Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector

Pre-clinical studies in mice and haemophilic dogs have shown that introduction of an adeno-associated viral (AAV) vector encoding blood coagulation factor IX (FIX) into skeletal muscle results in sustained expression of F.IX at levels sufficient to correct the haemophilic phenotype. On the basis of these data and additional pre-clinical studies demonstrating an absence of vector-related toxicity, we initiated a clinical study of intramuscular injection of an AAV vector expressing human F.IX in adults with severe haemophilia B. The study has a dose-escalation design, and all patients have now been enrolled in the initial dose cohort (2 x 10(11) vg/kg). Assessment in the first three patients of safety and gene transfer and expression show no evidence of germline transmission of vector sequences or formation of inhibitory antibodies against F.IX. We found that the vector sequences are present in muscle by PCR and Southern-blot analyses of muscle biopsies and we demonstrated expression of F.IX by immunohistochemistry. We observed modest changes in clinical endpoints including circulating levels of F.IX and frequency of FIX protein infusion. The evidence of gene expression at low doses of vector suggests that dose calculations based on animal data may have overestimated the amount of vector required to achieve therapeutic levels in humans, and that the approach offers the possibility of converting severe haemophilia B to a milder form of the disease.     

Molecular mechanism for duplication 17p11.2- the homologous recombination reciprocal of the Smith-Magenis microdeletion

Recombination between repeated sequences at various loci of the human genome are known to give rise to DNA rearrangements associated with many genetic disorders. Perhaps the most extensively characterized genomic region prone to rearrangement is 17p12, which is associated with the peripheral neuropathies, hereditary neuropathy with liability to pressure palsies (HNPP) and Charcot-Marie-Tooth disease type 1A (CMT1A;ref. 2). Homologous recombination between 24-kb flanking repeats, termed CMT1A-REPs, results in a 1.5-Mb deletion that is associated with HNPP, and the reciprocal duplication product is associated with CMT1A (ref. 2). Smith-Magenis syndrome (SMS) is a multiple congenital anomalies, mental retardation syndrome associated with a chromosome 17 microdeletion, del(17)(p11.2p11.2) (ref. 3,4). Most patients (>90%) carry deletions of the same genetic markers and define a common deletion. We report seven unrelated patients with de novo duplications of the same region deleted in SMS. A unique junction fragment, of the same apparent size, was identified in each patient by pulsed field gel electrophoresis (PFGE). Further molecular analyses suggest that the de novo17p11.2 duplication is preferentially paternal in origin, arises from unequal crossing over due to homologous recombination between flanking repeat gene clusters and probably represents the reciprocal recombination product of the SMS deletion. The clinical phenotype resulting from duplication [dup(17)(p11.2p11.2)] is milder than that associated with deficiency of this genomic region. This mechanism of reciprocal deletion and duplication via homologous recombination may not only pertain to the 17p11.2 region, but may also be common to other regions of the genome where interstitial microdeletion syndromes have been defined.     

某些近环上的可交换性

证明若分配生成近五Ｒ满足ｘｙ＝ｐ（ｘ,ｙ）性质,则Ｒ必可换,其中ｐ（ｘ,ｙ）是ａｉｘ＾ｐｉｙ＾ｎｉｘ＾ｑｉ的有限和,项数,ａｉ,ｐｉ,ｎｉ,ｑｉ均随ｘ,ｙ∈Ｒ变化,且ａｉ,ｐｉ,ｑｉ≥１,ｎｉ〉１。     

R&R Analysis for Measurement System Using Moving Range

1　IntroductionMetrology is an important aspect of manufacturing because measurements are necessaryfor monitoring and controlling processes. The quality of data depends on the gauges andother tools used for the measurementof measured variables.With the greater reliance onquantitative measurements in modern manufacturing industry,the criticality of gauge ca-pability analysis has increased.The goal of gauge capability analysis is the understandingand quantification of the sources of variability …     

STUDY ON AN SIS EPIDEMIC MODEL WITH TIME VARIANT DELAY

In this paper, we study an SIS epidemic model with a time variant delay. By means of Liapunov functional, some sufficient conditions of global stability to endemic equilibrium and disease free equilibrium have been obtained. The influence of time delay on the stability of equilibria is displayed.     

Distributed Penalized Modal Regression for Massive Data

Nowadays, researchers are frequently confronted with challenges from massive data computing by a number of limitations of computer primary memory. Modal regression(MR) is a good alternative of the mean regression and likelihood based methods, because of its robustness and high efficiency. To this end, the authors extend MR to massive data analysis and propose a computationally and statistically efficient divide and conquer MR method(DC-MR). The major novelty of this method consists of splitting ...     

Fixed-Time Controller Design for a Quadrotor UAV with Asymmetric Output Error Constraints

In this article, a fixed-time tracking control strategy is proposed for a quadrotor UAV(QUAV) with external disturbance and asymmetric output error constraints. Firstly, a dynamic model of the QUAV is transformed into a strict feedback system with external disturbance, and it is decoupled into attitude subsystem and position subsystem for simplifying controller design. Secondly,an asymmetric tangent barrier Lyapunov function(ATBLF) is applied to solve the tracking error constraints problem, and ...     

Parameter estimation of LFM signals based on time reversal

In this paper, parameter estimation of linear frequency modulation(LFM) signals containing additive white Gaussian noise is studied. Because the center frequency estimation of an LFM signal is affected by the error propagation effect,resulting in a higher signal to noise ratio(SNR) threshold, a parameter estimation method for LFM signals based on time reversal is proposed. The proposed method avoids SNR loss in the process of estimating the frequency, thus reducing the SNR threshold. The simulat...     

Barrier Lyapunov Function-Based Finite-Time Dynamic Surface Control for Output-Constrained Nonstrict-Feedback Systems

This paper investigates a finite-time tracking problem for the uncertainty nonlinear systems in nonstrict-feedback form, in which the output signal is restricted in a region. Based on the barrier Lyapunov function and dynamic surface control scheme, a novel adaptive neural controller is proposed by using the finite-time Lyapunov technology. Unlike the aforementioned literature on finite time tracking control, the violation of system output constraint is avoided by combining the barrier Lyapunov ...