Strength and Failure of Fibrin Fiber Branch Points

Blood clots form rapidly in the event of vascular injury, to prevent blood loss. They may also form in undesired places, causing heart attacks, strokes, and other diseases. Blood clots can rupture, and fragments of the clotmay lodge in distal blood vessels, causing, for example, ischemic strokes or embolisms. Thus, there has been great interest in understanding the mechanical behavior and failure mechanisms of blood clots and their constituents. To develop a mechanically realistic model of a blood clot, knowledge of the mechanical properties of its constituents is required. The major structural component providing mechanical strength to the clot is a mesh of fibrin fibers. Principally, three pieces of information are needed to develop realistic (fibrin fiber) network models: (i) the architecture of the network; (ii) the properties of the single fibers; and (iii) the properties of the fiber branchpoints

The Mechanical Properties of Single Fibrin Fibers

Background: Blood clots perform the mechanical task of stemming the flow of blood. Objectives: To advance understanding and realistic modeling of blood clot behavior we determined the mechanical properties of the major structural component of blood clots, fibrin fibers. Methods: We used a combined atomic force microscopy (AFM)/fluorescence microscopy technique to determine key mechanical properties of single crosslinked and uncrosslinked fibrin fibers. Results and conclusions: Overall, full crosslinking renders fibers less extensible, stiffer, and less elastic than their uncrosslinked counterparts. All fibers showed stress relaxation behavior (time-dependent weakening) with a fast and a slow relaxation time, 2 and 52 s. In detail, crosslinked and uncrosslinked fibrin fibers can be stretched to 2.5 and 3.3 times their original length before rupturing. Crosslinking increased the stiffness of fibers by a factor of 2, as the total elastic modulus, E0, increased from 3.9 to 8.0 MPa and the relaxed, elastic modulus, E∞, increased from 1.9 to 4.0 MPa upon crosslinking. Moreover, fibers stiffened with increasing strain (strain hardening), as E0 increased by a factor of 1.9 (crosslinked) and 3.0 (uncrosslinked) at strains ε \u3e 110%. At low strains, the portion of dissipated energy per stretch cycle was small (\u3c 10%) for uncrosslinked fibers, but significant (approximately 40%) for crosslinked fibers. At strains \u3e 100%, all fiber types dissipated about 70% of the input energy. We propose a molecular model to explain our data. Our single fiber data can now also be used to construct a realistic, mechanical model of a fibrin network

Current research into brain barriers and the delivery of therapeutics for neurological diseases: a report on CNS barrier congress London, UK, 2017.

This is a report on the CNS barrier congress held in London, UK, March 22-23rd 2017 and sponsored by Kisaco Research Ltd. The two 1-day sessions were chaired by John Greenwood and Margareta Hammarlund-Udenaes, respectively, and each session ended with a discussion led by the chair. Speakers consisted of invited academic researchers studying the brain barriers in relation to neurological diseases and industry researchers studying new methods to deliver therapeutics to treat neurological diseases. We include here brief reports from the speakers

Motherhood, Moral Authority and the Charismatic Matriarch in the Aftermath of Lethal Violence

Images of maternal suffering are an evocative and powerful means of communication in a world where the private grief of victims has increasingly become subject to commodification and public consumption. This article looks at the influence of bereaved mothers as symbols of respect, peace and dignity in the aftermath of violence, and as a result their persuasive presence in family activism. Drawing upon two case studies, this article explores the importance of victims’ stories in public life and, in particular, the presence of the charismatic matriarch in creating communities of solidarity, raising awareness of harms that have previously gone unheard and prompting policy change. It considers the ‘canonical’ story of the mother in public life and concludes by arguing that more attention should be paid to victims’ stories and their influence on policy-making, politics and eventually in becoming public grievances

A Fascinating Polynomial Sequence arising from an Electrostatics Problem on the Sphere

A positive unit point charge approaching from infinity a perfectly spherical isolated conductor carrying a total charge of +1 will eventually cause a negatively charged spherical cap to appear. The determination of the smallest distance $\rho(d)$ ($d$ is the dimension of the unit sphere) from the point charge to the sphere where still all of the sphere is positively charged is known as Gonchar's problem. Using classical potential theory for the harmonic case, we show that $1+\rho(d)$ is equal to the largest positive zero of a certain sequence of monic polynomials of degree $2d-1$ with integer coefficients which we call Gonchar polynomials. Rather surprisingly, $\rho(2)$ is the Golden ratio and $\rho(4)$ the lesser known Plastic number. But Gonchar polynomials have other interesting properties. We discuss their factorizations, investigate their zeros and present some challenging conjectures.Comment: 12 pages, 6 figures, 1 tabl

Endothelial Nitric Oxide Synthase is Regulated by ERK Phosphorylation at Ser602

eNOS (endothelial nitric oxide synthase) contains a MAPK (mitogen-activated protein kinase)-binding site associated with a major eNOS control element. Purified ERK (extracellular-signal-regulated kinase) phosphorylates eNOS with a stoichiometry of 2–3 phosphates per eNOS monomer. Phosphorylation decreases NO synthesis and cytochrome c reductase activity. Three sites of phosphorylation were detected by MS. All sites matched the SP and TP MAPK (mitogen-activated protein kinase) phosphorylation motif. Ser602 lies at the N-terminal edge of the 42-residue eNOS AI (autoinhibitory) element. The pentabasic MAPK-binding site lies at the opposite end of the AI, and other critical regulatory features are between them. Thr46 and Ser58 are located in a flexible region associated with the N terminus of the oxygenase domain. In contrast with PKC (protein kinase C), phosphorylation by ERK did not significantly interfere with CaM (calmodulin) binding as analysed by optical biosensing. Instead, ERK phosphorylation favours a state in which FMN and FAD are in close association and prevents conformational changes that expose reduced FMN to acceptors. The close associations between control sites in a few regions of the molecule suggest that control of signal generation is modulated by multiple inputs interacting directly on the surface of eNOS via overlapping binding domains and tightly grouped targets

The transcriptome of utricle hair cell regeneration in the avian inner ear

Sensory hair cell loss is the major cause of hearing and balance disorders. Mammals are incapable of sustained hair cell regeneration, but lower vertebrates can regenerate these mechano-electrical transducers. We present the first comprehensive transcriptome (by mRNA-Seq) of hair cell regeneration in the chick utricle. We provide pathway and pattern annotations and correlate these with the phenotypic events that occur during regeneration. These patterns are surprisingly synchronous and highly punctuated. We show how these patterns are a new resource for identifying components of the hair cell transcriptome and identify 494 new putative hair-cell-specific genes and validate three of these (of three tested) by immunohistochemical staining. We describe many surprising new components and dynamic expression patterns, particularly within NOTCH signaling. For example, we show that HES7 is specifically expressed during utricle hair cell regeneration and closely parallels the expression of HES5. Likewise, the expression of ATOH1 is closely correlated with HEYL and the HLH inhibitory transcription factors ID1, ID2, and ID4. We investigate the correlation between fibroblast growth factor signaling and supporting cell proliferation and show that FGF20 inhibits supporting cell proliferation. We also present an analysis of 212 differentially expressed transcription factor genes in the regenerative time course that fall into nine distinct gene expression patterns, many of which correlate with phenotypic events during regeneration and represent attractive candidates for future analysis and manipulation of the regenerative program in sensory epithelia and other vertebrate neuroepithelia

Redox signals at the ER-mitochondria interface control melanoma progression.

Reactive oxygen species (ROS) are emerging as important regulators of cancer growth and metastatic spread. However, how cells integrate redox signals to affect cancer progression is not fully understood. Mitochondria are cellular redox hubs, which are highly regulated by interactions with neighboring organelles. Here, we investigated how ROS at the endoplasmic reticulum (ER)-mitochondria interface are generated and translated to affect melanoma outcome. We show that TMX1 and TMX3 oxidoreductases, which promote ER-mitochondria communication, are upregulated in melanoma cells and patient samples. TMX knockdown altered mitochondrial organization, enhanced bioenergetics, and elevated mitochondrial- and NOX4-derived ROS. The TMX-knockdown-induced oxidative stress suppressed melanoma proliferation, migration, and xenograft tumor growth by inhibiting NFAT1. Furthermore, we identified NFAT1-positive and NFAT1-negative melanoma subgroups, wherein NFAT1 expression correlates with melanoma stage and metastatic potential. Integrative bioinformatics revealed that genes coding for mitochondrial- and redox-related proteins are under NFAT1 control and indicated that TMX1, TMX3, and NFAT1 are associated with poor disease outcome. Our study unravels a novel redox-controlled ER-mitochondria-NFAT1 signaling loop that regulates melanoma pathobiology and provides biomarkers indicative of aggressive disease

Student teachers' participation in learning activities and effective teaching behaviours

Teacher learning is essential to the teaching profession, because it has been strongly linked to improved teaching practices and teacher quality. The source for teacher learning is initial teacher education, a crucial phase in the learning-to-teach continuum. To gain insight into this influential period for student teachers’ long-term professional lives, this exploratory study investigates student teachers’ participation in learning activities and explores whether it is connected to their own effective teaching behaviours in a school-based teacher education setting for secondary education in the Netherlands. The results indicate that student teachers vary in their self-reported learning and that this learning relates positively to observations of their effective teaching behaviour. These findings have several implications for teacher education programmes that aim to enhance the likelihood that their student teachers will become career-long learning professionals