T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance

Furin is one of seven proprotein convertase family members that promote proteolytic maturation of proproteins. It is induced in activated T cells and is reported to process a variety of substrates including the anti-inflammatory cytokine transforming growth factor (TGF)-beta1 (refs 2-4), but the non-redundant functions of furin versus other proprotein convertases in T cells are unclear. Here we show that conditional deletion of furin in T cells allowed for normal T-cell development but impaired the function of regulatory and effector T cells, which produced less TGF-beta1. Furin-deficient T regulatory (Treg) cells were less protective in a T-cell transfer colitis model and failed to induce Foxp3 in normal T cells. Additionally, furin-deficient effector cells were inherently over-active and were resistant to suppressive activity of wild-type Treg cells. Thus, our results indicate that furin is indispensable in maintaining peripheral tolerance, which is due, at least in part, to its non-redundant, essential function in regulating TGF-beta1 production. Targeting furin has emerged as a strategy in malignant and infectious disease. Our results suggest that inhibiting furin might activate immune responses, but may result in a breakdown in peripheral tolerance.     

Widespread adoption of Bt cotton and insecticide decrease promotes biocontrol services

Over the past 16 years, vast plantings of transgenic crops producing insecticidal proteins from the bacterium Bacillus thuringiensis (Bt) have helped to control several major insect pests and reduce the need for insecticide sprays. Because broad-spectrum insecticides kill arthropod natural enemies that provide biological control of pests, the decrease in use of insecticide sprays associated with Bt crops could enhance biocontrol services. However, this hypothesis has not been tested in terms of long-term landscape-level impacts. On the basis of data from 1990 to 2010 at 36 sites in six provinces of northern China, we show here a marked increase in abundance of three types of generalist arthropod predators (ladybirds, lacewings and spiders) and a decreased abundance of aphid pests associated with widespread adoption of Bt cotton and reduced insecticide sprays in this crop. We also found evidence that the predators might provide additional biocontrol services spilling over from Bt cotton fields onto neighbouring crops (maize, peanut and soybean). Our work extends results from general studies evaluating ecological effects of Bt crops by demonstrating that such crops can promote biocontrol services in agricultural landscapes.     

Compartmentalized calcium dynamics in a C. elegans interneuron encode head movement

The confinement of neuronal activity to specific subcellular regions is a mechanism for expanding the computational properties of neurons. Although the circuit organization underlying compartmentalized activity has been studied in several systems, its cellular basis is still unknown. Here we characterize compartmentalized activity in Caenorhabditis elegans RIA interneurons, which have multiple reciprocal connections to head motor neurons and receive input from sensory pathways. We show that RIA spatially encodes head movement on a subcellular scale through axonal compartmentalization. This subcellular axonal activity is dependent on acetylcholine release from head motor neurons and is simultaneously present and additive with glutamate-dependent globally synchronized activity evoked by sensory inputs. Postsynaptically, the muscarinic acetylcholine receptor GAR-3 acts in RIA to compartmentalize axonal activity through the mobilization of intracellular calcium stores. The compartmentalized activity functions independently of the synchronized activity to modulate locomotory behaviour.     

Reconstructing Native American population history

The peopling of the Americas has been the subject of extensive genetic, archaeological and linguistic research; however, central questions remain unresolved. One contentious issue is whether the settlement occurred by means of a single migration or multiple streams of migration from Siberia. The pattern of dispersals within the Americas is also poorly understood. To address these questions at a higher resolution than was previously possible, we assembled data from 52 Native American and 17 Siberian groups genotyped at 364,470 single nucleotide polymorphisms. Here we show that Native Americans descend from at least three streams of Asian gene flow. Most descend entirely from a single ancestral population that we call 'First American'. However, speakers of Eskimo-Aleut languages from the Arctic inherit almost half their ancestry from a second stream of Asian gene flow, and the Na-Dene-speaking Chipewyan from Canada inherit roughly one-tenth of their ancestry from a third stream. We show that the initial peopling followed a southward expansion facilitated by the coast, with sequential population splits and little gene flow after divergence, especially in South America. A major exception is in Chibchan speakers on both sides of the Panama isthmus, who have ancestry from both North and South America.     

Reach and grasp by people with tetraplegia using a neurally controlled robotic arm

Paralysis following spinal cord injury, brainstem stroke, amyotrophic lateral sclerosis and other disorders can disconnect the brain from the body, eliminating the ability to perform volitional movements. A neural interface system could restore mobility and independence for people with paralysis by translating neuronal activity directly into control signals for assistive devices. We have previously shown that people with long-standing tetraplegia can use a neural interface system to move and click a computer cursor and to control physical devices. Able-bodied monkeys have used a neural interface system to control a robotic arm, but it is unknown whether people with profound upper extremity paralysis or limb loss could use cortical neuronal ensemble signals to direct useful arm actions. Here we demonstrate the ability of two people with long-standing tetraplegia to use neural interface system-based control of a robotic arm to perform three-dimensional reach and grasp movements. Participants controlled the arm and hand over a broad space without explicit training, using signals decoded from a small, local population of motor cortex (MI) neurons recorded from a 96-channel microelectrode array. One of the study participants, implanted with the sensor 5?years earlier, also used a robotic arm to drink coffee from a bottle. Although robotic reach and grasp actions were not as fast or accurate as those of an able-bodied person, our results demonstrate the feasibility for people with tetraplegia, years after injury to the central nervous system, to recreate useful multidimensional control of complex devices directly from a small sample of neural signals.     

金融市场和鞅——科学和思考中的观察

金融市场在当代经济生活中起着越来越重要的作用。由于各种金融产品的推出，数学金融学也成为20世纪90年代的一大热门。本书是这个领域的入门介绍。原文为法文，1998年出版，1999年获得法国高等金融学院的“最佳金融经济学图书奖”，2000年又获得另一大奖。     

IgG purification to measure the level of an iodinated thyroglobulin peptide,the 3,5,3′,5′ tetraiodo-l-tyrosyl-l-tyrosine in human serum

Summary Antibodies reacting with 3,5,3,5 tetraiodo-l-tyrosyl-l-tyrosine (I₂Tyr-I₂Tyr) were elicited in rabbits by immunization with an oxidized yeast conjugate coupled with I₂Tyr-I₂Tyr. Ion-exchange chromatography was used to purify immunoglobulins, in order to improve the specificity in measurement of I₂Tyr-I₂Tyr level in patient serum. IgG binding capacity versus I₂Tyr-I₂Tyr was considerably increased after immunoglobulin purification.Acknowledgments. The authors with to thank Mrs M. Ollier for her valuable technical assistance.     

T-cell recognition of chemicals, protein allergens and drugs: towards the development of in vitro assays

Chemicals can elicit T-cell-mediated diseases such as allergic contact dermatitis and adverse drug reactions. Therefore, testing of chemicals, drugs and protein allergens for hazard identification and risk assessment is essential in regulatory toxicology. The seventh amendment of the EU Cosmetics Directive now prohibits the testing of cosmetic ingredients in mice, guinea pigs and other animal species to assess their sensitizing potential. In addition, the EU Chemicals Directive REACh requires the retesting of more than 30,000 chemicals for different toxicological endpoints, including sensitization, requiring vast numbers of animals. Therefore, alternative methods are urgently needed to eventually replace animal testing. Here, we summarize the outcome of an expert meeting in Rome on 7 November 2009 on the development of T-cell-based in vitro assays as tools in immunotoxicology to identify hazardous chemicals and drugs. In addition, we provide an overview of the development of the field over the last two decades.