersion along the antiferromagnetic zone boundary, at energies that depend on the lattice of the film’s substrate. Using first principles simulations and an effective spin model, we demonstrate that the antiferromagnetic next-nearest neighbour coupling is a consequence of the two-orbital nature of La2NiO4. Altogether, we illustrate that compressive epitaxial strain enhances this coupling and, as a result, increases the level of incompatibility between exchange interactions within a model square-lattice system.

Abstract Background Treacher Collins syndrome (TCS; OMIM 154500) is a craniofacial developmental disorder. Methods To investigate the genetic features of a four-generation Chinese family with TCS, clinical examinations, hearing tests, computed tomography, whole-exome sequencing (WES), Sanger sequencing, reverse transcription (RT)-PCR, and the Minigene assay were performed. Results The probands, an 11-year-old male and his cousin exhibited typical clinical manifestations of TCS including conductive hearing loss, downward slanting palpebral fissures, and mandibular hypoplasia. Computed tomography revealed bilateral fusion of the anterior and posterior stapedial crura and malformation of the long crura of the incus. WES of both patients revealed a novel heterozygous intronic variant, i.e., c.4342 + 5_4342 + 8delGTGA (NM_001371623.1) in TCOF1. Minigene expression analysis revealed that the c.4342 + 5_4342 + 8delGTGA variant in TCOF1 caused a partial deletion of exon 24 (c.4115_4342del: p.Gly1373_Arg1448del), which was predicted to yield a truncated protein. The deletion was further confirmed via RT-PCR and sequencing of DNA from proband blood cells. A heterozygous variant in the POLR1C gene (NM_203290; exon6; c.525delG) was found almost co-segregated with the TCOF1 pathogenic variant. Conclusions In conclusion, we identified a heterozygous TCOF1 splicing variant c.4342 + 5_4342 + 8delGTGA (splicing) in a Chinese TSC family with ossicular chain malformations and facial anomalies. Our findings broadened the spectrum of TCS variants and will facilitate diagnostics and prognostic predictions.

The balance between the supply and demand of ecosystem services (ESSD) is important for sustainable regional development. The hilly regions of south China have rich natural resources and are rapidly being urbanized, which significantly impacts sustainable development in the region. Therefore, how to analyze ESSD from the perspective of social ecology is imperative. Ganzhou region, which is a typical hilly region in southern China, as an example, this paper creatively integrated ESSD into the social-ecological system (SES) framework, analyzed the spatial and temporal changes of ESSD in 2005, 2010, 2015, and 2020, and constructed a system of indicators from the SES, and analyzed the driving factors of ESSD, so as to provide a reference for balancing ESSD. Based on the classical SES framework proposed by Ostrom, this study first analyses the social-ecological system profile of the Ganzhou region at the macro-scale and constructs an SES indicator system. The innovation of combining the SES framework and ecosystem services lies in integrating the social and ecosystem perspectives and merging these two concepts to understand better and manage the relationship between humans and the natural environment. It provides a comprehensive analytical approach and decision support tool for achieving sustainable development. Our results demonstrate that: (1) From 2005 to 2020, ecosystem services in the study area were highly valued, lower areas had homogeneous distribution characteristics, total demand displayed spatial differentiation, there were high-value areas in the midwest, and low-value areas were concentrated in the region’s boundary. (2) There are obvious supply and demand deficits in the southeast and east of the study area, while supply–demand is equal in the north and supply exceeds demand in other regions. From 2005 to 2020, the overall coupling coordination degree of ESSD in the study area was lower than 0.5, indicating a mild to moderate imbalance. (3) The supply of ecosystem services (ESS) was primarily driven by carbon storage, habitat quality, and water yield, while the demand was primarily driven by forest and grassland areas. Factors related to the ecosystem, resource unit, resource system, social system, governance system, and actor all have experienced two-factor interactions, which can explain up to 99% of ESSD. Based on the SES framework, this paper studies the relationship between ESSD in typical areas of the southern hills to provide a reference for research on ESSD in relevant areas and provide a scientific basis for the Chinese government to evaluate ecological protections and improve compensation policies, which is important for ensuring China's ecological security.

Abstract Persistent room temperature phosphorescent materials with unique mechanical properties and robust optical properties have great potential in flexible electronics and photonics. However, developing such materials remains a formidable challenge. Here, we present highly stretchable, lightweight, and multicolored persistent luminescence elastomers, produced by incorporating ionic room temperature phosphorescent polymers and polyvinyl alcohol into a polydimethylsiloxane matrix. These prepared elastomers exhibit high optical transparency in daylight and emit bright persistent luminescence after the removal of 365 nm excitation. The homogeneous distribution of polymers within the matrix has been confirmed by confocal fluorescence microscopy, scanning electron microscopy, and atomic force microscopy. Mechanical property investigations revealed that the prepared persistent luminescence elastomers possess satisfactory stretchability. Impressively, these elastomers maintain robust optical properties even under extensive and repeated mechanical deformations, a characteristic previously unprecedented. These fantastic features make these persistent luminescence elastomers ideal candidates for potential applications in wearable devices, flexible displays, and anti-counterfeiting.

Over the past two decades, due to the combined effects of natural and human factors, the ecological environment and resources of the Qinghai–Tibet Plateau (QTP) have faced serious threats, profoundly impacting its ecosystem and the lives of its residents. Therefore, the establishment of the ecological security pattern (ESP) is crucial to cope with climate change, maintain ecosystem function, and sustainable development. Based on the Pressure–State–Response (PSR) model, this study constructed an evaluation index system for the ecological security (ES) of the QTP, evaluated the ES of the QTP during 2000–2020, and predicted the ES of the QTP during 2025–2035 based on the deep learning model. Combined with the residents’ perception of ES, the ES of the QTP was evaluated comprehensively. The results showed that: (1) From 2000 to 2020, the ES value of the QTP continued to rise, the number of dangerous and sensitive counties decreased, and the number of other counties increased. The overall spatial distribution features higher values in the southeast and lower values in the northwest and central regions. (2) From 2000 to 2020, both hot spots and cold spots on the QTP decreased, with the hot spots mainly concentrated in the southeast of the QTP, represented by Yunnan Province, and the cold spots shifting from west to east, mainly concentrated in the central QTP, represented by Qinghai Province. (3) The Long Short-Term Memory (LSTM) model demonstrates high prediction accuracy. Based on the prediction of LSTM, the ES value of the QTP will continue to rise from 2025 to 2035, and the number of safe counties will reach the highest level in history. The spatial distribution is still higher in the southeast and lower in the northwest and central regions. (4) By analyzing residents’ perception of 25 potential factors that may affect the ES of the QTP, the results show that residents generally believe that these factors have an important impact on ES, and their evaluation is between “important” and “very important”. In addition, there is a significant correlation between these factors and the predicted values of ES. The results of the study will help to improve our understanding of the overall ecological environment of the QTP, provide accurate positioning and reasonable help for the government to formulate relevant protection strategies, and lay a methodological and practical foundation for the sustainable development of the QTP.

Sustainability has become an indispensable core consideration when nations formulate their development policies. This study delves into the dynamic correlations between ecosystem services (ESs) and localized Sustainable Development Goals (SDGs) in a typical hilly region in southern China. Various ESs were computed using the InVEST model, while spatial econometric models were employed to assess ES responses to SDG targets at the county, sectoral, and overall spatial levels. The findings revealed the following. (1) From 2005 to 2020, there were differences in the development rates of various SDG targets in Ganzhou. Except for SDG 15, which declined, the development of the other targets showed an overall increasing trend. The development of the various SDG targets was relatively balanced, but SDG 9 and SDG 7 had the highest growth rates, ranging from 9.4% to 10.7% and 9.4% to 10.3%, respectively. The comprehensive SDG assessment index exhibited significant spatiotemporal variation, with a general trend of higher values in the north and lower values in the south. (2) The local ES showed a delayed response to SDG 1 and SDG 2, but there was a significant positive response to SDG 3, SDG 4, SDG 6, SDG 8, and SDG 9. However, responses to SDG 7, SDG 11, SDG 13, and SDG 15 showed regional differences. This study not only provides valuable insights for sustainable development in Ganzhou and other regions of China but also offers Chinese perspectives and experiences that may inform global efforts towards SDG implementation. This study fills the gap in existing research by constructing a localized SDG indicator system and quantifying each SDG indicator, further exploring the response of the ES to each SDG in the region. Looking ahead, we anticipate further research to deepen the understanding of the relationship between ESs and SDG targets on a broader geographical scale and over longer timeframes, aiming to provide a more robust scientific foundation for building a harmonious coexistence between humans and nature in the future.

The scientific quantification of the ecological effects of carbon emissions, the reduction of ecological risk (ER), and the evaluation of the interaction effect between carbon emissions and ER are the pivotal measures for ensuring the longevity and continuity of sustainability. However, a dearth of comprehensive and macro-level evaluations exist pertaining to the ER and carbon emissions within the entirety of the Yangtze River Economic Belt (YREB). We have constructed four distinct simulated scenarios within the YREB, which include natural development (ND), cultivated land protection (CLP), ecological conservation (EC), and low carbon (LC) scenarios. Based on the consideration of future uncertainty, we predicted LUCEs and ERI under different scenarios, and analyzed the spatial interaction effects of LUCEs and ERI from the dual perspectives of the spatial spillover effect and spatial coupling effect. The results showed that under the four outlined scenarios, encompassing diverse parameters, conversion possibilities, and areas subject to restrictions, the land utilization patterns of the YREB in 2030 have unveiled pronounced disparities. The LUCEs in the YREB showed significant spatial heterogeneity under the four scenarios; the maximum value was 6.65 under the CLP scenario and the minimum value was 4.65 under the LC scenario. The ER has the highest value under the ND scenario and the lowest value under LC scenario. Construction land is the largest contributor to increased LUCEs, and forest land is the form of terrestrial utilization that reduces the impact of LUCEs. In different scenarios, LUCEs have a significant negative spillover effect on ER, while the bidirectional spatial coupling effect between LUCEs and ERI presents significant differences. Under the LC scenario, land with a strong carbon sequestration capacity increased significantly, the fragmentation of water bodies was alleviated, and the CCD was the highest. This study offers scientific counsel for the sustainable development of various regions within the YREB, thereby fostering the achievement of a harmonious coexistence between the ecological milieu and economic development.

Achieving “carbon neutrality” is an inevitable requirement for tackling global warming. As one of the national ecological barriers, the southern hilly and mountainous region (SHMR) shoulder the important mission of taking the lead in achieving “carbon peak” and “carbon neutrality”. Thus, it has important scientific significance to explore and analyze how to coordinate ecological development under the background of “double carbon action”, and it is a key step to ensure that the region achieves synergistic development of promoting economic development and improving ecosystem health. Therefore, in this study, we aimed to address these gaps by adopting a refined grid scale of 10 km × 10 km to explore the spatial-temporal distribution characteristics of carbon emissions and ecosystem health. Additionally, we established a coupling coordination model of carbon emissions intensity (CEI) and ecosystem health index (EHI) to assess the impact of natural and socio-economic factors on the coupling coordination degree (CCD) in different regions. Our findings are as follows: 1) In the SHMR region, the EHI exhibited a progressive development trend, with spatially increasing values from the south to the north. 2) The spatial discrepancy in CEI has been on the rise, which assumed an increase of 4.69 times, and with an increasingly pronounced pattern of spatial imbalance. Carbon emissions tend to concentrate more in the eastern and northern areas, while they are comparatively lower in the western and southern regions. 3) The R2 of geographical weighted regression model (GWR) is all above 0.8, and the CCD between CEI and EHI demonstrated a positive developmental state. However, most regions still displayed an imbalanced development, albeit with a slight increase in areas exhibiting a more balanced development state. 4) The driving forces of natural and socio-economic factors had a dual-factor and non-linear enhancement effect on the CCD. The influence of natural factors on CCD has gradually diminished, whereas the influence of socio-economic factors has progressively strengthened.

Regional ecological risk assessment (ERA) is an important means towards sustainable regional development. Yet, existing ERA approaches often fall short of characterizing ecological processes as dynamic processes involving uncertainty. Using Inner Mongolia, a high ecological risk area in China, this study employed a framework for regional ERA that considers ecosystem service value (ESV) and four scenarios of future land use patterns to understand its regional ecological risk. The spatially explicit risk assessment method was implemented by a model combining multi-criteria evaluation (MCE), cellular automata (CA), and Markov chain to predict future land use/cover of 2030, an adjustment-based equivalence factor method to assess the ESV in each scenario, and Sharpe Index to assess regional ecological risk. The results show the following. First, the overall ESV increases from 2020 to 2030 under all but the socio-economic development (SED) scenarios considered in this study. Second, the overall regional ecological risk of Inner Mongolia is high in the central region and low in the east, north, and west regions. The low ecological risk areas account for the largest areal proportion in the ecosystem services protection (ESP) and natural development (ND) scenarios, while the medium ecological risk areas are the largest under SED. However, some low ecological risk areas are converted into medium ecological risk in ecological and socioeconomic balance scenario (ESB) scenario. Third, NDVI is the driving factor with the strongest explanatory power for the regional ecological risk in Inner Mongolia, followed by mean annual precipitation and temperature. The present study applied a framework for regional ERA that explicitly considers spatial heterogeneity and uncertainty, which can be useful for guiding decision-making for ecological risk control and the planning of the land use of ecosystems.

Abstract Studying the impact of large-scale ecological projects, such as the Grain-for-Green Program (GGP), on ecosystem services (ES) is currently a frontier and hot topic of ecological research. The GGP can directly change land use and land cover, thus affecting ES. By comparing the changes of ecosystem service value (ESV) and ecosystem service scarcity value (ESSV) in Qinghai before and after the implementation of the GGP, this paper clarified the impact of the GGP on Qinghai from the angles of ecology and economics. This paper quantified and evaluated the land use dynamics, ESV, and ESSV in Qinghai from 1995 to 2020. The results showed that in the past 25 years, the total annual Normalized Difference Vegetation Index (NDVI) of Qinghai showed a trend of sustained growth. From 1995 to 2020, the ESV increased by 6.80%. After considering supply and demand, the ESSV showed a continuous upward trend, increasing by 719.38%. After implementation of the GGP, the increase of NDVI inhibited the increase of the ESSV. These findings from evaluation of the effect of the GGP implementation provide a theoretical basis for future policy implementation and, in particular, a reference for the evaluation of the ESV and the ESSV in Qinghai.

With the rapid progress in urbanization and economic development, the impact of land use change (LUC) on ecosystem services is becoming increasingly significant. However, the accuracy of ecological risk assessment faces challenges due to the presence of uncertainty factors. Using the PLUS model, this study aims to simulate and predict land use changes (LUCs), focusing on the southern hilly regions in southeastern China as a case study, conducting an in-depth assessment of ecological risk uncertainty. Firstly, a spatiotemporal simulation of LUCs in the southern hilly region from 1990 to 2030 was conducted under multiple scenarios. Subsequently, differences in the spatial and temporal distribution of ecosystem service value (ESV) across different years and forecast scenarios in the southern hilly region were revealed, followed by a detailed analysis of the impact of LUCs on ESV. Finally, by calculating the Ecological Risk Index (ERI), the study systematically analyzed the evolution trend of ecological risk in the southern hilly region of China from 1990 to 2030. The main research findings are as follows: (1) the conversion proportions of different land use types vary significantly under different scenarios. Compared to 2020, under the 2030 National Development Scenarios (NDSs), there has been a slight decrease of around 3% in the total conversion area of farmland, forest, and grassland. However, under the Ecological Protection Scenario (EPS) and Urban Development Scenario (UDS) scenarios, there has been an increase in the area of forest and grassland, with a rise of approximately 1.5% in converted built-up land. (2) Western cities (e.g., Yueyang and Yiyang), central cities (e.g., Jiujiang), and northeastern cities (e.g., Suzhou) of China exhibit a relatively high ESV distribution, while ESV significantly decreased overall from 2010 to 2020. However, under the EPS and UDS, ESV shows a significant increasing trend, suggesting that these two scenarios may play a crucial role in ecosystem restoration. (3) The conversion of forest and water bodies to farmland has the most significant inhibitory effect on ESV, especially during the period from 1990 to 2000, providing substantial data support for relevant policy formulation. (4) From 1990 to 2030, ecological risk gradually increased in western, central, and southwestern cities of the southern hilly region, with the highest ecological risk values under the EPS scenario in northern cities (e.g., Chizhou and Tongling). Under the UDS scenario, there has been a significant decrease in ecological risk, providing valuable insights for future ecological conservation and sustainable development. However, a limitation lies in the need for further enhancement of the scenario’s simulation authenticity. This study offers a new perspective for understanding the impact of LUCs on ecosystem services and the uncertainty of ecological risks, providing crucial reference points for land resource management and the formulation of ecological conservation policies.

As one of the world’s critical ecological regions – often called the “Third Pole” – the Qinghai-Tibet Plateau (QTP) has outstanding ecosystem service values (ESV). However, its variable climate and fragile environmental conditions make it vulnerable to disturbance by human activities. Based on land use data from 2000, 2010, and 2020, we developed three simulated scenarios of land use distribution on the QTP: business as usual (BAU), farmland protection (FP), and ecological protection (EP). Finally, we employed the Sharpe Index to evaluate ecological risk across the QTP. The results showed that from 2000 to 2020, land use change was mainly in the form of conversion of grassland to unused land, totaling an area of 63,717 km2. The ecosystem service value showed an increasing trend, from US$752.6 billion to US$783.0 from 2010 to 2020. The simulation results from the three scenarios revealed significant differences. Farmland area shows a declining trend in both the EP and BAU scenarios, while exhibiting an increasing trend in the FP scenario. Forest area on the plateau experiences a decreasing trend in the EP and BAU scenarios, but shows an increase in the FP scenario, predominantly in the southeastern region, including Sichuan and Yunnan provinces. The ecological risk assessment results indicate that the eastern region has higher ecological risk compared to the western region, highlighting the western region as a priority area for risk control. The expansion of built-up land and unused land has had significant impacts on regional ecological risk. Integrating risk assessment outcomes with land use planning to identify focal areas can provide guidance for the sustainable development of this globally important ecoregion.

Summary: Functional cochlear hair cells (HCs) innervated by spiral ganglion neurons (SGNs) are essential for hearing, whereas robust models that recapitulate the peripheral auditory circuity are still lacking. Here, we developed cochlear organoids with functional peripheral auditory circuity in a staging three-dimensional (3D) co-culture system by initially reprogramming cochlear progenitor cells (CPCs) with increased proliferative potency that could be long-term expanded, then stepwise inducing the differentiation of cochlear HCs, as well as the outgrowth of neurites from SGNs. The function of HCs and synapses within organoids was confirmed by a series of morphological and electrophysiological evaluations. Single-cell mRNA sequencing revealed the differentiation trajectories of CPCs toward the major cochlear cell types and the dynamic gene expression during organoid HC development, which resembled the pattern of native HCs. We established the cochlear organoids with functional synapses for the first time, which provides a platform for deciphering the mechanisms of sensorineural hearing loss.

Abstract Mammalian sensory hair cells (HCs) have limited capacity for regeneration, which leads to permanent hearing loss after HC death. Here, we used in vitro RNA-sequencing to show that the Hippo signaling pathway is involved in HC damage and self-repair processes. Turning off Hippo signaling through Mst1/2 inhibition or Yap overexpression induces YAP nuclear accumulation, especially in supporting cells, which induces supernumerary HC production and HC regeneration after injury. Mechanistically, these effects of Hippo signaling work synergistically with the Notch pathway. Importantly, the supernumerary HCs not only express HC markers, but also have cilia structures that are able to form neural connections to auditory regions in vivo. Taken together, regulating Hippo suggests new strategies for promoting cochlear supporting cell proliferation, HC regeneration, and reconnection with neurons in mammals.

Aminoglycoside antibiotics (AGAs) are widely used in life-threatening infections, but they accumulate in cochlear hair cells (HCs) and result in hearing loss. Increases in adenosine triphosphate (ATP) concentrations and P2X7 receptor expression were observed after neomycin treatment. Here, we demonstrated that P2X7 receptor, which is a non-selective cation channel that is activated by high ATP concentrations, may participate in the process through which AGAs enter hair cells. Using transgenic knockout mice, we found that P2X7 receptor deficiency protects HCs against neomycin-induced injury in vitro and in vivo. Subsequently, we used fluorescent gentamicin–Fluor 594 to study the uptake of AGAs and found fluorescence labeling in wild-type mice but not in P2rx7−/− mice in vitro. In addition, knocking-out P2rx7 did not significantly alter the HC count and auditory signal transduction, but it did inhibit mitochondria-dependent oxidative stress and apoptosis in the cochlea after neomycin exposure. We thus conclude that the P2X7 receptor may be linked to the entry of AGAs into HCs and is likely to be a therapeutic target for auditory HC protection.

Abstract Hearing loss is the most common sensory neural disorder in humans, and according to a WHO estimation, 5.5% (466 million) of people worldwide have disabling hearing loss. In this study, a Chinese family with prelingual sensorineural hearing loss was investigated. The affected individuals showed moderately severe hearing loss at all frequencies. Using target genome enrichment and high-throughput sequencing, the homozygous variant c.2372del; p.(Ser791fs) was identified in PDZD7. This variant lies in exon 15 of PDZD7 and results in a frame shift followed by an early stop codon. It is classified as pathogenic according to the ACMG/AMP guidelines and ClinGen specifications. Our study expands the pathogenic variant spectrum of PDZD7 and strengthens the clinical importance of this gene in patients with moderately severe hearing loss.

Abstract Background Hereditary hearing loss is a heterogeneous class of disorders that exhibits various patterns of inheritance and involves many genes. Variants in the EYA4 gene in DFNA10 are known to lead to postlingual, progressive, autosomal dominant nonsyndromic hereditary hearing loss. Patients and methods We collected a four-generation Chinese family with autosomal-dominant nonsyndromic hearing loss (ADNSHL). We applied targeted next-generation sequencing (TNGS) in three patients of this pedigree and whole-genome sequencing (WGS) in the proband. The intrafamilial cosegregation of the variant and the deafness phenotype were confirmed by PCR, gap-PCR and Sanger sequencing. Results A novel CNV deletion at 6q23 in exons 8–11 of the EYA4 gene with a 10 bp insertion was identified by TNGS and WGS and segregated with the ADNSHL phenotypes. Conclusions Our results expanded the variant spectrum and genotype‒phenotype correlation of the EYA4 gene and autosomal dominant nonsyndromic hereditary hearing loss in Chinese Han individuals. WGS is an accurate and effective method for verifying the genomic features of CNVs.

As a result of the land degradation it causes, rapid urbanization can severely impact the form and function of the natural environment. Because of the limited availability of natural capital and the ecosystem services they provide in many regions, fluctuations in supply and demand should rigorously considered in decision-making. The Qinghai-Tibetan Plateau (QTP) is a globally-important ecoregion that generates significant ecosystem services value. Focusing on the QTP, we calculated the value change in the supply of ecosystem services using a coefficient table and the change in demand based on population, GDP, and income elasticity. The impact of supply and demand on the scarcity value of ecosystem services (ESSV) was then compared across four representative scenarios. The results showed that the ESSV on the QTP rose considerably between 1990 and 2020, particularly between 2000 and 2010. Between 1990 and 2020, the public-goods services grew faster than private-goods services. The most important element impacting the ESSV was demand-driven scarcity. The level of urbanization gradually increased during 1990–2020, with a consistent distribution of high ESSV and high urbanization across the region. High-High types and Low-Low types had a significant aggregation effect, located primarily in the north and west of the QTP, respectively. The Low-High type was scattered along with the Low-Low type, indicating fragile ecological conditions that merit greater protection from land degradation. The degree of coupling reveals an increasing degree of synergy between ESSV and urbanization on the QTP, indicating potential for more synergistic development.

Blast furnace slag and steelmaking slag, as the main accessory products of iron and steel smelting, are piled up in large quantities due to their huge output, high treatment difficulty and low comprehensive utilization rate, which has a serious impact on the land and environment. In order to improve the comprehensive utilization of steelmaking slag, low basicity blast furnace slag was added to the existing steel slag for quenching and tempering. The influence of basicity on the chemical composition and phase precipitation of mixed slag was analyzed. In the research process, the phase composition and morphology of blast furnace slag and steel slag of Baotou Steel were analyzed using FactSage7.1 thermodynamic calculation software, ZEISS high-resolution scanning electron microscope (SEM), modern fast high-resolution Bruker energy dispersive spectrometer and AMICS-Mining automatic mineral analysis software. The results show that the mineral phase composition of blast furnace slag is mainly calcium aluminum yellow feldspar and that of steelmaking slag is mainly dicalcium silicate(C2S), magnesium-iron phase solid solution, rose pyroxene and calcium iron aluminate. When the basicity of the mixed slag is 2.0, it can effectively inhibit the formation of non-cementitious mineral anorthite and promote the formation of better cementitious mineral C2S. At the same time, it is found that the melting temperature of mixed slag decreases with the increase in Al2O3 content.

Migraine is a common neuro⁃vascular disease with a global prevalence of about 15% and a heavy burden. Patent foramen ovale (PFO) is the most common congenital cardiac abnormality consisting of the main cause of right⁃to⁃left shunt (RLS). There is a correlation between PFO and migraine, especially migraine with aura (MA). The comorbidity rate of PFO and migraine is significantly higher than that of the general population. The exact pathophysiological mechanism of comorbidity between PFO and migraine is unclear. At present, it is considered that paradoxical embolism and vasoactive peptides may underlie this comorbidity. Some studies suggest that percutaneous closure of PFO can reduce the frequency and duration of migraine, but the effectiveness of closure of PFO is still controversial. At present, limited evidence suggests that migraine with aura, antiplatelet drugs, large amount of RLS, and comorbid with ischemic stroke and transient ischemic attack (TIA) may benefit more from closure of PFO. In the future, more multicenter, prospective, double⁃blind, randomized controlled large⁃scale clinical studies are needed to clarify the long⁃term efficacy and predictive factors of closure of PFO on migraine prophylactic treatment, so as to provide criteria for screening the eligible patients treated with closure of PFO.

The activity characteristics of the village and its symbiotic relationship with the environment play an important role in the sustainable development of the surrounding environment. Miao villages have a long history. In the process of long-term interaction with the surrounding natural environment, Miao villages have formed a unique forest culture, which has an important impact on the distribution of the surrounding forests and plays a crucial role in local forest management. In this study, we took the Miao villages of China that are distributed in Qiandongnan Miao and Dong Autonomous Prefecture of China as an example and constructed a research framework to study the interaction between the natural environment and human activities around the Miao villages and its impact on forest change based on partial least squares structural equation modeling (PLS-SEM) and geographically weighted regression modeling (GWR) methods. The validity and reliability evaluations showed that the PLS-SEM model was reasonable. The results showed that the Miao villages were randomly distributed within 0–2 km and clustered in the 8–10 km buffer zone. The temporal variation of the forest landscape around the Miao villages was small, and the spatial heterogeneity was obvious. Within the 0~2 km buffer zone, the proportion of closed-canopy forest was the largest, and with the increase in the buffer zone radius, the proportion of closed-canopy forest gradually decreased, the open-canopy forest gradually grew, and the proportion of shrubbery and other forests showed an upward trend first and then a downward trend. Temporally, the four forest landscapes did not change much, with closed and open forests sliding, and shrubbery and other forests increasing. Regarding the drivers of forest structure change, topographic factors and landscape patterns had a positive effect on forest structure, while human activities had a negative effect. The influence of topography on human activities in the Miao villages weakened the direct positive effect of topography on forests and promoted the positive effect of the landscape pattern on forests. There were significant spatial differences in the GWR regression coefficients of the effects of different factors on forest structure in 2020, with a pivotal negative correlation between NDVI and night-time light data. In addition, the higher the elevation, the more unfavorable the distribution of open-canopy forests and the better the distribution of closed-canopy forests. The higher the slope, the higher the NDVI but the more unfavorable the distribution of closed-canopy forests. In general, the impacts of Miao villages on forest structure are highly complex and interactive, with both direct and indirect effects. Different factors interact to affect the structure of the forest. The study on the effect of Miao villages on forests is helpful for more targeted forest protection and the formulation of laws and regulations, so as to find a balance between human activities and forest management, in order to maintain the ecological balance of local areas. This study introduced the PLS-SEM model to investigate the impacts of Miao villages on forest structure, which effectively enhanced our understanding of the drivers and impacts of forest change and provides theoretical support and a basis for forest protection and management.

A complex relationship exists between natural environmental and urban systems. This study focuses on the province of Qinghai, which is a major part of the Tibetan Plateau. For the period 1995–2020, we explore the relationships between ecosystem health and urbanization. We established an indicator system for ecosystem health and urbanization and quantitatively analyzed the spatiotemporal pattern of coupling coordination between the two. It shows that between 1995 and 2020, the urbanization level in Qinghai showed a continuous upward trend, with the urbanization index in 2020 increasing by 147.20% compared to 1995. The level of ecosystem health also showed an upward trend, with the ecosystem health index (EHI) value in 2020 increasing by 3.31% compared to 1995. The coupling coordination degree between ecosystem health and urbanization in Qinghai increased year-on-year. Areas with high coupling coordination between ecosystem health and urbanization basically overlapped with areas with high urbanization, and the area gradually increased during the study period. Locations with slightly unbalanced development were located on the periphery of high coupling-coordination areas, and that area expanded in the years covered in this study. The low coupling-coordination areas were located in the northwest and southwest of Qinghai, bounded by the Qinghai-Tibet Highway. These results can support the evaluation of ecosystem health and urbanization on the Tibetan Plateau and high-altitude river source areas similar to Qinghai in China and elsewhere, contributing to sustainable land use policy.

Rapid economic development and accelerated urbanization have seriously affected the development of traditional ethnic villages in China. We used the minimum cumulative resistance (MCR) model based on land use, landscape pattern, and ecosystem service value (ESV) to evaluate the spatio-temporal dynamics of sustainable development in Hani traditional ethnic villages from 1995 to 2020. By analyzing changes in sustainability indicators in the Hani area and different buffer zones, this paper aims to assess the impact of ethnic villages in the Hani Area on sustainable development and provide recommendations for the sustainable development of traditional ethnic Hani villages. The results indicated that: (1) The area of construction land and landscape fragmentation in the Hani area significantly increased and the value of ecosystem services and levels of sustainable development decreased each year during the study period; (2) The area of cropland in the 2 km buffer zone of the traditional ethnic villages increased, the degree of landscape fragmentation, the value of ecosystem services, and the level of sustainable development were lower than in the 4 km buffer zone during the study period. This is due to population increases in traditional ethnic Hani villages, as well as the intensive reclamation of cropland, increased construction land, and landscape fragmentation. We suggest that the Hani should implement scientific land planning and management policies to protect the local ecosystem and realize the sustainable development of traditional ethnic Hani villages.

As one of the first ecological civilization demonstration areas in China, Guizhou Province, an underdeveloped region, experienced rapid economic development. The resulting human activities at an accelerated rate in Guizhou Province put great pressure on its environmental carrying capacity, especially the Karst landscape in the region. Understanding the relationship between urbanization and ecosystem services in Guizhou Province is indispensable for the sustainable development of the region in the future. Based on remote sensing data from 1990 to 2020, this study explores the spatiotemporal dynamics of ecosystem services value (ESV) and urbanization, as well as the degree of coupling and coordination (CCD) between them. The result suggested that between 1990 and 2020, the ESV of Guizhou Province showed a two-step decline due to the conversion of forest land for agricultural and urban usage. In addition, the ESV of the western region is lower than its eastern counterpart. The CCD level between ESV and urbanization has increased over time, but most areas are still in an unbalanced state of development. Most areas are mainly urbanization lagging, but the central and north-central research areas are mainly ESV lagging. Identifying the regional differences of coupling coordination types has shed light on the degree of contradiction between local urbanization and ESV, and helped find the balance between ecological sustainability and urbanization.

Abstract Background The inner ear organ is a delicate tissue consisting of hair cells (HCs) and supporting cells (SCs).The mammalian inner ear HCs are terminally differentiated cells that cannot spontaneously regenerate in adults. Epithelial non‐hair cells (ENHCs) in the utricle include HC progenitors and SCs, and the progenitors share similar characteristics with SCs in the neonatal inner ear. Methods We applied single‐cell sequencing to whole mouse utricles from the neonatal period to adulthood, including samples from postnatal day (P)2, P7 and P30 mice. Furthermore, using transgenic mice and immunostaining, we traced the source of new HC generation. Results We identified several sensory epithelial cell clusters and further found that new HCs arose mainly through differentiation from Sox9+ progenitor cells and that only a few cells were produced by mitotic proliferation in both neonatal and adult mouse utricles. In addition, we identified the proliferative cells using the marker UbcH10 and demonstrated that in adulthood the mitotically generated HCs were primarily found in the extrastriola. Moreover, we observed that not only Type II, but also Type I HCs could be regenerated by either mitotic cell proliferation or progenitor cell differentiation. Conclusions Overall, our findings expand our understanding of ENHC cell fate and the characteristics of the vestibular organs in mammals over the course of development.

The presence of potassium oxide (K2O) and sodium oxide (Na2O) causes high reduction swelling of pellets of Bayan Obo iron concentrate during reduction and thus affects the permeability of blast gases during blast furnace operations. The influencing mechanism of K2O and Na2O on the swelling behavior of reduction reactions (1) Fe2O3 → Fe3O4, (2) Fe3O4 → FexO, and (3) FexO → Fe was researched by adding (K2O + Na2O) to Australian fine ore briquettes. The mineral composition and structure of the briquettes, as well as the reduction swelling after the three reactions coupled with the morphology and lattice parameters of the reduced products, were studied. From the results, the swelling index with 0.6% (K2O + Na2O) added was 8.52%, 7.91%, and 33.81%, respectively, and without were 12.36%, 3.27%, and 12.61%, respectively, for the three reactions. The swelling index of the first reaction (Fe2O3 → Fe3O4) is reduced because alkali metal suppresses crystal cracking. The swelling mainly occurs at the third stage (FexO → Fe), because K2O and Na2O enhance the oriented growth of iron whiskers, as well as make them smaller. Crystal transformation does not occur at the second stage (Fe3O4 → FexO) and the reduction swelling is small, but the swelling index of the briquettes with added with K2O and Na2O increases (7.91% compared to 3.27%). The main reason is that the alkali metal reduces the melting point of the slag phase and promotes the cascade crystallization of FeO. Therefore, the abnormal swelling of briquettes caused by K and Na is mainly caused by the growth of iron whiskers at the third stage.

The influence mechanism of basicity on the reduction swelling index (RSI) of iron ore briquettes was investigated using the SEM analysis and Factsage 7.3 thermodynamic calculations based on the addition of pure CaO to Bayan Obo iron concentrate. The results revealed that the solid solution of Ca2+ in the FeO lattice increased with the basicity of the briquettes, whereas the diffusion channels of Fe2+ ions increased during the reduction process from FeO to Fe and resulted in the formation of a great number of slender and anisotropic iron whiskers, which consequently increased the RSI. Furthermore, the melting point of the slag phase decreased as the CaO content increased; this reduced its ability to resist the reduction swelling of iron oxides. When the basicity was increased from 0.3 to 0.8, the RSI reached a maximum of 69.85%. However, due to the saturated solid solution of Ca2+ in FeO lattice, as the basicity further increased from 0.8 to 1.2, excess CaO melting into the slag phase promoted the precipitation of spinel minerals with high melting points and difficult reduction properties. Thus, the diffusion of Fe2+ and the growth of the iron whiskers were hindered, and the RSI was reduced.

Abstract Background Aging, noise, infection, and ototoxic drugs are the major causes of human acquired sensorineural hearing loss, but treatment options are limited. CRISPR/Cas9 technology has tremendous potential to become a new therapeutic modality for acquired non-inherited sensorineural hearing loss. Here, we develop CRISPR/Cas9 strategies to prevent aminoglycoside-induced deafness, a common type of acquired non-inherited sensorineural hearing loss, via disrupting the Htra2 gene in the inner ear which is involved in apoptosis but has not been investigated in cochlear hair cell protection. Results The results indicate that adeno-associated virus (AAV)-mediated delivery of CRISPR/SpCas9 system ameliorates neomycin-induced apoptosis, promotes hair cell survival, and significantly improves hearing function in neomycin-treated mice. The protective effect of the AAV–CRISPR/Cas9 system in vivo is sustained up to 8 weeks after neomycin exposure. For more efficient delivery of the whole CRISPR/Cas9 system, we also explore the AAV–CRISPR/SaCas9 system to prevent neomycin-induced deafness. The in vivo editing efficiency of the SaCas9 system is 1.73% on average. We observed significant improvement in auditory brainstem response thresholds in the injected ears compared with the non-injected ears. At 4 weeks after neomycin exposure, the protective effect of the AAV–CRISPR/SaCas9 system is still obvious, with the improvement in auditory brainstem response threshold up to 50 dB at 8 kHz. Conclusions These findings demonstrate the safe and effective prevention of aminoglycoside-induced deafness via Htra2 gene editing and support further development of the CRISPR/Cas9 technology in the treatment of non-inherited hearing loss as well as other non-inherited diseases.

CaO–MgO–Al2O3–SiO2 glass-ceramics with diopside as the main crystalline phase were prepared by melting blast furnace slag obtained from Baotou Iron and Steel Company. The effect of heat treatment on the crystallization behavior of glass-ceramics, containing a large proportion of melted blast furnace slag, was studied by means of differential thermal analysis and scanning electron microscopy. The optimum heat-treatment regime was obtained by orthogonal experimental results for glass-ceramics in which blast furnace slag comprised 70% of the composition and 1% Cr2O3 and 4% TiO2 were used as nucleating agents. The nucleation temperature was 750°C for 2.5 h and the crystallization temperature was 930°C for 1 h. Under this regime, the performance of the glass-ceramic was better than that of other groups in the orthogonal experiment.

Abstract Background Inner ear supporting cells (SCs) in the neonatal mouse cochlea are a potential source for hair cell (HC) regeneration, but several studies have shown that the regeneration ability of SCs decreases dramatically as mice age and that lost HCs cannot be regenerated in adult mice. To better understand how SCs might be better used to regenerate HCs, it is important to understand how the gene expression profile changes in SCs at different ages. Methods Here, we used Sox2 GFP/+ mice to isolate the Sox2+ SCs at postnatal day (P)3, P7, P14, and P30 via flow cytometry. Next, we used RNA-seq to determine the transcriptome expression profiles of P3, P7, P14, and P30 SCs. To further analyze the relationships between these age-related and differentially expressed genes in Sox2+ SCs, we performed gene ontology (GO) analysis. Results Consistent with previous reports, we also found that the proliferation and HC regeneration ability of isolated Sox2+ SCs significantly decreased as mice aged. We identified numerous genes that are enriched and differentially expressed in Sox2+ SCs at four different postnatal ages, including cell cycle genes, signaling pathway genes, and transcription factors that might be involved in regulating the proliferation and HC differentiation ability of SCs. We thus present a set of genes that might regulate the proliferation and HC regeneration ability of SCs, and these might serve as potential new therapeutic targets for HC regeneration. Conclusions In our research, we found several genes that might play an important role in regulating the proliferation and HC regeneration ability of SCs. These datasets are expected to serve as a resource to provide potential new therapeutic targets for regulating the ability of SCs to regenerate HCs in postnatal mammals.

Rapid expansions of urban areas and the intensification of human activities have severely impacted ecosystems and ecosystem service provisions. Considering limited availability of ecosystem services, the evaluation of ecosystem service value should consider its fluctuations supply and demand due to urbanization, i.e., the ecosystem service scarcity value (ESSV). Taking typical arid and semiarid regions of China and the Ningxia Hui Autonomous Region as an example, the effects of different scarcity factors on the scarcity value of ecosystem services were compared. At the same time, a geographically weighted regression model (GWR) was developed to analyze the spatial relationships between urbanization and the scarcity value of ecosystem services. The results suggest that demand-driven scarcity is the most important factor affecting the ESSV in Ningxia, and between 1990 and 2015, the ESSV in Ningxia increased significantly, with increase being more evident from 2005 to 2015. Among the different types of ecosystem services, the scarcity values of ecosystem services such as air quality, waste treatment, soil retention, biodiversity services, and recreation and culture increased significantly from 1990 to 2015. Spatially, the total ESSV and the ESSV of different ecosystem service types exhibited evident spatial heterogeneity due, to spatial distribution characteristics of land-use type, population density and per capita GDP. The GWR modeling result shows, that the impact of urbanization on ESSV was positively correlated overall. The ESSV of food production, raw material, air quality, climate regulation and water supply are greatly affected by urbanization, while the ESSV of biodiversity services and recreation and culture are less affected by urbanization. Meanwhile, the High-Low type and Low-High type had significant aggregation effects in the study area.

Given that ecological and environmental functions are greatly influenced by rapid urbanization, a clear understanding of the relationship between ecosystem services (ESs) and urbanization is urgently needed to improve sustainable development in Inner Mongolia. In this study, we first carried out ecosystem service valuation (ESV) using the value coefficient method. We then examined the urbanization level using a comprehensive indicator system. Finally, we applied the coupling coordination degree model to analyze the coordination relationship between ecosystem services and urbanization from 1995 to 2020 in Inner Mongolia. The results showed that there was an increase in both the urbanization level and all ecosystem services excluding climate regulation, environmental purification, and biodiversity services. The coupling coordination degree (CCD) of Inner Mongolia is not ideal, and most counties remain at a low level of coordination degree. Furthermore, spatiotemporal heterogeneity was evident in the CCD of ecosystem services and urbanization as it was higher in the center and east of the country, but lower in the north and west regions. Relevant policies should be implemented to strengthen the advantages of local ecology, encourage environmentally friendly industrialization, and promote ecologically and economically sustainable development.

In order to explore the influence of unburned pulverized coal on gasification reaction of coke in blast furnace, kinetic rules of gasification reaction between CO2 and coke powder adding pulverized coals with different volatiles were studied by thermogravimetric analysis. The results showed that weight-loss ratio of samples reacted with CO2 increased after adding pulverized coal, and the weight-loss ratio rose with the increase of coal’s addition. When the content of pulverized coal was up to 50%, the weight-loss ratio of the sample which adding pulverized coal with high volatile was higher under the same temperature. The activation energy about C-CO2 gasification reaction of samples reduced observably after adding pulverized coal. The activation energy of samples had a largest decrease with 83.408 kJ mol−1 at the range of 1223 K~1373 K and it was 28.97 kJ mol−1 at the range of 1373 K~1523 K. The addition of pulverized coal with high volatile can reduce the reaction activation energy of samples more effectively. In the soft melting zone, the gasification reaction model of coke blocks attached the unburned pulverized coal was up to unreacted core model and porous volume-reacted model jointly.

Changing land-use patterns in the Qinghai–Tibet Plateau (QTP) due to natural factors and human interference have led to higher ecological vulnerability and even more underlying issues related to time and space in this alpine area. Ecological vulnerability assessment provides not only a solution to surface-feature-related problems but also insight into sustainable eco-environmental planning and resource management as a response to potential climate changes if driving factors are known. In this study, the ecological vulnerability index (EVI) of Shannan City in the core area of the QTP was assessed using a selected set of ecological, social, and economic indicators and spatial principal component analysis (SPCA) to calculate their weights. The data included Landsat images and socio-economic data from 1990 to 2015, at five-year intervals. The results showed that the total EVI remains at a medium vulnerability level, with minor fluctuations over 25 years (peaks in 2000, when there was a sudden increase in slight vulnerability, which switched to extreme vulnerability), and gradually increases from east to west. In addition, spatial analysis showed a distinct positive correlation between the EVI and land-use degree, livestock husbandry output, desertification area, and grassland area. The artificial afforestation program (AAP) has a positive effect by preventing the environment from becoming more vulnerable. The results provide practical information and suggestions for planners to take measures to improve the land-use degree in urban and pastoral areas in the QTP based on spatial-temporal heterogeneity patterns of the EVI of Shannan City.

Adeno-associated virus (AAV) is the preferred vector for gene therapy of hereditary deafness, and different viral serotypes, promoters and transduction pathways can influence the targeting of AAV to different types of cells and the expression levels of numerous exogenous genes. To determine the transduction and expression patterns of AAV with different serotypes or promoters in hair cells and supporting cells in the neonatal mouse cochlea, we examined the expression of enhanced green fluorescent protein (eGFP) for five different types of AAV vectors [serotypes 2, 9, and Anc80L65 with promoter cytomegalovirus (CMV)-beta-Globin and serotypes 2 and 9 with promoter chicken beta-actin (CBA)] in in vitro cochlear explant cultures and we tested the transduction of AAV2/2-CBA, AAV2/9-CBA, and AAV2/Anc80L65-CMV by in vivo microinjection into the scala media of the cochlea. We found that each AAV vector had its own transduction and expression characteristics in hair cells and supporting cells in different regions of the cochlea. There was a tonotopic gradient for the in vitro transduction of AAV2/2-CBA, AAV2/9-CBA, AAV2/2-CMV, and AAV2/9-CMV in outer hair cells (OHCs), with more OHCs expressing eGFP at the base of the cochlea than at the apex. AAV2/2-CBA in vitro and AAV2/Anc80L65-CMV in vivo induced more supporting cells expressing eGFP at the apex than in the base. We found that AAV vectors with different promoters had different expression efficacies in hair cells and supporting cells of the auditory epithelium. The CMV-beta-Globin promoter could drive the expression of the delivered construct more efficiently in hair cells, while the CBA promoter was more efficient in supporting cells. The in vitro and in vivo experiments both demonstrated that AAV2/Anc80L65-CMV was a very promising vector for gene therapy of deafness because of its high transduction rates in hair cells. These results might be useful for selecting the appropriate vectors for gene delivery into different types of inner ear cells and thus improving the effectiveness of gene therapy.

The Yushu Tibetan Autonomous Prefecture is a typical Tibetan plateau area, and its ecological environment is very fragile. It is necessary to explore the terrain and cultural factors for the protection of the local ecological environment. We mainly investigated and quantified the effect of terrain factors and two typical plateau cultural landscapes (temples and villages) on the spatiotemporal variation characteristics of four types of forest landscape in the Yushu Tibetan Autonomous Prefecture from 1990 to 2015 using remote sensing (RS) and geographic information system (GIS) technology. The results showed that, under the influence of terrain factors, forest landscapes were only distributed in places with an altitude of 5055 meters above sea level (masl) to 6300 masl, with a slope of 0–27°, and the largest distribution area was shrubbery. The area of the forest decreased with the increase in altitude, and it first rose and then decreased with the increase in slope. Regression analysis results showed that the influence of altitude on closed forest land and open forest land followed a polynomial function, while that on shrubbery followed a logarithmic function, and the impact of slope on the three forest landscapes followed the amplitude version of a Gaussian peak function. Considering cultural factors, temples and villages did not determine the forest distribution in the same way as natural factors do, but they motivated the amount of forest over spatiotemporal scales. Temples had a greater influence on forest protection than villages, and this positive impact was stronger within 6 km. The area of forest distributed around the temple accounts for more than 45.67% of the total forest area, and this area has not changed significantly in 25 years. In summary, altitude and slope affect the natural distribution of the forest, and temples affect the scale of forest distribution. These results reveal the impact of terrain factors and cultural landscapes on forest distribution and could motivate an even more effective management for sustainable forest development.

Hair cell (HC) loss is irreversible because only very limited HC regeneration has been observed in the adult mammalian cochlea. Wnt/β-catenin signaling regulates prosensory cell proliferation and differentiation during cochlear development, and Wnt activation promotes the proliferation of Lgr5+ cochlear HC progenitors in newborn mice. Similar to Lgr5, Lgr6 is also a Wnt downstream target gene. Lgr6 is reported to be present in adult stem cells in the skin, nail, tongue, lung, and mammary gland, and this protein is very important for adult stem cell maintenance in rapidly proliferating organs. Our previous studies showed that Lgr6+ cells are a subpopulation of Lgr5+ progenitor cells and that both Lgr6+ and Lgr5+ progenitors can generate Myosin7a+ HCs in vitro. Thus we hypothesized that Lgr6+ cells are an enriched population of cochlear progenitor cells. However, the detailed distinctions between the Lgr5+ and Lgr6+ progenitors are unclear. Here, we systematically compared the proliferation, HC differentiation, and detailed transcriptome expression profiles of these two progenitor populations. We found that the same number of isolated Lgr6+ progenitors generated significantly more Myosin7a+ HCs compared to Lgr5+ progenitors; however, Lgr5+ progenitors formed more epithelial colonies and more spheres than Lgr6+ progenitors in vitro. Using RNA-Seq, we compared the transcriptome differences between Lgr5+ and Lgr6+ progenitors and identified a list of significantly differential expressed genes that might regulate the proliferation and differentiation of these HC progenitors, including 4 cell cycle genes, 9 cell signaling pathway genes, and 54 transcription factors. In conclusion, we demonstrate that Lgr6+ progenitors are an enriched population of inner ear progenitors that generate more HCs compared to Lgr5+ progenitors in the newborn mouse cochlea, and the our research provides a series of genes that might regulate the proliferation of progenitors and HC generation.

Dysfunctions in hearing and balance are largely connected with hair cell (HC) loss. Although regeneration of HCs in the adult cochlea does not occur, there is still limited capacity for HC regeneration in the mammalian utricle from a distinct population of supporting cells (SCs). In response to HC damage, these Lgr5+ SCs, especially those in the striolar region, can regenerate HCs. In this study, we isolated Lgr5+ SCs and Plp1+ SCs (which originate from the striolar and extrastriolar regions, respectively) from transgenic mice by flow cytometry so as to compare the properties of these two subsets of SCs. We found that the Lgr5+ progenitors had greater proliferation and HC regeneration ability than the Plp1+ SCs and that the Lgr5+ progenitors responded more strongly to Wnt and Notch signaling than Plp1+ SCs. We then compared the gene expression profiles of the two populations by RNA-Seq and identified several genes that were significantly differentially expressed between the two populations, including genes involved in the cell cycle, transcription and cell signaling pathways. Targeting these genes and pathways might be a potential way to activate HC regeneration.

Hair cell (HC) loss is the major cause of permanent sensorineural hearing loss in mammals. Unlike lower vertebrates, mammalian cochlear HCs cannot regenerate spontaneously after damage, although the vestibular system does maintain limited HC regeneration capacity. Thus HC regeneration from the damaged sensory epithelium has been one of the main areas of research in the field of hearing restoration. Hedgehog signaling plays important roles during the embryonic development of the inner ear, and it is involved in progenitor cell proliferation and differentiation as well as the cell fate decision. In this study, we show that recombinant Sonic Hedgehog (Shh) protein effectively promotes sphere formation, proliferation, and differentiation of Lgr5+ progenitor cells isolated from the neonatal mouse cochlea. To further explore this, we determined the effect of Hedgehog signaling on cell proliferation and HC regeneration in cultured cochlear explant from transgenic R26-SmoM2 mice that constitutively activate Hedgehog signaling in the supporting cells of the cochlea. Without neomycin treatment, up-regulation of Hedgehog signaling did not significantly promote cell proliferation or new HC formation. However, after injury to the sensory epithelium by neomycin treatment, the over-activation of Hedgehog signaling led to significant supporting cell proliferation and HC regeneration in the cochlear epithelium explants. RNA sequencing and real-time PCR were used to compare the transcripts of the cochleae from control mice and R26-SmoM2 mice, and multiple genes involved in the proliferation and differentiation processes were identified. This study has important implications for the treatment of sensorineural hearing loss by manipulating the Hedgehog signaling pathway.

Cochlear supporting cells (SCs) have been shown to be a promising resource for hair cell (HC) regeneration in the neonatal mouse cochlea. Previous studies have reported that Lgr5+ SCs can regenerate HCs both in vitro and in vivo and thus are considered to be inner ear progenitor cells. Lgr5+ progenitors are able to regenerate more HCs than Lgr5- SCs, and it is important to understand the mechanism behind the proliferation and HC regeneration of these progenitors. Here, we isolated Lgr5+ progenitors and Lgr5- SCs from Lgr5-EGFP-CreERT2/Sox2-CreERT2/Rosa26-tdTomato mice via flow cytometry. As expected, we found that Lgr5+ progenitors had significantly higher proliferation and HC regeneration ability than Lgr5- SCs. Next, we performed RNA-Seq to determine the gene expression profiles of Lgr5+ progenitors and Lgr5- SCs. We analyzed the genes that were enriched and differentially expressed in Lgr5+ progenitors and Lgr5- SCs, and we found 8 cell cycle genes, 9 transcription factors, and 24 cell signaling pathway genes that were uniquely expressed in one population but not the other. Last, we made a protein–protein interaction network to further analyze the role of these differentially expressed genes. In conclusion, we present a set of genes that might regulate the proliferation and HC regeneration ability of Lgr5+ progenitors, and these might serve as potential new therapeutic targets for HC regeneration.

In aeronautical machining industry, the most difficult problem to deal with is the distortion of aviation integral component, one main cause of which is the existence of quenching residual stress of forgings, especially for large-sized ones. Therefore, it is important to study the methods that can reduce the quenching residual stress. In this work, the distribution of quenching residual stress of 7A85 aluminum alloy thick block forging, as well as the effect of cold compression deformation method on reducing quenching residual stress, has been investigated by simulation. The results show that, in length direction of 7A85 aluminum alloy thick block with a large size of 260 (H) × 1150 (W) × 5300 (L) mm, quenching residual stress can be significantly reduced by about 2.5% cold compression deformation along the direction of highness, with residual stress in length direction ranging from −65 MPa to 60 MPa, compared with its counterpart after quenching from −170 MPa to 140 MPa. Then a cold compression experiment was carried out, in which the forging residual stress on the surface was measured by X-ray diffraction device. The experimental results indicate that the optimal compression deformation value is 1%-2%, reducing 70% residual stress for 7A85 aluminum alloy specimens in size of 100 (L) × 60 (W) × 40 (H) mm.

COD is regarded as an important index for representing the degree of organic pollution in water bodies, which has attracted wide attention. The water quality of 10.2% of the 972 state-controlled sections exceeded Ⅴ class among ten water areas such as the Yangtze River and the Yellow River in China in 2012. COD is one of the major pollution indicators in those water bodies. Therefore, it is of great importance to accurately monitor COD in water bodies. However, standard determination methods of COD have some disadvantages including complexity, low efficiency, high cost and severe secondary pollution. Aiming at the difficulties of traditional methods, instruments and equipment (sample digestion and determination), digestion reagents, and determination methods have been optimized and improved. In addition, certain environmentally friendly detection techniques with higher detection efficiency and accuracy have also been developed and applied. The most recent research progress of the determination methods of COD, including two main parts: the improved and optimized methods according to the standard ones, and new technologies or methods are reviewed in this paper. The traditional detection method is suitable for determining COD with the content range of 30-700 mg/L in light or moderate polluted water bodies. The improved and optimized methods extend the detection limits from 8.6 mg/L to 1600 mg/L, with the detection time shortened and cost of detection decreased significantly. However, the environmental pollution caused by chemical reagents could not be avoided, and oxidation ability to the refractory organics was insufficient. Flow injection, chemiluminescence or a combination of several techniques, which had already been used as the mature detection methods in drugs and immune analysis, mineral and rock analysis, have also been employed for the determination of COD in water bodies. Lower detection limit (0.16 mg/L) and faster detection time could be achieved, and the environmental pollution caused by the reagents was reduced dramatically. With the development of science and technology, some new methods such as ozone oxidation, electrochemical ones, especially as photocatalytic and photoelectrocatalytic determination technologies, based upon the reaction between hydroxyl radicals and organic compounds, have been developed recently. A wider detection range (0-23200 mg/L) was achieved by these new methods, which are capable of determining COD in water bodies with different pollution levels. The new techniques could provide a reference for the accurate, rapid, low-cost and on-line monitoring determination of COD.

DFNA9 is a late-onset, progressive, autosomal dominantly inherited sensorineural hearing loss with vestibular dysfunction, which is caused by mutations in the COCH (coagulation factor C homology) gene. In this study, we investigated a Chinese family segregating autosomal dominant nonsyndromic sensorineural hearing loss. We identified a missense mutation c.T275A p.V92D in the LCCL domain of COCH cosegregating with the disease and absent in 100 normal hearing controls. This mutation leads to substitution of the hydrophobic valine to an acidic amino acid aspartic acid. Our data enriched the mutation spectrum of DFNA9 and implied the importance for mutation screening of COCH in age related hearing loss with vestibular dysfunctions.

Located in Qinghai Province of China, the Three Rivers Headwaters Region is the source region of the Yangtze, Yellow and Lantsang Rivers, and plays an important role in biodiversity conservation and regulating water supply. Despite many efforts on land use change in Qinghai, knowledge of the spatial variation of land use change is still lacking. This study examines the patterns of land use change across various watersheds, prefectures and the temple surroundings. Remote sensing images of 1987, 1997 and 2007 were analyzed to derive land use distributions; patterns and structures of the landscape were then quantified with landscape metrics. The results illustrated that the Yangtze River headwater region had more diverse and more evenly distributed landscape, while the Lantsang and the Yellow headwater regions showed a decline in landscape diversity. Comparison of the land use patterns of four prefectures revealed that Yushu Prefecture experienced an increase in landscape diversity from 1987 to 2007 while the land use patches in Guoluo Prefecture exhibited more aggregated patterns than other prefectures. Analysis of the spatial variations of land use change in the temple surroundings illustrated that 19.7% and 35.9% of the temples in Guoluo and Yushu Prefectures, respectively, encountered land use change for their immediate areas within 2 km. Comparison of the surroundings of temples and human settlements found that land use change was not evenly distributed, and that greater land use change had occurred for the surroundings of human settlements. Such findings provided insights into the spatial variation of land use change in the Three Rivers Headwaters Region.

Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®.