Following damage to peripheral nerves, a remarkable process of clearance and regeneration takes place. Axons downstream of the injury degenerate, while the nerve is remodeled to direct axonal ...regrowth. Schwann cells are important for this regenerative process. “Sensing” damaged axons, they dedifferentiate to a progenitor-like state, in which they aid nerve regeneration. Here, we demonstrate that activation of an inducible Raf-kinase transgene in myelinated Schwann cells is sufficient to control this plasticity by inducing severe demyelination in the absence of axonal damage, with the period of demyelination/ataxia determined by the duration of Raf activation. Remarkably, activation of Raf-kinase also induces much of the inflammatory response important for nerve repair, including breakdown of the blood-nerve barrier and the influx of inflammatory cells. This reversible in vivo model identifies a central role for ERK signaling in Schwann cells in orchestrating nerve repair and is a powerful system for studying peripheral neuropathies and cancer.
► We describe an inducible and reversible in vivo model of nerve demyelination ► Raf/ERK signaling drives Schwann cell dedifferentiation and demyelination in vivo ► The duration of Raf/MEK/ERK signaling determines the period of demyelination ► The Schwann cells induce an inflammatory response in the absence of injury
Napoli et al. find that activation of ERK signaling in myelinated Schwann cells, using an inducible Raf-kinase transgene, is sufficient to promote plasticity in an in vivo model of demyelinating nerve injury, including activation of an inflammatory response that may contribute to nerve repair.
•We assessed a comprehensive accommodations model of selection into EEC settings and whether predictors of selection differed by child age.•Family needs, family resources, social norms and ...preferences, and contextual constraints significantly predicted EEC selection.•Race/ethnicity, maternal employment, and EEC availability most strongly predicted EEC type for infants.•Parental preferences for higher quality care were stronger predictors of EEC for preschoolers.
Early education and care programs (EEC) serve important functions in promoting children's school readiness skills and supporting parental employment. Yet knowledge remains limited concerning factors inhibiting or increasing families’ use of EEC programs for their young children and whether such factors function differently as children age. This study employed nationally representative data from the Early Childhood Longitudinal Study, Birth Cohort (ECLS-B) following 10,700 children from infancy through early childhood to assess predictors of home and center-based EEC and to delineate whether predictors differed by developmental period. Drawing on Meyers and Jordan's (2006) rich accommodations model of EEC selection, analyses found that factors associated with family needs and resources (parental employment, income, education, and family structure), cultural norms and preferences (race, ethnicity, and immigration status; geographic location; child characteristics; and parental priorities regarding EEC characteristics) and contextual opportunities and constraints (availability of care in the community) were all associated with selection into EEC settings. Many patterns were similar for infants, toddlers, and preschoolers, although race/ethnicity, employment, and availability were most strongly linked to EEC type during infancy, whereas parental priorities for features associated with higher-quality care programs predicted EEC most strongly for preschoolers. Results are discussed in terms of efforts to increase family choice and access to EEC programs.
Elastin is the primary component of elastic fibres in arteries, which contribute significantly to the structural integrity of the wall. Fibrillin-1 is a microfibrillar glycoprotein that appears to ...stabilize elastic fibres mechanically and thereby to delay a fatigue-induced loss of function due to long-term repetitive loading. Whereas prior studies have addressed some aspects of ageing-related changes in the overall mechanical properties of arteries in mouse models of Marfan syndrome, we sought to assess for the first time the load-carrying capability of the elastic fibres early in maturity, prior to the development of ageing-related effects, dilatation, or dissection.
We used elastase to degrade elastin in common carotid arteries excised, at 7-9 weeks of age, from a mouse model (mgR/mgR) of Marfan syndrome that expresses fibrillin-1 at 15-25% of normal levels. In vitro biaxial mechanical tests performed before and after exposure to elastase suggested that the elastic fibres exhibited a nearly normal load-bearing capability. Observations from nonlinear optical microscopy suggested further that competent elastic fibres not only contribute to load-bearing, they also increase the undulation of collagen fibres, which endows the normal arterial wall with a more compliant response to pressurization.
These findings support the hypothesis that it is an accelerated fatigue-induced damage to or protease-related degradation of initially competent elastic fibres that render arteries in Marfan syndrome increasingly susceptible to dilatation, dissection, and rupture.
Personality traits and diet can be used to predict if a person is predisposed to disordered eating. Results of this study demonstrate a strong significant relationship between the personality trait ...of selflessness, diet group, and disordered eating. Vegans were most likely to display selflessness tendencies associated with disordered eating; however when selflessness was controlled for, vegans displayed substantially less disordered eating pathology than non‐vegetarians.
Objective
To explore the relationship between diet group (non‐vegetarian, semi‐vegetarian, true‐vegetarian, and vegan) and disordered eating while investigating to what extent personality trait of selflessness mediates the relationship between diet group and disordered eating.
Method
Cross‐sectional data from 634 Australian nonclinical women who completed a series of online questionnaires including measures of diet group, disordered eating, and selflessness were used to examine associations between diet, personality (selflessness), and disordered eating.
Results
Selflessness was found to be a significant positive predictor of disordered eating. Results confirm that selflessness played a suppressing role in the relationship between the vegan diet group and disordered eating, when compared to non‐vegetarians. Surprisingly, vegans displayed significantly less disordered eating than non‐vegetarians and semi‐vegetarians.
Discussion
Results of the current study imply that the role of selflessness on disordered eating, when broken down across diet group, may be more complex than first thought. If replicated, these results suggest that targeted treatment of selflessness in different diet groups may improve treatment outcomes for disordered eating. Further research should explore why diet groups differ in terms of selflessness and how this impacts disordered eating.
Personality traits and diet can be used to predict if a person is predisposed to disordered eating. Results of this study demonstrate a strong significant relationship between the personality trait of selflessness, diet group, and disordered eating.
The γ-crystallins of the eye lens nucleus are among the longest-lived proteins in the human body. Synthesized in utero, they must remain folded and soluble throughout adulthood to maintain lens ...transparency and avoid cataracts. γD- and γS-crystallin are two major monomeric crystallins of the human lens. γD-crystallin is concentrated in the oldest lens fiber cells, the lens nucleus, whereas γS-crystallin is concentrated in the younger cells of the lens cortex. The kinetic stability parameters of these two-domain proteins and their isolated domains were determined and compared. Kinetic unfolding experiments monitored by fluorescence spectroscopy in varying concentrations of guanidinium chloride were used to extrapolate unfolding rate constants and half-lives of the crystallins in the absence of the denaturant. Consistent with their long lifespans in the lens, extrapolated half-lives for the initial unfolding step were on the timescale of years. Both proteins’ isolated N-terminal domains were less kinetically stable than their respective C-terminal domains at denaturant concentrations predicted to disrupt the domain interface, but at low denaturant concentrations, the relative kinetic stabilities were reversed. Cataract-associated aggregation has been shown to proceed from partially unfolded intermediates in these proteins; their extreme kinetic stability likely evolved to protect the lens from the initiation of aggregation reactions. Our findings indicate that the domain interface is the source of significant kinetic stability. The gene duplication and fusion event that produced the modern two-domain architecture of vertebrate lens crystallins may be the origin of their high kinetic as well as thermodynamic stability.
Abstract Systemic simvastatin is known to reduce cholesterol and stimulate modest bone formation, but local surgical placement in polylactic acid domes causes robust bone formation and local ...swelling. A less invasive and more flexible injection protocol was studied to evaluate the bone-inducing effects compared to surgical implantation. Bone formation rate, short- and long-term bone augmentation histology, and mechanical properties were evaluated to characterize the new bone in a rat bilateral mandible model (test and control sides in same animal). Results demonstrated that multiple (3) injections of 0.5 mg simvastatin effectively reduced soft tissue swelling while preserving bone growth (60% increase of bone width at 24 days) compared to simvastatin dome placement (43% increase at 24 days). Compared to controls, bone formation rate was significantly higher on the simvastatin side, especially in the dome. Three-point bending tests revealed higher maximum force to fracture and stiffness at 24 days with simvastatin injections. Long-term evaluation showed that 55% of maximum new bone formed 24 days post-injection was retained at 90 days.
Contemporary science is a field that is becoming increasingly computational. Today’s scientists not only leverage computational tools to conduct their investigations, they often must contribute to ...the design of the computational tools for their specific research. From a science education perspective, for students to learn authentic science practices, students must learn to use the tools of the trade. This necessity in science education has shaped recent K–12 science standards including the Next Generation Science Standards, which explicitly mention the use of computational tools and simulations. These standards, in particular, have gone further and mandated that
computational thinking
be taught and leveraged as a practice of science. While computational thinking is not a new term, its inclusion in K–12 science standards has led to confusion about what the term means in the context of science learning and to questions about how to differentiate computational thinking from other commonly taught cognitive skills in science like problem-solving, mathematical reasoning, and critical thinking. In this paper, we propose a definition of
computational thinking for science
(CT-S) and a framework for its operationalization in K–12 science education. We situate our definition and framework in Activity Theory, from the learning sciences, in order to position computational thinking as an input to and outcome of science learning that is mediated by computational tools.
The transparency of the eye lens depends on the high solubility and stability of the lens crystallin proteins. The monomeric γ‐crystallins and oligomeric β‐crystallins have paired homologous double ...Greek key domains, presumably evolved through gene duplication and fusion. Prior investigation of the refolding of human γD‐crystallin revealed that the C‐terminal domain folds first and nucleates the folding of the N‐terminal domain. This result suggested that the human N‐terminal domain might not be able to fold on its own. We constructed and expressed polypeptide chains corresponding to the isolated N‐ and C‐terminal domains of human γD‐crystallin, as well as the isolated domains of human γS‐crystallin. Both circular dichroism and fluorescence spectroscopy indicated that the isolated domains purified from Escherichia coli were folded into native‐like monomers. After denaturation, the isolated domains refolded efficiently at pH 7 and 37°C into native‐like structures. The in vitro refolding of all four domains revealed two kinetic phases, identifying partially folded intermediates for the Greek key motifs. When subjected to thermal denaturation, the isolated N‐terminal domains were less stable than the full‐length proteins and less stable than the C‐terminal domains, and this was confirmed in equilibrium unfolding/refolding experiments. The decrease in stability of the N‐terminal domain of human γD‐crystallin with respect to the complete protein indicated that the interdomain interface contributes of 4.2 kcal/mol to the overall stability of this very long‐lived protein.
Epigenetic marks such as cytosine methylation are important determinants of cellular and whole-body phenotypes. However, the extent of, and reasons for inter-individual differences in cytosine ...methylation, and their association with phenotypic variation are poorly characterised. Here we present the first genome-wide study of cytosine methylation at single-nucleotide resolution in an animal model of human disease. We used whole-genome bisulfite sequencing in the spontaneously hypertensive rat (SHR), a model of cardiovascular disease, and the Brown Norway (BN) control strain, to define the genetic architecture of cytosine methylation in the mammalian heart and to test for association between methylation and pathophysiological phenotypes. Analysis of 10.6 million CpG dinucleotides identified 77,088 CpGs that were differentially methylated between the strains. In F1 hybrids we found 38,152 CpGs showing allele-specific methylation and 145 regions with parent-of-origin effects on methylation. Cis-linkage explained almost 60% of inter-strain variation in methylation at a subset of loci tested for linkage in a panel of recombinant inbred (RI) strains. Methylation analysis in isolated cardiomyocytes showed that in the majority of cases methylation differences in cardiomyocytes and non-cardiomyocytes were strain-dependent, confirming a strong genetic component for cytosine methylation. We observed preferential nucleotide usage associated with increased and decreased methylation that is remarkably conserved across species, suggesting a common mechanism for germline control of inter-individual variation in CpG methylation. In the RI strain panel, we found significant correlation of CpG methylation and levels of serum chromogranin B (CgB), a proposed biomarker of heart failure, which is evidence for a link between germline DNA sequence variation, CpG methylation differences and pathophysiological phenotypes in the SHR strain. Together, these results will stimulate further investigation of the molecular basis of locally regulated variation in CpG methylation and provide a starting point for understanding the relationship between the genetic control of CpG methylation and disease phenotypes.
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