Block copolymer self-assembly derived mesoporous magnetic materials with three-dimensionally (3D) co-continuous gyroid nanostructure.

Magnetic nanomaterials are gaining interest for their many applications in technological areas from information science and computing to next-generation quantum energy materials. While magnetic materials have historically been nanostructured through techniques such as lithography and molecular beam epitaxy, there has recently been growing interest in using soft matter self-assembly. In this work, a triblock terpolymer, poly(isoprene-block-styrene-block-ethylene oxide) (ISO), is used as a structure directing agent for aluminosilicate sol nanoparticles and magnetic material precursors to generate organic-inorganic bulk hybrid films with co-continuous morphology. After thermal processing into mesoporous materials, results from a combination of small angle X-ray scattering (SAXS) and scanning electron microscopy (SEM) are consistent with the double gyroid morphology. Nitrogen sorption measurements reveal a type IV isotherm with H1 hysteresis, and yield a specific surface area of around 200 m2 g-1 and an average pore size of 23 nm. The magnetization of the mesostructured material as a function of applied field shows magnetic hysteresis and coercivity at 300 K and 10 K. Comparison of magnetic measurements between the mesoporous gyroid and an unstructured bulk magnetic material, derived from the identical inorganic precursors, reveals the structured material exhibits a coercivity of 250 Oe, opposed to 148 Oe for the unstructured at 10 K, and presence of remnant magnetic moment not conventionally found in bulk hematite; both of these properties are attributed to the mesostructure. This scalable route to mesoporous magnetic materials with co-continuous morphologies from block copolymer self-assembly may provide a pathway to advanced magnetic nanomaterials with a range of potential applications.

The impact of traffic noise on the capitalization of public walking area: A hedonic analysis of Vienna, Austria.

Traffic noise is a burden at home and outdoors. Economic literature confirms mostly negative effects of traffic noise on house prices, often based on distance between high noise and house location. We extend this literature using rich micro data to examine not only the impact of traffic noise at the house but also provide new results on the impact of traffic noise in public areas surrounding a home. Using Hedonic regression in Vienna, Austria, we confirm that very loud traffic noise (≥65 dB) experienced at the house reduces housing prices and further show that the value of public walking areas near a home, while positive overall, are substantially reduced when exposed to noise. Our findings help to establish spatial patterns in noise capitalization reflecting household exposure and the impact on the capitalized values of public areas in a context where active transportation (e.g. walking, biking) is an important mode of transportation. For policymakers, our findings help quantify and raise important questions as how to address and link the public bad nature of noise pollution to nearby residents.

Addressing Particle Compositional Heterogeneities in Super-Resolution-Enhanced Live-Cell Ratiometric pH Sensing with Ultrasmall Fluorescent Core-Shell Aluminosilicate Nanoparticles.

The interrogation of metabolic parameters like pH in live-cell experiments using optical super-resolution microscopy (SRM) remains challenging. This is due to a paucity of appropriate metabolic probes enabling live-cell SRM-based sensing. Here we introduce ultrasmall fluorescent core-shell aluminosilicate nanoparticle sensors (FAM-ATTO647N aC' dots) that covalently encapsulate a reference dye (ATTO647N) in the core and a pH-sensing moiety (FAM) in the shell. Only the reference dye exhibits optical blinking enabling live-cell stochastic optical reconstruction microscopy (STORM). Using data from cells incubated for 60 minutes with FAM-ATTO647N aC' dots, pixelated information from total internal reflection fluorescence (TIRF) microscopy-based ratiometric sensing can be combined with that from STORM-based localizations via the blinking reference dye in order to enhance the resolution of ratiometric pH sensor maps beyond the optical diffraction limit. A nearest-neighbor interpolation methodology is developed to quantitatively address particle compositional heterogeneity as determined by separate single-particle fluorescence imaging methods. When combined with STORM-based estimates of the number of particles per vesicle, vesicle size, and vesicular motion as a whole, this analysis provides detailed live-cell spatial and functional information, paving the way to a comprehensive mapping and understanding of the spatiotemporal evolution of nanoparticle processing by cells important, e.g. for applications in nanomedicine.

Fluorescent Silica Nanoparticles to Label Metastatic Tumor Cells in Mineralized Bone Microenvironments.

During breast cancer bone metastasis, tumor cells interact with bone microenvironment components including inorganic minerals. Bone mineralization is a dynamic process and varies spatiotemporally as a function of cancer-promoting conditions such as age and diet. The functional relationship between skeletal dissemination of tumor cells and bone mineralization, however, is unclear. Standard histological analysis of bone metastasis frequently relies on prior demineralization of bone, while methods that maintain mineral are often harsh and damage fluorophores commonly used to label tumor cells. Here, fluorescent silica nanoparticles (SNPs) are introduced as a robust and versatile labeling strategy to analyze tumor cells within mineralized bone. SNP uptake and labeling efficiency of MDA-MB-231 breast cancer cells is characterized with cryo-scanning electron microscopy and different tissue processing methods. Using a 3D in vitro model of marrow-containing, mineralized bone as well as an in vivo model of bone metastasis, SNPs are demonstrated to allow visualization of labeled tumor cells in mineralized bone using various imaging modalities including widefield, confocal, and light sheet microscopy. This work suggests that SNPs are valuable tools to analyze tumor cells within mineralized bone using a broad range of bone processing and imaging techniques with the potential to increase the understanding of bone metastasis.

Innovation in COVID-19 Response: ANNA COVID-19 Surge Support Process and Map.

The COVID-19 pandemic began with uncertainty in how to care for patients and protect staff. The American Nephrology Nurses Association (ANNA) immediately recognized the need to provide its members and others in the nephrology community with as much information as possible. Resources were collected and disseminated in many forms (e.g., publications, webinars, virtual conference sessions). As COVID-19 surges began occurring across the country and staffing reached a crisis level, ANNA collaborated with other organizations to find potential solutions. One solution developed by ANNA was the ANNA COVID-19 Surge Support Process and Map - a process to connect the areas in high need with skilled and available staff. This article describes the ANNA COVID-19 Surge Support Process and Map, which has continued to help address COVID-19 staffing challenges.

High-birefringence direct UV-written waveguides for use as heralded single-photon sources at telecommunication wavelengths.

Direct UV-written waveguides are fabricated in silica-on-silicon with birefringence of (4.9 ± 0.2) × 10-4, much greater than previously reported in this platform. We show that these waveguides are suitable for the generation of heralded single photons at telecommunication wavelengths by spontaneous four-wave mixing. A pulsed pump field at 1060 nm generates pairs of photons in highly detuned, spectrally uncorrelated modes near 1550 nm and 800 nm. Waveguide-to-fiber coupling efficiencies of 78-91 % are achieved for all fields. Waveguide birefringence is controlled through dopant concentration of GeCl4 and BCl3 using the flame hydrolysis deposition process. The technology provides a route towards the scalability of silica-on-silicon integrated components for photonic quantum experiments.

Lymphomagenic CARD11/BCL10/MALT1 signaling drives malignant B-cell proliferation via cooperative NF-κB and JNK activation.

The aggressive activated B cell-like subtype of diffuse large B-cell lymphoma is characterized by aberrant B-cell receptor (BCR) signaling and constitutive nuclear factor kappa-B (NF-κB) activation, which is required for tumor cell survival. BCR-induced NF-κB activation requires caspase recruitment domain-containing protein 11 (CARD11), and CARD11 gain-of-function mutations are recurrently detected in human diffuse large B-cell lymphoma (DLBCL). To investigate the consequences of dysregulated CARD11 signaling in vivo, we generated mice that conditionally express the human DLBCL-derived CARD11(L225LI) mutant. Surprisingly, CARD11(L225LI) was sufficient to trigger aggressive B-cell lymphoproliferation, leading to early postnatal lethality. CARD11(L225LI) constitutively associated with B-cell CLL/lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1) to simultaneously activate the NF-κB and c-Jun N-terminal kinase (JNK) signaling cascades. Genetic deficiencies of either BCL10 or MALT1 completely rescued the phenotype, and pharmacological inhibition of JNK was, similar to NF-κB blockage, toxic to autonomously proliferating CARD11(L225LI)-expressing B cells. Moreover, constitutive JNK activity was observed in primary human activated B cell-like (ABC)-DLBCL specimens, and human ABC-DLBCL cells were also sensitive to JNK inhibitors. Thus, our results demonstrate that enforced activation of CARD11/BCL10/MALT1 signaling is sufficient to drive transformed B-cell expansion in vivo and identify the JNK pathway as a therapeutic target for ABC-DLBCL.

BET and HDAC inhibitors induce similar genes and biological effects and synergize to kill in Myc-induced murine lymphoma.

The bromodomain and extraterminal (BET) domain family of proteins binds to acetylated lysines on histones and regulates gene transcription. Recently, BET inhibitors (BETi) have been developed that show promise as potent anticancer drugs against various solid and hematological malignancies. Here we show that the structurally novel and orally bioavailable BET inhibitor RVX2135 inhibits proliferation and induces apoptosis of lymphoma cells arising in Myc-transgenic mice in vitro and in vivo. We find that BET inhibition exhibits broad transcriptional effects in Myc-transgenic lymphoma cells affecting many transcription factor networks. By examining the genes induced by BETi, which have largely been ignored to date, we discovered that these were similar to those induced by histone deacetylase inhibitors (HDACi). HDACi also induced cell-cycle arrest and cell death of Myc-induced murine lymphoma cells and synergized with BETi. Our data suggest that BETi sensitize Myc-overexpressing lymphoma cells partly by inducing HDAC-silenced genes, and suggest synergistic and therapeutic combinations by targeting the genetic link between BETi and HDACi.

Measurement-Induced Macroscopic Superposition States in Cavity Optomechanics.

A novel protocol for generating quantum superpositions of macroscopically distinct states of a bulk mechanical oscillator is proposed, compatible with existing optomechanical devices operating in the bad-cavity limit. By combining a pulsed optomechanical quantum nondemolition (QND) interaction with nonclassical optical resources and measurement-induced feedback, the need for strong single-photon coupling is avoided. We outline a three-pulse sequence of QND interactions encompassing squeezing-enhanced cooling by measurement, state preparation, and tomography.

Widely Tunable Morphologies in Block Copolymer Thin Films Through Solvent Vapor Annealing Using Mixtures of Selective Solvents.

Thin films of block copolymers are extremely attractive for nanofabrication because of their ability to form uniform and periodic nanoscale structures by microphase separation. One shortcoming of this approach is that to date the design of a desired equilibrium structure requires synthesis of a block copolymer de novo within the corresponding volume ratio of the blocks. In this work, we investigated solvent vapor annealing in supported thin films of poly(2-hydroxyethyl methacrylate)-block-poly(methyl methacrylate) [PHEMA-b-PMMA] by means of grazing incidence small angle X-ray scattering (GISAXS). A spin-coated thin film of lamellar block copolymer was solvent vapor annealed to induce microphase separation and improve the long-range order of the self-assembled pattern. Annealing in a mixture of solvent vapors using a controlled volume ratio of solvents (methanol, MeOH, and tetrahydrofuran, THF), which are chosen to be preferential for each block, enabled selective formation of ordered lamellae, gyroid, hexagonal or spherical morphologies from a single block copolymer with a fixed volume fraction. The selected microstructure was then kinetically trapped in the dry film by rapid drying. To our knowledge, this paper describes the first reported case where in-situ methods are used to study the transition of block copolymer films from one initial disordered morphology to four different ordered morphologies, covering much of the theoretical diblock copolymer phase diagram.

Integrated source of broadband quadrature squeezed light.

An integrated silicon nitride resonator is proposed as an ultra-compact source of bright single-mode quadrature squeezed light at 850 nm. Optical properties of the device are investigated and tailored through numerical simulations, with particular attention paid to loss associated with interfacing the device. An asymmetric double layer stack waveguide geometry with inverse vertical tapers is proposed for efficient and robust fibre-chip coupling, yielding a simulated total loss of -0.75 dB/facet. We assess the feasibility of the device through a full quantum noise analysis and derive the output squeezing spectrum for intra-cavity pump self-phase modulation. Subject to standard material loss and detection efficiencies, we find that the device holds promises for generating substantial quantum noise squeezing over a bandwidth exceeding 1 GHz. In the low-propagation loss regime, approximately -6 dB squeezing is predicted for a pump power of only 75 mW.

Overcoming Barriers Associated with Oral Delivery of Differently Sized Fluorescent Core-Shell Silica Nanoparticles.

Oral delivery, while a highly desirable form of nanoparticle-drug administration, is limited by challenges associated with overcoming several biological barriers. Here, the authors study how fluorescent and poly(ethylene glycol)-coated (PEGylated) core-shell silica nanoparticles sized 5 to 50 nm interact with major barriers including intestinal mucus, intestinal epithelium, and stomach acid. From imaging fluorescence correlation spectroscopy studies using quasi-total internal reflection fluorescence microscopy, diffusion of nanoparticles through highly scattering mucus is progressively hindered above a critical hydrodynamic size around 20 nm. By studying Caco-2 cell monolayers mimicking the intestinal epithelia, it is observed that ultrasmall nanoparticles below 10 nm diameter (Cornell prime dots, [C' dots]) show permeabilities correlated with high absorption in humans from primarily enhanced passive passage through tight junctions. Particles above 20 nm diameter exclusively show active transport through cells. After establishing C' dot stability in artificial gastric juice, in vivo oral gavage experiments in mice demonstrate successful passage through the body followed by renal clearance without protein corona formation. Results suggest C' dots as viable candidates for oral administration to patients with a proven pathway towards clinical translation and may generate renewed interest in examining silica as a food additive and its effects on nutrition and health.

Stromal pleiotrophin regulates repopulation behavior of hematopoietic stem cells.

Pleiotrophin (Ptn) is strongly expressed by stromal cells which maintain HSCs. However, in vivo, Ptn deficiency does not alter steady-state hematopoiesis. However, knockdown of Ptn (Ptn(KD)) in stromal cells increases production of hematopoietic progenitors as well as HSC activity in cocultures, suggesting that Ptn may have a role in HSC activation. Indeed, transplantations of wild-type (Ptn(+/+)) HSCs into Ptn(-/-) mice show increased donor cell production in serial transplantations and dominant myeloid regeneration caused by Ptn-dependent regulation of HSC repopulation behavior. This regulation of Lin(-)Kit(+)Sca1(+) function is associated with increased proliferation and, on a molecular level, with up-regulated expression of cyclin D1 (Ccnd1) and C/EBPα (Cepba), but reduced of PPARγ. The known HSC regulator ß-catenin is, however, not altered in the absence of Ptn. In conclusion, our results point to different Ptn-mediated regulatory mechanisms in normal hemostasis and in hematopoietic regeneration and in maintaining the balance of myeloid and lymphoid regeneration. Moreover, our results support the idea that microenvironmental Ptn regulates hematopoietic regeneration through ß-catenin-independent regulation of Ccnd1 and Cebpa.

Quantum-enhanced micromechanical displacement sensitivity.

We report on a hitherto unexplored application of squeezed light: for quantum-enhancement of mechanical transduction sensitivity in microcavity optomechanics. Using a toroidal silica microcavity, we experimentally demonstrate measurement of the transduced phase modulation signal in the frequency range 4-5.8 MHz with a sensitivity -0.72(±0.01) dB below the shot noise level. This is achieved for resonant probing in the highly undercoupled regime, by preparing the probe in a weak coherent state with phase squeezed vacuum states at sideband frequencies.

Targeting ornithine decarboxylase in Myc-induced lymphomagenesis prevents tumor formation.

Checkpoints that control Myc-mediated proliferation and apoptosis are bypassed during tumorigenesis. Genes encoding polyamine biosynthetic enzymes are overexpressed in B cells from E mu-Myc transgenic mice. Here, we report that disabling one of these Myc targets, Ornithine decarboxylase (Odc), abolishes Myc-induced suppression of the Cdk inhibitors p21(Cip1) and p27(Kip1), thereby impairing Myc's proliferative, but not apoptotic, response. Moreover, lymphoma development was markedly delayed in E mu-Myc;Odc(+/-) transgenic mice and in E mu-Myc mice treated with the Odc inhibitor difluoromethylornithine (DFMO). Strikingly, tumors ultimately arising in E mu-Myc;Odc(+/-) transgenics lacked deletions of Arf, suggesting that targeting Odc forces other routes of transformation. Therefore, Odc is a critical Myc transcription target that regulates checkpoints that guard against tumorigenesis and is an effective target for cancer chemoprevention.

Non-Equilibrium Block Copolymer Self-Assembly Based Porous Membrane Formation Processes Employing Multicomponent Systems.

Porous polymer-derived membranes are useful for applications ranging from filtration and separation technologies to energy storage and conversion. Combining block copolymer (BCP) self-assembly with the industrially scalable, non-equilibrium phase inversion technique (SNIPS) yields membranes comprising periodically ordered top surface structures supported by asymmetric, hierarchical substructures that together overcome performance tradeoffs typically faced by materials derived from equilibrium approaches. This review first reports on recent advances in understanding the top surface structural evolution of a model SNIPS-derived system during standard membrane formation. Subsequently, the application of SNIPS to multicomponent systems is described, enabling pore size modulation, chemical modification, and transformation to non-polymeric materials classes without compromising the structural features that define SNIPS membranes. Perspectives on future directions of both single-component and multicomponent membrane materials are provided. This points to a rich and fertile ground for the study of fundamental as well as applied problems using non-equilibrium-derived asymmetric porous materials with tunable chemistry, composition, and structure.

Intravital imaging of osteocyte integrin dynamics with locally injectable fluorescent nanoparticles.

Osteocytes are the resident mechanosensory cells in bone. They are responsible for skeletal homeostasis and adaptation to mechanical cues. Integrin proteins play a prominent role in osteocyte mechanotransduction, but the details are not well stratified. Intravital imaging with multiphoton microscopy presents an opportunity to study molecular level mechanobiological events in vivo and presents an opportunity to study integrin dynamics in osteocytes. However, fluorescent imaging limitations with respect to excessive optical scattering and low signal to noise ratio caused by mineralized bone matrix make such investigations non-trivial. Here, we demonstrate that ultra-small and bright fluorescent core-shell silica nanoparticles (<7 nm diameter), known as Cornell Prime Dots (C'Dots), are well-suited for the in vivo bone microenvironment and can improve intravital imaging capabilities. We report validation studies for C'Dots as a novel, locally injectable in vivo osteocyte imaging tool for both non-specific cellular uptake and for targeting integrins. The pharmacokinetics of C'Dots reveal distinct sex differences in nanoparticle intracellular dynamics and clearance in osteocytes, which represents a novel topic of study in bone biology. Integrin-targeted C'Dots were used to study osteocyte integrin dynamics. To the best of our knowledge, we report here the first evidence of osteocyte integrin endocytosis and recycling in vivo. Our results provide novel insights in osteocyte biology and will open up new lines of investigation that were previously unavailable in vivo.

Directed Self-Assembly of Diamond Networks in Triblock Terpolymer Films on Patterned Substrates.

Block copolymers (BCPs) are particularly effective in creating soft nanostructured templates for transferring complex 3D network structures into inorganic materials that are difficult to fabricate by other methods. However, achieving control of the local ordering within these 3D networks over large areas remains a significant obstacle to advancing material properties. Here, we address this challenge by directing the self-assembly of a 3D alternating diamond morphology by solvent vapor annealing of a triblock terpolymer film on a chemically patterned substrate. The hexagonal substrate patterns were designed to match a (111) plane of the diamond lattice. Commensurability between the sparse substrate pattern and the BCP lattice produced a uniformly ordered diamond network within the polymer film, as confirmed by a combination of atomic force microscopy and cross-sectional imaging using focused ion beam scanning electron microscopy. The successful replication of the complex and well-ordered 3D network structure in gold promises to advance optical metamaterials and has potential applications in nanophotonics.

Radiation and Dose-densification of R-CHOP in Aggressive B-cell Lymphoma With Intermediate Prognosis: The UNFOLDER Study.

UNFOLDER (Unfavorable Young Low-Risk Densification of R-Chemo Regimens) is an international phase-3 trial in patients 18-60 years with aggressive B-cell lymphoma and intermediate prognosis defined by age-adjusted International Prognostic Index (aaIPI) of 0 and bulky disease (≥7.5 cm) or aaIPI of 1. In a 2 × 2 factorial design patients were randomized to 6× R-CHOP-14 or 6× R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prediso[lo]ne) and to consolidation radiotherapy to extralymphatic and bulky disease or observation. Response was assessed according to the standardized response criteria published in 1999, not including F-18 fluordesoxyglucose positron emission tomography/computed tomography (FDG-PET). Primary endpoint was event-free survival (EFS). A total of 695 of 700 patients were eligible for the intention-to-treat analysis. Totally 467 patients qualified for radiotherapy of whom 305 patients were randomized to receive radiotherapy (R-CHOP-21: 155; R-CHOP-14: 150) and 162 to observation (R-CHOP-21: 81, R-CHOP-14: 81). Two hundred twenty-eight patients not qualifying for radiotherapy were randomized for R-CHOP-14 versus R-CHOP-21. After a median observation of 66 months 3-year EFS was superior in the radiotherapy-arm versus observation-arm (84% versus 68%; P = 0.0012), due to a lower rate of partial responses (PR) (2% versus 11%). PR often triggered additional treatment, mostly radiotherapy. No significant difference was observed in progression-free survival (PFS) (89% versus 81%; P = 0.22) and overall survival (OS) (93% versus 93%; P = 0.51). Comparing R-CHOP-14 and R-CHOP-21 EFS, PFS and OS were not different. Patients randomized to radiotherapy had a superior EFS, largely due to a lower PR rate requiring less additional treatment (NCT00278408, EUDRACT 2005-005218-19).

Imaging polyatomic molecules in three dimensions using molecular frame photoelectron angular distributions.

We demonstrate a method for determining the full three-dimensional molecular-frame photoelectron angular distribution in polyatomic molecules using methane as a prototype. Simultaneous double Auger decay and subsequent dissociation allow measurement of the initial momentum vectors of the ionic fragments and the photoelectron in coincidence, allowing full orientation by observing a three-ion decay pathway, (H+, H+, CH2(+)). We find the striking result that at low photoelectron energies the molecule is effectively imaged by the focusing of photoelectrons along bond directions.