Implementation of an efficient Bayesian search for gravitational wave bursts with memory in pulsar timing array data

The standard Bayesian technique for searching pulsar timing data for gravitational wave (GW) bursts with memory (BWMs) using Markov Chain Monte Carlo (MCMC) sampling is very computationally expensive to perform. In this paper, we explain the implementation of an efficient Bayesian technique for searching for BWMs. This technique makes use of the fact that the signal model for Earth-term BWMs (BWMs passing over the Earth) is fully factorizable. We estimate that this implementation reduces the computational complexity by a factor of 100. We also demonstrate that this technique gives upper limits consistent with published results using the standard Bayesian technique, and may be used to perform all of the same analyses that standard MCMC techniques can perform.Comment: 19 pages, 3 figures, 1 table. Submitted to Astrophysical Journa

Incorporating chemical signalling factors into cell-based models of growing epithelial tissues

In this paper we present a comprehensive computational framework within which the effects of chemical signalling factors on growing epithelial tissues can be studied. The method incorporates a vertex-based cell model, in conjunction with a solver for the governing chemical equations. The vertex model provides a natural mesh for the finite element method (FEM), with node movements determined by force laws. The arbitrary Lagrangian–Eulerian formulation is adopted to account for domain movement between iterations. The effects of cell proliferation and junctional rearrangements on the mesh are also examined. By implementing refinements of the mesh we show that the finite element (FE) approximation converges towards an accurate numerical solution. The potential utility of the system is demonstrated in the context of Decapentaplegic (Dpp), a morphogen which plays a crucial role in development of the Drosophila imaginal wing disc. Despite the presence of a Dpp gradient, growth is uniform across the wing disc. We make the growth rate of cells dependent on Dpp concentration and show that the number of proliferation events increases in regions of high concentration. This allows hypotheses regarding mechanisms of growth control to be rigorously tested. The method we describe may be adapted to a range of potential application areas, and to other cell-based models with designated node movements, to accurately probe the role of morphogens in epithelial tissues

Near-Earth injection of MeV electrons associated with intense dipolarization electric fields: Van Allen Probes observations.

Substorms generally inject tens to hundreds of keV electrons, but intense substorm electric fields have been shown to inject MeV electrons as well. An intriguing question is whether such MeVelectron injections can populate the outer radiation belt. Here we present observations of a substorm injection of MeV electrons into the inner magnetosphere. In the premidnight sector at L ∼ 5.5, Van Allen Probes (Radiation Belt Storm Probes)-A observed a large dipolarization electric field (50 mV/m) over ∼40 s and a dispersionless injection of electrons up to ∼3 MeV. Pitch angle observations indicated betatron acceleration of MeV electrons at the dipolarization front. Corresponding signals of MeV electron injection were observed at LANL-GEO, THEMIS-D, and GOES at geosynchronous altitude. Through a series of dipolarizations, the injections increased the MeV electron phase space density by 1 order of magnitude in less than 3 h in the outer radiation belt (L > 4.8). Our observations provide evidence that deep injections can supply significant MeV electrons

Natural History of Experimental Coronary Atherosclerosis and Vascular Remodeling in Relation to Endothelial Shear Stress

Author Manuscript: 2011 May 18.Background— The natural history of heterogeneous atherosclerotic plaques and the role of local hemodynamic factors throughout their development are unknown. We performed a serial study to assess the role of endothelial shear stress (ESS) and vascular remodeling in the natural history of coronary atherosclerosis. Methods and Results— Intravascular ultrasound-based 3-dimensional reconstruction of all major coronary arteries (n=15) was performed serially in vivo in 5 swine 4, 11, 16, 23, and 36 weeks after induction of diabetes mellitus and hyperlipidemia. The reconstructed arteries were divided into 3-mm-long segments (n=304). ESS was calculated in all segments at all time points through the use of computational fluid dynamics. Vascular remodeling was assessed at each time point in all segments containing significant plaque, defined as maximal intima-media thickness ≥0.5 mm, at week 36 (n=220). Plaque started to develop at week 11 and progressively advanced toward heterogeneous, multifocal lesions at all subsequent time points. Low ESS promoted the initiation and subsequent progression of plaques. The local remodeling response changed substantially over time and determined future plaque evolution. Excessive expansive remodeling developed in regions of very low ESS, further exacerbated the low ESS, and was associated with the most marked plaque progression. The combined assessment of ESS, remodeling, and plaque severity enabled the early identification of plaques that evolved to high-risk lesions at week 36. Conclusions— The synergistic effect of local ESS and the remodeling response to plaque formation determine the natural history of individual lesions. Combined in vivo assessment of ESS and remodeling may predict the focal formation of high-risk coronary plaque

Biogenesis of Influenza A Virus Hemagglutinin Cross-Protective Stem Epitopes

Antigenic variation in the globular domain of influenza A virus (IAV) hemagglutinin (HA) precludes effective immunity to this major human pathogen. Although the HA stem is highly conserved between influenza virus strains, HA stem-reactive antibodies (StRAbs) were long considered biologically inert. It is now clear, however, that StRAbs reduce viral replication in animal models and protect against pathogenicity and death, supporting the potential of HA stem-based immunogens as drift-resistant vaccines. Optimally designing StRAb-inducing immunogens and understanding StRAb effector functions require thorough comprehension of HA stem structure and antigenicity. Here, we study the biogenesis of HA stem epitopes recognized in cells infected with various drifted IAV H1N1 strains using mouse and human StRAbs. Using a novel immunofluorescence (IF)-based assay, we find that human StRAbs bind monomeric HA in the endoplasmic reticulum (ER) and trimerized HA in the Golgi complex (GC) with similar high avidity, potentially good news for producing effective monomeric HA stem immunogens. Though HA stem epitopes are nestled among several N-linked oligosaccharides, glycosylation is not required for full antigenicity. Rather, as N-linked glycans increase in size during intracellular transport of HA through the GC, StRAb binding becomes temperature-sensitive, binding poorly to HA at 4°C and well at 37°C. A de novo designed, 65-residue protein binds the mature HA stem independently of temperature, consistent with a lack of N-linked oligosaccharide steric hindrance due to its small size. Likewise, StRAbs bind recombinant HA carrying simple N-linked glycans in a temperature-independent manner. Chemical cross-linking experiments show that N-linked oligosaccharides likely influence StRAb binding by direct local effects rather than by globally modifying the conformational flexibility of HA. Our findings indicate that StRAb binding to HA is precarious, raising the possibility that sufficient immune pressure on the HA stem region could select for viral escape mutants with increased steric hindrance from N-linked glycans.</p

The metabolome regulates the epigenetic landscape during naive-to-primed human embryonic stem cell transition.

For nearly a century developmental biologists have recognized that cells from embryos can differ in their potential to differentiate into distinct cell types. Recently, it has been recognized that embryonic stem cells derived from both mice and humans exhibit two stable yet epigenetically distinct states of pluripotency: naive and primed. We now show that nicotinamide N-methyltransferase (NNMT) and the metabolic state regulate pluripotency in human embryonic stem cells (hESCs).  Specifically, in naive hESCs, NNMT and its enzymatic product 1-methylnicotinamide are highly upregulated, and NNMT is required for low S-adenosyl methionine (SAM) levels and the H3K27me3 repressive state. NNMT consumes SAM in naive cells, making it unavailable for histone methylation that represses Wnt and activates the HIF pathway in primed hESCs. These data support the hypothesis that the metabolome regulates the epigenetic landscape of the earliest steps in human development

A tunable delivery platform to provide local chemotherapy for pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the most devastating and painful cancers. It is often highly resistant to therapy owing to inherent chemoresistance and the desmoplastic response that creates a barrier of fibrous tissue preventing transport of chemotherapeutics into the tumor. The growth of the tumor in pancreatic cancer often leads to invasion of other organs and partial or complete biliary obstruction, inducing intense pain for patients and necessitating tumor resection or repeated stenting. Here, we have developed a delivery device to provide enhanced palliative therapy for pancreatic cancer patients by providing high concentrations of chemotherapeutic compounds locally at the tumor site. This treatment could reduce the need for repeated procedures in advanced PDAC patients to debulk the tumor mass or stent the obstructed bile duct. To facilitate clinical translation, we created the device out of currently approved materials and drugs. We engineered an implantable poly(lactic-co-glycolic)-based biodegradable device that is able to linearly release high doses of chemotherapeutic drugs for up to 60 days. We created five patient-derived PDAC cell lines and tested their sensitivity to approved chemotherapeutic compounds. These in vitro experiments showed that paclitaxel was the most effective single agent across all cell lines. We compared the efficacy of systemic and local paclitaxel therapy on the patient-derived cell lines in an orthotopic xenograft model in mice (PDX). In this model, we found up to a 12-fold increase in suppression of tumor growth by local therapy in comparison to systemic administration and reduce retention into off-target organs. Herein, we highlight the efficacy of a local therapeutic approach to overcome PDAC chemoresistance and reduce the need for repeated interventions and biliary obstruction by preventing local tumor growth. Our results underscore the urgent need for an implantable drug-eluting platform to deliver cytotoxic agents directly within the tumor mass as a novel therapeutic strategy for patients with pancreatic cancer. Keywords: Pancreatic cancer; Chemoresistance; Local delivery; Patient-derived xenograft; Paclitaxel; Poly(lactic-co-glycolic acid)National Institutes of Health (U.S.) (Grant P30-CA14051

Integrating the digital and the traditional to deliver therapy for depression:lessons from a pragmatic study

Traditional approaches to psychotherapy emphasise face-to-face contact between patients and therapists. In contrast, current computerised approaches tend to minimise this contact. This can limit the range of mental health difficulties for which computerised approaches are effective. Here, we explore an alternative approach that integrates face-to-face contact, electronic contact, online collaboration, and support for between-session activities. Our discussion is grounded in the design of a platform to deliver psychotherapy for depression. We report findings of an 11-month pragmatic study in which 17 patients received treatment for depression via the platform. Results show how design decisions had a significant impact on the dynamics of therapeutic sessions and the establishment of patient-therapist relationships. For example, the use of instant messaging for synchronous, in-session contact slowed communication, but also provided a valuable space for reflection and helped to maintain session focus. We discuss the impact of flexibility and the potential of integrated approaches to both enhance and reduce patient engagement

Infrared based saliva screening test for COVID-19

Abstract: Severe acute respiratory syndrome coronavirus 2 has resulted in an unprecedented need for diagnostic testing that is critical in controlling the spread of COVID-19. We propose a portable infrared spectrometer with purpose-built transflection accessory for rapid point-of-care detection of COVID-19 markers in saliva. Initially, purified virion particles were characterized with Raman spectroscopy, synchrotron infrared (IR) and AFM-IR. A data set comprising 171 transflection infrared spectra from 29 patients testing positive for SARS-CoV-2 by RT-qPCR and 28 testing negative, was modeled using Monte Carlo Double Cross Validation with 50 randomized test and model sets. The testing sensitivity was 93 % (27/29) with a specificity of 82 % (23/28) that included positive samples on the limit of detection for RT-qPCR. Here, we demonstrate a proof-of-concept high throughput infrared COVID-19 test that is rapid, inexpensive, portable and utilizes sample self-collection thus minimizing the risk to healthcare workers and ideally suited to mass screening