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Abstract The current research of sandwich structures under dynamic loading mainly focus on the response characteristic of structure. The micro-topology of core layers would sufficiently influence the property of sandwich structure. However, the micro deformation and topology mechanism of structural deformation and energy absorption are unclear. In this paper, based on the bi-directional evolutionary structural optimization method and periodic base cell (PBC) technology, a topology optimization frame work is proposed to optimize the core layer of sandwich beams. The objective of the present optimization problem is to maximize shear stiffness of PBC with a volume constraint. The effects of the volume fraction, filter radius, and initial PBC aspect ratio on the micro-topology of the core were discussed. The dynamic response process, core compression, and energy absorption capacity of the sandwich beams under blast impact loading were analyzed by the finite element method. The results demonstrated that the over-pressure action stage was coupled with the core compression stage. Under the same loading and mass per unit area, the sandwich beam with a 20% volume fraction core layer had the best blast resistance. The filter radius has a slight effect on the shear stiffness and blast resistances of the sandwich beams. But increasing the filter radius could slightly improve the bending stiffness. Upon changing the initial PBC aspect ratio, there are three ways for PBC evolution: The first is to change the angle between the adjacent bars, the second is to further form holes in the bars, and the third is to combine the first two ways. However, not all three ways can improve the energy absorption capacity of the structure. Changing the aspect ratio of the PBC arbitrarily may lead to worse results. More studies are necessary for further detailed optimization. This research proposes a new topology sandwich beam structure by micro-topology optimization, which has sufficient shear stiffness. The micro mechanism of structural energy absorption is clarified, it is significant for structural energy absorption design.

ObjectiveIn order to explore the effects of different stiffening configurations on the bearing capacity and anti-blast performance of double stiffened cylindrical shells, a numerical study is made of the responses of four kinds of double stiffened cylindrical shells under hydrostatic pressure and underwater explosion load.MethodsFirst, finite element models of stiffened cylindrical shells with different structural forms are established. Next, finite element software ANSYS is used to calculate and analyze the influence of each structural form on the strength, stability and ultimate bearing capacity of the cylindrical shell. Finally, finite element software Abaqus/Explicit is used to calculate and analyze the influence of each structural form on the deformation deflection and plastic strain of the cylindrical shell under explosion load. ResultsCompared with a traditional single stiffened cylindrical shell with the same mass, the I-shaped double stiffened cylindrical shell has a great advantage in carrying capacity. When the explosion load level is low, the anti-blast performance of a double cylindrical shell with small rib spacing is similar, but decreases when the explosion load level is high.ConclusionThe reasonable design of double stiffened cylindrical shells can yield better design schemes for bearing capacity and anti-blast performance.

Abstract Despite the advent of genomic sequencing, molecular diagnosis remains unsolved in approximately half of patients with Mendelian disorders, largely due to unclarified functions of noncoding regions and the difficulty in identifying complex structural variations. In this study, we map a unique form of central iris hypoplasia in a large family to 6q15-q23.3 and 18p11.31-q12.1 using a genome-wide linkage scan. Long-read sequencing reveals a balanced translocation t(6;18)(q22.31;p11.22) with intergenic breakpoints. By performing Hi-C on induced pluripotent stem cells from a patient, we identify two chromatin topologically associating domains spanning across the breakpoints. These alterations lead the ectopic chromatin interactions between APCDD1 on chromosome 18 and enhancers on chromosome 6, resulting in upregulation of APCDD1. Notably, APCDD1 is specifically localized in the iris of human eyes. Our findings demonstrate that noncoding structural variations can lead to Mendelian diseases by disrupting the 3D genome structure and resulting in altered gene expression.

Bone is a multi-phase, non-homogeneous material that exhibits strain rate sensitivity, and it may fail under compression, tension, torsion, or a combination of these loading. The mechanical properties of cortical bone with strain rate effect under compression and tension have been obtained through the application of the split Hopkinson pressure/tension bar technique, but no such studies have been reported for determining the strain rate behavior properties of bony materials under torsion. In this study, the shear stress-strain curves with the rate-dependent cortical bone subjected to dynamic torsional loading were first obtained using a torsional split Hopkinson bar system. Based on the experiments, an improved mathematical model consisting of elastic, viscoelastic, and viscoplastic components was used to identify the material parameters of the cortical bone. Detailed material properties are derived through constitutive relations. The results may assist researchers in developing more accurate models of cortical bone behavior under different load conditions.

Photovoltaic (PV) and battery energy storage systems (BESSs) are key components in the energy market and crucial contributors to carbon emission reduction targets. These systems can not only provide energy but can also generate considerable revenue by providing frequency regulation services and participating in carbon trading. This study proposes a bidding strategy for PV and BESSs operating in joint energy and frequency regulation markets, with a specific focus on carbon reduction benefits. A two-stage bidding framework that optimizes the profit of PV and BESSs is presented. In the first stage, the day-ahead energy market takes into account potential real-time forecast deviations. In the second stage, the real-time balancing market uses a rolling optimization method to account for multiple uncertainties. Notably, a real-time frequency regulation control method is proposed for the participation of PV and BESSs in automatic generation control (AGC). This is particularly relevant given the uncertainty of grid frequency fluctuations in the optimization model of the real-time balancing market. This control method dynamically assigns the frequency regulation amount undertaken by the PV and BESSs according to the control interval in which the area control error (ACE) occurs. The case study results demonstrate that the proposed bidding strategy not only enables the PV and BESSs to effectively participate in the grid frequency regulation response but also yields considerable carbon emission reduction benefits and effectively improves the system operation economy.

The space situational awareness program places great significance on obtaining high-resolution images of satellite in space orbit. By utilizing space-borne inverse synthetic aperture radar (SBISAR) can achieve high-resolution imaging of observed satellite (OS) on-orbit especially in geosynchronous orbit (GEO). However, the complex and nonuniform relative motion of the OS on-orbit and SBISAR produces 2-D spatial variant phase errors, which has a high-order form during long coherent processing intervals. Up to now, the imaging problem of SBISAR has not been effectively tackled. In this work, a novel method to compensate for the 2-D spatial variant phase errors for SBISAR imaging based on minimum entropy and quasi-Newton's method is proposed. First, the geometric model that considers the relative motion state of SBISAR and the OS on-orbit is established and the optimal observation time period is determined. Second, we propose the echo signal model for the satellite on-orbit and deduce the specific form of the high-order spatial variant phase errors. Third, based on image entropy, quasi-Newton's method is adopted to obtain the optimal solution for the phase error coefficients. Finally, a new initial estimation method that aims to overcome the local convergence of quasi-Newton's method is proposed. By utilizing the optimal parameters, the well-focused SBISAR image can be achieved. Taking GEO satellite imaging as an example, experiments based on scattering point simulation data verify the effectiveness of the proposed method.

Abstract Backgrounds Unilateral high myopia (uHM), commonly observed in patients with retinal diseases or only with high myopia, is frequently associated with amblyopia with poor prognosis. This study aims to reveal the clinical and genetic spectrum of uHM in a large Chinese cohort. Methods A total of 75 probands with simplex uHM were included in our Pediatric and Genetic Eye Clinic. Patients with significant posterior anomalies other than myopic fundus changes were excluded. Variants were detected by exome sequencing and then analyzed through multiple-step bioinformatic and co-segregation analysis and finally confirmed by Sanger sequencing. Genetic findings were correlated with associated clinical data for analysis. Results Among the 75 probands with a mean age of 6.21 ± 4.70 years at the presentation, myopic fundus of C1 and C2 was observed in 73 (97.3%) probands. Surprisingly, specific peripheral changes were identified in 63 eyes involving 36 (48.0%) probands after extensive examination, including peripheral retinal avascular zone (74.6%, 47/63 eyes), neovascularization (54.0%), fluorescein leakage (31.7%), peripheral pigmentary changes (31.7%), and others. Exome sequencing identified 21 potential pathogenic variants of 13 genes in 20 of 75 (26.7%) probands, including genes for Stickler syndrome (COL11A1 and COL2A1; 6/20), FEVR (FZD4, LRP5, and TSPAN12; 5/20), and others (FBN1, GPR179, ZEB2, PAX6, GPR143, OPN1LW, FRMD7, and CACNA1F; 9/20). For the peripheral retinal changes in the 20 probands, variants in Stickler syndrome-related genes were predominantly associated with retinal pigmentary changes, lattice degeneration, and retinal avascular region, while variants in genes related to FEVR were mainly associated with the avascular zone, neovascularization, and fluorescein leakage. Conclusions Genetic defects were identified in about one-fourth of simplex uHM patients in which significant consequences may be hidden under a classic myopic fundus in up to half. To our knowledge, this is the first systematic genetic study on simplex uHM to date. In addition to routine care of strabismus and amblyopia, careful examination of the peripheral retina and genetic screening is warranted for patients with uHM in order to identify signs of risk for retinal detachment and other complications and provide meaningful genetic counseling.

Abstract Despite the ability of 3D convolutional methods to extract spatio-temporal information simultaneously, they also increase parameter redundancy and computational and storage costs. Previous work that has utilized the 2D convolution method has approached the problem in one of two ways: either using the entire body sequence as input to extract global features or dividing the body sequence into several parts to extract local features. However, global information tends to overlook detailed information specific to each body part, while local information fails to capture relationships between local regions. Therefore, this study proposes a new framework for constructing spatio-temporal representations, which involves extracting and fusing features in a novel manner. To achieve this, we introduce the multi-feature extraction-fusion (MFEF) module, which includes two branches: each branch extracts global features or local features individually, after which they are fused using multiple strategies. Additionally, as gait is a periodic action and different body parts contribute unequally to recognition during each cycle, we propose the periodic temporal feature modeling (PTFM) module, which extracts temporal features from adjacent frame parts during the complete gait cycle, based on the fused features. Furthermore, to capture fine-grained information specific to each body part, our framework utilizes multiple parallel PTFMs to correspond with each body part. We conducted a comprehensive experimental study on the widely used public dataset CASIA-B. Results indicate that the proposed approach achieved an average rank-1 accuracy of 97.2% in normal walking conditions, 92.3% while carrying a bag during walking, and 80.5% while wearing a jacket during walking.

Multistatic synthetic aperture radar (SAR) is a special mode of SAR system. The radar transmitter and receiver are located on different satellites, which brings many advantages, such as flexible baseline configuration, diverse receiving modes, and more detailed ground object classification information. The multistatic SAR has been widely used in interferometry, moving target detection, three-dimensional imaging, and other fields. The frequency offset between different oscillators will cause a modulation phase error in the signal. Therefore, phase synchronization is one of the most critical problems to be addressed in distributed SAR systems. This article reviews phase synchronization techniques, which are mainly divided into two methods: synchronization by direct microwave link and synchronization by a data-based estimation algorithm. Furthermore, the future development of synchronization technology is anticipated.

Aim: To compare all-cause and acute lymphoblastic leukemia (ALL)-related healthcare resource utilization (HCRU) and costs among patients receiving inotuzumab ozogamicin (InO) and blinatumomab (Blina) for ALL in the first relapsed/refractory (R/R) setting. Patients & methods: We studied retrospective claims for adult commercial and Medicare Advantage enrollees with ALL receiving InO (n = 29) or Blina (n = 23) from 1 January 2015 to 16 February 2021. Mean per-patient-per-month (PPPM) HCRU and total costs were described and multivariable-adjusted PPPM total all-cause and ALL-related predicted costs were calculated. Results: Mean monthly ALL-related hospitalizations were the same for patients receiving InO and Blina (PPPM = 0.8 stays); however, the length of ALL-related hospital stay was almost twice as long among patients receiving Blina versus InO (ALL-related: InO = 7.6 days; Blina = 14.1 days; p = 0.346). In multivariable models, total ALL-related costs were 43% lower for InO compared with Blina (PPPM costs: InO = $93,767; Blina = $163,470; p = 0.021). Conclusion: In the first R/R setting, patients who used InO had significantly lower all-cause and ALL-related costs compared with patients who used Blina, in part driven by hospitalization patterns.

Introduction Percutaneous coronary intervention (PCI) guided by coronary angiography-derived fractional flow reserve (FFR) or intravascular ultrasound (IVUS) has shown improved clinical outcomes compared with angiography-only-guided PCI. In patients with intermediate stenoses, FFR resulted in fewer coronary interventions and was non-inferior to IVUS with respect to clinical outcomes. However, whether this finding can be applied to angiography-derived FFR in significant coronary artery disease (CAD) remains unclear.Method and analysis The comparison of angiography-derived FFR-guided and IVUS-guided intervention strategies for clinical outcomes in patients with coronary artery disease (FLAVOUR II) trial is a multicentre, prospective, randomised controlled trial. A total of 1872 patients with angiographically significant CAD (stenoses of at least 50% as estimated visually through angiography) in a major epicardial coronary artery will be randomised 1:1 to receive either angiography-derived FFR-guided or IVUS-guided PCI. Patients will be treated with second-generation drug-eluting stent according to the predefined criteria for revascularisation: angiography-derived FFR≤0.8 and minimal lumen area (MLA)≤3 mm2 or 3 mm270%. The primary endpoint is a composite of all-cause death, myocardial infarction and revascularisation at 12 months after randomisation. We will test the non-inferiority of the angiography-derived FFR-guided strategy compared with the IVUS-guided decision for PCI and the stent optimisation strategy.The FLAVOUR II trial will provide new insights into optimal evaluation and treatment strategies for patients with CAD.Ethics and dissemination FLAVOUR II was approved by the institutional review board at each participating site (The Second Affiliated Hospital of Zhejiang University School of Medicine Approval No: 2020LSYD410) and will be conducted in line with the Declaration of Helsinki. Informed consent would be obtained from each patient before their participation. The study results will be submitted to a scientific journal.Trial registration number NCT04397211.

IntroductionRetinal degenerative or inflammatory changes may occur with hereditary immunological disorders (HID) due to variants in approximately 20 genes. This study aimed to investigate if such retinopathy may present as an initial sign of immunological disorders in eye clinic.MethodsThe variants in the 20 genes were selected from in-house exome sequencing data from 10,530 individuals with different eye conditions. Potential pathogenic variants were assessed by multistep bioinformatic analysis. Pathogenic variants were defined according to the ACMG/AMP criteria and confirmed by Sanger sequencing, co-segregation analysis, and consistency with related phenotypes. Ocular clinical data were thoroughly reviewed, especially fundus changes.ResultsA total of seven pathogenic variants in four of the 20 genes were detected in six probands from six families, including three with hemizygous nonsense variants p.(Q308*), p.(Q416*), and p.(R550*) in MSN, one with homozygous nonsense variants p.(R257*) in AIRE, one with compound heterozygous nonsense variants p.(R176*) and p.(T902*) in LAMB2, and one with a known c.1222T>C (p.W408R) heterozygous variant in CBL. Ocular presentation, as the initial signs of the diseases, was mainly retinopathy mimicking other forms of hereditary retinal degeneration, including exudative vitreoretinopathy in the three patients with MSN variants or tapetoretinal degeneration in the other three patients. Neither extraocular symptoms nor extraocular manifestations were recorded at the time of visit to our eye clinic. However, of the 19 families in the literature with retinopathy caused by variants in these four genes, only one family with an AIRE homozygous variant had retinopathy as an initial symptom, while the other 18 families had systemic abnormalities that preceded retinopathy.DiscussionThis study, for the first time, identified six unrelated patients with retinopathy as their initial and only presenting sign of HID, contrary to the previous reports where retinopathy was the accompanying sign of systemic HID. Recognizing such phenotype of HID may facilitate the clinical care of these patients. Follow-up visits to such patients and additional studies are expected to validate and confirm our findings.

Abstract Spinal sacral nerve injury represents one of the most serious conditions associated with many diseases such as sacral fracture, tethered cord syndrome and sacral canal tumor. Spinal sacral nerve injury could cause bladder denervation and detrusor underactivity. There is limited clinical experience resolving spinal sacral nerve injury associated detrusor underactivity patients, and thus the treatment options are also scarce. In this study, we established a spinal sacral nerve injury animal model for deeper understanding and further researching of this disease. Forty 8 w (week) old Sprague Dawley rats were included and equally divided into sham (n = 20) and crush group (n = 20). Bilateral spinal sacral nerves of rats were crushed in crush group, and sham group received same procedure without nerve crush. Comprehensive evaluations at three time points (1 w, 4 w and 6 w) were performed to comprehend the nature process of this disease. According to urodynamic test, ultrasonography and retrograde urography, we could demonstrate severe bladder dysfunction after spinal sacral nerve injury along the observation period compared with sham group. These functional changes were further reflected by histological examination (hematoxylin-eosin and Masson’s trichrome staining) of microstructure of nerves and bladders. Immunostaining of nerve/bladder revealed schwann cell death, axon degeneration and collagen remodeling of bladder. Polymerase Chain Reaction results revealed vigorous nerve inflammation and bladder fibrosis 1 week after injury and inflammation/fibrosis returned to normal at 4 w. The CatWalk gait analysis was performed and there was no obvious difference between two groups. In conclusion, we established a reliable and reproducible model for spinal sacral nerve injury, this model provided an approach to evaluate the treatment strategies and to understand the pathological process of spinal sacral nerve injuries. It allowed us to understand how nerve degeneration and bladder fibrosis changed following spinal sacral nerve injury and how recovery could be facilitated by therapeutic options for further research.

The coupling relationship between the removal of the fault current and the dissipation of the residual energy of the fault line during the fault isolation process of the multi-port capacitive current-limiting DC circuit breaker prolongs the breaking time of the fault to a certain extent. In order to solve the above problems, this paper proposes a multi-port DC circuit breaker based on dual-capacitor current limiting and energy sinking on the premise of decoupling the fault current attenuation and removal process and the fault line residual energy discharge process. Further reduce the fault breaking time and equipment withstand voltage requirements of the DC circuit breaker. Firstly, the topology and working principle of the proposed circuit breaker are analyzed, and then the parameters in the topology are designed. Then a simulation model is built in the PSCAD/EMTDC simulation platform to verify the fault breaking performance and breaking time. The effect of decoupling the fault current clearing process and the fault line residual energy discharge process on the effectiveness of shortening the fault breaking time is verified.

In order to deeply analyze the influence of core layer size parameters on the anti-explosion performance of sandwich panel under explosive load, on the basis of the fiber-reinforced three-layer honeycomb sandwich structure, the dynamic response of the double-layer gradient sandwich panel made of fiber-reinforced aluminum alloy panel and aluminum alloy honeycomb core layer under explosive load was studied by experiment and numerical simulation. First, the deformation failure modes of the double-layer gradient sandwich panel in the experiment were analyzed: large deformation of the whole sandwich structure, failure of the front panel in the central area and compression buckling of the core layer, and penetration failure of the front panel and the core layer in the central area. Second, the influence of the change in the hole length and wall thickness on the explosion resistance performance of the upper core layer was examined without changing the geometric size of the lower core layer by numerical simulation. The results show that the specimen with the same hole side length of the upper and lower core layer had better explosion resistance performance, and when the density ratio of the upper and lower core layer was 3∶1 while the side length of the upper and lower core layer was the same, the structure had the best anti-explosion performance.

Multiple system atrophy (MSA) is a common atypical parkinsonism, characterized by a varying combination of autonomic, cerebellar, and pyramidal systems. It has been noticed that the patients with MSA can be accompanied by some neuropsychiatric disorders, in particular depression. However, there is limited understanding of MSA-related depression. To bridge existing gaps, we summarized research progress on this topic and provided a new perspective regarding pathological, clinical, and imaging aspects. Firstly, we synthesized corresponding studies in order to investigate the relationship between depression and MSA from a pathological perspective. And then, from a clinical perspective, we focused on the prevalence of depression in MS patients and the comparison with other populations. Furthermore, the associations between depression and some clinical characteristics, such as life quality and gender, have been reported. The available neuroimaging studies were too sparse to draw conclusions about the radiological aspect of depression in MSA patients but we still described them in the presence of paper. Finally, we discussed some limitations and shortcomings existing in the included studies, which call for more high-quality basic research and clinical research in this field.

Model tests are carried out on the jacked single piles of different diameters and pile lengths under the model pile of different diameters and pile lengths in clayey soil, which aims to investigate the penetration mechanical mechanism. How to accurately test the pile end resistance and pile side resistance during jacked pile sinking is particularly important. In this paper, a full-section spoke-type pressure sensor, a double diaphragm temperature self-compensating fiber Bragg grating (FBG) earth pressure sensor and a sensitized miniature FBG strain sensor are jointly applied to a single pile penetration model test to test a single pile driving force, pile end resistance and pile body stress during penetration. The test results show that the load transfer performance of test piles will be affected by different diameters, and the axial force transfer capability of a large diameter in the depth direction is better than that of a small diameter since the compacting effect is more obvious. The unit skin friction of the pile increases gradually as the depth increases, which is larger due to the lateral extrusion force increasing as the diameter increases. At the same depth, the unit skin friction of two different diameter piles demonstrates “friction fatigue”, which also decreases obviously as the depth increases. Under the conditions of this test, the maximum frictional resistance of the pile TP1 pile side is about 27.7% higher than that of the test pile TP2. In the static pile sinking process of three test piles in cohesive soil, 50% is end bearing; therefore, there is 50% friction, and the diameter influences the end bearing and the length influences the friction.

Abstract Although inoculation of COVID-19 vaccines has rolled out globally, there is still a critical need for safe and effective vaccines to ensure fair and equitable supply for all countries. Here, we report on the development of a highly efficacious mRNA vaccine, SW0123 that is composed of sequence-modified mRNA encoding the full-length SARS-CoV-2 Spike protein packaged in core–shell structured lipopolyplex (LPP) nanoparticles. SW0123 is easy to produce using a large-scale microfluidics-based apparatus. The unique core–shell structured nanoparticle facilitates vaccine uptake and demonstrates a high colloidal stability, and a desirable biodistribution pattern with low liver targeting effect upon intramuscular administration. Extensive evaluations in mice and nonhuman primates revealed strong immunogenicity of SW0123, represented by induction of Th1-polarized T cell responses and high levels of antibodies that were capable of neutralizing not only the wild-type SARS-CoV-2, but also a panel of variants including D614G and N501Y variants. In addition, SW0123 conferred effective protection in both mice and non-human primates upon SARS-CoV-2 challenge. Taken together, SW0123 is a promising vaccine candidate that holds prospects for further evaluation in humans.

Compound 6d, a spiroindoline compound, exhibits antiproliferative capability against cancer cell lines. However, the exact underlying mechanism of this compound-mediated inhibitory capability remains unclear. Here, we showed that compound 6d is an inhibitor of Bcl-2, which suppresses CRC growth by inducing caspase 3-mediated intrinsic apoptosis of mitochondria. Regarding the underlying mechanism, we identified HDAC6 as a direct substrate for caspase 3, and caspase 3 activation induced by compound 6d directly cleaves HDAC6 into two fragments. Moreover, the cleavage site was located at D1088 in the DMAD-S motif HDAC6. Apoptosis stimulated by compound 6d promoted autophagy initiation by inhibiting interaction between Bcl-2 and Beclin 1, while it led to the accumulation of ubiquitinated proteins and the reduction of autophagic flux. Collectively, our findings reveal that the Bcl-2-caspase 3-HDAC6 cascade is a crucial regulatory pathway of autophagy and identify compound 6d as a novel lead compound for disrupting the balance between apoptosis and autophagy.

Variants in PRPH2 are a common cause of inherited retinal dystrophies with high genetic and phenotypic heterogeneity. In this study, variants in PRPH2 were selected from in-house exome sequencing data, and all reported PRPH2 variants were evaluated with the assistance of online prediction tools and the comparative validation of large datasets. All variants were classified based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. Individuals with pathogenic or likely pathogenic variants of PRPH2 were confirmed by Sanger sequencing. Clinical characteristics were summarized. Ten pathogenic or likely pathogenic variants of PRPH2 were identified in 14 families. In our cohort, the most frequent variant was p.G305Afs*19, accounting for 33.3% (5/15) of alleles, in contrast to the literature, where p.R172G (11.6%, 119/1028) was the most common variant. Nine in-house families (63.8%) were diagnosed with retinitis pigmentosa (RP), distinct from the phenotypic spectrum in the literature, which shows that RP accounts for 27.9% (283/1013) and macular degeneration is more common (45.2%, 458/1013). Patients carrying missense variants predicted as damaging by all seven prediction tools and absent in the gnomAD database were more likely to develop RP compared to those carrying missense variants predicted as damaging with fewer tools or with more than one allele number in the gnomAD database (p = 0.001). The population-specific genetic and phenotypic spectra of PRPH2 were explored, and novel insight into the genotype–phenotype correlation of PRPH2 was proposed. These findings demonstrated the importance of assessing PRPH2 variants in distinct populations and the value of providing practical suggestions for the genetic interpretation of PRPH2 variants.

Corneal dystrophies (CDs) represent a group of inherited diseases characterized by the progressive deposit of abnormal materials in the cornea. This study aimed to describe the variant landscape of 15 genes responsible for CDs based on a cohort of Chinese families and a comparative analysis of literature reports. Families with CDs were recruited from our eye clinic. Their genomic DNA was analyzed using exome sequencing. The detected variants were filtered using multi-step bioinformatics and confirmed using Sanger sequencing. Previously reported variants in the literature were summarized and evaluated based on the gnomAD database and in-house exome data. In 30 of 37 families with CDs, 17 pathogenic or likely pathogenic variants were detected in 4 of the 15 genes, including TGFBI, CHST6, SLC4A11, and ZEB1. A comparative analysis of large datasets revealed that 12 of the 586 reported variants are unlikely causative of CDs in monogenic mode, accounting for 61 of 2933 families in the literature. Of the 15 genes, the gene most frequently implicated in CDs was TGFBI (1823/2902, 62.82% of families), followed by CHST6 (483/2902, 16.64%) and SLC4A11 (201/2902, 6.93%). This study presents, for the first time, the landscape of pathogenic and likely pathogenic variants in the 15 genes responsible for CDs. Awareness of frequently misinterpreted variants, such as c.1501C>A, p.(Pro501Thr) in TGFBI, is crucial in the era of genomic medicine.

Abstract The work of Initiative on Promoting Inter-ethnic Unity and Common Progress (hereinafter referred to as “The Initiative Work”) originated from long-term historical practice and is a significant measure for China to promote inter-ethnic unity and progress. This article sorts out the development process of The Initiative Work in China, introduces the progress of its demonstration regions and units, elaborates the practices of The Initiative Work in the following aspects: consolidation of the top-level design, improvement of the quality and coverage, publicity of the national policies, cultivation of the demonstration models, management by the laws, and strengthening theoretical studies. This article also analyzes the shortcomings and challenges faced by the current work.

Scientific and effective supportability mechanisms have a profound impact on large-scale electromechanical systems and improve their performance quality, while decreasing costs. However, the contradiction between the static supportability strategy and time-varying performance quality conditions remains not sufficiently resolved. To solve this problem, this paper proposes a performance quality condition-based dynamic supportability mechanism. First, model-driven risk identification and control chart-based pattern recognition were used to trigger the dynamic allocation of the limit supportability resource. Second, the performance quality mode and effect analysis and the multiagent collaborative chain were defined to identify the resource lists of maintenance activities. Third, a general control framework was constructed to evaluate the compliance and applicability of maintenance activities. This study formulated a dynamic supportability mechanism for performance quality with a closed loop of activity triggering, resource guarantee, and maintenance effectiveness evaluation. As an expansion and improvement of condition-based maintenance, the dynamic supportability mechanism overcomes the several drawbacks of the existing supportability mechanisms of large-scale electromechanical systems. The proposed mechanism also advances the integration of management and technology in comprehensive supportability. Therefore, the proposed mechanism and methods can be flexibly and efficiently used for the dynamic supportability of electromechanical systems. Moreover, this study provides insights into risk identification, macro pattern recognition and process control and can be used for other engineering applications.

BMP4 variants have been reported to be associated with syndromic microphthalmia (MCOPS6, OMIM 607932). This study aims to describe BMP4 truncation mutations contributing to a novel phenotype in eight patients from four Chinese families. In this study, BMP4 variants were collected from a large dataset from in-house exome sequencing. Candidate variants were filtered by multiple in silico tools as well as comparison with data from multiple databases. Potential pathogenic variants were further confirmed by Sanger sequencing and cosegregation analysis. Four novel truncation variants in BMP4 were detected in four out of 7,314 unrelated probands with different eye conditions. These four mutations in the four families solely cosegregated in all eight patients with a specific form of pathologic myopia, characterized by significantly extended axial length, posterior staphyloma, macula patchy, chorioretinal atrophy, myopic optic neuropathy or glaucoma, vitreous opacity, and unique peripheral snow-grain retinopathy. The extreme rarity of the truncations in BMP4 (classified as intolerant in the gnomAD database, pLI = 0.96), the exclusive presence of these variants in the four families with pathologic myopia, variants fully co-segregated with the same specific phenotypes in eight patients from the four families, and the association of the pathogenicity of truncations with syndromic microphthalmia in previous studies, all support a novel association of BMP4 truncations with a specific form of pathologic myopia. The data presented in this study demonstrated that heterozygous BMP4 truncations contributed to a novel phenotype: pathologic myopia rather than microphthalmia. Mutations in the same gene resulting in both high myopia and microphthalmia have been observed for a few other genes like FZD5 and PAX6, suggesting bidirectional roles of these genes in early ocular development. Further studies are expected to elucidate the molecular mechanism of the bidirectional regulation.

Coherent change detection is a technology that utilizes phase information in complex-valued synthetic aperture radar images. It is mostly used to detect subtle changes that cannot be detected by amplitude images on the ground, and it also has excellent detection performance when it comes to low-coherence typical changed areas. However, due to its high sensitivity to changes, this technology will falsely detect areas of natural change such as vegetation disturbance, river flow, and low signal-to-noise ratio areas (e.g., uninteresting areas) as changes, resulting in false-alarm interference areas. In order to tackle this problem, this paper studies a coherent change detection method based on multi-scale analysis to extract typical changed areas in complicated scenes. The method uses an equal variance coherence estimator to calculate the coherence value, separates the interference areas and the typical changed areas using a multi-scale method, and then extracts a binary image of the typical changed areas through noise filtering and threshold segmentation. The method in this paper is experimentally verified with publicly available Airbus spaceborne SAR data, and ESAR airborne data, which is provided by the ESA. The experimental results are visualized and quantitatively evaluated. Through the results, by calculating the probability of correct classification and false-positive and other performance parameters, as well as drawing the receiver operating characteristic curve and the kappa coefficient curve of different threshold values, we find that the method has the capability to suppress the interference areas and the high detection performance of the typical changed areas. The experimental data are complicated scenes that include various types of ground object changes. The results show that the method is effective and universal and can provide reference value for the application of coherent change detection.

PurposeRPGR is the most common cause of X-linked retinitis pigmentosa (RP), of which female carriers are also frequently affected. The aim of the current study was to explore the RPGR variation spectrum and associated phenotype based on the data from our lab and previous studies.MethodsVariants in RPGR were selected from exome sequencing data of 7,092 probands with different eye conditions. The probands and their available family members underwent comprehensive ocular examinations. Similar data were collected from previous reports through searches in PubMed, Web of Science, and Google Scholar. Systematic analyses of genotypes, phenotypes and their correlations were performed.ResultsA total of 46 likely pathogenic variants, including nine missense and one in-frame variants in RCC1-like domain and 36 truncation variants, in RPGR were detected in 62 unrelated families in our in-house cohort. In addition, a total of 585 variants, including 491 (83.9%) truncation variants, were identified from the literature. Systematic analysis of variants from our in-house dataset, literature, and gnomAD suggested that most of the pathogenic variants of RPGR were truncation variants while pathogenic missense and in-frame variants were enriched in the RCC1-like domain. Phenotypic variations were present between males and female carriers, including more severe refractive error but better best corrected visual acuity (BCVA) in female carriers than those in males. The male patients showed a significant reduction of BCVA with increase of age and males with exon1-14 variants presented a better BCVA than those with ORF15 variants. For female carriers, the BCVA also showed significant reduction with increase of age, but BCVA in females with exon1-14 variants was not significant difference compared with those with ORF15 variants.ConclusionMost pathogenic variants of RPGR are truncations. Missense and in-frame variants located outside of the RCC1-like domain might be benign and the pathogenicity criteria for these variants should be considered with greater caution. The BCVA and refractive error are different between males and female carriers. Increase of age and location of variants in ORF15 contribute to the reduction of BCVA in males. These results are valuable for understanding genotypes and phenotypes of RPGR.

BackgroundHigh myopia with alopecia areata in the occipital region has been observed in patients with Knobloch syndrome caused by COL18A1 mutations. This study investigated other possible genetic causes of high myopia in patients with alopecia areata in the cranial midline.MethodsSix patients with early onset high myopia and alopecia areata in the cranial midline were recruited. Targeted high-throughput sequencing was performed on the proband’s DNA to detect potential pathogenic variants. Cosegregation analysis was performed for available family members. Minigene assay and RNA Sequencing were used to validate the abnormality of possible splicing change and gross deletion. Ophthalmological and neuroimaging examinations were performed.ResultsEight novel and one known loss-of-function mutants were detected in all six patients, including a gross deletion detected by RNA sequencing. Four COL18A1 mutants in three patients with scalp leisure in the occipital region; and five LAMA1 mutations in three patients with scalp leisure in the parietal region. Further assessments indicated that patients with COL18A1 mutations had Knobloch syndrome, and the patients with LAMA1 mutations had Poretti–Boltshauser syndrome.ConclusionOur study found that early onset high myopia with midline alopecia areata could be caused not only by mutations of the COL18A1 gene but also by mutations in the LAMA1 gene. To our knowledge, we are the first to observe scalp defects in patients with LAMA1 mutations. High myopia with alopecia areata in the cranial midline could be treated as an early diagnostic clue for ophthalmologists to consider the two kinds of rare diseases.

For inverse synthetic aperture radar (ISAR) imaging of rapidly spinning targets, the large migration through range cells (MTRC) results in weak coherence between adjacent echoes, which makes the conventional envelope alignment method unable to be applied. By analyzing the correlation between the echoes, a translational motion compensation (TMC) method for rapidly spinning targets is proposed. Firstly, the rotation period of the target is estimated by the incoherent accumulation method for the echo signal after range compression. Secondly, Kalman filtering is performed on the shift values required to maximize the correlation coefficient of the echoes with one rotation period difference in azimuth time to obtain the relative translational motion of the radar and the target. Finally, a translational compensation function is constructed according to the results of Kalman filtering to compensate the phase items caused by translational motion. Furthermore, the covariance matrix of observation noise required by Kalman filtering is also provided. This method is used to achieve high-precision envelope alignment, and the effectiveness of the proposed method is validated by simulations.

RP1 truncation variants, including frameshift, nonsense, and splicing, are a common cause of retinitis pigmentosa (RP). RP1 is a unique gene where truncations cause either autosomal dominant RP (adRP) or autosomal recessive RP (arRP) depending on the location of the variants. This study aims to clarify the boundaries between adRP and arRP caused by RP1 truncation variants based on a systemic analysis of 165 RP1 variants from our in-house exome-sequencing data of 7,092 individuals as well as a thorough review of 185 RP1 variants from published literature. In our cohort, potential pathogenic variants were detected in 16 families, including 11 new and five previously described families. Of the 16, seven families with adRP had heterozygous truncations in the middle portion, while nine families with either arRP (eight) or macular degeneration had biallelic variants in the N- and C-terminals, involving 10 known and seven novel variants. In the literature, 147 truncations in RP1 were reported to be responsible for either arRP (85) or adRP (58) or both (four). An overall evaluation of RP1 causative variants suggested three separate regions, i.e., the N-terminal from c.1 (p.1) to c.1837 (p.613), the middle portion from c.1981 (p.661) to c.2749 (p.917), and the C-terminal from c.2816 (p.939) to c.6471 (p.2157), where truncations in the middle portion were associated with adRP, while those in the N- and C-terminals were responsible for arRP. Heterozygous truncations alone in the N- and C- terminals were unlikely pathogenic. However, conflict reports with reverse situation were present for 13 variants, suggesting a complicated pathogenicity awaiting to be further elucidated. In addition, pathogenicity for homozygous truncations around c.5797 and thereafter might also need to be further clarified, so as for missense variants and for truncations located in the two gaps. Our data not only confirmed and refined the boundaries between dominant and recessive RP1 truncations but also revealed unsolved questions valuable for further investigation. These findings remind us that great care is needed in interpreting the results of RP1 variants in clinical gene testing as well as similar features may also be present in some other genes.

Background: Retinitis pigmentosa (RP) is the most common form of inherited retinal degeneration, but genetic defects in nearly half of families remain unresolved. This study aims to identify novel genes associated with RP based on whole exome sequencing (WES) data from 552 probands with RP. Methods: Biallelic loss-of-function (LoF) variants were selected from the WES data of 552 probands with RP and compared with that of 4728 in-house controls and the gnomAD database. Expression analysis and knockout mice model or knockdown zebrafish model were performed to confirm the association of a few candidate genes with RP. Findings: Unique biallelic LoF variants in ENSA, DACT2, DDR1, and CCDC188 were identified in four probands with RP, but were absent in 4728 in-house controls and were extremely rare in the gnomAD database. The expression of ENSA was enriched in the rod outer segments of human retina, and significant reduced responses of rods and cones were detected in Ensa knockout mice compared to wild-type mice by electroretinogram. The DACT2 transcript showed the highest expression in human retina and knockdown of dact2 in zebrafish resulted in photoreceptor disc membrane disarrangement. Interpretation: This study suggests that ENSA is likely a novel gene for RP and DACT2 is a potentially candidate gene for RP. Further studies are expected to evaluate the association between mutations in the other two genes and RP. To our knowledge, mutations in these genes have not been reported to be associated with RP before.

The dynamic large deflection response of RC beams under low-speed impact loading at their midspan is investigated in this paper. Two simple methods such as extended Hamilton’s principle and equivalent static hypothesis are used to establish the theoretical models for both simply supported and fully clamped RC beams; analytical formulas for the maximum midspan deflection-input impact energy are obtained. The “equal area” method based on the deflection history of beams is only used during these derivations to determine the plastic bending moment and the stress distribution of the structure. Then, finite element simulations are carried out to verify the validity of the proposed predictions. It is shown that the maximum deflections for both simply supported and fully clamped beams are almost proportional with respect to the input impact energy, which agrees well with both simulations and other experimental results. Also, the boundary condition has more effect on the deflection response of the RC beams which is relatively longer.

The buried depth of submarine cables is very important to avoid damage on the cable from dropping and dragging anchors. This study focused on the actual engineering needs of submarine power cable protection and laying construction. In order to investigate the buried depth protection index of submarine cable, physical model tests, theory analysis, and numerical simulations were conducted in this study. The effects of the bottoming velocity, dropping energy, and anchor mass on the anchor penetration depth were analyzed and investigated. The analytical model based on the impact and drag mechanism is presented to analyze the forces and energy on the anchor. The accuracy and reliable of the model test results are verified by the theory analysis and numerical simulation, indicating that the buried depth protection index of the submarine cable in the research area is recommended to be 3 m. The research results can provide guidance for operation of the submarine cable laying machine and submarine cable protection.

An innovative cable laying vessel for the grid connecting project of Zhoushan Island was designed and has been constructed. The stability of the vessel under the complex sea conditions is extremely important to the cable laying operations. Experimental and numerical studies are carried out in this study to investigate the stability performance of the mooring system designed for maintaining the position of the vessel. The experiments were conducted in a wave tank under the scale ratio of 1:49, and the motions in 6 degrees of freedom of the vessel model were measured together with the tension forces of the mooring lines, which can be utilized for the numerical model validation. More environmental hydrodynamic conditions were employed for further study numerically to justify the stability of the vessel under the complex operating conditions.

Interferometric phase filtering is a crucial step in multibaseline interferometric synthetic aperture radar (InSAR). Current multibaseline interferometric phase filtering methods mostly follow methods of single-baseline InSAR and do not bring its data superiority into full play. The joint filtering of multibaseline InSAR based on statistics is proposed in this paper. We study and analyze the fourth-order statistical quantity of interferometric phase: kurtosis. An empirical assumption that the kurtosis of interferograms with different baselines keeps constant is proposed and is named as the baseline-invariant property of kurtosis in this paper. Some numerical experiments and rational analyses confirm its validity and universality. The noise level estimation of nature images is extended to multibaseline InSAR by dint of the baseline-invariant property of kurtosis. A filtering method based on the non-subsampled shearlet transform (NSST) and Wiener filter with estimated noise variance is proposed then. Firstly, multi-scaled and multi-directional coefficients of interferograms are obtained by NSST. Secondly, the noise variance is represented as the solution of a constrained non-convex optimization problem. A pre-thresholded Wiener filtering with estimated noise variance is employed for shrinking or zeroing NSST coefficients. Finally, the inverse NSST is utilized to obtain the filtered interferograms. Experiments on simulated and real data show that the proposed method has excellent comprehensive performance and is superior to conventional single-baseline filtering methods.

Leber hereditary optic neuropathy (LHON) and dominant optic atrophy (DOA), the most common forms of hereditary optic neuropathy, are easily confused, and it is difficult to distinguish one from the other in the clinic, especially in young children. The present study was designed to survey the mutation spectrum of common pathogenic genes (OPA1, OPA3 and mtDNA genes) and to analyze the genotype-phenotype characteristics of Chinese patients with suspected childhood-onset hereditary optic neuropathy. Genomic DNA and clinical data were collected from 304 unrelated Chinese probands with suspected hereditary optic neuropathy with an age of onset below 14 years. Sanger sequencing was used to screen variants in the coding and adjacent regions of OPA1, OPA3 and the three primary LHON-related mutation sites in mitochondrial DNA (mtDNA) (m.3460G>A, m.11778G>A and m.14484T>C). All patients underwent a complete ophthalmic examination and were compared with age-matched controls. We identified 89/304 (29.3%) primary mtDNA mutations related to LHON in 304 probands, including 76 mutations at m.11778 (76/89, 85.4% of all mtDNA mutations), four at m.3460 (4/89, 4.5%) and nine at m.14484 (9/89, 10.1%). This result was similar to the mutation frequency among Chinese patients with LHON of any age. Screening of OPA1 revealed 23 pathogenic variants, including 11 novel and 12 known pathogenic mutations. This study expanded the OPA1 mutation spectrum, and our results showed that OPA1 mutation is another common cause of childhood-onset hereditary optic neuropathy in Chinese pediatric patients, especially those with disease onset during preschool age.

Aiming at the poor waveform quality of the new energy grid connected under the traditional PI control strategy, based on the theory of repetitive control method, a compound control trategy is proposed. Through the analysis of the compound control module and simulation, the results show that grid harmonic distortion rate can be reduced about 2% at the same nonlinear load, the compound control strategy can suppress the load disturbance signal effectively, and the simulation results demonstrate the effectiveness of the proposed method.

Stargardt disease (STGD) is the most common hereditary macular degeneration in juveniles, with loss of central vision occurring in the first or second decade of life. The aim of this study is to identify the genetic defects in 33 probands with Stargardt disease. Clinical data and genomic DNA were collected from 33 probands from unrelated families with STGD. Variants in coding genes were initially screened by whole exome sequencing. Candidate variants were selected from all known genes associated with hereditary retinal dystrophy and then confirmed by Sanger sequencing. Putative pathogenic variants were further validated in available family members and controls. Potential pathogenic mutations were identified in 19 of the 33 probands (57.6%). These mutations were all present in ABCA4, but not in the other four STGD-associated genes or in genes responsible for other retinal dystrophies. Of the 19 probands, ABCA4 mutations were homozygous in one proband and compound heterozygous in 18 probands, involving 28 variants (13 novel and 15 known). Analysis of normal controls and available family members in 12 of the 19 families further support the pathogenicity of these variants. Clinical manifestation of all probands met the diagnostic criteria of STGD. This study provides an overview of a genetic basis for STGD in Chinese patients. Mutations in ABCA4 are the most common cause of STGD in this cohort. Genetic defects in approximately 42.4% of STGD patients await identification in future studies.

PURPOSE: The aim of this study was to investigate the mutation spectrum and frequency of 34 known genes in 18 Chinese families with congenital cataracts. METHODS: Genomic DNA and clinical data was collected from 18 families with congenital cataracts. Variations in 34 cataract-associated genes were screened by whole exome sequencing and then validated by Sanger sequencing. RESULTS: Eleven candidate variants in seven of the 34 genes were detected by exome sequencing and then confirmed by Sanger sequencing, including two variants predicted to be benign and the other pathogenic mutations. The nine mutations were present in 9 of the 18 (50%) families with congenital cataracts. Of the four families with mutations in the X-linked NHS gene, no other abnormalities were recorded except for cataract, in which a pseudo-dominant inheritance form was suggested, as female carriers also had different forms of cataracts. CONCLUSION: This study expands the mutation spectrum and frequency of genes responsible for congenital cataract. Mutation in NHS is a common cause of nonsyndromic congenital cataract with pseudo-autosomal dominant inheritance. Combined with our previous studies, a genetic basis could be identified in 67.6% of families with congenital cataracts in our case series, in which mutations in genes encoding crystallins, genes encoding connexins, and NHS are responsible for 29.4%, 14.7%, and 11.8% of families, respectively. Our results suggest that mutations in NHS are the common cause of congenital cataract, both syndromic and nonsyndromic.

Leber congenital amaurosis (LCA) is the earliest and most severe retinal degeneration (RD), and the most common cause of incurable blindness diagnosed in children. It is occasionally the presenting symptom of multisystemic ciliopathies which diagnosis will require a specific care of patients. Nineteen LCA genes are currently identified and three of them account for both non-syndromic and syndromic forms of the disease. RD3 (LCA12) was implicated as a LCA gene based on the identification of homozygous truncating mutations in two LCA families despite the screening of large cohorts of patients. Here we provide a comprehensive survey of RD3 mutations and of their clinical expression through the screening of a cohort of 852 patients originating worldwide affected with LCA or early-onset and severe RD. We identified three RD3 mutations in seven unrelated consanguineous LCA families - i.e., a 2 bp deletion and two nonsense mutations - predicted to cause complete loss of function. Five families originating from the Southern Shores of the Mediterranean segregated a similar mutation (c.112C>T, p.R38*) suggesting that this change may have resulted from an ancient founder effect. Considering the low frequency of RD3 carriers, the recurrence risk for LCA in non-consanguineous unions is negligible for both heterozygote and homozygote RD3 individuals. The LCA12 phenotype in our patients is highly similar to those of patients with mutant photoreceptor-specific guanylate cyclase (GUCY2D/LCA1). This observation is consistent with the report of the role of RD3 in trafficking of GUCYs and gives further support to a common mechanism of photoreceptor degeneration in LCA12 and LCA1, i.e., inability to increase cytoplasmic cGMP concentration in outer segments and thus to recover the dark-state. Similar to LCA1, LCA12 patients have no extraocular symptoms despite complete inactivation of both RD3 alleles, supporting the view that extraocular investigations in LCA infants with RD3 mutations should be avoided.

The goal of this study was to identify mutations in 25 known causative genes in 47 unrelated Chinese families with cone-rod dystrophy (CORD).Forty-seven probands from unrelated families with CORD were recruited. Genomic DNA prepared from leukocytes was analyzed by whole exome sequencing. Variants in the 25 genes were selected and then validated by Sanger sequencing.Fourteen potential pathogenic mutations, including nine novel and five known, were identified in 10 of the 47 families (21.28%). Homozygous, compound heterozygous, and hemizygous mutations were detected in three, four, or three families, respectively. The 14 mutations in the 10 families were distributed among CNGB3 (three families), PDE6C (two families), ABCA4 (one family), RPGRIP1 (one family), RPGR (two families), and CACNA1F (one family).This study provides a brief view on mutation spectrum of the 25 genes in a Chinese cohort with CORD. Identification of novel mutations enriched our understanding of variations in these genes and their associated phenotypes. To our knowledge, this is the first systemic exome-sequencing analysis of all of the 25 CORD-associated genes.

Mitochondrial transfer RNA (mt-tRNA) mutations have been reported to be associated with a variety of diseases. In a previous paper that studied the mtDNA background effect on clinical expression of Leber's hereditary optic neuropathy (LHON) in 182 Chinese families with m.11778G>A, we found a strikingly high frequency (7/182) of m.593T>C in the mitochondrially encoded tRNA phenylalanine (MT-TF) gene in unrelated LHON patients. To determine the potential role of m.593T>C in LHON, we compared the frequency of this variant in 479 LHON patients with m.11778G>A, 843 patients with clinical features of LHON but without the three known primary mutations, and 2374 Han Chinese from the general populations. The frequency of m.593T>C was higher in LHON patients (14/479) than in suspected LHON subjects (12/843) or in general controls (49/2374), but the difference was not statistically significant. The overall penetrance of LHON in families with both m.11778G>A and m.593T>C (44.6%) was also substantially higher than that of families with only m.11778G>A (32.9%) (P = 0.083). Secondary structure prediction of the MT-TF gene with the wild type or m.593T>C showed that this nucleotide change decreases the free energy. Electrophoretic mobility of the MT-TF genes with the wild type or m.593T>C transcribed in vitro further confirmed the change of secondary structure in the presence of this variant. Although our results could suggest a modest synergistic effect of variant m.593T>C on the LHON causing mutation m.11778G>A, the lack of statistical significance probably due to the relatively small sample size analyzed, makes necessary more studies to confirm this effect.

Recent studies have shown that mtDNA background could affect the clinical expression of Leber hereditary optic neuropathy (LHON). We analyzed the mitochondrial DNA (mtDNA) variation of 304 Chinese patients with m.11778G>A (sample #1) and of 843 suspected LHON patients who lack the three primary mutations (sample #2) to discern mtDNA haplogroup effect on disease onset. Haplogroup frequencies in the patient group was compared to frequencies in the general Han Chinese population (n = 1,689; sample #3). The overall matrilineal composition of the suspected LHON population resembles that of the general Han Chinese population, suggesting no association with mtDNA haplogroup. In contrast, analysis of these LHON patients confirms mtDNA haplogroup effect on LHON. Specifically, the LHON sample significantly differs from the general Han Chinese and suspected LHON populations by harboring an extremely lower frequency of haplogroup R9, in particular of its main sub-haplogroup F (#1 vs. #3, P-value = 1.46×10(-17), OR = 0.051, 95% CI: 0.016-0.162; #1 vs. #2, P-value = 4.44×10(-17), OR = 0.049, 95% CI: 0.015-0.154; in both cases, adjusted P-value A but not suspected LHON. Haplogroup F has a protective effect against LHON, while M7b is a risk factor.

BACKGROUND: Leber congenital amaurosis (LCA) is the earliest onset and most severe form of hereditary retinal dystrophy. So far, full spectrum of variations in the 15 genes known to cause LCA has not been systemically evaluated in East Asians. Therefore, we performed comprehensive detection of variants in these 15 genes in 87 unrelated Han Chinese patients with LCA. METHODOLOGY/PRINCIPAL FINDINGS: The 51 most frequently mutated exons and introns in the 15 genes were selected for an initial scan using cycle sequencing. All the remaining exons in 11 of the 15 genes were subsequently sequenced. Fifty-three different variants were identified in 44 of the 87 patients (50.6%), involving 78 of the 88 alleles (11 homozygous and 56 heterozygous variants). Of the 53 variants, 35 (66%) were novel pathogenic mutations. In these Chinese patients, variants in GUCY2D are the most common cause of LCA (16.1% cases), followed by CRB1 (11.5%), RPGRIP1 (8%), RPE65 (5.7%), SPATA7 (4.6%), CEP290 (4.6%), CRX (3.4%), LCA5 (2.3%), MERTK (2.3%), AIPL1 (1.1%), and RDH12 (1.1%). This differs from the variation spectrum described in other populations. An initial scan of 55 of 215 PCR amplicons, including 214 exons and 1 intron, detected 83.3% (65/78) of the mutant alleles ultimately found in these 87 patients. In addition, sequencing only 9 exons would detect over 50% of the identified variants and require less than 5% of the labor and cost of comprehensive sequencing for all exons. CONCLUSIONS/SIGNIFICANCE: Our results suggest that specific difference in the variation spectrum found in LCA patients from the Han Chinese and other populations are related by ethnicity. Sequencing exons in order of decreasing risk is a cost-effective way to identify causative mutations responsible for LCA, especially in the context of genetic counseling for individual patients in a clinical setting.

BackgroundLeber hereditary optic neuropathy (LHON, MIM 535000) is one of the most common mitochondrial genetic disorders caused by three primary mtDNA mutations (m.3460G>A, m.11778G>A and m. 14484T>C). The clinical expression of LHON is affected by many additional factors, e.g. mtDNA background, nuclear genes, and environmental factors. Hitherto, there is no comprehensive study of Chinese LHON patients with m.14484T>C.Methodology/principal findingsIn this study, we analyzed the mtDNA sequence variations and haplogroup distribution pattern of the largest number of Chinese LHON patients with m.14484T>C to date. We first determined the complete mtDNA sequences in eleven LHON probands with m.14484T>C, to discern the potentially pathogenic mutations that co-segregate with m.14484T>C. We then dissected the matrilineal structure of 52 patients with m.14484T>C (including 14 from unrelated families and 38 sporadic cases) and compared it with the reported Han Chinese from general populations. Complete mtDNA sequencing showed that the eleven matrilines belonged to nine haplogroups including Y2, C4a, M8a, M10a1a, G1a1, G2a1, G2b2, D5a2a1, and D5c. We did not identify putatively pathogenic mutation that was co-segregated with m.14484T>C in these lineages based on the evolutionary analysis. Compared with the reported Han Chinese from general populations, the LHON patients with m.14484T>C had significantly higher frequency of haplogroups C, G, M10, and Y, but a lower frequency of haplogroup F. Intriguingly, we also observed a lower prevalence of F lineages in LHON subjects with m.11778G>A in our previous study, suggesting that this haplogroup may enact similar role during the onset of LHON in the presence of m.14484T>C or m.11778G>A.Conclusions/significanceOur current study provided a comprehensive profile regarding the mtDNA variation and background of Chinese patients with LHON and m.14484T>C. Matrilineal background might affect the expression of LHON in Chinese patients with m.14484T>C.