Hsp72 preserves muscle function and slows progression of severe muscular dystrophy

Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder caused by mutations in the dystrophin gene that result in the absence of the membrane-stabilizing protein dystrophin. Dystrophin-deficient muscle fibres are fragile and susceptible to an influx of Ca(2+), which activates inflammatory and muscle degenerative pathways. At present there is no cure for DMD, and existing therapies are ineffective. Here we show that increasing the expression of intramuscular heat shock protein 72 (Hsp72) preserves muscle strength and ameliorates the dystrophic pathology in two mouse models of muscular dystrophy. Treatment with BGP-15 (a pharmacological inducer of Hsp72 currently in clinical trials for diabetes) improved muscle architecture, strength and contractile function in severely affected diaphragm muscles in mdx dystrophic mice. In dko mice, a phenocopy of DMD that results in severe spinal curvature (kyphosis), muscle weakness and premature death, BGP-15 decreased kyphosis, improved the dystrophic pathophysiology in limb and diaphragm muscles and extended lifespan. We found that the sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA, the main protein responsible for the removal of intracellular Ca(2+)) is dysfunctional in severely affected muscles of mdx and dko mice, and that Hsp72 interacts with SERCA to preserve its function under conditions of stress, ultimately contributing to the decreased muscle degeneration seen with Hsp72 upregulation. Treatment with BGP-15 similarly increased SERCA activity in dystrophic skeletal muscles. Our results provide evidence that increasing the expression of Hsp72 in muscle (through the administration of BGP-15) has significant therapeutic potential for DMD and related conditions, either as a self-contained therapy or as an adjuvant with other potential treatments, including gene, cell and pharmacological therapies.     

New gene functions in megakaryopoiesis and platelet formation

Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.     

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.     

Water balance of global aquifers revealed by groundwater footprint

Groundwater is a life-sustaining resource that supplies water to billions of people, plays a central part in irrigated agriculture and influences the health of many ecosystems. Most assessments of global water resources have focused on surface water, but unsustainable depletion of groundwater has recently been documented on both regional and global scales. It remains unclear how the rate of global groundwater depletion compares to the rate of natural renewal and the supply needed to support ecosystems. Here we define the groundwater footprint (the area required to sustain groundwater use and groundwater-dependent ecosystem services) and show that humans are overexploiting groundwater in many large aquifers that are critical to agriculture, especially in Asia and North America. We estimate that the size of the global groundwater footprint is currently about 3.5 times the actual area of aquifers and that about 1.7 billion people live in areas where groundwater resources and/or groundwater-dependent ecosystems are under threat. That said, 80 per cent of aquifers have a groundwater footprint that is less than their area, meaning that the net global value is driven by a few heavily overexploited aquifers. The groundwater footprint is the first tool suitable for consistently evaluating the use, renewal and ecosystem requirements of groundwater at an aquifer scale. It can be combined with the water footprint and virtual water calculations, and be used to assess the potential for increasing agricultural yields with renewable groundwaterref. The method could be modified to evaluate other resources with renewal rates that are slow and spatially heterogeneous, such as fisheries, forestry or soil.     

An expanding radio nebula produced by a giant flare from the magnetar SGR 1806-20

Soft gamma-ray repeaters (SGRs) are 'magnetars', a small class of slowly spinning neutron stars with extreme surface magnetic fields, B approximately 10(15) gauss (refs 1 , 2 -3). On 27 December 2004, a giant flare was detected from the magnetar SGR 1806-20 (ref. 2), only the third such event recorded. This burst of energy was detected by a variety of instruments and even caused an ionospheric disturbance in the Earth's upper atmosphere that was recorded around the globe. Here we report the detection of a fading radio afterglow produced by this outburst, with a luminosity 500 times larger than the only other detection of a similar source. From day 6 to day 19 after the flare from SGR 1806-20, a resolved, linearly polarized, radio nebula was seen, expanding at approximately a quarter of the speed of light. To create this nebula, at least 4 x 10(43) ergs of energy must have been emitted by the giant flare in the form of magnetic fields and relativistic particles.     

Motion direction, speed and orientation in binocular matching

The spatial differences between the images seen by the two eyes, called binocular disparities, can be used to recover the volumetric (three-dimensional) aspects of a scene. The computation of disparity depends upon the correct identification of corresponding features in the two images. Understanding what image features are used by the brain to solve this matching problem is one of the main issues in stereoscopic vision. Many cortical neurons in visual areas V1 (ref. 2), MT (refs 3, 4) and MST (refs 5, 6) that are tuned to binocular disparity are also tuned to orientation, motion direction and speed. Although psychophysical work has shown that motion direction can facilitate binocular matching, the psychophysical literature on the role of orientation is mixed, and it has been argued that speed differences are ineffective in aiding correspondence. Here we use a different psychophysical paradigm to show that the visual system uses similarities in orientation, motion direction and speed to achieve binocular correspondence. These results indicate that cells that multiplex orientation, motion direction, speed and binocular disparity may help to solve the binocular matching problem.     

Opposite motivational effects of endogenous opioids in brain and periphery

Many psychoactive drugs, including the opiates, have been shown to have paradoxical reinforcing effects. Opiates produce positive reinforcing effects when they are paired with visual and textural environmental stimuli in rats, yet, at similar doses and over the same routes of administration, produce aversive effects, as shown when they are paired with taste stimuli. Similarly, in human, the positive reinforcing effects of opiates are well known to addicts and recreational drug users, yet patients receiving opiates as analgesics often report nauseous reactions. At present there is no evidence to differentiate between the neural substrates that mediate these opposite motivational effects. We now report an initial step in the resolution of this paradox by demonstrating that endogenous and exogenous opioids produce positive reinforcing effects through an action on brain opiate receptors, and aversive effects through an action on peripheral opiate receptors (especially in the gut).