Fast rates in statistical and online learning

The speed with which a learning algorithm converges as it is presented with more data is a central problem in machine learning --- a fast rate of convergence means less data is needed for the same level of performance. The pursuit of fast rates in online and statistical learning has led to the discovery of many conditions in learning theory under which fast learning is possible. We show that most of these conditions are special cases of a single, unifying condition, that comes in two forms: the central condition for 'proper' learning algorithms that always output a hypothesis in the given model, and stochastic mixability for online algorithms that may make predictions outside of the model. We show that under surprisingly weak assumptions both conditions are, in a certain sense, equivalent. The central condition has a re-interpretation in terms of convexity of a set of pseudoprobabilities, linking it to density estimation under misspecification. For bounded losses, we show how the central condition enables a direct proof of fast rates and we prove its equivalence to the Bernstein condition, itself a generalization of the Tsybakov margin condition, both of which have played a central role in obtaining fast rates in statistical learning. Yet, while the Bernstein condition is two-sided, the central condition is one-sided, making it more suitable to deal with unbounded losses. In its stochastic mixability form, our condition generalizes both a stochastic exp-concavity condition identified by Juditsky, Rigollet and Tsybakov and Vovk's notion of mixability. Our unifying conditions thus provide a substantial step towards a characterization of fast rates in statistical learning, similar to how classical mixability characterizes constant regret in the sequential prediction with expert advice setting.Comment: 69 pages, 3 figure

Non-parametric comparison of histogrammed two-dimensional data distributions using the Energy Test

When monitoring complex experiments, comparison is often made between regularly acquired histograms of data and reference histograms which represent the ideal state of the equipment. With the larger HEP experiments now ramping up, there is a need for automation of this task since the volume of comparisons could overwhelm human operators. However, the two-dimensional histogram comparison tools available in ROOT have been noted in the past to exhibit shortcomings. We discuss a newer comparison test for two-dimensional histograms, based on the Energy Test of Aslan and Zech, which provides more conclusive discrimination between histograms of data coming from different distributions than methods provided in a recent ROOT release.The Science and Technology Facilities Council, U

On a minimal model for estimating climate sensitivity

In a recent issue of this journal, Loehle (2014) presents a "minimal model" for estimating climate sensitivity, identical to that previously published by Loehle and Scafetta (2011). The novelty in the more recent paper lies in the straightforward calculation of an estimate of transient climate response based on the model and an estimate of equilibrium climate sensitivity derived therefrom, via a flawed methodology. We demonstrate that the Loehle and Scafetta model systematically underestimates the transient climate response, due to a number of unsupportable assumptions regarding the climate system. Once the flaws in Loehle and Scafetta's model are addressed, the estimates of transient climate response and equilibrium climate sensitivity derived from the model are entirely consistent with those obtained from general circulation models, and indeed exclude the possibility of low climate sensitivity, directly contradicting the principal conclusion drawn by Loehle. Further, we present an even more parsimonious model for estimating climate sensitivity. Our model is based on observed changes in radiative forcings, and is therefore constrained by physics, unlike the Loehle model, which is little more than a curve-fitting exercise

Lecture capture: Early lessons learned and experiences shared

Lecture capture has been on the minds of university level teachers for some time. The ability to record teaching sessions for delivery online has a number of potential impacts, not all of them positive. The technology now exists to make it feasible and relatively affordable to deliver entire lectures online. But should we do it just because we can? This article aims to share our experiences in recording a series of organic chemistry lectures, and the findings of the evaluation that followed

Stem Cell Differentiation and Effects of Three-Dimensional Cellular Microenvironments

The cellular microenvironment has been shown to play a fundamental role in the regulation of cell function, stem cell fate determination, maintenance of cell potency and tissue homeostasis. Our laboratory focuses on the study of the effects of cellular microenvironment in the context of cancer and neurological models, based on the observation that a healthy environment can induce the suppression of tumorigenesis in mouse models. Insights concerning the molecular mechanisms that drive these processes are very limited, partly due to the inability of the current traditional methods of investigation, such as two-dimensional cell cultures and animal models, to accurately represent the human in vivo cellular microenvironment. Three-dimensional cell cultures allow to overcome the structural limitations posed by monolayer cultures, and maintain the ease of experiment design, monitoring and data analysis associated with in vitro procedures. Our laboratory has established systems to overcome some of these limitations and rely on the strengths of three-dimensional culture methods to elucidate mechanisms that govern stem cell differentiation. A customized 3D extrusion-based bioprinter was developed starting from a commercially available model, allowing for precise and controlled injection of cells within three-dimensional substrates. This tool allows for design of highly controlled experiments, in which the effects of cellular microenvironment on stem cell differentiation can be studied at a single-cell resolution. For increased levels of biomimicry, tissue specific substrates are generated from extracted tissue. Collected tissue is subjected to a chemical decellularization process, followed by lyophilization, enzymatic digestion and neutralization, to generate a self-gelling product upon incubation at 37°C. Mammary and brain extracellularmatrix-derived substrates have been shown to support the growth of cells of the epithelial and neuronal lineages, respectively. Here, we apply these established systems to study the effects of the environment constituted by the three-dimensional substrates on the differentiation of injected stem cells.https://digitalcommons.odu.edu/engineering_batten/1016/thumbnail.jp

A Spectroscopic Survey of a Sample of Active M Dwarfs

A moderate resolution spectroscopic survey of Fleming's sample of 54 X-ray selected M dwarfs with photometric distances less than 25 pc is presented. Radial and rotation velocities have been measured by fits to the H-alpha profiles. Radial velocities have been measured by cross correlation. Artificial broadening of an observed spectrum has produced a relationship between H-alpha FWHM and rotation speed, which we use to infer rotation speeds for the entire sample by measurement of the H-alpha emission line. We find 3 ultra-fast rotators (UFRs, vsini > 100km/s), and 8 stars with 30 < vsini < 100 km/s. The UFRs have variable emission. Cross-correlation velocities measured for ultra-fast rotators (UFRs) are shown to depend on rotation speed and the filtering used. The radial velocity dispersion of the sample is 17 km/s. A new double emission line spectroscopic binary with a period of 3.55 days has been discovered, and another known one is in the sample. Three other objects are suspected spectroscopic binaries, and at least six are visual doubles. The only star in the sample observed to have significant lithium is a known TW Hya Association member, TWA 8A. These results show that there are a number of young (< 10^8 yr) and very young (< 10^7 yr) low mass stars in the immediate solar neighbourhood. The H-alpha activity strength does not depend on rotation speed. Our fast rotators are less luminous than similarly fast rotators in the Pleiades. They are either younger than the Pleiades, or gained angular momentum in a different way.Comment: 38 pages incl. 14 figures and 4 tables, plus 12 pages of table for electronic journal only; LaTeX, aastex.cls. Accepted 07/18/02 for publication in The Astronomical Journa

Accessible Bioprinting: Adaptation of a Low-Cost 3D-Printer for Precise Cell Placement and Stem Cell Differentiation

The precision and repeatability offered by computer-aided design and computer-numerically controlled techniques in biofabrication processes is quickly becoming an industry standard. However, many hurdles still exist before these techniques can be used in research laboratories for cellular and molecular biology applications. Extrusion-based bioprinting systems have been characterized by high development costs, injector clogging, difficulty achieving small cell number deposits, decreased cell viability, and altered cell function post-printing. To circumvent the high-price barrier to entry of conventional bioprinters, we designed and 3D printed components for the adaptation of an inexpensive \u27off-the-shelf\u27 commercially available 3D printer. We also demonstrate via goal based computer simulations that the needle geometries of conventional commercially standardized, \u27luer-lock\u27 syringe-needle systems cause many of the issues plaguing conventional bioprinters. To address these performance limitations we optimized flow within several microneedle geometries, which revealed a short tapered injector design with minimal cylindrical needle length was ideal to minimize cell strain and accretion. We then experimentally quantified these geometries using pulled glass microcapillary pipettes and our modified, low-cost 3D printer. This systems performance validated our models exhibiting: reduced clogging, single cell print resolution, and maintenance of cell viability without the use of a sacrificial vehicle. Using this system we show the successful printing of human induced pluripotent stem cells (hiPSCs) into Geltrex and note their retention of a pluripotent state 7 d post printing. We also show embryoid body differentiation of hiPSC by injection into differentiation conducive environments, wherein we observed continuous growth, emergence of various evaginations, and post-printing gene expression indicative of the presence of all three germ layers. These data demonstrate an accessible open-source 3D bioprinter capable of serving the needs of any laboratory interested in 3D cellular interactions and tissue engineering

Systems biology studies of adult Paragonimus lung flukes facilitate the identification of immunodominant parasite antigens

Paragonimiasis is a food-borne trematode infection acquired by eating raw or undercooked crustaceans. It is a major public health problem in the far East, but it also occurs in South Asia, Africa, and in the Americas. Paragonimus worms cause chronic lung disease with cough, fever and hemoptysis that can be confused with tuberculosis or other non-parasitic diseases. Treatment is straightforward, but diagnosis is often delayed due to a lack of reliable parasitological or serodiagnostic tests. Hence, the purpose of this study was to use a systems biology approach to identify key parasite proteins that may be useful for development of improved diagnostic tests.The transcriptome of adult Paragonimus kellicotti was sequenced with Illumina technology. Raw reads were pre-processed and assembled into 78,674 unique transcripts derived from 54,622 genetic loci, and 77,123 unique protein translations were predicted. A total of 2,555 predicted proteins (from 1,863 genetic loci) were verified by mass spectrometric analysis of total worm homogenate, including 63 proteins lacking homology to previously characterized sequences. Parasite proteins encoded by 321 transcripts (227 genetic loci) were reactive with antibodies from infected patients, as demonstrated by immunoaffinity purification and high-resolution liquid chromatography-mass spectrometry. Serodiagnostic candidates were prioritized based on several criteria, especially low conservation with proteins in other trematodes. Cysteine proteases, MFP6 proteins and myoglobins were abundant among the immunoreactive proteins, and these warrant further study as diagnostic candidates.The transcriptome, proteome and immunolome of adult P. kellicotti represent a major advance in the study of Paragonimus species. These data provide a powerful foundation for translational research to develop improved diagnostic tests. Similar integrated approaches may be useful for identifying novel targets for drugs and vaccines in the future

A 3D Bioprinter Platform for Mechanistic Analysis of Tumoroids and Chimeric Mammary Organoids

The normal mammary microenvironment can suppress tumorigenesis and redirect cancer cells to adopt a normal mammary epithelial cell fate in vivo. Understanding of this phenomenon offers great promise for novel treatment and detection strategies in cancer, but current model systems make mechanistic insights into the process difficult. We have recently described a low-cost bioprinting platform designed to be accessible for basic cell biology laboratories. Here we report the use of this system for the study of tumorigenesis and microenvironmental redirection of breast cancer cells. We show our bioprinter significantly increases tumoroid formation in 3D collagen gels and allows for precise generation of tumoroid arrays. We also demonstrate that we can mimic published in vivo findings by co-printing cancer cells along with normal mammary epithelial cells to generate chimeric organoids. These chimeric organoids contain cancer cells that take part in normal luminal formation. Furthermore, we show for the first time that cancer cells within chimeric structures have a significant increase in 5-hydroxymethylcytosine levels as compared to bioprinted tumoroids. These results demonstrate the capacity of our 3D bioprinting platform to study tumorigenesis and microenvironmental control of breast cancer and highlight a novel mechanistic insight into the process of microenvironmental control of cancer

Epigenetic Alterations Mediate iPSC Normalization of DNA-Repair Expression and TNR Stability in Huntington\u27s Disease

Huntington\u27s disease (HD) is a rare autosomal dominant neurodegenerative disorder caused by a cytosine-adenine-guanine (CAG) trinucleotide repeat (TNR) expansion within the HTT gene. The mechanisms underlying HD-associated cellular dysfunction in pluripotency and neurodevelopment are poorly understood. We had previously identified downregulation of selected DNA repair genes in HD fibroblasts relative to wild-type fibroblasts, as a result of promoter hypermethylation. Here, we tested the hypothesis that hypomethylation during cellular reprogramming to the induced pluripotent stem cell (iPSC) state leads to upregulation of DNA repair genes and stabilization of TNRs in HD cells. We sought to determine how the HD TNR region is affected by global epigenetic changes through cellular reprogramming and early neurodifferentiation. We find that early stage HD-affected neural stem cells (HD-NSCs) contain increased levels of global 5-hydroxymethylation (5-hmC) and normalized DNA repair gene expression. We confirm TNR stability is induced in iPSCs, and maintained in HD-NSCs. We also identify that upregulation of 5-hmC increases ten-eleven translocation 1 and 2 (TET1/2) protein levels, and show their knockdown leads to a corresponding decrease in the expression of select DNA repair genes. We further confirm decreased expression of TET1/2-regulating miR-29 family members in HD-NSCs. Our findings demonstrate that mechanisms associated with pluripotency induction lead to a recovery in the expression of select DNA repair gene and stabilize pathogenic TNRs in HD