IDENTIFICATION OF FUNCTIONAL DOMAINS IN NON-CODING RNA

Long non-coding RNAs (lncRNAs) are known to be important regulators of gene expres- sion and other cellular functions. However, only a very small proportion of lncRNAs have been extensively studied. The remainder exist largely as annotations in a database with no known function, if any. A primary challenge to understanding how lncRNAs function is the poorly understood sequence-to-function relationship relative to protein coding genes. Within lncRNA transcripts, boundaries of functional sequence are not explicitly defined by exon-intron boundaries, and the code by which lncRNAs derive function is not nearly as explicit as in a protein coding reading frame. To address these challenges, we have de- veloped a probabilistic framework, hmmSEEKR, for identifying where within a non-coding RNA functional regions may be located based off of enrichment of short motifs, or k-mers. We used hmmSEEKR to identify functional sequence domains in several lncRNAs that silence gene expression through recruitment of Polycomb, using XIST as a model tran- script. These predicted sequence domains share no detectable linear sequence alignment with XIST; however, they share high k-mer based similarity with known functional do- mains in XIST and precisely coincided with the location of RNA binding protein (RBP) interactions known to be important for Polycomb mediated silencing. Furthermore, we were able to extend our analysis to the entire transcriptome and identify many XIST-like sequence domains throughout the transcriptome that interact with Polycomb-associated RBPs. We have packaged these algorithms into python-based software and have included an in-depth walk-through of the code and tutorial of how to analyze sequences using hmm- SEEKR.Doctor of Philosoph

Modelling health behaviour

Many diseases can be prevented or mitigated through behaviour change, but we lack a quantitative model that can accurately predict these changes and inform policies designed to promote them. Here we introduce a quantitative model of health behaviour that takes into account individual-level barriers, the health system, and spread between individuals. We investigate limits of the model where each of these determining factors is dominant, and use them to predict behaviour from data. We apply the model to individual-level geographic barriers to mothers giving birth in a health facility, and find evidence that ease-of-access is a major determinant of delivery location. The geographic barriers allow us to explain the observed spatial distribution of this behaviour, and to accurately predict low prevalence regions. We then apply the model to the role of the health system in determining health facility usage by mothers of sick children. We show that local health facility quality does predict usage, but that this predictive power is significantly less than that gained by including unaccounted-for spatial correlation such as social influence. We also show evidence that results-based funding, rather than traditional input-based funding, increases usage. We develop a psychologically-motivated ‘complex contagion’ model for social influence and incorporate it into a general model of behaviour spread. We apply this model to short-lived behavioural fads, and show that ‘nudges’ can be very effective in systems with social influence. We successfully fit the model to data for the online spread of real-world behaviour, and use it to predict the peak time and duration of a fad before the peak occurred. Finally, we discuss ways to incorporate disease state into the model, and to relax the limits used in the rest of the thesis. We consider a model which links health behaviour to disease, and show that complex contagion leads to a feature that is not present in traditional models of disease: the survival of an epidemic depends non-trivially on the initial fraction of the population that is infected. We then introduce two possible models that include both social influence and an inhomogeneous population, and discuss the type of data that might be required to use them predictively. The model introduced here can be used to understand and predict health behaviours, and we therefore believe that it provides a valuable tool for informing policies to combat disease

Sucroferric oxyhydroxide for hyperphosphatemia: A review of real-world evidence

Hyperphosphatemia is a common complication in dialysis-dependent patients with chronic kidney disease. Most dialysis-dependent patients need oral phosphate binder therapy to control serum phosphorus concentrations. Most phosphate binders have a high daily pill burden, which may reduce treatment adherence and impair phosphorus control. Sucroferric oxyhydroxide is a potent iron-based phosphate binder approved for use in dialysis-dependent patients in 2013. A randomized controlled trial of sucroferric oxyhydroxide demonstrated its efficacy for reduction of serum phosphorus with a lower pill burden than sevelamer carbonate. Clinical trials carefully select patients, monitor adherence, and routinely titrate medications to a protocol-defined goal. Consequently, trials may not reflect real-world use of medications. Since its approval, we and others have performed retrospective and prospective analyses of sucroferric oxyhydroxide in real-world clinical practice in \u3e 6400 hemodialysis and approximately 500 peritoneal dialysis patients in the USA and Europe. Consistent with the clinical trial data, real-world observational studies have demonstrated that sucroferric oxyhydroxide can effectively reduce serum phosphorus with a lower daily pill burden than most other phosphate binders. These studies have also shown sucroferric oxyhydroxide provides effective serum phosphorus control in different treatment settings, including as monotherapy in phosphate binder-naïve patients, in patients switching from other phosphate binders, or when used in combination with other phosphate binders. These observational studies indicate a favorable safety and tolerability profile, and minimal, if any, systemic iron absorption. This article reviews the key results from these observational studies of sucroferric oxyhydroxide and evaluates its role in the management of hyperphosphatemia in clinical practice

Molecular analysis of endocrine disruption in hornyhead turbot at wastewater outfalls in southern california using a second generation multi-species microarray.

Sentinel fish hornyhead turbot (Pleuronichthysverticalis) captured near wastewater outfalls are used for monitoring exposure to industrial and agricultural chemicals of ~ 20 million people living in coastal Southern California. Although analyses of hormones in blood and organ morphology and histology are useful for assessing contaminant exposure, there is a need for quantitative and sensitive molecular measurements, since contaminants of emerging concern are known to produce subtle effects. We developed a second generation multi-species microarray with expanded content and sensitivity to investigate endocrine disruption in turbot captured near wastewater outfalls in San Diego, Orange County and Los Angeles California. Analysis of expression of genes involved in hormone [e.g., estrogen, androgen, thyroid] responses and xenobiotic metabolism in turbot livers was correlated with a series of phenotypic end points. Molecular analyses of turbot livers uncovered altered expression of vitellogenin and zona pellucida protein, indicating exposure to one or more estrogenic chemicals, as well as, alterations in cytochrome P450 (CYP) 1A, CYP3A and glutathione S-transferase-α indicating induction of the detoxification response. Molecular responses indicative of exposure to endocrine disruptors were observed in field-caught hornyhead turbot captured in Southern California demonstrating the utility of molecular methods for monitoring environmental chemicals in wastewater outfalls. Moreover, this approach can be adapted to monitor other sites for contaminants of emerging concern in other fish species for which there are few available gene sequences

TRP drop, TRP drop: a steady patter of anti-schistosomal target illumination

Infections caused by parasitic flatworms impart a significant disease burden. This is well exemplified by the neglected tropical disease schistosomiasis, which afflicts millions of people worldwide. The anti-schistosomal activity of various chemotypes has been known for decades, but the parasite targets of many of these remain undefined. Until recently, this included the current clinical therapy, praziquantel (PZQ). However, the tempo of target discovery has recently gathered pace, with discoveries of schistosome targets for praziquantel (PZQ) and the anthelmintic benzodiazepine, meclonazepam (MCLZ). This steady patter of target illumination has also revealed a pattern in that both PZQ and MCLZ target members of the same ion channel subgroup—transient receptor potential ion channels of the melastatin family (TRPM channels). PZQ activates one member of this family (TRPMPZQ) and MCLZ activates a different channel (TRPMMCLZ). Here, similarities and differences between these two new targets are discussed. These data highlight the need for further study of TRPM channels in parasitic flatworms given their vulnerability to chemotherapeutic attack

A Comprehensive Economic Stimulus for our Failing Economy

This paper presents a comprehensive plan to fix the ailing American economy, through a five-step approach. First, the Federal Reserve must continue to broaden the scope of monetary policy, by purchasing and selling long-term securities. Manipulating expectations through FOMC statements is another tool at the Federal Reserve’s disposal. Secondly, the government must enact fiscal stimulus to stabilize the economy in the short and medium runs, through investment in infrastructure projects, green technology, fusion technology, and science education. Additionally, the new fiscal policy must tackle the mortgage meltdown, which is weighing down the entire economy. Third, the regulatory system must be changed to reduce the likelihood of another financial collapse, starting with the nationalization of the ratings agencies. Ratings should be updated faster, with a numeric grading system rather than the pre-existing letter grades. Fourth, our globalized economy insures that a coordinated globalized response is necessary to recover. Global cooperation to reduce inflation and avoid protectionist policies is vital. Finally, the American bailout policy must be made clear, only giving bailouts to companies that are sound but financially strapped and those that are too big to fail

Dissecting the polar dichotomy of the noncondensable gas enhancement on Mars using the NASA Ames Mars General Circulation Model

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95628/1/jgre2298.pd

Characterization of critical spawning habitats of weakfish, spotted seatrout and red drum in Pamlico Sound using hydrophone surveys

This report is not available elsewhere in electronic form.Final report for "Characterization of critical spawning habitats of weakfish, spotted seatrout and red drum in Pamlico Sound using hydrophone surveys."This grant was conducted under the Federal Aid in Sport Fish Restoration Program (Dingell- Johnson) Act through the Wallop-Breaux Amendment, and funded in part by the U.S. Department of the Interior, Fish and Wildlife Service, Grant Number F-62