Retracing micro-epidemics of Chagas disease using epicenter regression

Vector-borne transmission of Chagas disease has become an urban problem in the city of Arequipa, Peru, yet the debilitating symptoms that can occur in the chronic stage of the disease are rarely seen in hospitals in the city. The lack of obvious clinical disease in Arequipa has led to speculation that the local strain of the etiologic agent, Trypanosoma cruzi, has low chronic pathogenicity. The long asymptomatic period of Chagas disease leads us to an alternative hypothesis for the absence of clinical cases in Arequipa: transmission in the city may be so recent that most infected individuals have yet to progress to late stage disease. Here we describe a new method, epicenter regression, that allows us to infer the spatial and temporal history of disease transmission from a snapshot of a population's infection status. We show that in a community of Arequipa, transmission of T. cruzi by the insect vector Triatoma infestans occurred as a series of focal micro-epidemics, the oldest of which began only around 20 years ago. These micro-epidemics infected nearly 5% of the community before transmission of the parasite was disrupted through insecticide application in 2004. Most extant human infections in our study community arose over a brief period of time immediately prior to vector control. According to our findings, the symptoms of chronic Chagas disease are expected to be absent, even if the strain is pathogenic in the chronic phase of disease, given the long asymptomatic period of the disease and short history of intense transmission. Traducción al espa?ol disponible en Alternative Language Text S1/A Spanish translation of this article is available in Alternative Language Text S1.     

Preclinical safety evaluations supporting pediatric drug development with biopharmaceuticals: strategy,challenges, current practices

Evaluation of pharmaceutical agents in children is now conducted earlier in the drug development process. An important consideration for this pediatric use is how to assess and support its safety. This article is a collaborative effort of industry toxicologists to review strategies, challenges, and current practice regarding preclinical safety evaluations supporting pediatric drug development with biopharmaceuticals. Biopharmaceuticals include a diverse group of molecular, cell‐based or gene therapeutics derived from biological sources or complex biotechnological processes. The principles of preclinical support of pediatric drug development for biopharmaceuticals are similar to those for small molecule pharmaceuticals and in general follow the same regulatory guidances outlined by the Food and Drug Administration and European Medicines Agency. However, many biopharmaceuticals are also inherently different, with limited species specificity or immunogenic potential which may impact the approach taken. This article discusses several key areas to aid in the support of pediatric clinical use, study design considerations for juvenile toxicity studies when they are needed, and current practices to support pediatric drug development based on surveys specifically targeting biopharmaceutical development. Birth Defects Res (Part B) 92:359–380, 2011. © 2011 Wiley‐Liss, Inc.     

Architecture and development of the Neurospora crassa hypha -- a model cell for polarized growth

Neurospora crassa has been at the forefront of biological research from the early days of biochemical genetics to current progress being made in understanding gene and genetic network function. Here, we discuss recent developments in analysis of the fundamental form of fungal growth, development and proliferation -- the hypha. Understanding the establishment and maintenance of polarity, hyphal elongation, septation, branching and differentiation are at the core of current research. The advances in the identification and functional dissection of regulatory as well as structural components of the hypha provide an expanding basis for elucidation of fundamental attributes of the fungal cell. The availability and continuous development of various molecular and microscopic tools, as utilized by an active and co-supportive research community, promises to yield additional important new discoveries on the biology of fungi.     

Isolation of Pure Cultures of Algae from Contaminated Cultures

Algal cultures have been freed of bacterial contamination by a procedure involving treatment with a detergent and phenol, followed by plating on an agar medium for selection of pure cultures.     

THE AUXILIARY TREATMENT OF PSYCHOTIC WOMEN—Group Therapy for Their Husbands

Group therapy for the husbands of hospitalized psychotic women relieved the anxiety and feeling of guilt of the husbands and led to better communication between husband and wife. It was particularly helpful just before and after the wife came home from the hospital. The group meetings saved various members of the hospital staff considerable time which they otherwise would have had to devote to the husbands individually.     

Ligand Specificity of a High Affinity Cytokinin-binding Protein

A soluble cytokinin-binding protein from wheat germ that has a high affinity for a range of purine cytokinins also interacts with a variety of nonpurine compounds that can affect cytokinin-modified processes in animal or plant cells or which bind to proteins known to interact with certain cytokinins. A variety of structurally disparate compounds which inhibit chloroplast photosystem II activity (including phenylurea, carbanilate, and alkylamino-2-chloro-sym-triazine compounds) displace kinetin from the protein in an apparently competitive fashion. However, various energy transfer inhibitors (including organotin compounds and N,N′-dicy-clohexylcarbodiimide) also inhibit kinetin binding to the protein. N⁶,2-0′-Dibutyryl-3′,5′-cyclic AMP and 1-methyl-3-isobutylxanthine (the effects of which on fibroblast morphology and motility can be mimicked by cytokinins) are inhibitors of kinetin binding to the protein. A variety of compounds that can have antimitotic effects (including 1-methyl-3-isobutylxanthine and certain alkylated cyclic nucleotide, carbanilate, and tryptamine compounds) displace kinetin from the protein. However, a variety of indole derivatives also displace kinetin from the cytokinin-binding protein, which in a qualitative sense has a broad ligand specificity.     

Spatio-temporal modeling of localized brain activity

Functional neuroimaging, including positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), plays an important role in identifying specific brain regions associated with experimental stimuli or psychiatric disorders such as schizophrenia. PET and fMRI produce massive data sets that contain both temporal correlations from repeated scans and complex spatial correlations. Several methods exist for handling temporal correlations, some of which rely on transforming the response data to induce either a known or an independence covariance structure. Despite the presence of spatial correlations between the volume elements (voxels) comprising a brain scan, conventional methods perform voxel-by-voxel analyses of measured brain activity. We propose a two-stage spatio-temporal model for the estimation and testing of localized activity. Our second-stage model specifies a spatial auto-regression, capturing correlations within neural processing clusters defined by a data-driven cluster analysis. We use maximum likelihood methods to estimate parameters from our spatial autoregressive model. Our model protects against type-I errors, enables the detection of both localized and regional activations (including volume of interest effects), provides information on functional connectivity in the brain, and establishes a framework to produce spatially smoothed maps of distributed brain activity for each individual. We illustrate the application of our model using PET data from a study of working memory in individuals with schizophrenia.     

Study of primary amines for nucleophilic cleavage of cyanylated cystinyl proteins in disulfide mass mapping methodology

In a study of primary (methyl to butyl) amines as nucleophiles for cyano-induced cleavage of cysteinyl proteins, methylamine was found to be superior to ammonia for cyanylation (CN)-based disulfide mass mapping methodology. Reaction conditions such as nucleophile concentration, temperature, and reaction time were systematically studied using ribonuclease A as a model protein. The CN-induced cleavage products were monitored using reverse-phase chromatography and matrix-assisted laser desorption ionization mass spectrometry. Results showed that low temperature, short reaction time, and high nucleophile concentration optimize the cleavage reaction and minimize side reactions. These conditions shorten the analysis time and substantially improve the yield of cleavage products. Further, the concurrent use of homologous nucleophiles (e.g., ammonia and methylamine) facilitates recognition and identification of cleavage products.