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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®.

The identification of ecosystem health and its influencing factors is crucial to the sustainable management of ecosystems and ecosystem restoration. Although numerous studies on ecosystem health have been carried out from different perspectives, few studies have systematically investigated the spatiotemporal heterogeneity between ecosystem health and its influencing factors. Considering this gap, the spatial relationships between ecosystem health and its factors concerning climate, socioeconomic, and natural resource endowment at the county level were estimated based on a geographically weighted regression (GWR) model. The spatiotemporal distribution pattern and driving mechanism of ecosystem health were systematically analysed. The results showed the following: (1) the ecosystem health level in Inner Mongolia spatially increases from northwest to southeast, displaying notable global spatial autocorrelation and local spatial aggregation. (2) The factors influencing ecosystem health exhibit significant spatial heterogeneity. Annual average precipitation (AMP) and biodiversity (BI) are positively correlated with ecosystem health, and annual average temperature (AMT) and land use intensity (LUI) are estimated to be negatively correlated with ecosystem health. (3) Annual average precipitation (AMP) significantly improves ecosystem health, whereas annual average temperature (AMT) significantly worsens eco-health in the eastern and northern regions. LUI negatively impacts ecosystem health in western counties (such as Alxa, Ordos, and Baynnur). This study contributes to extending our understanding of ecosystem health depending on spatial scale and can inform decision-makers about how to control various influencing factors to improve the local ecology under local conditions. Finally, this study also proposes some relevant policy suggestions and provides effective ecosystem preservation and management support in Inner Mongolia.

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®.

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.

SummaryOlfactory neuroblastoma (ONB) is an uncommon malignant tumor known to originate from the olfactory epithelial. The complex tumor ecosystem of this pathology remained unclear. Here, we explored the cellular components with ONB tumors based on scRNA profiles of 96,325 single-cells derived from 10 tumors and 1 olfactory mucosa sample. We discovered 11 major cell types, including 6 immune cell, 3 stromal cell subtypes and epithelial cluster in the tumor microenvironment (TME), and identified 5 common expression programs from malignant epithelial cells. We analyzed subclusters of TME and the interactions among different cell types in the TME. An innovative three-classification of ONB was established via scRNA analysis. Markers for categorizing tumor samples into new subtypes were elucidated. Different responses towards certain chemotherapy regimens could be inferred according to the molecular features of three tumor types. Relative abundance of immunosuppressive TAMs indicated the benefits of immunotherapies targeting myeloid cells.

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 (R). 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 (R).

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®. 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®.

One new 2-arylbenzo[b]furan named iteafuranal F (1) as well as two known analogues (2–3) were isolated from the 95% EtOH extract of aerial parts of Itea omeiensis. Their chemical structures were constructed based on extensive analyses of UV, IR, 1D/2D NMR and HRMS spectra. Antioxidant assays revealed significant superoxide anion radical scavenging capacity of 1 with IC50 value of 0.66 mg/mL, which was comparable to the efficiency of positive control of luteolin. In addition, the preliminary MS fragmentation patterns in negative ion mode were established to distinguish 2-arylbenzo[b]furans with C-10 in different oxidation states: the characteristic loss of CO molecule [M-H-28]- was observed for 3-formyl-2-arylbenzo[b]furans, and the loss of CH2O fragment [M-H-30]- for 3-hydroxymethyl-2-arylbenzo[b]furans, and the loss of CO2 fragment [M-H-44]- for 2-arylbenzo[b]furan-3-carboxylic acids.

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.

The identification of ecosystem health and its influencing factors is crucial to sustainable management of ecosystem and ecosystem restoration. In spite of numerous studies on ecosystem health have been carried out in different perspectives, few studies have investigated the spatiotemporal heterogeneity between ecosystem health and its influencing factors systematically. Considering this gap, the spatial relationships between ecosystem health and its factors concerning climate, socioeconomic and natural resource endowment at the county level were estimated based on a geographically weighted regression (GWR) model. The spatio-temporal distribution pattern and driving mechanism of ecosystem health were systematically analyzed. Results showed that:(1)The ecosystem health level in Inner Mongolia spatially increases from northwest to southeast, displaying notable global spatial autocorrelation and local spatial aggregation.(2)The factors influencing ecosystem health exhibit significant spatial heterogeneity. Annual average precipitation (AMP),biodiversity(BI) was positively correlated with ecosystem health, annual average temperature(AMT) and land use intensity(LUI)are estimated to be negative.(3) Annual average precipitation (AMP) significantly improves ecosystem health, whereas annual average temperature (AMT) significantly worsens eco-health in the eastern and northern regions. LUI negatively impacts ecosystem health in western counties (such as Alxa, Ordos, and Baynnur).This study contributes to extending our understanding of ecosystem health depend on spatial scale, and could inform decision-makers about how to control various influencing factors to improve the local ecology under local conditions. Finally, this study also proposed some relevant policy suggestions and provide effective ecosystem preservation and management support in Inner Mongolia.

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.

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.

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.

The pathogenic variants in KCNQ4 cause DFNA2 nonsyndromic hearing loss. However, the understanding of genotype-phenotype correlations between KCNQ4 and hearing is limited. Here, we identified a novel KCNQ4 mutation p.G228D from a Chinese family, including heterozygotes characterized by high-frequency hearing loss that is progressive across all frequencies and homozygotes with more severe hearing loss. We constructed a novel murine model with humanized homologous Kcnq4 mutation. The heterozygotes had mid-frequency and high-frequency hearing loss at 4 weeks, and moved toward all frequencies hearing loss at 12 weeks, while the homozygotes had severe-to-profound hearing loss at 8 weeks. The degeneration of outer hair cells (OHCs) was observed from basal to apical turn of cochlea. The reduced K

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.

Kearns–Sayre Syndrome (KSS) is a severe mitochondrial disorder involving the central nervous system, eyes, ears, skeletal muscles, and heart. The mitochondrial DNA (mtDNA) rearrangements, especiall...

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.

Hearing loss is the most common sensory neural disorder in human, and according to WHO estimation, 5.5% (466 million) 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, a homozygous mutation c.2372delC, p.S791Ffs*17 was identified in PDZD7. The deletion mutation lies in exon 15 of PDZD7 and resultes in a frame shift followed by an early stop codon. Our study expand the mutation spectrum of PDZD7 and strengthens the clinical importance of this gene in patients with moderately-severe hearing loss.

The urban green space (UGS) is essential for characterizing urban spatial configurations, ecological properties and environmental conservation. Thus, the urban green space is fundamental to urban planning management and renewal. UGS is mainly composed of park green areas, which are the public service facility providing people with outdoor activity spaces, so that UGS has a great impact on the protection of residents’ mental and physical health. Therefore, the reasonable layout of urban green space is of great significance. In this study, we took central area of Chongqing City as an example to study the accessibility of urban green spaces using very-high-resolution (VHR) remote sensing images by the network analysis model. The result showed that (1) both the spatial distribution information of urban green spaces and road network can be presented to provide urban-function information using VHR; (2)the accessible service area of urban green spaces in the study area accounted for 27.80% within 45 minutes;(3) and the equity of accessibility of UGS in Yuzhong District was the best.The accessibility analysis of urban green spaces is the basis of sustainable urban Planning.

Urban green space (UGS), as public services facilities that provide lots of outdoor space for people’s activities and exercise, has a significant impact on urban residents' social, psychological, and physical benefits. The reasonable distribution of the urban green space is of great significance for enhancing the overall well-being of urban dwellers. In this study, we selected Wuhan City center as a research area, extracted the spatial distribution information of urban green space, roads networks from high-resolution remote sensing images in 2019. The urban green space service situation in different travel modes, travel times, and parks types are subsequently calculated with a network analysis model in GIS. The results showed that the services area of urban green space in the city center of Wuhan was within a driving distance of 30 min, accounting for 70.38% of the total study area, and the use of high-resolution remote images spatial data can measure equity on a more precise scale.

Context The Sanjiangyuan region of the Qinghai-Tibetan Plateau—also known as the “Three Rivers’ Headwaters”—is the origin of the Yellow, Yangtze, and Mekong Rivers and therefore the key water source for hundreds of millions of downstream residents. Protecting this region’s ecosystems is a key priority for sustainable development in China and Asia. An important social dimension of Sanjiangyuan is the long-established and widespread presence of Tibetan Buddhism, particularly as manifested in the large number of monasteries throughout the region. However, the influence of cultural factors on environmental change remains largely understudied here. Objective We focus on two types of spatial associations—point-point and point-area features—to quantitatively investigate the effects of Buddhist monasteries on land use/cover change (LUCC) in surrounding landscapes. Methods We conduct a spatially-explicit analysis of Sanjiangyuan for two periods, 1990–2000 and 2010–2015, to identify and quantify the influence of the presence and spatial distributions of Buddhist monasteries on LUCC compared to village communities that lack monasteries. Results We found that the presence of monasteries is highly correlated with the preservation of natural ecosystems, specifically of grasslands and forests. Within monastery buffer zones with radii between 1 and 10 km, 7.13–9.30% more grassland area and 7.14–7.47% more forest area remained around monasteries compared to villages. This contrast decreased with increasing distance to the monastery/village. Overall, built-up areas were also much smaller around monasteries than around villages, while unused land was more commonly transformed to forests and grasslands around monasteries. Conclusions These findings strongly support the idea that Buddhist culture, as manifested through its physical institutions and communities, are instrumental in achieving desired landscape conservation outcomes.

The combined impacts of drastic natural environment change and increasing human interference are making the uncertainty of the Tibetan Plateau’s ecological vulnerability the world’s largest. In this study, an ecological vulnerability index (EVI) of Tibet in the core area of the Tibetan Plateau was assessed using a selected set of ecological, social, and economic indicators and using a spatial principal component analysis (SPCA) to calculate their weights. The data included Landsat images and socio-economic data from 1990 to 2015 in five-year intervals. The results showed that the total EVI remained at a high vulnerability level, with drastic fluctuation from 1990 to 2000 (a peak in 1995, when there was a sudden increase in light vulnerability, which moved to extreme vulnerability in the next period), and minor fluctuations after 2000, gradually increasing from southeast to northwest. In addition, the spatial analysis showed a distinct positive correlation between the EVI and grassland area (0.33), land use degree (0.15), NDVI (0.14), livestock husbandry output, and a negative correlation in terms of desertification area. The artificial afforestation program (AAP) had a positive significant correlation with NDVI (R2 = 0.88), preventing the environment from becoming more vulnerable. The results provide practical information and suggestions for planners to improve the land use degree in urban areas and the vegetation coverage in pastoral regions of the Tibetan Plateau based on the spatial–temporal heterogeneity patterns of the EVI of Tibet.

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.

Myosin VI is an actin-associated molecular motor vital for auditory and vestibular function. It is encoded by MYO6 located on chromosome 6q13 in human. Pathogenic variants in MYO6 have been associated with both dominant and recessive forms of hearing loss. However, the molecular mechanisms remain unclear. We established a humanized knock-in mouse model, Myo6-C442Y, to mimic the p.C442Y missense variant identified in human patients with autosomal dominant nonsyndromic hearing loss designated as DFNA22. We characterized hearing and inner ear morphologies of Myo6-C442Y and wild-type control mice. We found that both homozygous and heterozygous Myo6-C442Y mice exhibited hearing loss from three weeks after birth that rapidly progressed to profound deafness by six to nine weeks of age. The hearing loss corresponded to the degeneration of hair cells in the organ of Corti. We also observed disorganized stereocilia with irregular morphological features by immunohistochemistry and scanning electron microscopy. Additionally, hearing loss and inner-ear morphological anomalies were more pronounced and deteriorated more drastically in homozygous than in heterozygous Myo6-C442Y mice, indicating a semi-dominant inheritance pattern. Heterozygous Myo6-C442Y mice recapitulated the progressive postlingual sensorineural deafness in human, thus providing a useful model for elucidating the role myosin VI plays in the mammalian auditory system. Furthermore, the late-onset hearing loss of this mouse model may provide a therapeutic window for the emerging gene therapy, a promising strategy to treat certain forms of genetic deafness.

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.

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.

The karst region of Southwest China is one of the largest continuous karst areas in the world, and the ecosystem in the karst region is extremely fragile. The city of Liupanshui, a typical karst area in southwestern China, has provided the main energy and raw materials during China&rsquo, s rapid urbanization in the past few decades. With the continuous deterioration of the environment in Liupanshui and from the viewpoint of sustainable development strategies, research on ecosystem health (ESH) and the assessments of correlations between urbanization and ESH plays an important role in regional sustainable eco-environmental development. Therefore, the impact of urbanization on the ecosystem health of the study area was discussed in this study using a series of remote sensing images and socio-economic data from 1990 to 2015. Studies showed that Liupanshui is undergoing rapid urbanization, and the growth of urbanized land reached a peak between 2010 and 2015. From 1990 to 2015, the level of ESH in Liupanshui trended downward and then increased. During 2000 to 2010, due to the policy of returning farmland to grassland and forestland, the substantial increase in woodland and grassland and the management policy of mining areas have caused a turn in ESH. Although the value of ecosystem health in 2010&ndash, 2015 increased, the process of urbanization is rapid, so we should pay more attention to the trend in future ecosystem health changes. The findings revealed that urbanization significantly negatively affects the ecosystem health of Liupanshui, and mining has the greatest impact. Therefore, in future urban development, strengthening the management of resource extraction and the supervision of environmental protection, continuing to return farmland to grassland and forestry, and controlling rocky desertification can improve the health of the urban ecosystem in the study area.

Sensory hair cells (HCs) are highly susceptible to damage by noise, ototoxic drugs, and aging. Although HCs cannot be spontaneously regenerated in adult mammals, previous studies have shown that signaling pathways are involved in HC regeneration in the damaged mouse cochlea. Here, we used a Notch antagonist (DAPT), a Wnt agonist (QS11), and recombinant Sonic hedgehog (SHH) protein to investigate their concerted actions underlying HC regeneration in the mouse cochlea after neomycin-induced damage both in vivo and in vitro. With DAPT, the numbers of HCs increased, and supporting cell (SC) proliferation was seen in both the intact and damaged cochlear sensory epithelia, while these numbers were unchanged in the presence of QS11. When simultaneously treated with DAPT and QS11, the number of HCs increased dramatically, and much greater SC proliferation was seen in the cochlear epithelium. In transgenic mice with both Notch1 conditional knockout and β-catenin over-expression, cochlear SC proliferation and HC regeneration were more obvious than in either Notch1 knockout or β-catenin over-expressing mice separately. When cochleae were treated with DAPT, QS11, and SHH together, SC proliferation was even greater, and this proliferation was seen in both the HC region and the greater epithelial ridge. High-throughput RNA sequencing was used to identify the differentially expressed genes between all groups, and the results showed that the SHH and Wnt signaling pathways are involved in SC proliferation. Our study suggests that co-regulation of the Notch, Wnt, and SHH signaling pathways promotes extensive cell proliferation and regeneration in the mouse cochlea.

Hong Liu,1,2 Yan-li Zhan,2,3 Guo-jing Luo,2,4 Ling-ling Zou,2,5 Yun Li,2 Hong-yun Lu2,4 1Department of Nutrition, The Third Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 2Department of Endocrinology & Metabolism, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, People’s Republic of China; 3Department of Rheumatology, Jiaozuo People’s Hospital, Jiaozuo, Henan, People’s Republic of China; 4Department of Endocrinology & Metabolism, Zhuhai Hospital Affiliated with Jinan University, Zhuhai People’s Hospital, Zhuhai, Guangdong, People’s Republic of China; 5Department of Endocrinology, The Second People’s Hospital of Hefei, Anhui, People’s Republic of ChinaCorrespondence: Hong-yun LuDepartment of Endocrinology & Metabolism, The Fifth Affiliated Hospital of Sun Yat-Sen University, No. 52 Meihua East Road, Zhuhai, Guangdong 519000, People’s Republic of ChinaTel +86 756-252 8741Fax +86 75 6252 8300Email luhongy@mail.sysu.edu.cnBackground: Glucagon-like peptide-1 (GLP-1) has been reported to have beneficial impacts on improving human’s metabolism and ameliorating insulin resistance. While insulin is another important and conventional drug in diabetes treatment, but it has an adverse effect on weight gain.Purpose: To make sure whether GLP-1 and insulin play different roles in human adipose-derived stem cells (hADSCs).Methods: We examined the in vitro roles and molecular mechanisms of liraglutide, a GLP-1 analogue, and human insulin on hADSCs isolated from subcutaneous adipose tissue. Different concentrations (0, 0.1, 1, 10, 100nM) of liraglutide and insulin were added to proliferation and differentiation medium of hADSCs, respectively.Results: Liraglutide inhibits while insulin promotes the proliferation and differentiation at the concentration of 100nM. Moreover, the levels of GSK-3 increase during differentiation and liraglutide could down-regulate it when compared with insulin. We also find that the activation of phosphorylated GSK-3α and GSK-3β is involved in the differentiation roles. And classical and non-classical Wnt pathways all play roles in the differentiation, which are characterized with the up/down-regulation of the expression of adipogenesis genes such as PPAR-γ and CEBP-α.Conclusion: Liraglutide and insulin have contrary effects on the proliferation and adipogenesis via Wnt pathway in primary cultured ADSCs. Those effects could partly explain the different roles of GLP-1 and insulin on weight gain and insulin resistance.Keywords: liraglutide, insulin, human adipose-derived stem cells, obesity, Wnt signaling pathway

Rapid urbanization has caused a reduction in green lands, negatively affecting the functions of ecosystem services (ESs). The 11th goal and other goals of the United Nations Sustainable Development Goals (SDGs) have highlighted the importance of the balanced development of cities and the environment. ESs are essential for human well-being, so their application in sustainable development study is indispensable. The ecological security pattern (ESP) provides an integrated strategy for maintaining a balance between a sustainable supply of ESs and urbanization. However, establishing an ESP with the goal of satisfying human requirements for ESs in a rapidly urbanizing area has not been well studied. Thus, it is necessary to build an ESP based on ecosystem service value (ESV) reconstruction to manage urban ecosystems sustainably. Based on land use data and field data, this study approached the research gap by related analyses. The first analysis involved dynamic reconstruction of ESVs using the static ESV and importance indices of ESs from 1999&ndash, 2013. The second analysis involved using hot spot analysis (Getis-Ord Gi * statistics) to distinguish heterogeneous units of the dynamic ESV to identify ecological sources. The third analysis involved establishing the ESP in Zhuhai city, using the minimum cumulative resistance (MCR) model. The results indicated that the ESV of Zhuhai city displayed an upward trend. The functions of water conservation and waste treatment contributed most to the total ESV, while grain production and raw material contributed least in the study area. In the restructuring of ESVs in 2005, 2009, and 2013, the per unit area of the ESV decreased slightly. The areas with high ESVs continued to shrink, while the areas with low ESVs gradually expanded. The ESP of Zhuhai city exhibits great connectivity and strong plasticity, which specifically provides a reliable and visual way to build sustainable cities from a quantitative perspective, generally consistent with the urban ecological planning of Zhuhai city. This study provides an important reference for the application of ESs to achieve SDGs in coastal, rapidly urbanizing regions.

The Green-for-Grain program (GGP) is the largest environmental restoration program in China. It is effective in controlling land desertification but at the same time is highly affected by regional differences. Ecosystem health, as an important indicator of ecosystem sustainability, can effectively assess the ecological impact of the GGP and provide a basis for follow-up actions. As a typical agro-pastoral ecotone along the Great Wall, the Xilin Gol League has seen increasing land-use intensity, thus, it is crucial to understand the ecological conditions of the region in order to deploy a policy of the GGP in accordance with local conditions. In this study, using remote sensing images and social statistics data from 1990–2015, land-use transformation and the turning point of vegetation coverage was determined. Based on the pressure-state-response (PSR) model, an ecological health evaluation system was constructed to quantify the temporal and spatial variation of ecosystem health. Then, the spatial correlation between the changes in forest and grass coverage, as well as the changes in the ecosystem health index (EHI), was evaluated using GeoDa software. The results showed that (1) grassland was the primary land-use/land-cover (LULC) in the Xilin Gol League. Since 2000, land-use transfer types changed significantly and grassland degradation weakened; landscape connectivity increased, and vegetation coverage increased. (2) Over the past 25 years, the ecosystem in the study area was at a subhealthy level and showed a trend toward a healthy level. (3) The spatial correlation between △Area% (change in forest and grass coverage) and △EHI (change in ecosystem health index) was positive between 2000 and 2015 and the correlation gradually increased, indicating that the GGP did enhance the health of the ecosystem of Xilin Gol. This study provided a specific reference for the evaluation of ecosystem health in the agro-pastoral ecotone of China and a theoretical basis for the implementation of sustainable management policies in the study area.