Divide-and-Conquer Monte Carlo Fusion

Combining several (sample approximations of) distributions, which we term sub-posteriors, into a single distribution proportional to their product, is a common challenge. For instance, in distributed `big data' problems, or when working under multi-party privacy constraints. Many existing approaches resort to approximating the individual sub-posteriors for practical necessity, then representing the resulting approximate posterior. The quality of the posterior approximation for these approaches is poor when the sub-posteriors fall out-with a narrow range of distributional form. Recently, a Fusion approach has been proposed which finds a direct and exact Monte Carlo approximation of the posterior (as opposed to the sub-posteriors), circumventing the drawbacks of approximate approaches. Unfortunately, existing Fusion approaches have a number of computational limitations, particularly when unifying a large number of sub-posteriors. In this paper, we generalise the theory underpinning existing Fusion approaches, and embed the resulting methodology within a recursive divide-and-conquer sequential Monte Carlo paradigm. This ultimately leads to a competitive Fusion approach, which is robust to increasing numbers of sub-posteriors.Comment: 24 pages, 8 figure

Acetylcholine Contributes to Head Direction Cell Stability During Path Integration and Landmark Navigation

Perceived directional heading is represented in the brain by head direction (HD) cells, which fire rapidly when the head is pointed in one direction and become virtually silent when the head is pointed in all other directions. The HD signal is dominantly controlled by the position of visual landmarks, but can be maintained by path integration when familiar landmarks are not available. The neural mechanism(s) that allow path integration to maintain the HD signal have not been investigated, but a possible component of this mechanism is acetylcholine, given that selective cholinergic lesions impair path integration-based navigation. To test this, we recorded HD cell activity from the anterodorsal thalamus while rats foraged for food within a cylinder, or navigated within a dual chamber apparatus, after systemic injection of saline or atropine sulfate. In the cylinder, a prominent cue card served as the sole landmark for a standard session, after which the cue was removed for a no-cue session. Saline or atropine sulfate was then injected, and a second no-cue session was conducted, followed by standard, 90° cue rotation, standard, and no-cue sessions. During the first no-cue session after injection, some cells in atropine-treated rats showed slightly more drift in preferred firing direction (PFD) than control cells, but otherwise appeared to be unaffected by atropine. With the cue rotated 90º, 10 of the 19 (53%) cells in atropine-treated rats and 12 of the 17 (71%) control cells shifted within ± 30° of 90º. In the dual chamber apparatus, rats walked from a familiar cylinder to a novel rectangle via an alleyway, and then returned to the familiar cylinder. Control HD cells (n = 7) showed a slight PFD shift as the rat entered the novel rectangle (mean absolute shift = 17.14 ± 3.80°, range = -30 to 12°), suggesting the HD signal was maintained relatively well between arenas by path integration; upon return, the PFD returned to that of the first session (mean absolute shift = 5.14 ± 1.56°, range = -12 to 6°). In contrast, 7 of the 9 HD cells in atropine-treated rats (78%) showed greater PFD shifts between the familiar cylinder and novel rectangle (mean absolute shift = 86.00 ± 12.17°, angular shift range = -102 to 114°) and between the first and last sessions in the familiar cylinder (mean absolute shift = 24.00 ± 10.16°, angular shift range = 0 to -72°); 2 of the 9 cells (22%) showed considerable PFD drift during the novel rectangle or return cylinder sessions. Thus, acetylcholine is not critical for normal HD cell activity within a familiar environment, but facilitates the stability of the HD signal during both path integration and landmark navigation

Toxicity Evaluation of Magnetic Hyperthermia Induced by Remote Actuation of Magnetic Nanoparticles in 3D Micrometastasic Tumor Tissue Analogs for Triple Negative Breast Cancer

Magnetic hyperthermia as a treatment modality is acquiring increased recognition for loco-regional therapy of primary and metastatic lung malignancies by pulmonary delivery of magnetic nanoparticles (MNP). The unique characteristic of magnetic nanoparticles to induce localized hyperthermia in the presence of an alternating magnetic field (AMF) allows for preferential killing of cells at the tumor site. In this study we demonstrate the effect of hyperthermia induced by low and high dose of MNP under the influence of an AMF using 3D tumor tissue analogs (TTA) representing the micrometastatic, perfusion independent stage of triple negative breast cancer (TNBC) that infiltrates the lungs. While application of inhalable magnetic nanocomposite microparticles (MnMs) to the micrometastatic TNBC model comprised of TTA generated from cancer and stromal cells, showed no measureable adverse effects in the absence of AMF-exposure, magnetic hyperthermia generated under the influence of an AMF in TTA incubated in a high concentration of MNP (1 mg/ mL) caused significant increase in cellular death/ damage with mechanical disintegration and release of cell debris indicating the potential of these inhalable composites as a promising approach for thermal treatment of diseased lungs. The novelty and significance of this study lies in the development of methods to evaluate in vitro the application of inhalable composites containing MNPs in thermal therapy using a physiologically relevant metastatic TNBC model representative of the microenvironmental characteristics in secondary lung malignancies

Microbiota-Produced N-Formyl Peptide fMLF Promotes Obesity-Induced Glucose Intolerance.

The composition of the gastrointestinal microbiota and associated metabolites changes dramatically with diet and the development of obesity. Although many correlations have been described, specific mechanistic links between these changes and glucose homeostasis remain to be defined. Here we show that blood and intestinal levels of the microbiota-produced N-formyl peptide, formyl-methionyl-leucyl-phenylalanine, are elevated in high-fat diet-induced obese mice. Genetic or pharmacological inhibition of the N-formyl peptide receptor Fpr1 leads to increased insulin levels and improved glucose tolerance, dependent upon glucagon-like peptide 1. Obese Fpr1 knockout mice also display an altered microbiome, exemplifying the dynamic relationship between host metabolism and microbiota. Overall, we describe a new mechanism by which the gut microbiota can modulate glucose metabolism, providing a potential approach for the treatment of metabolic disease

A picogram and nanometer scale photonic crystal opto-mechanical cavity

We describe the design, fabrication, and measurement of a cavity opto-mechanical system consisting of two nanobeams of silicon nitride in the near-field of each other, forming a so-called "zipper" cavity. A photonic crystal patterning is applied to the nanobeams to localize optical and mechanical energy to the same cubic-micron-scale volume. The picrogram-scale mass of the structure, along with the strong per-photon optical gradient force, results in a giant optical spring effect. In addition, a novel damping regime is explored in which the small heat capacity of the zipper cavity results in blue-detuned opto-mechanical damping.Comment: 15 pages, 4 figure

An enhanced CRISPR repressor for targeted mammalian gene regulation.

The RNA-guided endonuclease Cas9 can be converted into a programmable transcriptional repressor, but inefficiencies in target-gene silencing have limited its utility. Here we describe an improved Cas9 repressor based on the C-terminal fusion of a rationally designed bipartite repressor domain, KRAB-MeCP2, to nuclease-dead Cas9. We demonstrate the system's superiority in silencing coding and noncoding genes, simultaneously repressing a series of target genes, improving the results of single and dual guide RNA library screens, and enabling new architectures of synthetic genetic circuits

3D tumor tissue analogs and their orthotopic implants for understanding tumor-targeting of microenvironment-responsive nanosized chemotherapy and radiation

AbstractAn appropriate representation of the tumor microenvironment in tumor models can have a pronounced impact on directing combinatorial treatment strategies and cancer nanotherapeutics. The present study develops a novel 3D co-culture spheroid model (3D TNBC) incorporating tumor cells, endothelial cells and fibroblasts as color-coded murine tumor tissue analogs (TTA) to better represent the tumor milieu of triple negative breast cancer in vitro. Implantation of TTA orthotopically in nude mice, resulted in enhanced growth and aggressive metastasis to ectopic sites. Subsequently, the utility of the model is demonstrated for preferential targeting of irradiated tumor endothelial cells via radiation-induced stromal enrichment of galectin-1 using anginex conjugated nanoparticles (nanobins) carrying arsenic trioxide and cisplatin. Demonstration of a multimodal nanotherapeutic system and inclusion of the biological response to radiation using an in vitro/in vivo tumor model incorporating characteristics of tumor microenvironment presents an advance in preclinical evaluation of existing and novel cancer nanotherapies.From the Clinical EditorExisting in-vivo tumor models are established by implanting tumor cells into nude mice. Here, the authors described their approach 3D spheres containing tumor cells, enodothelial cells and fibroblasts. This would mimic tumor micro-environment more realistically. This interesting 3D model should reflect more accurately tumor response to various drugs and would enable the design of new treatment modalities

A consideration of the challenges involved in supervising international masters students

This paper explores the challenges facing supervisors of international postgraduate students at the dissertation stage of the masters programme. The central problems of time pressure, language difficulties, a lack of critical analysis and a prevalence of personal problems among international students are discussed. This paper makes recommendations for the improvement of language and critical thinking skills, and questions the future policy of language requirements at HE for international Masters students

Closing the gap on causal processes of infection risk from cross-sectional data:structural equation models to understand infection and co-infection

BACKGROUND: Epidemiological studies of disease exposure risk are frequently based on observational, cross-sectional data, and use statistical approaches as crucial tools for formalising causal processes and making predictions of exposure risks. However, an acknowledged limitation of traditional models is that the inferred relationships are correlational, cannot easily distinguish direct from indirect determinants of disease risk, and are often considerable simplifications of complex interrelationships. This may be particularly important when attempting to infer causality in patterns of co-infection through pathogen-facilitation. METHODS: We describe analyses of cross-sectional data using structural equation models (SEMs), a contemporary advancement on traditional regression approaches, based on our study system of feline gammaherpesvirus (FcaGHV1) in domestic cats. RESULTS: SEMs strongly supported a latent (host phenotype) variable associated with FcaGHV1 exposure and co-infection risk, suggesting these individuals are simply more likely to become infected with multiple pathogens. However, indications of pathogen-covariance (potential facilitation) were also variably detected: potentially among FcaGHV1, Bartonella spp and Mycoplasma spp. CONCLUSIONS: Our models suggest multiple exposures are primarily driven by host phenotypic traits, such as aggressive male phenotypes, and secondarily by pathogen-pathogen interactions. The results of this study demonstrate the application of SEMs to understanding epidemiological processes using observational data, and could be used more widely as a complementary tool to understand complex cross-sectional information in a wide variety of disciplines