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In seed processing for commercial production, the collision or friction between mechanical parts and seed is inevitable. These collisions or friction can cause cracks on the surface of the seed, which can affect germination rates and ultimately reduce crop yields. Using the difference of the seed motion trajectories with different crack degrees in the magnetic field, the grading of the surface crack seed can be realized. In this study, the motion law of seed in a non-uniform magnetic field was analyzed by taking the delinted cottonseed as an object. A magnetic separation device for crop seeds was developed. This device was essentially composed of the feed throat, magnetic roller, conveyor belt, and variable-frequency adjustablespeed motor. The magnetic powder adhering seeds enter the magnetic separation device through the feed throat and are conveyed to the magnetic roller through the conveyor belt. The magnetic roller has different adsorption forces on seeds with different degrees of cracking, and seeds fall into different outlets, thus completing the grading of the seeds. By adjusting working parameters such as the magnetic field strength and the speed of the conveyor belt, magnetic separation could be made. In order to verify the grading effect, the magnetic separation accuracy was taken as the inspection index, the magnetic powder's mesh number, the mass mixing ratio between magnetic powder and delinted cottonseed, and the rotation speed of the magnetic roller were taken as the inspection factors. The response surface methodology was used to optimize the working parameters of the experimental device. The results showed that the optimal process parameters of the magnetic separation device were as follows: the number of magnetic powder meshes was 250, the mass mixing ratio between magnetic powder and delinted cottonseed was 1:20, and when the rotational speed of the magnetic separation roller was 20 r/min, the detection rate reached 92.5%. The designed magnetic separation device can realize the non-destructive batch detection of seed surface cracks with high work efficiency and has guiding significance for the high-precision and low-damage classification detection and classification of commercial seed. [ABSTRACT FROM AUTHOR]

Using the fractional complex transform, the fractional partial differential equations can be reduced to ordinary differential equations which can be solved by the auxiliary equation method. Non-linear superposition formulation of Riccati equation is applied, and a complex infinite sequence solution is obtained. [ABSTRACT FROM AUTHOR]

Land surface temperature (LST) is a key parameter in the interaction of the land-atmosphere system. However, clouds affect the retrieval of LST data from thermal-infrared remote sensing data. Thus, it is important to determine a method for estimating LSTs at times when the sky is overcast. Based on a one-dimensional heat transfer equation and on the evolution of daily temperatures and net shortwave solar radiation (NSSR), a new method for estimating LSTs under cloudy skies (Tcloud) from diurnal NSSR and surface temperatures is proposed. Validation is performed against in situ measurements that were obtained at the ChangWu ecosystem experimental station in China. The results show that the root-mean-square error (RMSE) between the actual and estimated LSTs is as large as 1.23 K for cloudy data. A sensitivity analysis to the errors in the estimated LST under clear skies (Tclear) and in the estimated NSSR reveals that the RMSE of the obtained Tcloud is less than 1.5 K after adding a 0.5 K bias to the actual Tclear and 10 percent NSSR errors to the actual NSSR. Tcloud is estimated by the proposed method using Tclear and NSSR products of MSG-SEVIRI for southern Europe. The results indicate that the new algorithm is practical for retrieving the LST under cloudy sky conditions, although some uncertainty exists. Notably, the approach can only be used during the daytime due to the assumption of the variation in LST caused by variations in insolation. Further, if there are less than six Tclear observations on any given day, the method cannot be used. [ABSTRACT FROM AUTHOR]

Two-dimensional polyvinyl alcohol based graphene films with the thickness of less than 20 nm were fabricated directly by using polyvinyl alcohol/graphite solution or polyvinyl alcohol/ash solution by electrospinning. It was found that ash particles are good candidate for substitution of graphite particles to fabricate nanographene films. The relationship between the thickness and width of the film is elucidated, and the periodic morphology of the film is explained. [ABSTRACT FROM AUTHOR]

Frame synchronization time of geostationary Earth orbit (GEO) satellites is faster than that of incline geosynchronous satellite orbit and medium Earth orbit satellites in Beidou navigation satellite system (BDS). So time to first fix can be reduced greatly with GEO satellites (GEOs) to provide emergency positioning service during the cold start process. Meanwhile, GEOs can also be utilized to provide radio determination satellite services. Therefore, it is meaningful to research the emergency positioning algorithm based on GEOs. However, due to the poor geometry of the GEOs, the availability and accuracy degrade distinctly. To solve this problem, a low-cost high resolution MS5534B barometric (baro-) module is applied to BDS. Firstly, the principle of emergency positioning based on a baro-altimeter sensor and its performance such as the accuracy are elaborated. Then the effects of baro-altimeter sensor measurement error on positioning are analyzed. Finally, after analyzing the limitation of the conventional algorithms, a new high-accuracy emergency positioning algorithm with baro-altimeter sensor aiding is proposed, which is not limited by the integration and user's altitude. In comparison to the conventional algorithms, the stimulant and experimental results validate the effectiveness, robustness, and higher performance of the proposed algorithms incorporated with sensors. [ABSTRACT FROM AUTHOR]

Achromatopsia is a rare autosomal recessive disorder which shows color blindness, severely impaired visual acuity, and extreme sensitivity to bright light. Mutations in the alpha subunits of the cone cyclic nucleotide-gated channels (CNGA3) are responsible for about 1/4 of achromatopsia in the U.S. and Europe. Here, we test whether gene replacement therapy using an AAV5 vector could restore cone-mediated function and arrest cone degeneration in the cpfl5 mouse, a naturally occurring mouse model of achromatopsia with a CNGA3 mutation. We show that gene therapy leads to significant rescue of cone-mediated ERGs, normal visual acuities and contrast sensitivities. Normal expression and outer segment localization of both M- and S-opsins were maintained in treated retinas. The therapeutic effect of treatment lasted for at least 5 months post-injection. This study is the first demonstration of substantial, relatively long-term restoration of cone-mediated light responsiveness and visual behavior in a naturally occurring mouse model of CNGA3 achromatopsia. The results provide the foundation for development of an AAV5-based gene therapy trial for human CNGA3 achromatopsia. [ABSTRACT FROM AUTHOR]

The retinal degeneration 10 (rd10) mouse is a well-characterized model of autosomal recessive retinitis pigmentosa (RP), which carries a spontaneous mutation in the β subunit of rod cGMP-phosphodiesterase (PDEβ). Rd10 mouse exhibits photoreceptor dysfunction and rapid rod photoreceptor degeneration followed by cone degeneration and remodeling of the inner retina. Here, we evaluate whether gene replacement using the fast-acting tyrosine-capsid mutant AAV8 (Y733F) can provide long-term therapy in this model. AAV8 (Y733F)-smCBA-PDEβ was subretinally delivered to postnatal day 14 (P14) rd10 mice in one eye only. Six months after injection, spectral domain optical coherence tomography (SD-OCT), electroretinogram (ERG), optomotor behavior tests, and immunohistochemistry showed that AAV8 (Y733F)-mediated PDEβ expression restored retinal function and visual behavior and preserved retinal structure in treated rd10 eyes for at least 6 months. This is the first demonstration of long-term phenotypic rescue by gene therapy in an animal model of PDEβ-RP. It is also the first example of tyrosine-capsid mutant AAV8 (Y733F)-mediated correction of a retinal phenotype. These results lay the groundwork for the development of PDEβ-RP gene therapy trial and suggest that tyrosine-capsid mutant AAV vectors may be effective for treating other rapidly degenerating models of retinal degeneration. [ABSTRACT FROM AUTHOR]

In this paper, a new auxiliary equation method is used to find exact travelling wave solutions to the (1+1)-dimensional KdV equation. Some exact travelling wave solutions with parameters have been obtained, which cover the existing solutions. Compared to other methods, the presented method is more direct, more concise, more effective, and easier for calculations. In addition, it can be used to solve other nonlinear evolution equations in mathematical physics. [ABSTRACT FROM AUTHOR]

The fundamental difference between quantum and traditional plasmas is the electron and ion composition, the former has a much higher density and extremely lower temperature, and it can be modelled by Zakharov-Kuznetsov (ZK) equation. In this paper, the Hirota bilinear method is used to study its solution properties. [ABSTRACT FROM AUTHOR]

The micro-electro-mechanical system is widely used for energy harvesting and thermal wind sensor, its efficiency and reliability depend upon the pull-in instability. This paper studies a micro-electro-mechanical system using He-Liu [34] formulation for finding its frequency-amplitude relationship. The system periodic motion, pull-in instability and pseudo-periodic motion are discussed. This paper offers a new window for security monitoring of the system reliable operation. [ABSTRACT FROM AUTHOR]

Based on Hirota bilinear formulation, the lump solutions to dimensionally reduced generalized variable coefficient B-type Kadomtsev-Petviashvili equation are obtained. The solution process is figured out and the solution properties are illustrated graphically. The present method can be extended to other non-linear equations. [ABSTRACT FROM AUTHOR]

The second elliptic equation method is a more general form of Jacobi elliptic function expansion method, which can obtain more kinds of solutions of a non-linear evolution equation. In this paper, the method is used to solve the Kdv-Burgers-Kuramoto (Benny) equation with variable coefficients, and its extremely rich solution properties are elucidated, among which the biperiodic solutions, solitary wave solutions and trigonometric periodic solutions are analyzed graphically. [ABSTRACT FROM AUTHOR]

As an important index of soil crushing performance of rotary tiller, the soil fragmentation rate is still limited to manual measurement. In this study, an automatic detection platform for soil fragmentation rate was designed, which integrated soil intake, screening, weighing and calculation of soil fragmentation rate. This platform can solve the problem that the index of the soil fragmentation rate cannot be detected quickly and effectively after rotary tillage, which leads to difficulty in field quality evaluation. The platform was mainly composed of a shovel soil module, conveying module, screening module, weighing module and automatic control system, which could realize single-line and multi-point automatic soil fragmentation rate detection. Based on the homogeneous dry slope model, the tilting angles of soil intake and soil feeding after rotary tillage on the platform were determined to be 30.10° and 26.67°, respectively. According to the principle of flow conservation, a rotary circulation screening module was designed to obtain soil particle size grading. A method based on the principle of multi-line and multi-point measurement was developed to detect soil fragmentation rate. The influence of screening speed on screening effect was analyzed, and the reasonable value of screening speed was determined to be 0.5 m/s. A field performance test was carried out in October 2019 to verify the detection performance of the platform. The results showed that, compared with the manual test method, the maximum test error was no more than 11%, the minimum test error was less than 4%, the maximum single test time was no more than 2 min, and the total test time of each test area was no more than 30 min. The efficiency of single-point detection was significantly better than the manual detection, which indicated that the design in this study met the requirements of rapid detection of soil fragmentation rate, and provided a new idea for the automatic detection of quality of rotary tillage. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetic subjects often have hypertriglyceridemia and an increased concentration of apolipoprotein B-48 (apoB-48) in circulation, particularly during the postprandial period. There is an accumulating body of evidence to suggest that apoB-48 plays a central role in the development of atherosclerosis. Statins are the frontline therapy to reduce cardiovascular risk, however, a large residual risk still remains. This residual risk suggests that additional therapeutic interventions may be required to further reduce CVD risk. Aim: To investigate the effect of niacin on the metabolism of triglyceride-rich lipoprotein (TRL) apoB-48 in men with type 2 diabetes on background statin therapy. Methods: Twelve type 2 diabetic men were recruited for this randomized, crossover design study. Patients required a statin-treated low density lipoprotein (LDL) cholesterol of less than 2.5 mmol/L to enter the trial. Patients were then randomized to rosuvastatin alone or rosuvastatin plus niacin (titrated up from 1 to 2 g daily) for a period of 12 weeks and then were crossed over to the alternate therapy with a 3 week washout period in between. Metabolic studies were performed at the end of each treatment period. A bolus intravenous infusion of D3- leucine was administered as subjects consumed a standardised high-fat liquid meal. Blood samples were collected over 24 hours and TRL apoB-48 tracer/tracee ratios were measured using gas chromatography-mass spectrometry. Kinetic parameters, including fractional catabolic rate (FCR) and production rate (PR), were derived using a multicompartmental model. Results: Niacin significantly reduced triglyceride, plasma cholesterol, LDL cholesterol and apoB (all p<0.005). TRL apoB-48 concentration was lower with niacin (8.24 ± 1.98 vs 5.48 ± 1.14 mg/L, p=0.03). ApoB-48 FCR was not altered with niacin (8.78 ± 1.04 vs 9.17 ± 1.26 pools/day; p=0.79). Basal apoB-48 PR (3.21 ± 0.34 vs 2.50 ± 0.31 mg/kg/day; p=0.04) and postprandial apoB-48 PR were significantly lower (1.35 ± 0.19 vs 0.84 ± 0.12 mg/kg; p=0.02) on niacin. Conclusion: Niacin reduces TRL apoB-48 concentration by lowering basal and postprandial apoB-48 PR. This effect on apoB-48 metabolism may be beneficial for reducing atherogenic postprandial TRL particles and may provide CVD risk benefit to patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Emerging drug resistance is generating an urgent need for novel and effective antibiotics. A promising target that has not yet been addressed by approved antibiotics is the bacterial DNA gyrase subunit B (GyrB), and GyrB inhibitors could be effective against drug-resistant bacteria, such as methicillin-resistant S. aureus (MRSA). Here, we used the 4-hydroxy-2-quinolone fragment to search the Specs database of purchasable compounds for potential inhibitors of GyrB and identified AG-690/11765367, or f1, as a novel and potent inhibitor of the target protein (IC50: 1.21 µM). Structural modification was used to further identify two more potent GyrB inhibitors: f4 (IC50: 0.31 µM) and f14 (IC50: 0.28 µM). Additional experiments indicated that compound f1 is more potent than the others in terms of antibacterial activity against MRSA (MICs: 4-8 mg/mL), non-toxic to HUVEC and HepG2 (CC50: approximately 50 µM), and metabolically stable (t1/2: > 372.8 min for plasma; 24.5 min for liver microsomes). In summary, this study showed that the discovered N-quinazolinone-4-hydroxy-2-quinolone-3-carboxamides are novel GyrB-targeted antibacterial agents; compound f1 is promising for further development. [ABSTRACT FROM AUTHOR]

Abstract: This paper is concerned with a new algorithm for giving the analytical and approximate solutions of a class of boundary value problems in the reproducing kernel space. The analytical solution and approximate solution are represented in terms of series. For any initial function , we prove , , . Two numerical examples are studied to demonstrate the accuracy of the present method. Results obtained by the method indicate the method is simple and effective. [Copyright &y& Elsevier]

Background: MicroRNAs play an important role in many fundamental biological and pathological processes. Defining the microRNAs profile underlying the processes by beneficial and detrimental lifestyles, including caloric restriction (CR), exercise and high-fat diet (HF), is necessary for understanding both normal physiology and the pathogenesis of metabolic disease. We used the microarray to detect microRNAs expression in livers from CR, EX and HF mice models. After predicted potential target genes of differentially expressed microRNAs with four algorithms, we applied GO and KEGG to analyze the function of predicted microRNA targets. Results: We describe the overall microRNAs expression pattern, and identified 84 differentially expressed microRNAs changed by one or two or even all the three lifestyle modifications. The common and different enriched categories of gene function and main biochemical and signal transduction pathways were presented. Conclusions: We provided for the first time a comprehensive and thorough comparison of microRNAs expression profiles in liver among these lifestyle modifications. With this knowledge, our findings provide us with an overall vision of microRNAs in the molecular impact of lifestyle on health as well as useful clues for future and thorough research of the role of microRNAs. [ABSTRACT FROM AUTHOR]

In China, low degree of automation seriously affects the working efficiency and quality in vegetable transplanting. As one of the most important vegetables in China even in the world, tomato was taken as the research object in this study. An automatic single-row transplanting device was designed, based on the statistical analysis of the physical and mechanical properties of tomato seedlings of a typical variety. Based on the technology of mechatronics, the device integrated the functions of transporting seedling tray, automatic seedling extraction and mechanical planting. The kinematics orthogonality solution combined with the dynamic sequence solution method was used to optimize and analyze the kinematic parameters of the automatic seeding mechanism, and the "sickle" trajectory was obtained. According to the position and movement requirement for taking and dropping seedling, the mechanical conditions and the working parameters of key execution parts were obtained by using analytic drawing method to analyze the mechanical condition of seedling collecting mechanism. The transplanting experiment was conducted at room temperature of 25°C, and the age and moisture content of the seedlings were 40 d and 55%, respectively. The results showed that the highest success rate was 92.59%, and the lowest rate of leakage was 23.13%, when the transplanting frequency was 60 plants/min. The lowest success rate was 77.78%, and the highest rate of leakage was 38.75%, when transplanting frequency was 120 plants/min. When the transplanting frequency is between 60-90 plants/min, the device can meet the requirement of high speed transplanting for potted vegetable seedling. [ABSTRACT FROM AUTHOR]

Background: Ovulation rate and litter size are important reproductive traits in sheep with high economic value. Recent work has revealed a potential link between DNA methylation and prolificacy. However, a genome-wide study that sought to identify potential DNA methylation sites involved in sheep prolificacy indicated that it is still unknown. Here, we aimed to investigate the genome-wide DNA methylation profiles of Hu sheep ovaries by comparing a highprolificacy group (HP, litter size of three for at least 2 consecutive lambings) and low prolificacy group (LP, litter size of one for at least 2 consecutive lambings) using deep whole-genome bisulfite sequencing (WGBS). Results: First, our results demonstrated lower expression levels of DNA methyltransferase (DNMT) genes in the ovaries of the HP group than that in the ovaries of the LP group. Both groups showed similar proportions of methylation at CpG sites but different proportions at non-CpG sites. Subsequently, we identified 70,899 differential methylated regions (DMRs) of CG, 16 DMRs of CHG, 356 DMRs of CHH and 12,832 DMR-related genes(DMGs). Gene Ontology (GO) analyses revealed that some DMGs were involved in regulating female gonad development and ovarian follicle development. Finally, we found that 10 DMGs, including BMP7, BMPR1B, CTNNB1, FST, FSHR, LHCGR, TGFB2 and TGFB3, are more likely to be involved in prolificacy of Hu sheep, as assessed by correlation analysis and listed in detail. Conclusions: This study revealed the global DNA methylation pattern of sheep ovaries associated with high and low prolificacy groups, which may contribute to a better understanding of the epigenetic regulation of sheep reproductive capacity. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To assess safety and effectiveness of symmetric and asymmetric occluders in perventricular device closure without cardiopulmonary bypass of perimembranous ventricular septal defects (pmVSDs). METHODS: The present retrospective study enrolled 581 patients who underwent perventricular device closure of pmVSDs under transoesophageal echocardiography guidance from May 2011 to April 2016, and outpatient electrocardiography and transthoracic echocardiography assessments at 1, 3, 6 and 12 months, and yearly thereafter. RESULTS: The overall success rate of device implantation was 92.6% (43 surgical conversions immediately). Between patients receiving symmetric (n = 353) and asymmetric (n = 185) occluders, there were no significant differences in age, weight and defect diameter distributions; however, both before discharge and at mean 28.6 ± 21.2 (range, 1-60)-month follow-up, the symmetric group had lower rates of trivial residual shunt (5.7% vs 11.4%, P = 0.018; and 0.8% vs 5.9%, P = 0.001) and bundle branch block (0.8% vs 5.4%, P = 0.002; and 0.6% vs 3.8%, P = 0.009); and at follow-up, the asymmetric group had lower residual shunt (47.6% vs 85.0%, P = 0.020) and similar branch block (30.0% vs 33.3%, P = 1.000) disappearance rates. There were no severe complications, i.e. aortic regurgitation, malignant arrhythmias, haemolysis or device dislocation. CONCLUSIONS: Perventricular device closure of pmVSDs appears safe and effective with symmetric and asymmetric occluders. However, the lower residual shunt disappearance and higher branch block incidence rates for asymmetric occluders would favour more proactive conversion to surgical repair immediately when residual shunt is present intraoperatively. [ABSTRACT FROM AUTHOR]

Background: The associations of sarcopenia with adverse health status have highlighted the importance of sarcopenia research and intervention. This study was designed to analyze the characteristics of aging-related differences in appendicular skeletal muscle mass (ASM), handgrip strength (HS), gait speed (GS) and their associated factors in older Chinese, in order to generate guidance for sarcopenia intervention in this population. Methods: Population-based cross-sectional study. The criteria proposed by Asian Working Group for Sarcopenia were used to define low ASM, HS, and GS. The time required for five repeated chair stands (RCS) was also measured to evaluate physical performance. The differences of continuous variables were compared using one-way ANOVA tests and the Pearson correlation was used to analyze the relationship of each measurement adjusted by gender and age. Stepwise logistic regression was used to determine associated factors of low HS and low physical performance. Results: The data were analyzed in a total of 218 younger adults (aged 20-59, 76 males, 142 females) and 461 older adults (=60 year, 207 males and 254 females). There were significant differences among age groups for HS, GS, and RCS while females were found to have significantly lower HS and GS values. ASM was significantly correlated with HS but not with other measures. Correlations among HS and GS, RCS were influenced by age differences. In the older group, unstructured daily routine (OR = 2.77) was associated with the risk of low GS, while physical exercise (OR = 0.27), and engaging in hobbies (OR = 0.11) were associated with faster GS. Co-morbidity (OR = 1.99) was associated with the risk of reduced performance of RCS, while engaging in hobbies was associated with faster RCS performance (OR = 0.35). Conclusions: Muscle strength and physical performance varied with aging in older Chinese. Measures of GS, HS, and RCS provide a readily available and effective method for assessing the risk of functional mobility decline. Maintaining a healthy life style and physical activity throughout life is beneficial for older people to improve their physical performance, especially in the early stages of aging. [ABSTRACT FROM AUTHOR]

The regulatory mechanism of mammary gland development and lactation is important, as lactation not only provides healthy milk for infants, but also provides health benefits to mothers. Circular RNAs (circRNAs) have recently received much attention, but only a few have been functionally characterized. In the present study, the structure and expression profile of a rat Tc2n-derived circular RNA (cTc2n) was investigated by several protocols. The cTc2n comprised exons 10 and 11 of the Tc2n gene and had no poly(A) structure. The expression of cTc2n was significantly higher in the mammary gland of rat than in other tissues, including the heart, liver, spleen, lung, kidney, uterus and ovary. The abundance of cTc2n was the highest on day 1, and significantly declined on day 7, slightly increasing on day 21 postpartum. This finding indicates that cTc2n might play an important role in lactation. [ABSTRACT FROM AUTHOR]

Vectors based on adeno-associated virus serotype 2 (AAV2) have been used extensively in many gene-delivery applications, including several successful clinical trials for one type of Leber congenital amaurosis in the retina. Many studies have focused on improving AAV2 transduction efficiency and cellular specificity by genetically engineering its capsid. We have previously shown that vectors-containing single-point mutations of capsid surface tyrosines in serotypes AAV2, AAV8, and AAV9 displayed significantly increased transduction efficiency in the retina compared with their wild-type counterparts. In the present study, we evaluated the transduction characteristics of AAV2 vectors containing combinations of multiple tyrosine to phenylalanine mutations in seven highly conserved surface-exposed capsid tyrosine residues following subretinal or intravitreal delivery in adult mice. The multiply mutated vectors exhibited different in vivo transduction properties, with some having a unique ability of transgene expression in all retinal layers. Such novel vectors may be useful in developing valuable new therapeutic strategies for the treatment of many genetic diseases. [ABSTRACT FROM AUTHOR]

AbstractHuman gene therapy with rAAV2-vector was performed for the RPE65form of childhood blindness called Leber congenital amaurosis. In three contemporaneous studies by independent groups, the procedure was deemed safe and there was evidence of visual gain in the short term. At 12 months after treatment, our young adult subjects remained healthy and without vector-related serious adverse events. Results of immunological assays to identify reaction to AAV serotype 2 capsid were unchanged from baseline measurements. Results of clinical eye examinations of study and control eyes, including visual acuities and central retinal structure by in vivomicroscopy, were not different from those at the 3-month time point. The remarkable improvements in visual sensitivity we reported by 3 months were unchanged at 12 months. The retinal extent and magnitude of rod and cone components of the visual sensitivity between 3 and 12 months were also the same. The safety and efficacy of human retinal gene transfer with rAAV2-RPE65vector extends to at least 1 year posttreatment. [ABSTRACT FROM AUTHOR]

Vectors derived from adeno-associated viruses (AAVs) have become important gene delivery tools for the treatment of many inherited ocular diseases in well-characterized animal models. Previous studies have determined that the viral capsid plays an essential role in the cellular tropism and efficiency of transgene expression. Recently, it was shown that phosphorylation of surface-exposed tyrosine residues from AAV2 capsid targets the viral particles for ubiquitination and proteasome- mediated degradation, and mutations of these tyrosine residues lead to highly efficient vector transduction in vitro and in vivo. Because the tyrosine residues are highly conserved in other AAV serotypes, in this study we evaluated the intraocular transduction characteristics of vectors containing point mutations in surface- exposed capsid tyrosine residues in AAV serotypes 2, 8, and 9. Several of these novel AAV mutants were found to display a strong and widespread transgene expression in many retinal cells after subretinal or intravitreal delivery compared with their wild-type counterparts. For the first time, we show efficient transduction of the ganglion cell layer by AAV serotype 8 or 9 mutant vectors, thus providing additional tools besides AAV2 for targeting these cells. These enhanced AAV vectors have a great potential for future therapeutic applications for retinal degenerations and ocular neovascular diseases.Molecular Therapy (2009) 17 3, 463–471 doi:10.1038/mt.2008.269 [ABSTRACT FROM AUTHOR]

The RPE65 gene encodes the isomerase of the retinoid cycle, the enzymatic pathway that underlies mammalian vision. Mutations in RPE65 disrupt the retinoid cycle and cause a congenital human blindness known as Leber congenital amaurosis (LCA). We used adeno-associated virus-2-based RPE65 gene replacement therapy to treat three young adults with RPE65-LCA and measured their vision before and up to 90 days after the intervention. All three patients showed a statistically significant increase in visual sensitivity at 30 days after treatment localized to retinal areas that had received the vector. There were no changes in the effect between 30 and 90 days. Both coneand rod-photoreceptor-based vision could be demonstrated in treated areas. For cones, there were increases of up to 1.7 log units (i.e., 50 fold); and for rods, there were gains of up to 4.8 log units (i.e., 63,000 fold). To assess what fraction of full vision potential was restored by gene therapy, we related the degree of light sensitivity to the level of remaining photoreceptors within the treatment area. We found that the intervention could overcome nearly all of the loss of light sensitivity resulting from the biochemical blockade. However, this reconstituted retinoid cycle was not completely normal. Resensitization kinetics of the newly treated rods were remarkably slow and required 8 h or more for the attainment of full sensitivity, compared with <1 h in normal eyes. Cone-sensitivity recovery time was rapid. These results demonstrate dramatic, albeit imperfect, recovery of rodand cone-photoreceptor-based vision after RPE65 gene therapy. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To evaluate a novel hybrid balloon valvuloplasty procedure for severe congenital valvular aortic stenosis in low-weight infants, performed through the ascending aorta via median sternotomy. METHODS: Eighteen infants (<90 days of age) with severe congenital aortic stenosis were included in this study. Hybrid balloon valvuloplasty procedures were performed in a hybrid operating room. Patients were followed up at 3 months, 6 months, 1 year and then annually following the procedure. RESULTS: The hybrid balloon valvuloplasty procedure was successful in all patients. Eight patients were successfully rescued from left ventricular systolic dysfunction by cardiac compression under direct vision. The aortic valve pressure gradient decreased from 80.3 ± 20.8 mmHg preoperatively to 16.0 ± 3.6 mmHg immediately postoperatively (P < 0.001). None of the patients developed significant aortic insufficiency. The fluoroscopy time was 6.2 ± 2.9 min. Intraoperative blood transfusions and pacing were not required. The patients were all alive and healthy at the end of the follow-up period (mean 21.3 months; range 3-41 months), and the aortic valve pressure gradient remained low (21.7 ± 5.3 mmHg). Reintervention was not required in any of the patients. CONCLUSIONS: Hybrid balloon valvuloplasty through the ascending aorta via median sternotomy is an effective and safe procedure for infants with severe congenital aortic stenosis. [ABSTRACT FROM AUTHOR]

Loss of cone function in the central retina is a pivotal event in the development of severe vision impairment for many prevalent blinding diseases. Complete achromatopsia is a genetic defect resulting in cone vision loss in 1 in 30,000 individuals. Using adeno-associated virus (AAV) gene therapy, we show that it is possible to target cones and rescue both the cone-mediated electroretinogram response and visual acuity in the Gnat2 cpfl3 mouse model of achromatopsia. [ABSTRACT FROM AUTHOR]