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"Craig, Tim"
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Strain Partitioning in the Southeastern Tibetan Plateau From Kinematic Modeling of High‐Resolution Sentinel‐1 InSAR and GNSS
Fault slip rates estimated from geodetic data are being integrated into seismic hazard models. The standard approach requires modeling velocities and relative (micro‐)plate motions, which is challenging for fault‐based models. We present a new approach to directly invert strain rates to solve for slip rates and distributed strain simultaneously. We generate velocity and strain rate fields over the southeastern Tibetan Plateau, utilizing Sentinel‐1 Interferometric Synthetic Aperture Radar data spanning 2014–2023. We derive slip rates using block modeling and by inverting strain rates. Our results show a partitioning between localized strain on faults and distributed deformation. The direct inversion of strain rates matches the geodetic data best when incorporating distributed moment sources, accounting for a similar proportion to on‐fault sources. The direct strain methodology also aligns best with the independent geological slip rates, especially near fault tips. As high‐resolution strain rate fields become increasingly available, we recommend direct inversion as the preferred practice. Plain Language Summary We focus on understanding earthquake potential in the southeastern Tibetan Plateau by measuring how and how fast the crust deforms. By analyzing 9 years of satellite radar images, we estimate how fast faults are slipping, which is crucial for assessing the hazard of future earthquakes. We tested two methods and found that the method directly incorporating measurements of surface strain rates provides more accurate results when compared to field‐based geologic slip rates. We show that the total deformation field is roughly equally split between energy accumulation on mapped active faults and distributed deformation away from the faults. The large amount of diffuse strain is an important constraint for rates of background seismicity. We discuss the limitations of various techniques used in modeling Earth's interseismic deformation and suggest prioritizing the direct strain methodology. Key Points We construct velocity and strain rate fields covering 1.3 million km2 of SE Tibet from Sentinel‐1 Interferometric Synthetic Aperture Radar Deformation is partitioned approximately equally between focused strain on the main mapped faults and diffuse deformation Direct inversion of strain rates removes the requirement to define artificial “blocks” and gives a better match to geological slip rates
Journal Article
The Flash
\"When Wally West, the adolescent nephew of the Flash's fiancee accidentally gained powers of superspeed, he became the Scarlet Speedster's sidekick. Growing up as his hero's protege, Kid Flash had a childhood of amazing action and adventure. But on the day that The Flash died, Wally's carefree adolescence abruptly ended and his life as an adult began. THE FLASH BY MARK WAID BOOK ONE looks back at Wally's earliest days as the Kid Flash and explores the gamut of his emotions and experiences from his first day as a child hero to his succession of Barry Allen as the new Flash. A journey full of humor and drama, this story shows just how much Wally West loves being the fastest man alive\"-- Provided by publisher.
Book
Differentiation of SH-SY5Y neuroblastoma cells using retinoic acid and BDNF: a model for neuronal and synaptic differentiation in neurodegeneration
There has been much interest in the use of cell culture models of neurones, to avoid the animal welfare and cost issues of using primary and human-induced pluripotent stem cell (hiPSC)-derived neurones respectively. The human neuroblastoma cell line, SH-SY5Y, is extensively used in laboratories as they can be readily expanded, are of low cost and can be differentiated into neuronal-like cells. However, much debate remains as to their phenotype once differentiated, and their ability to recapitulate the physiology of
bona fide
neurones. Here, we characterise a differentiation protocol using retinoic acid and BDNF, which results in extensive neurite outgrowth/branching within 10 days, and expression of key neuronal and synaptic markers. We propose that these differentiated SH-SY5Y cells may be a useful substitute for primary or hiPSC-derived neurones for cell biology studies, in order to reduce costs and animal usage. We further propose that this characterised differentiation timecourse could be used as an in vitro model for neuronal differentiation, for proof-of principle studies on neurogenesis, e.g. relating to neurodegenerative diseases. Finally, we demonstrate profound changes in Tau phosphorylation during differentiation of these cells, suggesting that they should not be used for neurodegeneration studies in their undifferentiated state.
Journal Article
SUMOylation Is Required for Glycine-Induced Increases in AMPA Receptor Surface Expression (ChemLTP) in Hippocampal Neurons
Multiple pathways participate in the AMPA receptor trafficking that underlies long-term potentiation (LTP) of synaptic transmission. Here we demonstrate that protein SUMOylation is required for insertion of the GluA1 AMPAR subunit following transient glycine-evoked increase in AMPA receptor surface expression (ChemLTP) in dispersed neuronal cultures. ChemLTP increases co-localisation of SUMO-1 and the SUMO conjugating enzyme Ubc9 and with PSD95 consistent with the recruitment of SUMOylated proteins to dendritic spines. In addition, we show that ChemLTP increases dendritic levels of SUMO-1 and Ubc9 mRNA. Consistent with activity dependent translocation of these mRNAs to sites near synapses, levels of the mRNA binding and dendritic transport protein CPEB are also increased by ChemLTP. Importantly, reducing the extent of substrate protein SUMOylation by overexpressing the deSUMOylating enzyme SENP-1 or inhibiting SUMOylation by expressing dominant negative Ubc9 prevent the ChemLTP-induced increase in both AMPAR surface expression and dendritic SUMO-1 mRNA. Taken together these data demonstrate that SUMOylation of synaptic protein(s) involved in AMPA receptor trafficking is necessary for activity-dependent increases in AMPAR surface expression.
Journal Article
A Helicopter Survey for Cliff-Nesting Raptors Along the Dalton Highway in Northern Alaska, 2010
We conducted a helicopter survey in 2010 for cliff-nesting raptors along the Dalton Highway in northern Alaska. The study area extended from the Yukon River northward ~395 km through the Brooks Range to the Arctic Plain. We documented 55 occupied raptor nesting territories, including 25 Golden Eagle (Aquila chrysaetos), 11 Gyrfalcon (Falco rusticolus), and 10 Peregrine Falcon (Falco peregrinus) territories. We also recorded vacant stick nests and raptor perch sites on cliffs. We identified more occupied eagle territories and hundreds more vacant eagle stick nests than were previously known in the study area. The average number of Golden Eagle nestlings/nesting pairs at the time of the survey was 1.5 ± 0.6. The most productive Golden Eagle pairs were located in the northern part of the study area. The number of occupied eagle territories in 2010 is far fewer than the number of eagle stick nests we recorded. Our data indicate that the distribution of nesting eagles in the 2010 study area is different than in the past. Whether this reflects changes in eagle density; a response to availability of prey, climate change, human activities, or a combination of these; or some other factor warrants further investigation. Intensive surveys along the Dalton Highway in the 1970s found no occupied nests for Peregrine Falcons or Gyrfalcons but we found 10 and 11, respectively. Therefore, the Peregrine Falcon and Gyrfalcon nests we recorded in 2010 reflect an increase in the number of known nesting pairs there.
Journal Article
SUMOylation of Syntaxin1A regulates presynaptic endocytosis
Neurotransmitter release from the presynaptic terminal is under very precise spatial and temporal control. Following neurotransmitter release, synaptic vesicles are recycled by endocytosis and refilled with neurotransmitter. During the exocytosis event leading to release, SNARE proteins provide most of the mechanical force for membrane fusion. Here, we show one of these proteins, Syntaxin1A, is SUMOylated near its C-terminal transmembrane domain in an activity-dependent manner. Preventing SUMOylation of Syntaxin1A reduces its interaction with other SNARE proteins and disrupts the balance of synaptic vesicle endo/exocytosis, resulting in an increase in endocytosis. These results indicate that SUMOylation regulates the emerging role of Syntaxin1A in vesicle endocytosis, which in turn, modulates neurotransmitter release and synaptic function.
Journal Article
SUMOylation of synapsin Ia maintains synaptic vesicle availability and is reduced in an autism mutation
Synapsins are key components of the presynaptic neurotransmitter release machinery. Their main role is to cluster synaptic vesicles (SVs) to each other and anchor them to the actin cytoskeleton to establish the reserve vesicle pool, and then release them in response to appropriate membrane depolarization. Here we demonstrate that SUMOylation of synapsin Ia (SynIa) at K687 is necessary for SynIa function. Replacement of endogenous SynIa with a non-SUMOylatable mutant decreases the size of the releasable vesicle pool and impairs stimulated SV exocytosis. SUMOylation enhances SynIa association with SVs to promote the efficient reclustering of SynIa following neuronal stimulation and maintain its presynaptic localization. The A548T mutation in SynIa is strongly associated with autism and epilepsy and we show that it leads to defective SynIa SUMOylation. These results identify SUMOylation as a fundamental regulator of SynIa function and reveal a novel link between reduced SUMOylation of SynIa and neurological disorders.
Synapsins anchor synaptic vesicles (SVs) to the actin cytoskeleton to establish the reserve vesicle pool. Here Tang
et al
. show that SUMOylation of synapsin 1a enhances its interaction with SVs to promote efficient reclustering following stimulation, and a mutation linked to autism and epilepsy leads to defective SUMOylation.
Journal Article
Polydopamine-Lysophosphatidate-Functionalised Titanium: A Novel Hybrid Surface Finish for Bone Regenerative Applications
Aseptic loosening of total joint replacements (TJRs) continues to be the main cause of implant failures. The socioeconomic impact of surgical revisions is hugely significant; in the United Kingdom alone, it is estimated that £135m is spent annually on revision arthroplasties. Enhancing the longevity of titanium implants will help reduce the incidence and overall cost of failed devices. In realising the development of a superior titanium (Ti) technology, we took inspiration from the growing interest in reactive polydopamine thin films for biomaterial surface functionalisations. Adopting a “one-pot” approach, we exposed medical-grade titanium to a mildly alkaline solution of dopamine hydrochloride (DHC) supplemented with (3S)1-fluoro-3-hydroxy-4-(oleoyloxy)butyl-1-phosphonate (FHBP), a phosphatase-resistant analogue of lysophosphatidic acid (LPA). Importantly, LPA and selected LPA analogues like FHBP synergistically cooperate with calcitriol to promote human osteoblast formation and maturation. Herein, we provide evidence that simply immersing Ti in aqueous solutions of DHC-FHBP afforded a surface that was superior to FHBP-Ti at enhancing osteoblast maturation. The facile step we have taken to modify Ti and the biological performance of the final surface finish are appealing properties that may attract the attention of implant manufacturers in the future.
Journal Article
Protein SUMOylation regulates insulin secretion at multiple stages
Type-II Diabetes Mellitus (T2DM) is one of the fastest growing public health issues of modern times, consuming 12% of worldwide health budgets and affecting an estimated 400 million people. A key pathological trait associated with this disease is the failure of normal glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells. Several lines of evidence suggest that vesicle trafficking events such as insulin secretion are regulated by the post-translational modification, SUMOylation, and indeed SUMOylation has been proposed to act as a ‘brake’ on insulin exocytosis. Here, we show that diabetic stimuli which inhibit GSIS are correlated with an increase in cellular protein SUMOylation, and that inhibition of deSUMOylation reduces GSIS. We demonstrate that manipulation of cellular protein SUMOylation levels, by overexpression of several different components of the SUMOylation pathway, have varied and complex effects on GSIS, indicating that SUMOylation regulates this process at multiple stages. We further demonstrate that inhibition of syntaxin1A SUMOylation, via a knockdown-rescue strategy, greatly enhances GSIS. Our data are therefore consistent with the model that SUMOylation acts as a brake on GSIS, and we have identified SUMOylation of syntaxin 1 A as a potential component of this brake. However, our data also demonstrate that the role of SUMOylation in GSIS is complex and may involve many substrates.
Journal Article