Limits of economy and fidelity for programmable assembly of size-controlled triply periodic polyhedra.

We propose and investigate an extension of the Caspar-Klug symmetry principles for viral capsid assembly to the programmable assembly of size-controlled triply periodic polyhedra, discrete variants of the Primitive, Diamond, and Gyroid cubic minimal surfaces. Inspired by a recent class of programmable DNA origami colloids, we demonstrate that the economy of design in these crystalline assemblies-in terms of the growth of the number of distinct particle species required with the increased size-scale (e.g., periodicity)-is comparable to viral shells. We further test the role of geometric specificity in these assemblies via dynamical assembly simulations, which show that conditions for simultaneously efficient and high-fidelity assembly require an intermediate degree of flexibility of local angles and lengths in programmed assembly. Off-target misassembly occurs via incorporation of a variant of disclination defects, generalized to the case of hyperbolic crystals. The possibility of these topological defects is a direct consequence of the very same symmetry principles that underlie the economical design, exposing a basic tradeoff between design economy and fidelity of programmable, size controlled assembly.

Geometrically programmed self-limited assembly of tubules using DNA origami colloids.

Self-assembly is one of the most promising strategies for making functional materials at the nanoscale, yet new design principles for making self-limiting architectures, rather than spatially unlimited periodic lattice structures, are needed. To address this challenge, we explore the tradeoffs between addressable assembly and self-closing assembly of a specific class of self-limiting structures: cylindrical tubules. We make triangular subunits using DNA origami that have specific, valence-limited interactions and designed binding angles, and we study their assembly into tubules that have a self-limited width that is much larger than the size of an individual subunit. In the simplest case, the tubules are assembled from a single component by geometrically programming the dihedral angles between neighboring subunits. We show that the tubules can reach many micrometers in length and that their average width can be prescribed through the dihedral angles. We find that there is a distribution in the width and the chirality of the tubules, which we rationalize by developing a model that considers the finite bending rigidity of the assembled structure as well as the mechanism of self-closure. Finally, we demonstrate that the distributions of tubules can be further sculpted by increasing the number of subunit species, thereby increasing the assembly complexity, and demonstrate that using two subunit species successfully reduces the number of available end states by half. These results help to shed light on the roles of assembly complexity and geometry in self-limited assembly and could be extended to other self-limiting architectures, such as shells, toroids, or triply periodic frameworks.

Building blocks of non-Euclidean ribbons: size-controlled self-assembly via discrete frustrated particles.

Geometric frustration offers a pathway to soft matter self-assembly with controllable finite sizes. While the understanding of frustration in soft matter assembly derives almost exclusively from continuum elastic descriptions, a current challenge is to understand the connection between microscopic physical properties of misfitting "building blocks" and emergent assembly behavior at the mesoscale. We present and analyze a particle-based description of what is arguably the best studied example for frustrated soft matter assembly, negative-curvature ribbon assembly, observed in both assemblies of chiral surfactants and shape-frustrated nanoparticles. Based on our particle model, known as saddle wedge monomers, we numerically test the connection between microscopic shape and interactions of the misfitting subunits and the emergent behavior at the supra-particle scale, specifically focussing on the propagation and relaxation of inter-particle strains, the emergent role of extrinsic shape on frustrated ribbons and the equilibrium regime of finite width selection. Beyond the intuitive role of shape misfit, we show that self-limitation is critically dependent on the finite range of cohesive interactions, with larger size finite assemblies requiring increasing short-range interparticle forces. Additionally, we demonstrate that non-linearities arising from discrete particle interactions alter self-limiting behavior due to both strain-softening in shape-flattened assembly and partial yielding of highly strained bonds, which in turn may give rise to states of hierarchical, multidomain assembly. Tracing the regimes of frustration-limited assembly to the specific microscopic features of misfitting particle shapes and interactions provides necessary guidance for translating the theory of size-programmable assembly into design of intentionally-frustrated colloidal particles.

Morphology selection via geometric frustration in chiral filament bundles.

In assemblies, the geometric frustration of a locally preferred packing motif leads to anomalous behaviours, from self-limiting growth to defects in the ground state. Here, we demonstrate that geometric frustration selects the equilibrium morphology of cohesive bundles of chiral filaments, an assembly motif critical to a broad range of biological and synthetic nanomaterials. Frustration of inter-filament spacing leads to optimal shapes of self-twisting bundles that break the symmetries of packing and of the underlying inter-filament forces, paralleling a morphological instability in spherical two-dimensional crystals. Equilibrium bundle morphology is controlled by a parameter that characterizes the relative costs of filament bending and the straining of cohesive bonds between filaments. This parameter delineates the boundaries between stable, isotropic cylindrical bundles and anisotropic, twisted-tape bundles. We also show how the mechanical and interaction properties of constituent amyloid fibrils may be extracted from the mesoscale dimensions of the anisotropic bundles that they form.

Mechanisms of enhanced osteoblast gene expression in the presence of hydroxyapatite coated iron oxide magnetic nanoparticles.

Hydroxyapatite (HA) coated iron oxide (Fe(3)O(4)) magnetic nanoparticles have been shown to enhance osteoblast (bone forming cells) proliferation and osteoblast differentiation into calcium depositing cells (through increased secretion of alkaline phosphatase, collagen and calcium deposition) compared to control samples without nanoparticles. Such nanoparticles are, thus, very promising for numerous orthopedic applications including magnetically directed osteoporosis treatment. The objective of the current study was to elucidate the mechanisms of the aforementioned improved osteoblast responses in the presence of HA coated Fe(3)O(4) nanoparticles. Results demonstrated large amounts of fibronectin (a protein known to increase osteoblast functions) adsorption on HA coated Fe(3)O(4) nanoparticles. Specifically, fibronectin adsorption almost doubled when HA coated Fe(3)O(4) nanoparticle concentrations increased from 12.5 to 100 µg ml(-1), and from 12.5 to 200 µg ml(-1), a four fold increase was observed. Results also showed greater osteoblast gene regulation (specifically, osteocalcin, type I collagen and cbfa-1) in the presence of HA coated Fe(3)O(4) nanoparticles. Collectively, these results provide a mechanism for the observed enhanced osteoblast functions in the presence of HA coated iron oxide nanoparticles, allowing their further investigation for a number of orthopedic applications.

Thermodynamic Size Control in Curvature-Frustrated Tubules: Self-Limitation with Open Boundaries.

We use computational modeling to investigate the assembly thermodynamics of a particle-based model for geometrically frustrated assembly, in which the local packing geometry of subunits is incompatible with uniform, strain-free large-scale assembly. The model considers discrete triangular subunits that drive assembly toward a closed, hexagonal-ordered tubule, but have geometries that locally favor negative Gaussian curvature. We use dynamical Monte Carlo simulations and enhanced sampling methods to compute the free energy landscape and corresponding self-assembly behavior as a function of experimentally accessible parameters that control assembly driving forces and the magnitude of frustration. The results determine the parameter range where finite-temperature self-limiting assembly occurs, in which the equilibrium assembly size distribution is sharply peaked around a well-defined finite size. The simulations also identify two mechanisms by which the system can escape frustration and assemble to unlimited size, and determine the particle-scale properties of subunits that suppress unbounded growth.

PIK3R1W624R Is an Actionable Mutation in High Grade Serous Ovarian Carcinoma.

Identifying cancer drivers and actionable mutations is critical for precision oncology. In epithelial ovarian cancer (EOC) the majority of mutations lack biological or clinical validation. We fully characterized 43 lines of Patient-Derived Xenografts (PDXs) and performed copy number analysis and whole exome sequencing of 12 lines derived from naïve, high grade EOCs. Pyrosequencing allowed quantifying mutations in the source tumours. Drug response was assayed on PDX Derived Tumour Cells (PDTCs) and in vivo on PDXs. We identified a PIK3R1W624R variant in PDXs from a high grade serous EOC. Allele frequencies of PIK3R1W624R in all the passaged PDXs and in samples of the source tumour suggested that it was truncal and thus possibly a driver mutation. After inconclusive results in silico analyses, PDTCs and PDXs allowed the showing actionability of PIK3R1W624R and addiction of PIK3R1W624R carrying cells to inhibitors of the PI3K/AKT/mTOR pathway. It is noteworthy that PIK3R1 encodes the p85α regulatory subunit of PI3K, that is very rarely mutated in EOC. The PIK3R1W624R mutation is located in the cSH2 domain of the p85α that has never been involved in oncogenesis. These data show that patient-derived models are irreplaceable in their role of unveiling unpredicted driver and actionable variants in advanced ovarian cancer.

Reflections on calling and careers in community psychology.

The current essay discusses the narratives of five community psychologists from the perspective of a career "calling." Each of the essays highlight different components of a calling: employing deep discernment to know the right path for oneself; experiencing a calling to do one's work, an invitation to which we choose to respond; serving community; discovering your quintessential self or "genius"; and using your gifts for the common good. Moreover, the author discusses how the essays not only illustrate calling, but also the emergence of confidence and the subjective career.

Phosphatized tungsten-metabolizing coccoid microbes interpreted from oil shale of an Eocene lake, Green River Formation, Utah, USA.

Microscopic globular structures have been observed in some beds of oil shale from eastern Utah. These beds comprise carbonate-dominated mud that is interlaminated with variably thick and continuous organic-rich layers. Collectively they are enriched in phosphorus, REEs, and actinides. The beds are considered of lacustrine origin and assigned to the Eocene Green River Formation. The globules themselves are of microcrystalline carbonate fluorapatite (µCFA), often contain concentric internal structures, and usually group together in clusters of up to 80, possibly more. Detailed SEM and microprobe analyses have revealed tungsten (W) to be almost exclusively associated with the globular clusters found within the more organic-rich laminae, often at concentrations of over 200 ppm, two orders of magnitude above shale standards. The globular structures are present in freshly cut sections where they occasionally grade into a µCFA matrix cement. This, together with the draping of the clusters by stringers of organic matter that would have accumulated in the Eocene lake, confirms that the structures are not a contaminant. The limited range of sizes and globular shapes is consistent with the morphology of coccoidal bacteria: Concentric internal structures may represent remnants of the nucleoid and cell wall. Paired concentric structures may indicate cell division (reproduction) processes were occurring until mineralization. The phosphate mineralization itself may have been promoted by release of phosphate from the stressed cells, bringing porewaters to supersaturation, or by the cells acting as nucleation sites. The recording of trace amounts of W almost exclusively in globular clusters preserved in the most organic-rich stringers (anoxia prone) further suggests facultative use of W-enzymes in a microbial metabolism. Combined, their context, morphology, and indication of biogenic process are strong evidence that the structures are fossilized (phosphatized) microbes, possibly sulfate-reducing bacteria, or methanogenic archaea.

How geometric frustration shapes twisted fibres, inside and out: competing morphologies of chiral filament assembly.

Chirality frustrates and shapes the assembly of flexible filaments in rope-like, twisted bundles and fibres by introducing gradients of both filament shape (i.e. curvature) and packing throughout the structure. Previous models of chiral filament bundle formation have shown that this frustration gives rise to several distinct morphological responses, including self-limiting bundle widths, anisotropic domain (tape-like) formation and topological defects in the lateral inter-filament order. In this paper, we employ a combination of continuum elasticity theory and discrete filament bundle simulations to explore how these distinct morphological responses compete in the broader phase diagram of chiral filament assembly. We show that the most generic model of bundle formation exhibits at least four classes of equilibrium structure-finite-width, twisted bundles with isotropic and anisotropic shapes, with and without topological defects, as well as bulk phases of untwisted, columnar assembly (i.e. 'frustration escape'). These competing equilibrium morphologies are selected by only a relatively small number of parameters describing filament assembly: bundle surface energy, preferred chiral twist and stiffness of chiral filament interactions, and mechanical stiffness of filaments and their lateral interactions. Discrete filament bundle simulations test and verify continuum theory predictions for dependence of bundle structure (shape, size and packing defects of two-dimensional cross section) on these key parameters.

Lubricin: a novel means to decrease bacterial adhesion and proliferation.

This study investigated the ability of lubricin (LUB) to prevent bacterial attachment and proliferation on model tissue culture polystyrene surfaces. The findings from this study indicated that LUB was able to reduce the attachment and growth of Staphylococcus aureus on tissue culture polystyrene over the course of 24 h by approximately 13.9% compared to a phosphate buffered saline (PBS)-soaked control. LUB also increased S. aureus lag time (the period of time between the introduction of bacteria to a new environment and their exponential growth) by approximately 27% compared to a PBS-soaked control. This study also indicated that vitronectin (VTN), a protein homologous to LUB, reduced bacterial S. aureus adhesion and growth on tissue culture polystyrene by approximately 11% compared to a PBS-soaked control. VTN also increased the lag time of S. aureus by approximately 43%, compared to a PBS-soaked control. Bovine submaxillary mucin was studied because there are similarities between it and the center mucin-like domain of LUB. Results showed that the reduction of S. aureus and Staphylococcus epidermidis proliferation on mucin coated surfaces was not as substantial as that seen with LUB. In summary, this study provided the first evidence that LUB reduced the initial adhesion and growth of both S. aureus and S. epidermidis on a model surface to suppress biofilm formation. These reductions in initial bacteria adhesion and proliferation can be beneficial for medical implants and, although requiring more study, can lead to drastically improved patient outcomes.

Vaginectomy with pelvic herniorrhaphy for prolapse.

OBJECTIVE: The study was undertaken to report our experience with vaginectomy and pelvic herniorrhaphy for vaginal prolapse. STUDY DESIGN: This was an observational study of patients undergoing vaginectomy (n=41) or hysterovaginectomy (n=13) for stage III/IV vaginal prolapse. Morbidity was compared with cohorts who had undergone transvaginal repair of prolapse, by using the Mann-Whitney U test. RESULTS: Morbidity did not differ significantly (estimated blood loss) between the vaginectomy and hysterovaginectomy groups. There were no recurrent hernias (6-56 months). Operative time, estimated blood loss, and day of discharge were significantly greater for the posthysterectomy prolapse group compared with the vaginectomy group. Operative time was significantly greater for the uterovaginal prolapse group versus the hysterovaginectomy group. CONCLUSIONS: Vaginectomy with or without hysterectomy with pelvic herniorrhaphy is associated with a low rate of morbidity in a high-risk patient population. Hysterovaginectomy is not associated with a clinically significant difference in morbidity over vaginectomy alone. Vaginectomy with or without hysterectomy should be offered as a surgical option to selected patients with severe genital prolapse.