Mark C. Greenwood

Carotenoid Pigmentation in Antarctic Heterotrophic Bacteria as a Strategy to Withstand Environmental Stresses

Abstract Bacterial strains isolated from Antarctic environments were used to assess the role of carotenoid pigments as cryo- and solar radiation protectants. Isolates were subjected to one hundred 12-hr freeze-thaw cycles and exposed to ambient simulated solar radiation (300 Wm−2) with growth recovery evaluated after pre-set time intervals. Differences in survival were observed between carotenoid pigmented and non-pigmented strains in response to the different stresses based upon the enumeration of colony forming units. On average carotenoid pigmented strains were more resistant to freeze-thaw cycles as compared to the non-pigmented strains. Survival for non-pigmented strains decreased precipitously from 2 × 107 to 1.5 × 104 cells mL−1, on average, within the first 20 cycles. Similar results were found in the solar radiation experiments. After 2 hrs of solar radiation exposure, 61% of the pigmented organisms survived versus 0.01% for the non-pigmented isolates. We applied an additive mixed model to estimate differences between the carotenoid pigmented and non-pigmented bacterial groups. Modeled results confirmed a positive effect of pigmentation on survivability and provide evidence that carotenoid pigmentation in heterotrophic bacteria isolated from Antarctic environments increases resistance to environmental stressors.

Cerebrospinal fluid markers reveal intrathecal inflammation in progressive multiple sclerosis.

The management of complex patients with neuroimmunological diseases is hindered by an inability to reliably measure intrathecal inflammation. Currently implemented laboratory tests developed >40 years ago either are not dynamic or fail to capture low levels of central nervous system (CNS) inflammation. Therefore, we aimed to identify and validate biomarkers of CNS inflammation in 2 blinded, prospectively acquired cohorts of untreated patients with neuroimmunological diseases and embedded controls, with the ultimate goal of developing clinically useful tools.

Object-oriented crop classification using multitemporal ETM+ SLC-off imagery and random forest

The utility of Enhanced Thematic Mapper Plus (ETM+) has been diminished since the 2003 scan-line corrector (SLC) failure. Uncorrected images have data gaps of approximately 22% and gap-filling schemes have been developed to improve their usability. We present a method to classify a northeast Montana agricultural landscape using ETM+ SLC-off imagery without gap-filling. We use multitemporal data analysis and employ an object-oriented approach to define objects, agricultural fields, with cadastral data. This approach was assessed by comparison to a pixel-based approach. Results indicate that an ETM+ SLC-off image can be classified with better than 85% overall accuracy without gap-filling.

Evidence for the effect of homes on wildfire suppression costs

This paper uses wildfires in the Sierra Nevada area of California to estimate the relationship between housing and fire suppression costs. We investigated whether the presence of homes was associated with increased costs of firefighting after controlling for the effects of potential confounding variables including fire size, weather, terrain and human factors such as road access. This paper investigates wildfires in a way that other published studies have not; we analysed costs at the daily level, retaining information that would have been lost had we aggregated the data. We used linear mixed models to estimate the effects of homes on daily costs while incorporating within-fire variation. We conclude that the expected increase in the log daily cost with each unit increase in the log count of homes within 6 miles (~9.7 km) of an active fire is 0.07 (P = 0.005). The findings of this study are in agreement with most other previous empirical studies that have investigated the relationship between fire suppression costs and housing using cumulative fire costs and more generalised data on home locations. The study adds to mounting evidence that increases in housing lead to increases in fire suppression costs. Language: en

When a habitat freezes solid: Microorganisms over-winter within the ice column of a coastal Antarctic lake

A major impediment to understanding the biology of microorganisms inhabiting Antarctic environments is the logistical constraint of conducting field work primarily during the summer season. However, organisms that persist throughout the year encounter severe environmental changes between seasons. In an attempt to bridge this gap, we collected ice core samples from Pony Lake in early November 2004 when the lake was frozen solid to its base, providing an archive for the biological and chemical processes that occurred during winter freezeup. The ice contained bacteria and virus-like particles, while flagellated algae and ciliates over-wintered in the form of inactive cysts and spores. Both bacteria and algae were metabolically active in the ice core melt water. Bacterial production ranged from 1.8 to 37.9 μg CL(-1) day(-1). Upon encountering favorable growth conditions in the melt water, primary production ranged from 51 to 931 μg CL(-1) day(-1). Because of the strong H(2) S odor and the presence of closely related anaerobic organisms assigned to Pony Lake bacterial 16S rRNA gene clones, we hypothesize that the microbial assemblage was strongly affected by oxygen gradients, which ultimately restricted the majority of phylotypes to distinct strata within the ice column. This study provides evidence that the microbial community over-winters in the ice column of Pony Lake and returns to a highly active metabolic state when spring melt is initiated.

Basal conditions and glacier motion during the winter/spring transition, Worthington Glacier, Alaska, U.S.A.

Observations of the motion and basal conditions of Worthington Glacier, Alaska, U.S.A., during late-winter and spring melt seasons revealed no evidence of relationship between water pressure and sliding velocity. Measurements included borehole water levels (used as a proxy for basal water pressure), surface velocity, englacial deformation, sliding velocity, and time-lapse videography of subglacial water flow and bed characteristics. The boreholes were spaced 10-15 m apart; six were instrumented in 1997, and five in 1998. In late winter, the water-pressure field showed spatially synchronous fluctuations with a diurnal cycle. The glaciers motion was relatively slow and non-cyclic. In spring, the motion was characterized by rapid, diurnally varying sliding. The basal water pressure displayed no diurnal signal, but showed high-magnitude fluctuations and often strong gradients between holes. This transition in character of the basal water-pressure field may represent a seasonal evolution of the drainage system from linked cavities to a network of isolated patches and conduits. These changes occurred as the glacier was undergoing a seasonal-velocity peak. The apparent lack of correlation between sliding velocity and water pressure suggests that local-scale water pressure does not directly control sliding during late winter or early in the melt season.

The logic of Simpson’s paradox

There are three distinct questions associated with Simpson’s paradox. (i) Why or in what sense is Simpson’s paradox a paradox? (ii) What is the proper analysis of the paradox? (iii) How one should proceed when confronted with a typical case of the paradox? We propose a “formal” answer to the first two questions which, among other things, includes deductive proofs for important theorems regarding Simpson’s paradox. Our account contrasts sharply with Pearl’s causal (and questionable) account of the first two questions. We argue that the “how to proceed question?” does not have a unique response, and that it depends on the context of the problem. We evaluate an objection to our account by comparing ours with Blyth’s account of the paradox. Our research on the paradox suggests that the “how to proceed question” needs to be divorced from what makes Simpson’s paradox “paradoxical.”

Functional Analysis of Variance for Association Studies

While progress has been made in identifying common genetic variants associated with human diseases, for most of common complex diseases, the identified genetic variants only account for a small proportion of heritability. Challenges remain in finding additional unknown genetic variants predisposing to complex diseases. With the advance in next-generation sequencing technologies, sequencing studies have become commonplace in genetic research. The ongoing exome-sequencing and whole-genome-sequencing studies generate a massive amount of sequencing variants and allow researchers to comprehensively investigate their role in human diseases. The discovery of new disease-associated variants can be enhanced by utilizing powerful and computationally efficient statistical methods. In this paper, we propose a functional analysis of variance (FANOVA) method for testing an association of sequence variants in a genomic region with a qualitative trait. The FANOVA has a number of advantages: (1) it tests for a joint effect of gene variants, including both common and rare; (2) it fully utilizes linkage disequilibrium and genetic position information; and (3) allows for either protective or risk-increasing causal variants. Through simulations, we show that FANOVA outperform two popularly used methods – SKAT and a previously proposed method based on functional linear models (FLM), – especially if a sample size of a study is small and/or sequence variants have low to moderate effects. We conduct an empirical study by applying three methods (FANOVA, SKAT and FLM) to sequencing data from Dallas Heart Study. While SKAT and FLM respectively detected ANGPTL 4 and ANGPTL 3 associated with obesity, FANOVA was able to identify both genes associated with obesity.

Development of a Sensitive Outcome for Economical Drug Screening for Progressive Multiple Sclerosis Treatment

Therapeutic advance in progressive multiple sclerosis (MS) has been very slow. Based on the transformative role magnetic resonance imaging (MRI) contrast-enhancing lesions had on drug development for relapsing-remitting MS, we consider the lack of sensitive outcomes to be the greatest barrier for developing new treatments for progressive MS. The purpose of this study was to compare 58 prospectively acquired candidate outcomes in the real-world situation of progressive MS trials to select and validate the best-performing outcome. The 1-year pre-treatment period of adaptively designed IPPoMS (ClinicalTrials.gov #NCT00950248) and RIVITaLISe (ClinicalTrials.gov #NCT01212094) Phase II trials served to determine the primary outcome for the subsequent blinded treatment phase by comparing 8 clinical, 1 electrophysiological, 1 optical coherence tomography, 7 MRI volumetric, 9 quantitative T1 MRI, and 32 diffusion tensor imaging MRI outcomes. Fifteen outcomes demonstrated significant progression over 1 year (Δ) in the predetermined analysis and seven out of these were validated in two independent cohorts. Validated MRI outcomes had limited correlations with clinical scales, relatively poor signal-to-noise ratios (SNR) and recorded overlapping values between healthy subjects and MS patients with moderate-severe disability. Clinical measures correlated better, even though each reflects a somewhat different disability domain. Therefore, using machine-learning techniques, we developed a combinatorial weight-adjusted disability score (CombiWISE) that integrates four clinical scales: expanded disability status scale (EDSS), Scripps neurological rating scale, 25 foot walk and 9 hole peg test. CombiWISE outperformed all clinical scales (Δ = 9.10%; p = 0.0003) and all MRI outcomes. CombiWISE recorded no overlapping values between healthy subjects and disabled MS patients, had high SNR, and predicted changes in EDSS in a longitudinal assessment of 98 progressive MS patients and in a cross-sectional cohort of 303 untreated subjects. One point change in EDSS corresponds on average to 7.50 point change in CombiWISE with a standard error of 0.10. The novel validated clinical outcome, CombiWISE, outperforms the current broadly utilized MRI brain atrophy outcome and more than doubles sensitivity in detecting clinical deterioration in progressive MS in comparison to the scale traditionally used for regulatory approval, EDSS.

Meta-analysis of the Age-Dependent Efficacy of Multiple Sclerosis Treatments

Objective To perform a meta-analysis of randomized, blinded, multiple sclerosis (MS) clinical trials, to test the hypothesis that efficacy of immunomodulatory disease-modifying therapies (DMTs) on MS disability progression is strongly dependent on age. Methods We performed a literature search with pre-defined criteria and extracted relevant features from 38 clinical trials that assessed efficacy of DMTs on disability progression. We fit a linear regression, weighted for trial sample size, and duration, to examine the hypothesis that age has a defining effect on the therapeutic efficacy of immunomodulatory DMTs. Results More than 28,000 MS subjects participating in trials of 13 categories of immunomodulatory drugs are included in the meta-analysis. The efficacy of immunomodulatory DMTs on MS disability strongly decreased with advancing age (R2 = 0.6757, p = 6.39e−09). Inclusion of baseline EDSS did not significantly improve the model. The regression predicts zero efficacy beyond approximately age 53 years. The comparative efficacy rank derived from the regression residuals differentiates high- and low-efficacy drugs. High-efficacy drugs outperform low-efficacy drugs in inhibiting MS disability only for patients younger than 40.5 years. Conclusion The meta-analysis supports the notion that progressive MS is simply a later stage of the MS disease process and that age is an essential modifier of a drug efficacy. Higher efficacy treatments exert their benefit over lower efficacy treatments only during early stages of MS, and, after age 53, the model suggests that there is no predicted benefit to receiving immunomodulatory DMTs for the average MS patient.