Comprehensive analysis of ADA2 genetic variants and estimation of carrier frequency driven by a function-based approach.

BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is an autoinflammatory disease caused by deleterious ADA2 variants. The frequency of these variants in the general population, and hence the expected disease prevalence, remain unknown. OBJECTIVE: We aimed to characterize the functional impact and carrier frequency of ADA2 variants. METHODS: We performed functional studies and in silico analysis on 163 ADA2 variants, including DADA2-associated variants and population variants identified in the Genome Aggregation Database. We estimated the carrier rate using the aggregate frequency of deleterious variants. RESULTS: Functional studies of ADA2 variants revealed that 77 (91%) of 85 of DADA2-associated variants reduced ADA2 enzymatic function by >75%. Analysis of 100 ADA2 variants in the database showed a full spectrum of impact on ADA2 function, rather than a dichotomy of benign versus deleterious variants. We found several in silico algorithms that effectively predicted the impact of ADA2 variants with high sensitivity and specificity, and confirmed a correlation between the residual function of ADA2 variants in vitro and the plasma ADA2 activity of individuals carrying these variants (n = 45; r = 0.649; P < .0001). Using <25% residual enzymatic activity as the cutoff to define potential pathogenicity, integration of our results with the database population data revealed an estimated carrier frequency of at least 1 in 236 individuals, corresponding to an expected DADA2 disease prevalence of ~1 in 222,000 individuals. CONCLUSIONS: Functional annotation guides the interpretation of ADA2 variants to create a framework that enables estimation of DADA2 carrier frequency and disease prevalence.

Strategy of Enhancing Built-in Field to Promote the Application of C-TiO2 /SnO2 Bilayer Electron Transport Layer in High-Efficiency Perovskite Solar Cells (24.3%).

Combining two kinds of electron transport layer (ETL) which have complementary advantages into a bilayer structure to form a bilayer ETL is an effective way to transcend inherent limitations of single-layer ETL, which is very helpful in the development of perovskite solar cells (PSCs). In this work, a strategy is proposed to break constraints on the application of the staggered bilayer ETL in high-efficiency PSC, namely utilizing a built-in field to overcome the dilemma in ECBM making it possible to improve VOC and FF simultaneously by tuning the Fermi level of ETLs properly. According to the strategy, a bilayer ETL structure comprised of C-TiO2 and SnO2 layer and corresponding Li-doping process are developed, and the characterization results confirm the effectiveness of the strategy, making the potentials of the C-TiO2 (Li)/SnO2 bilayer ETL fully released for its application in high-efficiency PSCs: a VOC of 1.201 V for an ordinary triple-cation-perovskite-based PSC and a photoelectric conversion efficiency of 24.3% for a low-bandgap-perovskite-based PSC with high haze FTO superstrate are successfully achieved, indicating that the C-TiO2 (Li)/SnO2 bilayer ETL is a successful application paradigm of the proposed strategy and very promising in the application of high-efficiency PSCs.

Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2).

BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is a syndrome with pleiotropic manifestations including vasculitis and hematologic compromise. A systematic definition of the relationship between adenosine deaminase 2 (ADA2) mutations and clinical phenotype remains unavailable. OBJECTIVE: We sought to test whether the impact of ADA2 mutations on enzyme function correlates with clinical presentation. METHODS: Patients with DADA2 with severe hematologic manifestations were compared with vasculitis-predominant patients. Enzymatic activity was assessed using expression constructs reflecting all 53 missense, nonsense, insertion, and deletion genotypes from 152 patients across the DADA2 spectrum. RESULTS: We identified patients with DADA2 presenting with pure red cell aplasia (n = 5) or bone marrow failure (BMF, n = 10) syndrome. Most patients did not exhibit features of vasculitis. Recurrent infection, hepatosplenomegaly, and gingivitis were common in patients with BMF, of whom half died from infection. Unlike patients with DADA2 with vasculitis, patients with pure red cell aplasia and BMF proved largely refractory to TNF inhibitors. ADA2 variants associated with vasculitis predominantly reflected missense mutations with at least 3% residual enzymatic activity. In contrast, pure red cell aplasia and BMF were associated with missense mutations with minimal residual enzyme activity, nonsense variants, and insertions/deletions resulting in complete loss of function. CONCLUSIONS: Functional interrogation of ADA2 mutations reveals an association of subtotal function loss with vasculitis, typically responsive to TNF blockade, whereas more extensive loss is observed in hematologic disease, which may be refractory to treatment. These findings establish a genotype-phenotype spectrum in DADA2.

Adenosine deaminase 2 as a biomarker of macrophage activation syndrome in systemic juvenile idiopathic arthritis.

OBJECTIVE: Macrophage activation syndrome (MAS) is a life-threatening complication of systemic juvenile idiopathic arthritis (sJIA) characterised by a vicious cycle of immune amplification that can culminate in overwhelming inflammation and multiorgan failure. The clinical features of MAS overlap with those of active sJIA, complicating early diagnosis and treatment. We evaluated adenosine deaminase 2 (ADA2), a protein of unknown function released principally by monocytes and macrophages, as a novel biomarker of MAS. METHODS: We established age-based normal ranges of peripheral blood ADA2 activity in 324 healthy children and adults. We compared these ranges with 173 children with inflammatory and immune-mediated diseases, including systemic and non-systemic JIA, Kawasaki disease, paediatric systemic lupus erythematosus and juvenile dermatomyositis. RESULTS: ADA2 elevation beyond the upper limit of normal in children was largely restricted to sJIA with concomitant MAS, a finding confirmed in a validation cohort of sJIA patients with inactive disease, active sJIA without MAS or sJIA with MAS. ADA2 activity strongly correlated with MAS biomarkers including ferritin, interleukin (IL)-18 and the interferon (IFN)-γ-inducible chemokine CXCL9 but displayed minimal association with the inflammatory markers C reactive protein and erythrocyte sedimentation rate. Correspondingly, ADA2 paralleled disease activity based on serial measurements in patients with recurrent MAS episodes. IL-18 and IFN-γ elicited ADA2 production by peripheral blood mononuclear cells, and ADA2 was abundant in MAS haemophagocytes. CONCLUSIONS: These findings collectively identify the utility of plasma ADA2 activity as a biomarker of MAS and lend further support to a pivotal role of macrophage activation in this condition.

Core-sheath micro/nano fiber membrane with antibacterial and osteogenic dual functions as biomimetic artificial periosteum for bone regeneration applications.

The traditional Chinese medicine icariin (ICA) and broad-spectrum antibacterial drug moxifloxacin hydrochloride (MOX) were introduced into a polycaprolactone core and gelatin shell, respectively, to develop osteogenic and antibacterial biomimetic periosteum by coaxial electrospinning. The physical properties, drug release, degradation, antibacterial property, in vitro and in vivo osteogenesis performances were investigated. Results demonstrated that stepwise and controlled drug release profiles were achieved based on the core-shell configuration and disparate degradation rate of PCL and gelatin. Only 20% ICA was released from this dual drug-loaded membrane after 1 month while the release of MOX was almost completed. Moreover, clear in vitro antibacterial effect and enhancement in osteogenic marker expressions including osteocalcin, type-I collagen expression, and calcium deposition were observed. Notably, the dual drug-loaded membrane displayed fascinating properties contributing to in vivo bone formation in terms of quality and quantity in a rabbit radius defect model.

Barrier Strategy for Strain-Free Encapsulation of Perovskite Solar Cells.

The performance loss caused by encapsulation has been an obstacle to guarantee the excellent power conversion efficiency of perovskite solar cells (PSCs) in practical application. This work revealed that the encapsulation-induced performance loss is highly related to the tensile strains imposed on the functional layers of the device when the PSC is exposed directly to the deformed encapsulant. A barrier strategy is developed by employing a nonadhesive barrier layer to isolate the deformed encapsulant from the PSC functional layer, achieving a strain-free encapsulation of the PSCs. The encapsulated device with a barrier layer effectively reduced the relative performance loss from 21.4% to 5.7% and dramatically improved the stability of the device under double 85 environment conditions. This work provides an effective strategy to mitigate the negative impact of encapsulation on the performance of PSCs as well as insight into the underlying mechanism of the accelerated degradation of PSCs under external strains.

Amino Pyridine Iodine as an Additive for Defect-Passivated Perovskite Solar Cells.

Defect passivation of the perovskite surface and grain boundary (GBs) has become a widely adopted approach to reduce charge recombination. Research has demonstrated that functional groups with Lewis acid or base properties can successfully neutralize trap states and limit nonradiative recombination. Unlike traditional Lewis acid-base organic molecules that only bind to a single anionic or cationic defect, zwitterions can passivate both anionic and cationic defects simultaneously. In this work, zwitterions organic halide salt 1-amino pyridine iodine (AmPyI) is used as a perovskite for defect passivation. It is found that a pair of amino lone electrons in AmPyI can passivate defects surface and GBs through hydrogen bonding with perovskite, and the introduced I- can bind to uncoordinated Pb2+ while also controlling the surface morphology of the film and improving the crystallinity. In the presence of the AmPyI additive, we obtained about 1.24 µm of amplified perovskite grains and achieved an efficiency of 23.80% with minimal hysteresis.

One-Step Formation of Low Work-Function, Transparent and Conductive MgFx Oy Electron Extraction for Silicon Solar Cells.

The development of high-performance dopant-free silicon solar cells is severely bottlenecked by opaque electron selective contact. In this paper, high transmittance (80.5% on glass) and low work function (2.92 eV) lithium fluoride (LiFx )/MgFx Oy electron contact stack by tailoring the composition of MgFx Oy hybrid film is reported. This hybrid structure exhibits a high conductivity (2978.4 S cm-1 ) and a low contact resistivity (2.0 mΩ cm2 ). The element profile of LiFx /MgFx Oy contact is measured and the reaction kinetics is analyzed. As a proof-of-concept, this electron selective contact is applied for dopant-free silicon solar cells. An impressive efficiency of 21.3% is achieved on dopant-free monofacial solar cell with molybdenum oxide (MoOx )/zinc-doped indium oxide (IZO) hole contact. An efficiency bifaciality of 71% is obtained for dopant-free bifacial solar cell with full-area LiFx /MgFx Oy /ITO (tin-doped indium oxide) transparent electron contact. It is the highest efficiency bifaciality so far for dopant-free bifacial solar cells to the best knowledge. Both cell configurations with LiFx /MgFx Oy contacts show excellent environment stability. The cell efficiency maintains more than 95% of its initial value after keeping in air for 1500 h. This work provides a new idea to achieve transparent electron contact, showing a great potential for high-efficiency and low-cost optoelectronic devices.

Dietary Patterns Are Associated With Multi-Dimensional Cognitive Functions Among Adults Aged 55 and Older in China.

BACKGROUND: The intake of certain food and nutrients may play a crucial role in cognitive health. However, research on the relationship between dietary patterns and cognitive function is limited. This study aims to investigate the associations between dietary patterns and multi-dimensional cognitive functions, such as global cognitive status and related domain profiles, mild cognitive impairment (MCI), and four major subtypes of Chinese adults. METHODS: Using the baseline data from the Community-based Cohort Study on Nervous System Diseases (2018-2019), we selected 4,309 Chinese adults aged 55 years and older as subjects with complete diet, cognition, and other related data. We collected food data for the past 12 months with a valid semi-quantitative food frequency questionnaire. Diving 49 food items into 13 subgroups, we used factor analysis to derive the main dietary patterns. We evaluated cognitive functions based on the scores of the Montreal Cognitive Assessment (MoCA) and used quantile regression and multivariable logistic regression to examine the relationship between dietary patterns and cognitive-related outcomes. RESULTS: We identified four dietary patterns, explaining 50.11% of the total variance: "meat-preferred" pattern, "plant-preferred" pattern, "eggs- and dairy-preferred" pattern, and "grain-preferred" pattern. After adjusting for all potential confounders, the "meat-preferred" pattern and the "plant-preferred" pattern were associated with higher scores of global cognition and several cognitive domains (p <0.05), while the "grain-preferred" pattern was associated with lower scores of global cognition (ß = -0.36, p <0.05), execution (ß = -0.19, p <0.05), visuospatial (ß = -0.09, p <0.05), and language (ß = -0.05, p <0.05). Adults adhering to the "meat-preferred" pattern and the "plant-preferred" pattern had decreased odds of MCI and some MCI subtypes (p-trend <0.05); in contrast, those in the top quartiles of the "grain-preferred" pattern had increased odds of MCI [adjusted odds ratio (AOR) = 1.34, 95% CI: 1.11-1.63, p-trend = 0.003]. CONCLUSIONS: Adhering to the "plant-preferred" pattern and the "meat-preferred" pattern may help improve the multi-dimensional cognitive functions; on the contrary, adhering to the "grain-preferred" pattern may worse cognitive health. More prospective studies in this field are needed to strengthen the evidence.

The efficacy of dexmedetomidine for the prevention of catheter-related bladder discomfort: A systematic review and meta-analysis.

BACKGROUND: The effective therapy to reduce postoperative catheter-related bladder discomfort (CRBD) remained unknown. OBJECTIVE: We attempted to manage the systematic review and a meta-analysis to clarify the efficacy of dexmedetomidine (DEX) in potential prevention on CRBD. METHODS: We performed the meta-analysis on randomized clinical trials (RCTs), and searched the databases from Web of Sciences, Embase and referred Cochrane Library published from October 2016 to September 2020. Data extraction was carefully conducted by 2 authors, respectively. Meta-analysis that was applied synthetically concerns the incidence and severity of CRBD and the treatment effect of DEX on CRBD. RESULTS: We acquired 5 RCTs with interventions of DEX on CRBD. Meta-analysis showed DEX has significantly reduced the incidence and severity of CRBD compared with control at 0 hour (risk ratios [RR] = 0.40, 95% CI = 0.53-0.29, P < .01), 1 hour (RR = 0.44, 95% CI = 0.34-0.57, P < .01), and 2 hours (RR = 0.43, 95% CI = 0.32-0.58, P < .01) and 6 hours (RR = 0.43, 95% CI = 0.29-0.63, P < .01). DEX was also associated with lower incidence of moderate to severe CRBD at 0, 1, and 6 hours after surgery. There were no significant differences in adverse events other than bradycardia, hypotension, and hypertension. CONCLUSION: The 5 RCTs showed great effectiveness in reducing the incidence and severity of the early and later postoperative CRBD. Meta-analysis showed that DEX interventions were useful in preventing the early and later postoperative CRBD without significant side effects.

Effective delivery of mitomycin-C and meloxicam by double-layer electrospun membranes for the prevention of epidural adhesions.

Epidural adhesion between the spinal dura and the surrounding fibrous tissue often occurs post-laminectomy, resulting in clinical symptoms such as nerve compression and severe pain. In this study, we report a drug-loaded double-layered electrospun nanofiber membrane to prevent the occurrence of epidural adhesion. The nanofibers in both layers are made of a mixture of polycaprolactone (PCL) and chitosan (CS) but at different weight ratios. The bottom layer contacting to the spinal dura is loaded with meloxicam (MX) to prevent inflammation. The top layer that contacts to the fibrous tissue is doped with mitomycin-C (MMC) to inhibit the synthesis of DNA and collagen. The two types of drugs are released from the double-layered membrane within about 12 days. Meanwhile, the membrane can inhibit fibroblasts proliferation in vitro while show no cytotoxicity. In a rabbit laminectomy model, the double-layered membrane can effectively prevent the epidural adhesion formation based on the adhesion scores, histological and biochemical evaluations. The combination release of MX and MMC can signally reduce the inflammation reaction and collagen I/III expression relative to the case with the membranes loaded with only either one type of the drugs. This approach offers new progresses in constructing dual drug delivery system and provides innovative barrier strategy in inhibiting epidural adhesion post-laminectomy.

Projection of premature mortality from noncommunicable diseases for 2025: a model based study from Hunan Province, China, 1990-2016.

BACKGROUND: In 2011, the United Nations set a target to reduce premature mortality from non-communicable diseases (NCDs) by 25% by 2025. While studies have reported the target in some countries, no studies have been done in China. This study aims to project the ability to reach the target in Hunan Province, China, and establish the priority for future interventions. METHODS: We conducted the study during 2019-2020. From the Global Burden of Disease Study 2016, we extracted death data for Hunan during 1990-2016 for four main NCDs, namely cancer, cardiovascular disease (CVD), chronic respiratory diseases, and diabetes. We generated estimates for 2025 by fitting a linear regression to the premature mortality over the most recent trend identified by a joinpoint regression model. We also estimated excess premature mortality attributable to unfavorable changes over time. RESULTS: The rate of premature mortality from all NCDs in Hunan will be 19.5% (95% CI [19.0%-20.1%]) by 2025, with the main contributions being from CVD (8.2%, 95% CI [7.9%-8.5%]) and cancer (7.9%, 95% CI [7.8%-8.1%]). Overall, it will be impossible to achieve the target, with a relative reduction of 16.4%. Women may be able to meet the target except with respect to cancer, and men will not except with respect to chronic respiratory diseases. Most of the unfavorable changes have occurred since 2008-2009. DISCUSSION: More urgent efforts, especially for men, should be exerted in Hunan by integrating population-wide interventions into a stronger health-care system. In the post lock-down COVID-19 era in China, reducing the NCD risk factors can also lower the risk of death from COVID-19.

Oxidization-Free Spiro-OMeTAD Hole-Transporting Layer for Efficient CsPbI2Br Perovskite Solar Cells.

The inorganic CsPbI2Br perovskite faces serious challenges of low phase stability and high moisture sensitivity. The moisture controllable process of a hole-transporting layer (HTL) is crucial for the development of stable and efficient inorganic perovskite solar cells (IPSCs). In this work, we proposed an oxidization-free spiro-OMeTAD hole-transport layer (HTL) with a preoxidized spiro-OMeTAD solution to prevent moisture and completely avoid the phase transition of CsPbI2Br from the α-phase to ß-phase. The oxidization-free HTL exhibited improved surface hydrophobic properties, smoother morphology, and optimized energy-level alignment compared with a traditional HTL. As a result, the CsPbI2Br-based IPSCs achieved an efficiency of up to 14.2 and 86.6% of the initial power conversion efficiency (PCE) with 2000 h storage. Meanwhile, this oxidization-free HTL was applied in CH3NH3PbI3-based PSCs and obtained 13.8% PCE enhancement, which proved the universality of the solution preoxidization tactic. We believe that the oxidization-free HTL could be an efficient strategy to replace traditional HTLs and can be widely used in perovskite solar cells, especially in moisture-sensitive PSCs.

Nicotinamide as Additive for Microcrystalline and Defect Passivated Perovskite Solar Cells with 21.7% Efficiency.

Passivation of electronic defects on the surface and at grain boundaries (GBs) of perovskite films has become one of the most effective tactics to suppress charge recombination in perovskite solar cells. It is demonstrated that trap states can be effectively passivated by Lewis acid or base functional groups. In this work, nicotinamide (NTM, commonly known as vitamin B3 or vitamin PP) serving as a Lewis base additive is introduced into the PbI2 and/or FAI: MABr: MACl precursor solution to obtain NTM modified perovskite films. It has been found that the NTM in the perovskite film can well passivate surface and GBs defects, control the film morphology and enhance the crystallinity via its interaction with a lone pair of electrons in nitrogen. In the presence of the NTM additive, we obtained enlarged perovskite crystal grain about 3.6 µm and a champion planar perovskite solar cell with efficiency of 21.72% and negligible hysteresis. Our findings provide an effective route for crystal growth and defect passivation to bring further increases on both efficiency and stability of perovskite solar cells.

Rising from the Ashes: Gaseous Therapy for Robust and Large-Area Perovskite Solar Cells.

Scalable fabrication of perovskite solar cells (PSCs) with high reliability is one of the most pivotal concerns that must be addressed before they get into the photovoltaic (PV) market. Scaling large-area high-quality perovskite films is of great importance in this process. Here, gaseous therapy has been proposed for the post-treatment of perovskite films with high scalability and low cost. An inspiring evolvement from poor perovskite films to high quality ones is demonstrated under a joint treatment of methylamine gas and hot solvent vapors. The perovskite films are completely reconstructed and repaired regardless of the morphology of the original films. As a consequence, small-area (0.09 cm2) and large-area (4 cm2) PSCs based on the healed MAPbI3 films can afford J-V scanned efficiencies of 19.2 and 16.5% under a reverse sweep, respectively. Furthermore, stabilized power outputs of 18.5 and 15.2% are obtained from the small one and large one under continuous maximum power point tracking.

Effects of Annealing Time on Triple Cation Perovskite Films and Their Solar Cells.

Cesium (Cs) contained triple-cation and mixed halide perovskite (CsFAMA) is broadly employed as light absorption layers for efficient and stable perovskite solar cells (PSCs) fabrication with high reproducibility. On the other hand, thermal annealing is a universal post-treatment method for perovskite films preparation. Moreover, thermal management highly depends on perovskite materials. However, no specialized study has been reported on CsFAMA perovskite to date. Herein, we have systematically investigated the influence of thermal annealing and annealing time on CsFAMA films and their solar cells. We demonstrated that heating time of 45 or 60 min at 100 °C is desirable. More interestingly, we found that the unannealed CsFAMA films exhibit ultrahigh photoluminescence (PL) intensities, much stronger than that of annealed films. Note that PL intensities gradually weaken as a function of annealing time. In particular, the PL intensities of fresh films (after antisolvent dripping) are at least 200 times higher than that of 60 min annealed films. To our knowledge, it is the first time to report this PL behavior. We speculate that it is due to quantum confinement effect of perovskite crystal nuclei and "cage effect" of DMSO intermediates in the fresh films. To this point, the unannealed CsFAMA films may have great potential in PL emission applications.

An assessment for health education and health promotion in chronic disease demonstration districts: a comparative study from Hunan Province, China.

BACKGROUND: Cost-effective strategies of chronic disease control, integrated health education and health promotion play important roles in the programs of chronic disease demonstration districts in China. The performance of these districts can be directly assessed by their health education and promotion work. However, there have been only a few performance assessments done on these programs, most of which made without the inclusion of proper quality indicators. This study was designed to establish a framework of indicators for outcome evaluation of health education and promotion efforts in Chinese districts, and explore the factors involved in promoting these efforts. METHODS: A modified two-round Delphi survey was first used to construct quality indicators on a nine-point Likert scale. With those indicators, the rank sum ratio (RSR) method was then conducted through rank conversion and parametric statistics, to assess and classify the performance of ten districts or counties randomly chosen both from demonstration and non-demonstration districts in the Hunan province. RESULTS: The Delphi process produced seven themes and 25 sub-themes as quality indicators. The seven themes included organizational management, financial support, professional personnel, health education and promotion, residents' health awareness and behaviors, residents' satisfaction, and residents' health literacy. The districts were classified into four levels by RSR as follows: One demonstration district at the first-ranked level, five other demonstration districts at the second-ranked level, all non-demonstration districts at the third-ranked level. None were at the fourth-qualified level. DISCUSSION: Chronic disease demonstration districts performed better on the work of health education and health promotion than the non-demonstration districts. The work should be focused on the following measures of chronic diseases: organizational management, financial support, media-related broadcasting, technical support, community-based promotion and supportive environment, and people's enhanced awareness and health literacy.

Current advances for bone regeneration based on tissue engineering strategies.

Bone tissue engineering (BTE) is a rapidly developing strategy for repairing critical-sized bone defects to address the unmet need for bone augmentation and skeletal repair. Effective therapies for bone regeneration primarily require the coordinated combination of innovative scaffolds, seed cells, and biological factors. However, current techniques in bone tissue engineering have not yet reached valid translation into clinical applications because of several limitations, such as weaker osteogenic differentiation, inadequate vascularization of scaffolds, and inefficient growth factor delivery. Therefore, further standardized protocols and innovative measures are required to overcome these shortcomings and facilitate the clinical application of these techniques to enhance bone regeneration. Given the deficiency of comprehensive studies in the development in BTE, our review systematically introduces the new types of biomimetic and bifunctional scaffolds. We describe the cell sources, biology of seed cells, growth factors, vascular development, and the interactions of relevant molecules. Furthermore, we discuss the challenges and perspectives that may propel the direction of future clinical delivery in bone regeneration.

Elevated expression of hypoxia-inducible factor-2alpha regulated catabolic factors during intervertebral disc degeneration.

HEADINGS AIMS: The present study determined whether nucleus pulposus (NP) cells express hypoxia-inducible factor-2alpha (HIF-2α) and assessed its role in regulating the expression of catabolic factors during intervertebral disc degeneration. MATERIALS AND METHODS: Human degenerated NP tissues were acquired to examine the HIF-2α expression levels using immunohistochemistry, western blotting, and Real-time PCR. Human NP cells were cultivated under normoxic or hypoxic conditions, and the HIF-2α expression was determined. Then, human NP cells were treated with HIF-2α plasmids, HIF-2α siRNA, and tumor necrosis factor-alpha (TNF-α) to evaluate the role of HIF-2α in regulating matrix metalloproteinase (MMP) and aggrecanase expression. An in vivo rabbit disc degeneration model was established to demonstrate that HIF-2α plays a critical role in disc degeneration. KEY FINDINGS: We found that HIF-2α had a markedly elevated expression in human degenerated discs in the Grade III stage. HIF-2α protein and gene transcript levels in vitro were relatively higher under hypoxic conditions. The expression of MMP-13, ADAMTS-4 was decreased significantly in HIF-2α silencing condition, while the over-expression resulted in significantly increased levels of MMP-13 and ADAMTS-4. When cytokine TNF-α was added, HIF-2α was induced by nuclear factor-κB (NF-κB). The in vivo experiments showed that the HIF-2α controlled the catabolic factors MMP-13 and ADAMTS-4 that regulated the collagen II and aggrecan metabolism in disc degeneration. SIGNIFICANCE: HIF-2α is a catabolic regulator in disc degeneration and directly controls the catabolic genes. The suppression of HIF-2α expression leads to decelerates extracellular matrix degradation that might represent a therapeutic target for the degenerative disc.