PQSDC: a parallel lossless compressor for quality scores data via sequences partition and run-length prediction mapping.

MOTIVATION: The quality scores data (QSD) account for 70% in compressed FastQ files obtained from the short and long reads sequencing technologies. Designing effective compressors for QSD that counterbalance compression ratio, time cost, and memory consumption is essential in scenarios such as large-scale genomics data sharing and long-term data backup. This study presents a novel parallel lossless QSD-dedicated compression algorithm named PQSDC, which fulfills the above requirements well. PQSDC is based on two core components: a parallel sequences-partition model designed to reduce peak memory consumption and time cost during compression and decompression processes, as well as a parallel four-level run-length prediction mapping model to enhance compression ratio. Besides, the PQSDC algorithm is also designed to be highly concurrent using multicore CPU clusters. RESULTS: We evaluate PQSDC and four state-of-the-art compression algorithms on 27 real-world datasets, including 61.857 billion QSD characters and 632.908 million QSD sequences. (1) For short reads, compared to baselines, the maximum improvement of PQSDC reaches 7.06% in average compression ratio, and 8.01% in weighted average compression ratio. During compression and decompression, the maximum total time savings of PQSDC are 79.96% and 84.56%, respectively; the maximum average memory savings are 68.34% and 77.63%, respectively. (2) For long reads, the maximum improvement of PQSDC reaches 12.51% and 13.42% in average and weighted average compression ratio, respectively. The maximum total time savings during compression and decompression are 53.51% and 72.53%, respectively; the maximum average memory savings are 19.44% and 17.42%, respectively. (3) Furthermore, PQSDC ranks second in compression robustness among the tested algorithms, indicating that it is less affected by the probability distribution of the QSD collections. Overall, our work provides a promising solution for QSD parallel compression, which balances storage cost, time consumption, and memory occupation primely. AVAILABILITY AND IMPLEMENTATION: The proposed PQSDC compressor can be downloaded from https://github.com/fahaihi/PQSDC.

Intraocular mRNA delivery with endogenous MmPEG10-based virus-like particles.

Virus-like particles (VLP) are a promising tool for intracellular gene delivery, yet their potential in ocular gene therapy remains underexplored. In this study, we bridged this knowledge gap by demonstrating the successful generation and application of vesicular stomatitis virus glycoprotein (VSVG)-pseudotyped mouse PEG10 (MmPEG10)-VLP for intraocular mRNA delivery. Our findings revealed that PEG10-VLP can efficiently deliver GFP mRNA to adult retinal pigment epithelial cell line-19 (ARPE-19) cells, leading to transient expression. Moreover, we showed that MmPEG10-VLP can transfer SMAD7 to inhibit epithelial-mesenchymal transition (EMT) in RPE cells effectively. In vivo experiments further substantiated the potential of these vectors, as subretinal delivery into adult mice resulted in efficient transduction of retinal pigment epithelial (RPE) cells and GFP reporter gene expression without significant immune response. However, intravitreal injection did not yield efficient ocular expression. We also evaluated the transduction characteristics of MmPEG10-VLP following intracameral delivery, revealing transient GFP protein expression in corneal endothelial cells without significant immunotoxicities. In summary, our study established that VSVG pseudotyped MmPEG10-based VLP can transduce mitotically inactive RPE cells and corneal endothelial cells in vivo without triggering an inflammatory response, underscoring their potential utility in ocular gene therapy.

Effects of sex and aging on the immune cell landscape as assessed by single-cell transcriptomic analysis.

Sex and aging influence the human immune system, resulting in disparate responses to infection, autoimmunity, and cancer. However, the impact of sex and aging on the immune system is not yet fully elucidated. Using small conditional RNA sequencing, we found that females had a lower percentage of natural killer (NK) cells and a higher percentage of plasma cells in peripheral blood compared with males. Bioinformatics revealed that young females exhibited an overrepresentation of pathways that relate to T and B cell activation. Moreover, cell-cell communication analysis revealed evidence of increased activity of the BAFF/APRIL systems in females. Notably, aging increased the percentage of monocytes and reduced the percentage of naïve T cells in the blood and the number of differentially expressed genes between the sexes. Aged males expressed higher levels of inflammatory genes. Collectively, the results suggest that females have more plasma cells in the circulation and a stronger BAFF/APRIL system, which is consistent with a stronger adaptive immune response. In contrast, males have a higher percentage of NK cells in blood and a higher expression of certain proinflammatory genes. Overall, this work expands our knowledge of sex differences in the immune system in humans.

PMFFRC: a large-scale genomic short reads compression optimizer via memory modeling and redundant clustering.

BACKGROUND: Genomic sequencing reads compressors are essential for balancing high-throughput sequencing short reads generation speed, large-scale genomic data sharing, and infrastructure storage expenditure. However, most existing short reads compressors rarely utilize big-memory systems and duplicative information between diverse sequencing files to achieve a higher compression ratio for conserving reads data storage space. RESULTS: We employ compression ratio as the optimization objective and propose a large-scale genomic sequencing short reads data compression optimizer, named PMFFRC, through novelty memory modeling and redundant reads clustering technologies. By cascading PMFFRC, in 982 GB fastq format sequencing data, with 274 GB and 3.3 billion short reads, the state-of-the-art and reference-free compressors HARC, SPRING, Mstcom, and FastqCLS achieve 77.89%, 77.56%, 73.51%, and 29.36% average maximum compression ratio gains, respectively. PMFFRC saves 39.41%, 41.62%, 40.99%, and 20.19% of storage space sizes compared with the four unoptimized compressors. CONCLUSIONS: PMFFRC rational usage big-memory of compression server, effectively saving the sequencing reads data storage space sizes, which relieves the basic storage facilities costs and community sharing transmitting overhead. Our work furnishes a novel solution for improving sequencing reads compression and saving storage space. The proposed PMFFRC algorithm is packaged in a same-name Linux toolkit, available un-limited at https://github.com/fahaihi/PMFFRC .

The BET PROTAC inhibitor dBET6 protects against retinal degeneration and inhibits the cGAS-STING in response to light damage.

BACKGROUND: Chronic inflammation significantly contributes to photoreceptor death in blinding retinal diseases such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP). Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that act as key proinflammatory factors. We recently found the first-generation BET inhibitor JQ1 alleviated sodium iodate-induced retinal degeneration by suppressing cGAS-STING innate immunity. Here, we investigated the effects and mechanism of dBET6, a proteolysis­targeting chimera (PROTAC) small molecule that selectively degrades BET by the ubiquitin‒proteasome system, in light-induced retinal degeneration. METHODS: Mice were exposed to bright light to induce retinal degeneration, and the activation of cGAS-STING was determined by RNA-sequencing and molecular biology. Retinal function, morphology, photoreceptor viability and retinal inflammation were examined in the presence and absence of dBET6 treatment. RESULTS: Intraperitoneal injection of dBET6 led to the rapid degradation of BET protein in the retina without detectable toxicity. dBET6 improved retinal responsiveness and visual acuity after light damage (LD). dBET6 also repressed LD-induced retinal macrophages/microglia activation, Müller cell gliosis, photoreceptor death and retinal degeneration. Analysis of single-cell RNA-sequencing results revealed cGAS-STING components were expressed in retinal microglia. LD led to dramatic activation of the cGAS-STING pathway, whereas dBET6 suppressed LD-induced STING expression in reactive macrophages/microglia and the related inflammatory response. CONCLUSIONS: This study indicates targeted degradation of BET by dBET6 exerts neuroprotective effects by inhibiting cGAS-STING in reactive retinal macrophages/microglia, and is expected to become a new strategy for treatment of retinal degeneration.

Single-Cell Analysis Reveals the Heterogeneity of Monocyte-Derived and Peripheral Type-2 Conventional Dendritic Cells.

Dendritic cells (DCs) are critical for pathogen recognition and Ag processing/presentation. Human monocyte-derived DCs (moDCs) have been extensively used in experimental studies and DC-based immunotherapy approaches. However, the extent of human moDC and peripheral DCs heterogeneity and their interrelationship remain elusive. In this study, we performed single-cell RNA sequencing of human moDCs and blood DCs. We identified seven subtypes within moDCs: five corresponded to type 2 conventional DCs (cDC2s), and the other two were CLEC10A+CD127+ cells with no resemblance to any peripheral DC subpopulations characterized to date. Moreover, we defined five similar subtypes in human cDC2s, revealed the potential differentiation trajectory among them, and unveiled the transcriptomic differences between moDCs and cDC2s. We further studied the transcriptomic changes of each moDC subtype during maturation, demonstrating SLAMF7 and IL15RA as maturation markers and CLEC10A and SIGLEC10 as markers for immature DCs. These findings will enable more accurate functional/developmental analyses of human cDC2s and moDCs.

High-dimensional single-cell analysis reveals the immune characteristics of COVID-19.

Coronavirus disease 2019 (COVID-19), driven by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a global pandemic in March 2020. Pathogenic T cells and inflammatory monocytes are regarded as the central drivers of the cytokine storm associated with the severity of COVID-19. In this study, we explored the characteristic peripheral cellular profiles of patients with COVID-19 in both acute and convalescent phases by single-cell mass cytometry (CyTOF). Using a combination of algorithm-guided data analyses, we identified peripheral immune cell subsets in COVID-19 and revealed CD4+ T-cell depletion, T-cell differentiation, plasma cell expansion, and the reduced antigen presentation capacity of innate immunity. Notably, COVID-19 induces a dysregulation in the balance of monocyte populations by the expansion of the monocyte subsets. Collectively, our results represent a high-dimensional, single-cell profile of the peripheral immune response to SARS-CoV-2 infection.

Genomic Elucidation of a COVID-19 Resurgence and Local Transmission of SARS-CoV-2 in Guangzhou, China.

While China experienced a peak and decline in coronavirus disease 2019 (COVID-19) cases at the start of 2020, regional outbreaks continuously emerged in subsequent months. Resurgences of COVID-19 have also been observed in many other countries. In Guangzhou, China, a small outbreak, involving less than 100 residents, emerged in March and April 2020, and comprehensive and near-real-time genomic surveillance of SARS-CoV-2 was conducted. When the numbers of confirmed cases among overseas travelers increased, public health measures were enhanced by shifting from self-quarantine to central quarantine and SARS-CoV-2 testing for all overseas travelers. In an analysis of 109 imported cases, we found diverse viral variants distributed in the global viral phylogeny, which were frequently shared within households but not among passengers on the same flight. In contrast to the viral diversity of imported cases, local transmission was predominately attributed to two specific variants imported from Africa, including local cases that reported no direct or indirect contact with imported cases. The introduction events of the virus were identified or deduced before the enhanced measures were taken. These results show the interventions were effective in containing the spread of SARS-CoV-2, and they rule out the possibility of cryptic transmission of viral variants from the first wave in January and February 2020. Our study provides evidence and emphasizes the importance of controls for overseas travelers in the context of the pandemic and exemplifies how viral genomic data can facilitate COVID-19 surveillance and inform public health mitigation strategies.

A Peer-to-Peer Live-Streaming Intervention for Children During COVID-19 Homeschooling to Promote Physical Activity and Reduce Anxiety and Eye Strain: Cluster Randomized Controlled Trial.

BACKGROUND: The COVID-19 pandemic has led to worldwide school closures, with millions of children confined to online learning at home. As a result, children may be susceptible to anxiety and digital eye strain, highlighting a need for population interventions. OBJECTIVE: The objective of our study was to investigate whether a digital behavior change intervention aimed at promoting physical activity could reduce children's anxiety and digital eye strain while undergoing prolonged homeschooling during the COVID-19 pandemic. METHODS: In this cluster randomized controlled trial, homeschooled grade 7 students at 12 middle schools in southern China were recruited through local schools and randomly assigned by the school to receive (1:1 allocation): (1) health education information promoting exercise and ocular relaxation, and access to a digital behavior change intervention, with live streaming and peer sharing of promoted activities (intervention), or (2) health education information only (control). The primary outcome was change in self-reported anxiety score. Secondary outcomes included change in self-reported eye strain and sleep quality. RESULTS: On March 16, 2020, 1009 children were evaluated, and 954 (94.5%) eligible children of consenting families were included in the intention-to-treat analysis. Children in the intervention (n=485, 6 schools) and control (n=469, 6 schools) groups were aged 13.5 (SD 0.5) years, and 52.3% (n=499) were male. The assigned interventions were completed by 896 children (intervention: n=467, 96.3%; control: n=429, 91.5%). The 2-week change in square-root-transformed self-reported anxiety scores was greater in the intervention (-0.23, 95% CI -0.27 to -0.20) vs control group (0.12, 95% CI 0.09-0.16; unadjusted difference -0.36, 95% CI -0.63 to -0.08; P=.02). There was a significant reduction in square-root-transformed eye strain in the intervention group (-0.08, 95% CI -0.10 to 0.06) compared to controls (0.07, 95% CI 0.05-0.09; difference -0.15, 95% CI -0.26 to -0.03; P=.02). Change in sleep quality was similar between the two groups. CONCLUSIONS: This digital behavior change intervention reduced children's anxiety and eye strain during COVID-19-associated online schooling. TRIAL REGISTRATION: ClinicalTrials.gov NCT04309097; http://clinicaltrials.gov/ct2/show/NCT04309097.

Differential expression of α6 and ß1 integrins reveals epidermal heterogeneity at single-cell resolution.

Skin epidermis is a constantly renewing epithelium that is composed of various cell types and provides an ideal model system for tissue regeneration and heterogeneity studies. Integrins are a family of transmembrane receptors that mediate cell adhesion in the epidermis, and integrin expression spatially reflects epidermal heterogeneity. It remains unclear whether differential expression of integrins can characterize cell types in skin epidermis. This study applied a fluorescence-activated cell sorting (FACS) strategy based on differential expression of α6 and ß1 integrins, and used transcriptome analysis to explore epidermal heterogeneity. First, epidermal cells were acquired from C57BL/6 mice back skin. Nine bulk-cell populations were sorted with differential expressions of α6 and ß1 integrins, and were successfully characterized as the main cell types in the epidermis through RNA-seq and transcriptome analysis. Then, tetOKrt14-H2BGFP mice were used to trace the cell proliferation rate during wound healing with GFP intensity. Epidermal cells were acquired from the re-epithelialized back skin wounds, and a total of 576 single cells were sorted, combining integrin expression and GFP tracing. FACS single-cell RNA-seq enabled high resolution in the classification of subtypes in both interfollicular epidermis and hair follicle, and both quiescent and intermediate cell states of the basal and infundibulum stem cell populations were distinguished. This study proposed a presorted method to investigate the relationship between integrin expression and epidermal heterogeneity. Multiple epidermal cell types and their expression profiles were identified, which provides data resources for dermatology research.

Development and preliminary evaluation of a decision aid to support informed choice among patients with age-related cataract.

OBJECTIVE: Shared decision making and meaningful patient involvement are key in improving cataract treatment outcomes, but no decision aid has been formally developed and validated for this purpose. Our aims were to develop a patient decision aid to guide patients' decision about when to undergo cataract surgery, and to determine patient's comprehension and booklet's acceptability. METHODS: The patient decision aid was developed and included evidence-based information about general cataract, its benefits, risks of treatment options, and value clarification exercise. A total of 30 patients with age-related cataract aged between 50 and 80 years were interviewed after using either the patient decision aid (n = 15) or the traditional education booklet (n = 15). RESULTS: The patients who received the decision aid agreed that the information was new (n = 15, 100%), the length of the aid was "just about right" (n = 13, 87%), the information was clear and easy to understand (n = 13, 87%), the decision aid was helpful in making decision (n = 13, 87%) and would like to recommend this decision aid to others (n = 14, 93%). CONCLUSIONS: The decision aid was assessed positively by patients with age-related cataract. There is a need for its further verification in the context of primary eye care setting.

Knowledge about benefits and risks of undergoing cataract surgery among cataract patients in Southern China.

PURPOSE: To develop a theoretical framework for assessing knowledge about the possible outcomes of undergoing cataract surgery, and explore the association of knowledge level with psychological status and decision quality among patients with cataract in Southern China. METHODS: The details of the knowledge scale were based on the health education information booklet provided by National Eye Institute, NIH. We used a theory-based approach to assess gist knowledge, which comprises 12 questions related to knowledge of the possible surgical outcomes. The scale was then used in a cross-sectional study to assess the association of knowledge score with psychological status and decision quality among cataract patients. RESULTS: A total of 489 participants with age-related cataract were included in this study, and 10.2% (50/489) of them had adequate level of knowledge. The knowledge scale was significantly associated to the levels of worry (Odds Ratio (OR) = 0.36, 95%CI: 0.18, 0.70; P = 0.003), anxiety (beta coefficient = - 5.36, 95%CI - 8.88, - 1.84; P = 0.003), inaction regret (OR = 0.49, 95%CI: 0.28, 0.88; P = 0.016) and decision conflict (beta coefficient = - 7.93, 95%CI - 12.81, - 3.04; P = 0.002) in multivariate analyses adjusted for age, sex, education level and literacy level. CONCLUSION: Knowledge adequacy with cataract surgery outcomes was negatively associated with cataract worry, anxiety and decisional conflict. Patients with adequate knowledge were more likely to postpone cataract surgery.

Dynamic expression of α6 integrin indicates epidermal cell behaviors.

Skin epidermis is a stratified epithelium that composed of interfollicular epidermis (IFE) and hair follicles (HFs). Integrins are cell-cell and cell-matrix adhesive ligands that play important roles in epidermal cell proliferation, migration and differentiation behaviors. Here, we analyzed the expression of both α6 and ß1 integrins. In vitro epidermal cell culture, both α6 and ß1 integrins displayed downregulation upon high Ca2+ induced differentiation. During wound healing (WH), α6 integrin showed dynamic expression, first greatly upregulated in unclosed wounds and then downregulated upon re-epithelialization. Further analysis of different wound regions confirmed α6 integrin significantly increased in migratory cells and migration was coupled with differentiation. However, expression level of ß1 integrin did not show significant correlation with migration. We discovered that α6 integrin directly indicates epidermal cell differentiation and wound directed migration behaviors with its expression level.

Noncovalent SUMO-interaction motifs in HIV integrase play important roles in SUMOylation, cofactor binding, and virus replication.

BACKGROUND: HIV integrase (IN) and its cellular cofactors, including lens-epithelium-derived growth factor (LEDGF/p75), Ku70, p300, and Rad52, are subject to small ubiquitin-like modifier (SUMO) modification. In addition to covalent SUMOylation, SUMO paralogs can also noncovalently bind proteins through SUMO-interacting motifs (SIMs). However, little is known about whether HIV IN contains SIMs and the roles of these motifs. RESULTS: We searched for the amino acid sequence of HIV IN and investigated three putative SIMs of IN: SIM1 72VILV75, SIM2 200IVDI203 and SIM3 257IKVV260. Our mutational analysis showed that 200IVDI203 and 257IKVV260 are two bona fide SIMs that mediate IN-SUMO noncovalent interactions. Additionally, a cell-based SUMOylation assay revealed that IN SIMs negatively regulate the SUMOylation of IN, as well as the interaction between IN and SUMO E2 conjugation enzyme Ubc9. Conversely, IN SIMs are required for its interactions with LEDGF/p75 but not with Ku70. Furthermore, our study reveals that SIM2 and SIM3 are required for the nuclear localization of IN. Finally, we investigated the impact of IN SIM2 and SIM3 on HIV single cycle replication in CD4+ C8166 T cells, and the results showed that viruses carrying IN SIM mutants are replication defective at the steps of the early viral life cycle, including reverse transcription, nuclear import and integration. CONCLUSION: Our data suggested that the INSIM-SUMO interaction constitutes a new regulatory mechanism of IN functions and might be important for HIV-1 replication.

Multimodal imaging of the retina and choroid in healthy Macaca fascicularis at different ages.

PURPOSE: The aim of this study was to identify the morphological features of the retina and choroid in Macaca fascicularis of different ages using multimodal imaging. METHODS: A total of 27 Macaca fascicularis with no ocular diseases were studied (mean age, 104.2 months; range, 1.2-223.6 months). Multimodal imaging was obtained from each subject. The morphological features were compared within four subgroups according to age. RESULTS: On spectrum-domain optical coherence tomography (SD-OCT), four hyper-reflective bands could be observed in the outer retina in non-infant macaques (21/21, 100%), while the interdigitation zone could not be observed in the six infant macaques. A narrow hypo-reflective band just posterior to the retinal pigment epithelium (RPE) was noted in most eyes (25/27, 92.6%). The choroidal-scleral junction (CSJ) was visible in 83.3% of infants but only in 12.5% of adults and 14.3% of the geriatric population, and it could not be seen in juveniles. There was a significant difference in CSJ visibility between the infant group and the other three groups (P < 0.001). Tessellated fundus, in which the choroidal vessels are visible through the retina, could be observed clearly with near-infrared reflectance imaging (NIR). Some granular spots were noted in juveniles, and they accumulated dramatically with age, but were absent in infants. CONCLUSION: Notable morphological features can be observed in the Macaca fascicularis subjects using multimodal imaging, and these features vary distinctly according to their age. It is important to note that infant macaques had no interdigitation zone, while the other macaques had no visible CSJ but did have well-defined choroidal capillaries. Age and the features should be considered seriously in future animal studies.

Prediction of myopia development among Chinese school-aged children using refraction data from electronic medical records: A retrospective, multicentre machine learning study.

BACKGROUND: Electronic medical records provide large-scale real-world clinical data for use in developing clinical decision systems. However, sophisticated methodology and analytical skills are required to handle the large-scale datasets necessary for the optimisation of prediction accuracy. Myopia is a common cause of vision loss. Current approaches to control myopia progression are effective but have significant side effects. Therefore, identifying those at greatest risk who should undergo targeted therapy is of great clinical importance. The objective of this study was to apply big data and machine learning technology to develop an algorithm that can predict the onset of high myopia, at specific future time points, among Chinese school-aged children. METHODS AND FINDINGS: Real-world clinical refraction data were derived from electronic medical record systems in 8 ophthalmic centres from January 1, 2005, to December 30, 2015. The variables of age, spherical equivalent (SE), and annual progression rate were used to develop an algorithm to predict SE and onset of high myopia (SE ≤ -6.0 dioptres) up to 10 years in the future. Random forest machine learning was used for algorithm training and validation. Electronic medical records from the Zhongshan Ophthalmic Centre (a major tertiary ophthalmic centre in China) were used as the training set. Ten-fold cross-validation and out-of-bag (OOB) methods were applied for internal validation. The remaining 7 independent datasets were used for external validation. Two population-based datasets, which had no participant overlap with the ophthalmic-centre-based datasets, were used for multi-resource validation testing. The main outcomes and measures were the area under the curve (AUC) values for predicting the onset of high myopia over 10 years and the presence of high myopia at 18 years of age. In total, 687,063 multiple visit records (≥3 records) of 129,242 individuals in the ophthalmic-centre-based electronic medical record databases and 17,113 follow-up records of 3,215 participants in population-based cohorts were included in the analysis. Our algorithm accurately predicted the presence of high myopia in internal validation (the AUC ranged from 0.903 to 0.986 for 3 years, 0.875 to 0.901 for 5 years, and 0.852 to 0.888 for 8 years), external validation (the AUC ranged from 0.874 to 0.976 for 3 years, 0.847 to 0.921 for 5 years, and 0.802 to 0.886 for 8 years), and multi-resource testing (the AUC ranged from 0.752 to 0.869 for 4 years). With respect to the prediction of high myopia development by 18 years of age, as a surrogate of high myopia in adulthood, the algorithm provided clinically acceptable accuracy over 3 years (the AUC ranged from 0.940 to 0.985), 5 years (the AUC ranged from 0.856 to 0.901), and even 8 years (the AUC ranged from 0.801 to 0.837). Meanwhile, our algorithm achieved clinically acceptable prediction of the actual refraction values at future time points, which is supported by the regressive performance and calibration curves. Although the algorithm achieved balanced and robust performance, concerns about the compromised quality of real-world clinical data and over-fitting issues should be cautiously considered. CONCLUSIONS: To our knowledge, this study, for the first time, used large-scale data collected from electronic health records to demonstrate the contribution of big data and machine learning approaches to improved prediction of myopia prognosis in Chinese school-aged children. This work provides evidence for transforming clinical practice, health policy-making, and precise individualised interventions regarding the practical control of school-aged myopia.

Cause-specific mortality for 240 causes in China during 1990-2013: a systematic subnational analysis for the Global Burden of Disease Study 2013.

BACKGROUND: China has experienced a remarkable epidemiological and demographic transition during the past three decades. Far less is known about this transition at the subnational level. Timely and accurate assessment of the provincial burden of disease is needed for evidence-based priority setting at the local level in China. METHODS: Following the methods of the Global Burden of Disease Study 2013 (GBD 2013), we have systematically analysed all available demographic and epidemiological data sources for China at the provincial level. We developed methods to aggregate county-level surveillance data to inform provincial-level analysis, and we used local data to develop specific garbage code redistribution procedures for China. We assessed levels of and trends in all-cause mortality, causes of death, and years of life lost (YLL) in all 33 province-level administrative units in mainland China, all of which we refer to as provinces, for the years between 1990 and 2013. FINDINGS: All provinces in mainland China have made substantial strides to improve life expectancy at birth between 1990 and 2013. Increases ranged from 4.0 years in Hebei province to 14.2 years in Tibet. Improvements in female life expectancy exceeded those in male life expectancy in all provinces except Shanghai, Macao, and Hong Kong. We saw significant heterogeneity among provinces in life expectancy at birth and probability of death at ages 0-14, 15-49, and 50-74 years. Such heterogeneity is also present in cause of death structures between sexes and provinces. From 1990 to 2013, leading causes of YLLs changed substantially. In 1990, 16 of 33 provinces had lower respiratory infections or preterm birth complications as the leading causes of YLLs. 15 provinces had cerebrovascular disease and two (Hong Kong and Macao) had ischaemic heart disease. By 2013, 27 provinces had cerebrovascular disease as the leading cause, five had ischaemic heart disease, and one had lung cancer (Hong Kong). Road injuries have become a top ten cause of death in all provinces in mainland China. The most common non-communicable diseases, including ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and cancers (liver, stomach, and lung), contributed much more to YLLs in 2013 compared with 1990. INTERPRETATION: Rapid transitions are occurring across China, but the leading health problems and the challenges imposed on the health system by epidemiological and demographic change differ between groups of Chinese provinces. Localised health policies need to be implemented to tackle the diverse challenges faced by local health-care systems. FUNDING: China National Science & Technology Pillar Program 2013 (2013BAI04B02) and Bill & Melinda Gates Foundation.

ABCC5, a gene that influences the anterior chamber depth, is associated with primary angle closure glaucoma.

Anterior chamber depth (ACD) is a key anatomical risk factor for primary angle closure glaucoma (PACG). We conducted a genome-wide association study (GWAS) on ACD to discover novel genes for PACG on a total of 5,308 population-based individuals of Asian descent. Genome-wide significant association was observed at a sequence variant within ABCC5 (rs1401999; per-allele effect size =  -0.045 mm, P = 8.17 × 10(-9)). This locus was associated with an increase in risk of PACG in a separate case-control study of 4,276 PACG cases and 18,801 controls (per-allele OR = 1.13 [95% CI: 1.06-1.22], P = 0.00046). The association was strengthened when a sub-group of controls with open angles were included in the analysis (per-allele OR = 1.30, P = 7.45 × 10(-9); 3,458 cases vs. 3,831 controls). Our findings suggest that the increase in PACG risk could in part be mediated by genetic sequence variants influencing anterior chamber dimensions.

Meta-analysis of genome-wide association studies in multiethnic Asians identifies two loci for age-related nuclear cataract.

Age-related cataract is a leading cause of blindness worldwide, especially in developing countries where access to cataract surgery remains limited. Previous linkage and candidate gene studies suggested genetic influences on age-related nuclear cataract but few genetic markers have been identified thus far. We conducted genome-wide association studies on 4569 Asians (including 2369 Malays and 2200 Indians), and replicated our analysis in 2481 Chinese from two independent cohorts (1768 Chinese in Singapore and 803 Chinese in Beijing). We confirmed two genome-wide significant loci for nuclear cataract in the combined meta-analysis of four cohorts (n = 7140). The first locus was at chromosome 3q25.31 in KCNAB1 (rs7615568, fixed-effect Pmeta = 2.30 × 10(-8); random-effect Pmeta = 1.08 × 10(-8)). The second locus was at chromosome 21 in the proximity of CRYAA (rs11911275, fixed-effect Pmeta = 2.77 × 10(-8); random-effect Pmeta = 1.98 × 10(-9)), a major protein component of eye lens. The findings were further supported by up-regulation and down-regulation of KCNAB1 and CRYAA in human lens capsule, respectively, as the severity of nuclear cataract increases. The results offer additional insights into the pathogenesis of nuclear cataract in Asians.

Nine loci for ocular axial length identified through genome-wide association studies, including shared loci with refractive error.

Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways.