13 research outputs found
The NASA Roadmap to Ocean Worlds
In this article, we summarize the work of the NASA Outer Planets Assessment Group (OPAG) Roadmaps to Ocean Worlds (ROW) group. The aim of this group is to assemble the scientific framework that will guide the exploration of ocean worlds, and to identify and prioritize science objectives for ocean worlds over the next several decades. The overarching goal of an Ocean Worlds exploration program as defined by ROW is to identify ocean worlds, characterize their oceans, evaluate their habitability, search for life, and ultimately understand any life we find. The ROW team supports the creation of an exploration program that studies the full spectrum of ocean worlds, that is, not just the exploration of known ocean worlds such as Europa but candidate ocean worlds such as Triton as well. The ROW team finds that the confirmed ocean worlds Enceladus, Titan, and Europa are the highest priority bodies to target in the near term to address ROW goals. Triton is the highest priority candidate ocean world to target in the near term. A major finding of this study is that, to map out a coherent Ocean Worlds Program, significant input is required from studies here on Earth; rigorous Research and Analysis studies are called for to enable some future ocean worlds missions to be thoughtfully planned and undertaken. A second finding is that progress needs to be made in the area of collaborations between Earth ocean scientists and extraterrestrial ocean scientists
The James Webb Space Telescope Mission
Twenty-six years ago a small committee report, building on earlier studies,
expounded a compelling and poetic vision for the future of astronomy, calling
for an infrared-optimized space telescope with an aperture of at least .
With the support of their governments in the US, Europe, and Canada, 20,000
people realized that vision as the James Webb Space Telescope. A
generation of astronomers will celebrate their accomplishments for the life of
the mission, potentially as long as 20 years, and beyond. This report and the
scientific discoveries that follow are extended thank-you notes to the 20,000
team members. The telescope is working perfectly, with much better image
quality than expected. In this and accompanying papers, we give a brief
history, describe the observatory, outline its objectives and current observing
program, and discuss the inventions and people who made it possible. We cite
detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space
Telescope Overview, 29 pages, 4 figure
Studies on hereditary spastic paraplegia proteins
The hereditary spastic paraplegias (HSPs) are a clinically and
genetically diverse group of inherited neurological disorders that
primarily cause progressive spasticity and weakness in the lower limbs
due to a length-dependent, retrograde degradation of the corticospinal
motor neurons. Purely spastic paraplegia is also known as uncomplicated
HSP, but complicated forms of HSP exist as well, with symptoms such as
mental retardation, dementia, seizures, and optic, cortical, and
cerebellar atrophy. Twenty gene products have been identified from over
40 different known SPG spastic gait loci (SPG1-46), which may be
inherited in autosomal dominant, autosomal recessive, or X-linked
manners.
The work presented in this thesis focuses on two different HSP proteins:
atlastin-1, a member of the dynamin superfamily of large GTPases through
sequence similarity, and maspardin Mast syndrome, spastic paraplegia,
autosomal recessive with dementia. Mutations in the atlastin-1 gene,
SPG3A, are the second most common cause of autosomal dominant HSP
around 10% of all cases many of which are quite early in onset (in
childhood) when compared to other forms of HSP. Diseasecausing point
mutations are distributed throughout the coding region, although most are
clustered in known domains GTP binding/GTPase functional areas, a
coiled coil region in the middle of the protein product, and in the
transmembrane areas at the Cterminal end. On the other hand, the only
causative mutation in SPG21/MAST (maspardin) that has been found is a
frameshift-producing alteration after the second third of the gene, which
induces a premature truncation of the gene product and loss of the last
95 amino acids of the wild type protein. This mutation is only inherited
in an autosomal recessive manner, and causes a complicated HSP with
additional symptoms such as dementia, white matter abnormalities, and
cerebellar and extrapyramidal signs.
Atlastin-1 is localized to the ER and cis-Golgi apparatus in the adult
brain, and appears to exist natively as oligomers, most likely tetramers.
Wild-type atlastin-1 is a functional GTPase, but in paper I we found that
several missense atlastin-1 mutations have impaired GTPase activity. We
also found that atlastin-1 is highly enriched in vesicular structures
within growth cones, varicosities, and axonal branch points. Knockdown of
atlastin-1 using small hairpin RNAs impairs axon formation and elongation
during neuronal development and reduces the total number of neuronal
processes. In paper II we examined a novel SPG3A mutation causative for
HSP that did not affect GTPase activity or interactions between atlastin
and spastin, the gene most mutated in HSP. However, immunoblots from
patient lymphoblasts showed a reduction in atlastin-1 protein levels,
indicating that mutant atlastin-1 may cause disease pathogenesis through
a dominant-negative, loss-of-function manner through protein
destabilization.
Mast syndrome is likely caused by a loss of protein function. In paper IV
we generated SPG21-/- transgenic mice as a possible model for SPG21.
Though SPG21-/- mice appeared normal at birth, within several months they
developed a mild but progressive hind limb dysfunction. Cultured cerebral
cortical neurons from SPG21-/- mice exhibited significantly more axonal
branching than neurons cultured from wildtype animals, although a
comprehensive neuropathological analysis did not reveal any abnormalities
consistent with those observed in human HSP.
While a unifying mechanism for all the genes and proteins known to be
involved in HSP has yet to be found, our data support the idea that
axonal trafficking and proper neurite branching may represent a common
cellular pathogenic theme
An endophilin-dynamin complex promotes budding of clathrin-coated vesicles during synaptic vesicle recycling
Clathrin-mediated vesicle recycling in synapses is maintained by a unique set of endocytic proteins and interactions. We show that endophilin localizes in the vesicle pool at rest and in spirals at the necks of clathrin-coated pits (CCPs) during activity in lamprey synapses. Endophilin and dynamin colocalize at the base of the clathrin coat. Protein spirals composed of these proteins on lipid tubes in vitro have a pitch similar to the one observed at necks of CCPs in living synapses, and lipid tubules are thinner than those formed by dynamin alone. Tubulation efficiency and the amount of dynamin recruited to lipid tubes are dramatically increased in the presence of endophilin. Blocking the interactions of the endophilin SH3 domain in situ reduces dynamin accumulation at the neck and prevents the formation of elongated necks observed in the presence of GTPγS. Therefore, endophilin recruits dynamin to a restricted part of the CCP neck, forming a complex, which promotes budding of new synaptic vesicles
Fibronectin Matrix Assembly after Spinal Cord Injury
After spinal cord injury (SCI), a fibrotic scar forms at the injury site that is best characterized by the accumulation of perivascular fibroblasts and deposition of the extracellular matrix protein fibronectin. While fibronectin is a growth-permissive substrate for axons, the fibrotic scar is inhibitory to axon regeneration. The mechanism behind how fibronectin contributes to the inhibitory environment and how the fibronectin matrix is assembled in the fibrotic scar is unknown. By deleting fibronectin in myeloid cells, we demonstrate that fibroblasts are most likely the major source of fibronectin in the fibrotic scar. In addition, we demonstrate that fibronectin is initially present in a soluble form and is assembled into a matrix at 7 d post-SCI. Assembly of the fibronectin matrix may be mediated by the canonical fibronectin receptor, integrin α5β1, which is primarily expressed by activated macrophages/microglia in the fibrotic scar. Despite the pronounced cavitation after rat SCI, fibrotic scar also is observed in a rat SCI model, which is considered to be more similar to human pathology. Taken together, our study provides insight into the mechanism of fibrotic scar formation after spinal cord injury
Perivascular Fibroblasts Form the Fibrotic Scar after Contusive Spinal Cord Injury
Injury to the CNS leads to formation of scar tissue, which is important in sealing the lesion and inhibiting axon regeneration. The fibrotic scar that comprises a dense extracellular matrix is thought to originate from meningeal cells surrounding the CNS. However, using transgenic mice, we demonstrate that perivascular collagen1α1 cells are the main source of the cellular composition of the fibrotic scar after contusive spinal cord injury in which the dura remains intact. Using genetic lineage tracing, light sheet fluorescent microscopy, and antigenic profiling, we identify collagen1α1 cells as perivascular fibroblasts that are distinct from pericytes. Our results identify collagen1α1 cells as a novel source of the fibrotic scar after spinal cord injury and shift the focus from the meninges to the vasculature during scar formation
Atlastin GTPases are required for Golgi apparatus and ER morphogenesis
The hereditary spastic paraplegias (SPG1-33) comprise a cluster of inherited neurological disorders characterized principally by lower extremity spasticity and weakness due to a length-dependent, retrograde axonopathy of corticospinal motor neurons. Mutations in the gene encoding the large oligomeric GTPase atlastin-1 are responsible for SPG3A, a common autosomal dominant hereditary spastic paraplegia. Here we describe a family of human GTPases, atlastin-2 and -3 that are closely related to atlastin-1. Interestingly, while atlastin-1 is predominantly localized to vesicular tubular complexes and cis-Golgi cisternae, mostly in brain, atlastin-2 and -3 are localized to the endoplasmic reticulum (ER) and are most enriched in other tissues. Knockdown of atlastin-2 and -3 levels in HeLa cells using siRNA (small interfering RNA) causes disruption of Golgi morphology, and these Golgi structures remain sensitive to brefeldin A treatment. Interestingly, expression of SPG3A mutant or dominant-negative atlastin proteins lacking GTPase activity causes prominent inhibition of ER reticularization, suggesting a role for atlastin GTPases in the formation of three-way junctions in the ER. However, secretory pathway trafficking as assessed using vesicular stomatitis virus G protein fused to green fluorescent protein (VSVG-GFP) as a reporter was essentially normal in both knockdown and dominant-negative overexpression conditions for all atlastins. Thus, the atlastin family of GTPases functions prominently in both ER and Golgi morphogenesis, but they do not appear to be required generally for anterograde ER-to-Golgi trafficking. Abnormal morphogenesis of the ER and Golgi resulting from mutations in atlastin-1 may ultimately underlie SPG3A by interfering with proper membrane distribution or polarity of the long corticospinal motor neurons
3D Imaging of Axons in Transparent Spinal Cords from Rodents and Nonhuman Primates
The histological assessment of spinal cord tissue in three dimensions has previously been very time consuming and prone to errors of interpretation. Advances in tissue clearing have significantly improved visualization of fluorescently labelled axons. While recent proof-of-concept studies have been performed with transgenic mice in which axons were prelabeled with GFP, investigating axonal regeneration requires stringent axonal tracing methods as well as the use of animal models in which transgenic axonal labeling is not available. Using rodent models of spinal cord injury, we labeled axon tracts of interest using both adeno-associated virus and chemical tracers and performed tetrahydrofuran-based tissue clearing to image multiple axon types in spinal cords using light sheet and confocal microscopy. Using this approach, we investigated the relationships between axons and scar-forming cells at the injury site as well as connections between sensory axons and motor pools in the spinal cord. In addition, we used these methods to trace axons in nonhuman primates. This reproducible and adaptable virus-based approach can be combined with transgenic mice or with chemical-based tract-tracing methods, providing scientists with flexibility in obtaining axonal trajectory information from transparent tissue
3D Imaging of Axons in Transparent Spinal Cords from Rodents and Nonhuman Primates
The histological assessment of spinal cord tissue in three dimensions has previously been very time consuming and prone to errors of interpretation. Advances in tissue clearing have significantly improved visualization of fluorescently labelled axons. While recent proof-of-concept studies have been performed with transgenic mice in which axons were prelabeled with GFP, investigating axonal regeneration requires stringent axonal tracing methods as well as the use of animal models in which transgenic axonal labeling is not available. Using rodent models of spinal cord injury, we labeled axon tracts of interest using both adeno-associated virus and chemical tracers and performed tetrahydrofuran-based tissue clearing to image multiple axon types in spinal cords using light sheet and confocal microscopy. Using this approach, we investigated the relationships between axons and scar-forming cells at the injury site as well as connections between sensory axons and motor pools in the spinal cord. In addition, we used these methods to trace axons in nonhuman primates. This reproducible and adaptable virus-based approach can be combined with transgenic mice or with chemical-based tract-tracing methods, providing scientists with flexibility in obtaining axonal trajectory information from transparent tissue