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.     

Importance of stirring in the development of an iron-fertilized phytoplankton bloom

The growth of populations is known to be influenced by dispersal, which has often been described as purely diffusive. In the open ocean, however, the tendrils and filaments of phytoplankton populations provide evidence for dispersal by stirring. Despite the apparent importance of horizontal stirring for plankton ecology, this process remains poorly characterized. Here we investigate the development of a discrete phytoplankton bloom, which was initiated by the iron fertilization of a patch of water (7 km in diameter) in the Southern Ocean. Satellite images show a striking, 150-km-long bloom near the experimental site, six weeks after the initial fertilization. We argue that the ribbon-like bloom was produced from the fertilized patch through stirring, growth and diffusion, and we derive an estimate of the stirring rate. In this case, stirring acts as an important control on bloom development, mixing phytoplankton and iron out of the patch, but also entraining silicate. This may have prevented the onset of silicate limitation, and so allowed the bloom to continue for as long as there was sufficient iron. Stirring in the ocean is likely to be variable, so blooms that are initially similar may develop very differently.     

The amino acid sequence of the agglutinin isolated from the red marine alga Bryothamnion triquetrum defines a novel lectin structure

The primary structure of a lectin isolated from the red alga Bryothamnion triquetrum was established by combination of Edman degradation of sets of overlapping peptides and mass spectrometry. It contains 91 amino acids and two disulphide bonds. The primary structure of the B. triquetrum lectin does not show amino acid sequence similarity with known plant and animal lectin structures. Hence, this protein may be the paradigm of a novel lectin family.     

方程验根的讨论

<正> 我们知道方程在中学数学中占的比重较大,从初一到高三都有,一般给中学生留下很深印象,提起代数自然想到方程。这也不奇怪,从历史上看代数的发展和方程分不开,并且方程历史悠久,三千六百年前就有相当于今天的方程“x(2/3+1/2+1/7+1)=37”,在十九世纪以前就是把代数理解为方程的科学.因此方程在中学代数教学中是公认的中心问题之一.但是关于解方程的概念,不少人说不清楚,现就几个具体问题进行讨论.     

煤灰中矿物的化学组成与灰熔融性的关系

以神府煤煤灰化学成分和灰熔融性为研究对象，讨论了煤灰化学成分与熔融性的关系，发现煤灰化学成分中碱性氧化物及SO1含量对煤灰熔融性有较大影响，提出了用熔融指数FI(FI=wSO3 ωFe2O3 ωCaO ωMgO ωK2O ωNa2O)来预测煤灰熔融特征温度的回归公式，用FI回归公式计算的煤灰熔融特征温度计算值与实测值之差小于国家标准规定的误差值(再现性≤80℃)。     

Alzheimer’s disease: the impact of age-related changes in reproductive hormones

No Abstract.  .     

First evidence of a venom delivery apparatus in extinct mammals

Numerous non-mammalian vertebrates have evolved lethal venoms to aid either in securing prey or as protection from predators, but modern mammals that use venoms in these ways are rare, including only the duck-billed platypus (Ornithorhynchus), the Caribbean Solenodon, and a few shrews (Soricidae) (Order Insectivora). Here we report evidence of a venom delivery apparatus in extinct mammals, documented by well-preserved specimens recovered from late Palaeocene rocks in Alberta, Canada. Although classified within Eutheria, these mammals are phylogenetically remote from modern Insectivora and have evolved specialized teeth as salivary venom delivery systems (VDSs) that differ markedly from one another and from those of Solenodon and shrews. Our discoveries therefore show that mammals have been much more flexible in the evolution of VDSs than previously believed, contradicting currently held notions that modern insectivorans are representative of the supposedly limited role of salivary venoms in mammalian history. Evidently, small predatory eutherians have paralleled colubroid snakes in evolving salivary venoms and their delivery systems several times independently.     

The receptors and coding logic for bitter taste

The sense of taste provides animals with valuable information about the nature and quality of food. Bitter taste detection functions as an important sensory input to warn against the ingestion of toxic and noxious substances. T2Rs are a family of approximately 30 highly divergent G-protein-coupled receptors (GPCRs) that are selectively expressed in the tongue and palate epithelium and are implicated in bitter taste sensing. Here we demonstrate, using a combination of genetic, behavioural and physiological studies, that T2R receptors are necessary and sufficient for the detection and perception of bitter compounds, and show that differences in T2Rs between species (human and mouse) can determine the selectivity of bitter taste responses. In addition, we show that mice engineered to express a bitter taste receptor in 'sweet cells' become strongly attracted to its cognate bitter tastants, whereas expression of the same receptor (or even a novel GPCR) in T2R-expressing cells resulted in mice that are averse to the respective compounds. Together these results illustrate the fundamental principle of bitter taste coding at the periphery: dedicated cells act as broadly tuned bitter sensors that are wired to mediate behavioural aversion.