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The Thrilling adventure hour : Martian manhunt
Shine your astro spurs and don your robot fists! Justice rides a rocket steed across the crimson plains of the fourth planet, where one man brings hope to humans who make this frontier world their home. He is...Sparks Nevada: Marshal on Mars. Alongside his trusty Martian sidekick Croach, Sparks protects Mars from robot outlaws, alien invaders, and any galactic threat foolish enough to target the red planet.
Book
How To Build a Bone: PHOSPHO1, Biomineralization, and Beyond
Since its characterization two decades ago, the phosphatase PHOSPHO1 has been the subject of an increasing focus of research. This work has elucidated PHOSPHO1's central role in the biomineralization of bone and other hard tissues, but has also implicated the enzyme in other biological processes in health and disease. During mineralization PHOSPHO1 liberates inorganic phosphate (Pi) to be incorporated into the mineral phase through hydrolysis of its substrates phosphocholine (PCho) and phosphoethanolamine (PEA). Localization of PHOSPHO1 within matrix vesicles allows accumulation of Pi within a protected environment where mineral crystals may nucleate and subsequently invade the organic collagenous scaffold. Here, we examine the evidence for this process, first discussing the discovery and characterization of PHOSPHO1, before considering experimental evidence for its canonical role in matrix vesicle–mediated biomineralization. We also contemplate roles for PHOSPHO1 in disorders of dysregulated mineralization such as vascular calcification, along with emerging evidence of its activity in other systems including choline synthesis and homeostasis, and energy metabolism. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
Journal Article
Conditional deletion of E11/podoplanin in bone protects against load-induced osteoarthritis
Background
Subchondral bone (SCB) thickening is one of the earliest detectable changes in osteoarthritic joints and is considered a potential trigger for subsequent articular cartilage degeneration. In this manuscript, we examine whether disruption to the SCB osteocyte network contributes to the initiation and pathogenesis of osteoarthritis.
Methods
We examined expression patterns of the glycoprotein E11/podoplanin by immunohistochemical labelling in murine, human and canine osteoarthritis models. We also examined the effects of twice-weekly administration of Bortezomib, a proteasome inhibitor which stabilises osteocyte E11 levels, to C57/BL6 wild-type male mice (1 mg/kg/day) for 8 weeks after surgical destabilisation of the medial meniscus. By inducing osteoarthritis-like changes in the right knee joint of 12-week-old male E11 hypomorphic mice (and corresponding controls) using a post-traumatic joint loading model, we also investigated whether a bone-specific E11 deletion in mice increases joint vulnerability to osteoarthritis. Articular cartilage degradation and osteophyte formation were assessed by histology and in line with the OARSI grading system.
Results
Our studies reveal increased E11 expression in osteocytes of human and canine osteoarthritic SCB. We found that Bortezomib administration had no effect on surgically-induced osteoarthritis, potentially due to a lack of the expected stabilisation of E11 in the SCB. We also found, in concordance with our previous work, wild-type mice exhibited significant load-induced articular cartilage lesions on the lateral femoral condyle (
p
< 0.01) and osteophyte formation. In contrast, E11 hypomorphic mice did not develop osteophytes or any corresponding articular lesions.
Conclusions
Overall, these data suggest that an intact osteocyte network in the SCB contributes to the development of mechanically-driven osteoarthritis. Further, the data presented here indicate that the molecular pathways that preserve the osteocyte network, such as those driven by E11, may be targeted to limit osteoarthritis pathogenesis.
Journal Article
Genotype‐function‐phenotype correlations for SCN1A variants identified by clinical genetic testing
Interpretation of clinical genetic testing, which identifies a potential genetic etiology in 25% of children with epilepsy, is limited by variants of uncertain significance. Understanding functional consequences of variants can help distinguish pathogenic from benign alleles. We combined automated patch clamp recording with neurophysiological simulations to discern genotype-function-phenotype correlations in a real-world cohort of children with SCN1A-associated epilepsy.
Clinical data were extracted for children with SCN1A variants identified by clinical genetic testing. Functional properties of non-truncating Na
1.1 variant channels were determined using automated patch clamp recording. Functional data were incorporated into a parvalbumin-positive (PV+) interneuron computer model to predict variant effects on neuron firing and were compared with longitudinal clinical data describing epilepsy types, neurocognitive outcomes, and medication response.
Twelve SCN1A variants were identified (nine non-truncating). Six non-truncating variants exhibited no measurable sodium current in heterologous cells consistent with complete loss of function (LoF). Two variants caused either partial LoF (L479P) or a mixture of gain and loss of function (I1356M). The remaining non-truncating variant (T1250M) exhibited normal function. Functional data changed classification of pathogenicity for six variants. Complete LoF variants were universally associated with seizure onset before one year of age and febrile seizures, and were often associated with drug resistant epilepsy and below average cognitive outcomes. Simulations demonstrated abnormal firing in heterozygous model neurons containing dysfunctional variants.
In SCN1A-associated epilepsy, functional analysis and neuron simulation studies resolved variants of uncertain significance and correlated with aspects of phenotype and medication response.
Journal Article
A comparison of the bone and growth phenotype of mdx , mdx:Cmah−/− and mdx:Utrn +/− murine models with the C57BL/10 wild-type mouse
The muscular dystrophy X-linked (mdx) mouse is commonly used as a mouse model of Duchenne muscular dystrophy (DMD). Its phenotype is, however, mild, and other mouse models have been explored. The mdx:Cmah−/− mouse carries a human-like mutation in the Cmah gene and has a severe muscle phenotype, but its growth and bone development are unknown. In this study, we compared male mdx, mdx:Utrn+/−, mdx:Cmah−/− and wild-type (WT) mice at 3, 5 and 7 weeks of age to determine the suitability of the mdx:Cmah−/− mouse as a model for assessing growth and skeletal development in DMD. The mdx:Cmah−/− mice were lighter than WT mice at 3 weeks, but heavier at 7 weeks, and showed an increased growth rate at 5 weeks. Cortical bone fraction as assessed by micro-computed tomography was greater in both mdx and mdx:Cmah−/− mice versus WT mice at 7 weeks. Tissue mineral density was also higher in mdx:Cmah−/− mice at 3 and 7 weeks. Gene profiling of mdx:Cmah−/− bone identified increased expression of Igf1, Igf1r and Vegfa. Both the mdx and mdx:Cmah−/− mice showed an increased proportion of regulated bone marrow adipose tissue (BMAT) but a reduction in constitutive BMAT. The mdx:Cmah−/− mice show evidence of catch-up growth and more rapid bone development. This pattern does not mimic the typical DMD growth trajectory and therefore the utility of the mdx:Cmah−/− mouse for studying growth and skeletal development in DMD is limited. Further studies of this model may, however, shed light on the phenomenon of catch-up growth. This article has an associated First Person interview with the first author of the paper.
Journal Article
Ablation of Enpp6 Results in Transient Bone Hypomineralization
Biomineralization is a fundamental process key to the development of the skeleton. The phosphatase orphan phosphatase 1 (PHOSPHO1), which likely functions within extracellular matrix vesicles, has emerged as a critical regulator of biomineralization. However, the biochemical pathways that generate intravesicular PHOSPHO1 substrates are currently unknown. We hypothesized that the enzyme ectonucleotide pyrophosphatase/phosphodiesterase 6 (ENPP6) is an upstream source of the PHOSPHO1 substrate. To test this, we characterized skeletal phenotypes of mice homozygous for a targeted deletion of Enpp6 (Enpp6−/−). Micro‐computed tomography of the trabecular compartment revealed transient hypomineralization in Enpp6−/− tibias (p < 0.05) that normalized by 12 weeks of age. Whole‐bone cortical analysis also revealed significantly hypomineralized proximal bone in 4‐ but not 12‐week‐old Enpp6−/− mice (p < 0.05) compared with WT animals. Back‐scattered SEM revealed a failure in 4‐week‐old trabecular bone of mineralization foci to propagate. Static histomorphometry revealed increased osteoid volume (p > 0.01) and osteoid surface (p < 0.05), which recovered by 12 weeks but was not accompanied by changes in osteoblast or osteoclast number. This study is the first to characterize the skeletal phenotype of Enpp6−/− mice, revealing transient hypomineralization in young animals compared with WT controls. These data suggest that ENPP6 is important for bone mineralization and may function upstream of PHOSPHO1 as a novel means of generating its substrates inside matrix vesicles. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
Journal Article
Metabolic blueprints of monocultures enable prediction and design of synthetic microbial consortia
Synthetic microbial ecology aims at designing communities with desired properties based on mathematical models of individual organisms. It is unclear whether simplified models harbor enough detail to predict the composition of synthetic communities in metabolically complex environments. Here, we use longitudinal exometabolite data of monocultures for 15 rhizosphere bacteria to parametrize a consumer-resource model, which we use to predict pairwise co-cultures and higher order communities. The capacity to artificially \"switch off\" cross-feeding interactions in the model demonstrates their importance in ecosystem structure. Leave-one-out and leave-two-out experiments demonstrate that pairwise co-cultures do not necessarily capture inter-species interactions within larger communities and broadly highlight the nonlinearity of interactions. Finally, we demonstrate that our model can be used to identify new sub-communities of three strains with high likelihood of coexistence. Our results establish hybrid mechanistic and data-driven metabolic models as a promising and extendable framework for predicting and engineering microbial communities.
Journal Article
Multiscale Characterization of Process-Structure-Property Relationships in Additively Manufactured IN718
Additive manufacturing has become a popular tool in a variety of different industries. However, there remain many unknowns regarding the processing-structure-property relationships and the corresponding quality, reliability, and performance of the parts. Laser powder bed fusion, which is one of the most common metal additive manufacturing techniques, has many benefits over traditional manufacturing and other metal additive manufacturing techniques. Inconel, which is a nickel-based superalloy, is a commonly used alloy for nuclear, aerospace, and marine industries due to its excellent mechanical properties at high temperatures. Although there is a significant amount of previous literature investigating processing-structure-property relationships of laser powder bed fused Inconel 718, few studies exist in the open literature that have investigated the variability of the pore structure, microstructure, tensile properties, and fatigue life in the as-built condition (i.e., no heat treatments or stress relieving). However, there are potential applications, such as deployment of additive manufacturing machines in the field, where it may not be possible to perform heat treatments. There is a need to better understand the relationships among laser-energy density, build orientation, pore structures, microstructures, and mechanical properties for the as-built condition.In this dissertation, a multiscale experimental approach is implemented, wherein each chapter leverages progressively smaller specimens (all derived from the same initial build) intended to investigate different aspects of property-process-structure relationships in as-built laser powder bed fused Inconel 718. The research addresses three main objectives: (1) to investigate the mechanisms driving high-cycle fatigue life with respect to different processing conditions; (2) to investigate the effects of laser-energy density and build orientation on the pore structure, microstructure, and tensile properties; and (3) to modify and validate a void descriptor function to uniquely characterize pore networks and predict fracture location in mesoscale tensile specimens. The primary findings from each study are described in subsequent chapters.
Dissertation