Improving probabilistic infectious disease forecasting through coherence

With an estimated $10.4 billion in medical costs and 31.4 million outpatient visits each year, influenza poses a serious burden of disease in the United States. To provide insights and advance warning into the spread of influenza, the U.S. Centers for Disease Control and Prevention (CDC) runs a challenge for forecasting weighted influenza-like illness (wILI) at the national and regional level. Many models produce independent forecasts for each geographical unit, ignoring the constraint that the national wILI is a weighted sum of regional wILI, where the weights correspond to the population size of the region. We propose a novel algorithm that transforms a set of independent forecast distributions to obey this constraint, which we refer to as probabilistically coherent. Enforcing probabilistic coherence led to an increase in forecast skill for 79% of the models we tested over multiple flu seasons, highlighting the importance of respecting the forecasting system’s geographical hierarchy.     

Ichnology of a Pennsylvanian Equatorial Tidal Flat—The Stull Shale Member at Waverly,Eastern Kansas

Ichnology of a Pennsylvanian Equatorial Tidal Flat—The Stull Shale Member at Waverly, Eastern Kansas, M. Gabriela Mángano, Luis A. Buatois, Ronald R. West, and Christopher G. Maples, 2002, Kansas Geological Survey, Bulletin 245, 133 p., ISBN 1-58806-321-6.     

Damage to the plasma membrane in Escherichia coli K-12 induced by far-ultraviolet radiation and its repair

Escherichia coli cells treated with low fluences of far-uv radiation (up to 90 J/m2) showed repairable damage to the plasma membrane. The loss of the ability of the cells to exclude citrate was evident from the respiratory stimulation of irradiated cells when citrate was provided exogenously. This loss of a barrier was a result of a structural disorganization of the plasma membrane as seen by freeze-etching electron microscopy. Analysis of the plasma membrane proteins by sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed a characteristic loss of certain membrane proteins. When irradiated cells were incubated in glucose minimal medium at 37 degrees C for various times, a gradual recovery of membrane structure and function was observed. The recovery process was inhibited in the absence of an energy source as well as protein synthesis. The majority of the recovery occurred in the initial 1 h of the postirradiation holding. These results demonstrated that far-uv radiation at a fluence less than the D10 value had a direct or indirect effect on plasma membrane proteins, causing their release from the membrane bilayer. The lost proteins were subsequently regained by de novo protein synthesis.     

Pericyte ALK5/TIMP3 Axis Contributes to Endothelial Morphogenesis in the Developing Brain

1. Download high-res image (160KB)
2. Download full-size image

     

Determination of Degradation Kinetics and Effect of Anion Exchange Resin on Dissolution of Novel Anticancer Drug Rigosertib in Acidic Conditions

Rigosertib is a novel anticancer drug in clinical development by Onconova therapeutics, Inc. Currently, it is in pivotal phase III clinical trials for myelodysplastic syndrome (MDS) patients. Chemically, it is a sodium salt of weak acid with low solubility in lower pH solutions. In the preliminary studies, it was found that rigosertib is unstable in acidic conditions and forms multiple degradation products. In this research, drug degradation kinetics of rigosertib were studied in acidic conditions. Rigosertib follows pseudo-first-order general acid catalysis reaction. Cholestyramine, which is a strong anion exchange resin, was used to form complex with drug to improve stability and dissolution in acidic conditions. Drug complex with cholestyramine showed better dissolution profile compared to drug alone. Effect of polyethylene glycol was investigated on the release of drug from the drug resin complex. Polyethylene glycol further improved dissolution profile by improving drug solubility in acidic medium.     

Novel KV7 ion channel openers for the treatment of epilepsy and implications for detrusor tissue contraction

Neuronal voltage-gated potassium channels, K_V7s, are the molecular mediators of the M current and regulate membrane excitability in the central and peripheral neuronal systems. Herein, we report novel small molecule K_V7 openers that demonstrate anti-seizure activities in electroshock and pentylenetetrazol-induced seizure models without influencing Rotarod readouts in mice. The anti-seizure activity was determined to be proportional to the unbound concentration in the brain. K_V7 channels are also expressed in the bladder smooth muscle (detrusor) and activation of these channels may cause localized undesired effects. Therefore, the impact of individual K_V7 isoforms was investigated in human detrusor tissue using a panel of K_V7 openers with distinct activity profiles among K_V7 isoforms. KCNQ4 and KCNQ5 mRNA were highly expressed in detrusor tissue, yet a compound that has significantly reduced activity on homomeric K_V7.4 did not reduce detrusor contraction. This may suggest that the homomeric K_V7.4 channel plays a less significant role in bladder contraction and further investigation is needed.     

Feeding ecology and ecomorphology of cichlid assemblages in a large Mesoamerican river delta

Fish assemblages in tropical lowland rivers are characterized by a high richness of species that feed on a diverse array of food resources. Although closely related species often have similar feeding ecology, species within the family Cichlidae display a broad spectrum of trophic niches, and resource partitioning has been inferred from studies conducted in Neotropical rivers. We investigated interspecific variation in food resource use and its relationship to morphological variation among cichlid fishes within the Pantanos de Centla Biosphere Reserve, a coastal area encompassing the delta of the Grijalva-Usumacinta River in Tabasco, Mexico. Most species consumed benthic crustaceans, aquatic insect larvae, and detritus, but some were more herbivorous, and one species was a specialized piscivore. Dietary niche overlap among species was higher than expected for one assemblage, and similar to random expectations for another, suggesting a lesser role for resource partitioning than has been shown for some cichlid assemblages, perhaps due to availability of abundant resources, even in low-water conditions. Canonical correspondence analysis revealed that greatest morphological differences am7ong species involved functional traits directly associated with resource use. Relationships between feeding ecology and morphology were similar to those described for other riverine cichlids. Strong ecomorphological relationships facilitate inferences about the ecology of cichlid species, including species that currently lack data from field studies. Knowledge of ecological relationships will be important for conservation in the Pantanos de Centla, an ecosystem of global significance for biodiversity and ecosystem services.     

Biochemical and histochemical evidence of nonspecific binding of alpha7nAChR antibodies to mouse brain tissue.

Alpha 7 nicotinic acetylcholine receptors are involved in learning and memory, and are implicated in the pathology of Alzheimer's disease and schizophrenia. Detection of alpha7 subunits can be accomplished via immunodetection or alpha-bungarotoxin-binding techniques. Standard protocols for immunohistochemistry and Western blotting were followed using several commercially available antibodies. Various mice were evaluated, including non-transgenics, APP, PS1, APP+PS1, and alpha7 knockouts. Initial results with amyloid-depositing mice revealed alpha7 immunolabeled astrocytes, in addition to expected neuronal staining. Subsequent studies with intrahippocampal injections of lipopolysaccharide (LPS) into alpha7 knockout mice showed that both neuronal and astrocytic labeling by alpha7 antibodies was nonspecific. On Western blots of mouse brain proteins, none of the bands detected with antibodies directed against alpha7 subunits diminished in the alpha7 knockout mice. Although LPS-related changes in the expression of some bands were found, these also were unaffected by the alpha7 genotype of the mice. In general, the Western staining patterns for these antibodies revealed few overlapping bands. These immunodetection data are in contrast to genotyping results and mRNA analyses that confirmed the disruption of the alpha7 allele and lack of alpha7 message in the knockouts. These findings suggest caution in interpreting results when using several commercially available alpha7 nicotinic receptor antibodies.