CEP41 is mutated in Joubert syndrome and is required for tubulin glutamylation at the cilium

Tubulin glutamylation is a post-translational modification that occurs predominantly in the ciliary axoneme and has been suggested to be important for ciliary function. However, its relationship to disorders of the primary cilium, termed ciliopathies, has not been explored. Here we mapped a new locus for Joubert syndrome (JBTS), which we have designated as JBTS15, and identified causative mutations in CEP41, which encodes a 41-kDa centrosomal protein. We show that CEP41 is localized to the basal body and primary cilia, and regulates ciliary entry of TTLL6, an evolutionarily conserved polyglutamylase enzyme. Depletion of CEP41 causes ciliopathy-related phenotypes in zebrafish and mice and results in glutamylation defects in the ciliary axoneme. Our data identify CEP41 mutations as a cause of JBTS and implicate tubulin post-translational modification in the pathogenesis of human ciliary dysfunction.     

Snake venoms: attractive antimicrobial proteinaceous compounds for therapeutic purposes

Gram-positive and -negative bacteria are dangerous pathogens that may cause human infection diseases, especially due to the increasingly high prevalence of antibiotic resistance, which is becoming one of the most alarming clinical problems. In the search for novel antimicrobial compounds, snake venoms represent a rich source for such compounds, which are produced by specialized glands in the snake’s jawbone. Several venom compounds have been used for antimicrobial effects. Among them are phospholipases A₂, which hydrolyze phospholipids and could act on bacterial cell surfaces. Moreover, metalloproteinases and l-amino acid oxidases, which represent important enzyme classes with antimicrobial properties, are investigated in this study. Finally, antimicrobial peptides from multiple classes are also found in snake venoms and will be mentioned. All these molecules have demonstrated an interesting alternative for controlling microorganisms that are resistant to conventional antibiotics, contributing in medicine due to their differential mechanisms of action and versatility. In this review, snake venom antimicrobial compounds will be focused on, including their enormous biotechnological applications for drug development.     

Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia

The brachyolmias constitute a clinically and genetically heterogeneous group of skeletal dysplasias characterized by a short trunk, scoliosis and mild short stature. Here, we identify a locus for an autosomal dominant form of brachyolmia on chromosome 12q24.1-12q24.2. Among the genes in the genetic interval, we selected TRPV4, which encodes a calcium permeable cation channel of the transient receptor potential (TRP) vanilloid family, as a candidate gene because of its cartilage-selective gene expression pattern. In two families with the phenotype, we identified point mutations in TRPV4 that encoded R616Q and V620I substitutions, respectively. Patch clamp studies of transfected HEK cells showed that both mutations resulted in a dramatic gain of function characterized by increased constitutive activity and elevated channel activation by either mechano-stimulation or agonist stimulation by arachidonic acid or the TRPV4-specific agonist 4alpha-phorbol 12,13-didecanoate (4alphaPDD). This study thus defines a previously unknown mechanism, activation of a calcium-permeable TRP ion channel, in skeletal dysplasia pathogenesis.     

Microfabricated tissues for investigating traction forces involved in cell migration and tissue morphogenesis

Cell-generated forces drive an array of biological processes ranging from wound healing to tumor metastasis. Whereas experimental techniques such as traction force microscopy are capable of quantifying traction forces in multidimensional systems, the physical mechanisms by which these forces induce changes in tissue form remain to be elucidated. Understanding these mechanisms will ultimately require techniques that are capable of quantifying traction forces with high precision and accuracy in vivo or in systems that recapitulate in vivo conditions, such as microfabricated tissues and engineered substrata. To that end, here we review the fundamentals of traction forces, their quantification, and the use of microfabricated tissues designed to study these forces during cell migration and tissue morphogenesis. We emphasize the differences between traction forces in two- and three-dimensional systems, and highlight recently developed techniques for quantifying traction forces.     

与顾客更密切的交流

在市场营销中,我们常常谈及个性化问题,比如个性化的设计网页和电子邮件。通过个性化手段是否可以增加回复率并且与顾客的联系更密切?这就是营销技术,关键在于如何定义个性化。根据Webster字典的注解,个性化(personalization)的意思是:在物品上标出个人姓名或地址。如果这就是我们正在做的事情——将名字标在印刷物上——那意义就不是很大,并且事实上,由于人们保护隐私的意识日益增强,它可能会产生副作用。站在顾客立场思考经营者如果够聪明的话,应该站在顾客的立场来想问题。当我们对杂七杂八的信件进行分类,发现很多注有公司名称或我们根…     

Surface composition of Hyperion

Hyperion, Saturn's eighth largest icy satellite, is a body of irregular shape in a state of chaotic rotation. The surface is segregated into two distinct units. A spatially dominant high-albedo unit having the strong signature of H2O ice contrasts with a unit that is about a factor of four lower in albedo and is found mostly in the bottoms of cup-like craters. Here we report observations of Hyperion's surface in the ultraviolet and near-infrared spectral regions with two optical remote sensing instruments on the Cassini spacecraft at closest approach during a fly-by on 25-26 September 2005. The close fly-by afforded us the opportunity to obtain separate reflectance spectra of the high- and low-albedo surface components. The low-albedo material has spectral similarities and compositional signatures that link it with the surface of Phoebe and a hemisphere-wide superficial coating on Iapetus.     

Genetics and molecular pathogenesis of mitochondrial respiratory chain diseases

Dysfunction of the mitochondrial respiratory chain has been recognised as a cause of human disease for over 30 years. Advances in the past 10 years have led to a better understanding of the genetics and molecular pathogenesis of many of these disorders. Over 100 primary defects in mitochondrial DNA (mtDNA) are now implicated in the pathogenesis of a group of disorders which are collectively known as the mitochondrial encephalomyopathies, and which most frequently involve skeletal muscle and/or the central nervous system. Although impaired oxidative phosphorylation is likely to be the final common pathway leading to the cellular dysfunction associated with such mtDNA mutations, the complex relationship between genotype and phenotype remains largely unexplained. Most of the genes which encode the respiratory chain reside in the nucleus, yet only five nuclear genes have been implicated in human respiratory chain diseases. There is evidence that respiratory chain dysfunction is present in common neurological diseases such as Parkinson's disease and Huntington's disease. The precise cause of this respiratory chain dysfunction and its relationship to the disease process are unclear. This review focuses upon respiratory chain disorders associated with primary defects in mtDNA.     

A sagebrush wilt disease of unknown cause

In a rare 1969 epidemic, spruce cone rust caused by Chrysomyxa pirolata infected 40 – 100 percent of trees and 20 – 67 percent of cones on riparian Colorado blue spruce on plots located in a 2200 – 2400 m elevational zone in Huntington Canyon of central Utah. Uredinial and telial sporulation on Pyrola spp. began in mid - June, a time closely correlated with opening of pistillate spruce cones. Come phenology and host habitat, as influenced by elevation, are apparently important factors in the restricted niche of the cone rust fungus in Utah. Several preceding consecutive years with extended periods of spring and fall moisture were associated with occurrence of the epidemic, although no cause - and - effect relationship was established. Weather records indicate that these events are infrequent in this climatic zone, and there was no detectable recurrence of cone rust for at least 9 years following 1969. Outwardly normal seeds developed in diseased cones, but seed germinability was reduced by 25 percent. Aecial spore masses between cone scales, cone resinosis, and distortion of cone scales prevented seed dispersal to the extent that the seed crop was effectually destroyed.     

Alkaloidal relationships in the genus Arctomecon (Papaveraceae) and herbivory in A. humilis

The previously reported alkaloids (including protopines, benzophenanthridines, tetrahydrobenzylisoquinolines, and protoberberines) of the genus Arctomecon (Papaveraceae) are discussed in relation to their distribution in the plant kingdom, in the Papaveraceae, and among the three species of Arctomecon . The biological activity of these alkaloids is discussed, and possible implications for herbivore and plant-insect interactions in A. humilis are presented.