Solution structure of a repeated unit of the ABA-1 nematode polyprotein allergen of ascaris reveals a novel fold and two discrete lipid-binding sites

Parasitic nematode worms cause serious health problems in humans and other animals. They can induce allergic-type immune responses, which can be harmful but may at the same time protect against the infections. Allergens are proteins that trigger allergic reactions and these parasites produce a type that is confined to nematodes, the nematode polyprotein allergens (NPAs). These are synthesized as large precursor proteins comprising repeating units of similar amino acid sequence that are subsequently cleaved into multiple copies of the allergen protein. NPAs bind small lipids such as fatty acids and retinol (Vitamin A) and probably transport these sensitive and insoluble compounds between the tissues of the worms. Nematodes cannot synthesize these lipids, so NPAs may also be crucial for extracting nutrients from their hosts. They may also be involved in altering immune responses by controlling the lipids by which the immune and inflammatory cells communicate. We describe the molecular structure of one unit of an NPA, the well-known ABA-1 allergen of Ascaris and find its structure to be of a type not previously found for lipid-binding proteins, and we describe the unusual sites where lipids bind within this structur

Surgical Cavity Constriction and Local Progression Between Resection and Adjuvant Radiosurgery for Brain Metastases

Stereotactic radiosurgery (SRS) to a surgical cavity after brain metastasis resection is a promising treatment for improving local control. The optimal timing of adjuvant SRS, however, has yet to be determined. Changes in resection cavity volume and local progression in the interval between surgery and SRS are likely important factors in deciding when to proceed with adjuvant SRS. We conducted a retrospective review of patients with a brain metastasis treated with surgical resection followed by SRS to the resection cavity. Post-operative and pre-radiosurgery magnetic resonance imaging (MRI) was reviewed for evidence of cavity volume changes, amount of edema, and local tumor progression. Resection cavity volume and edema volume were measured using volumetric analysis. We identified 21 consecutive patients with a brain metastasis treated with surgical resection and radiosurgery to the resection cavity. Mean age was 57 yrs. The most common site of metastasis was the frontal lobe (38%), and the most common primary neoplasms were lung adenocarcinoma and melanoma (24% each). The mean postoperative resection cavity volume was 7.8 cm(3) and shrank to a mean of 4.5 cm(3) at the time of repeat imaging for radiosurgical planning (median 41 days after initial post-operative MRI), resulting in a mean reduction in cavity volume of 43%. Patients who underwent pre-SRS imaging within 1 month of their initial post-operative MRI had a mean volume reduction of 13% compared to 61% in those whose pre-SRS imaging was ≥1 month (p=0.0003). Post-resection edema volume was not related to volume reduction (p=0.59). During the interval between MRIs, 52% of patients showed evidence of tumor progression within the resection cavity wall. There was no significant difference in local recurrence if the interval between resection and radiosurgery was <1 month (n=8) versus ≥1 month (n=13, p=0.46). These data suggest that the surgical cavity after brain metastasis resection constricts over time with greater constriction seen in patients whose pre-SRS imaging is ≥1 month after initial post-operative imaging. Given that there was no difference in local recurrence rate, the data suggest there is benefit in waiting in order to treat a smaller resection cavity

High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines.

Hundreds of genetically characterized cell lines are available for the discovery of genotype-specific cancer vulnerabilities. However, screening large numbers of compounds against large numbers of cell lines is currently impractical, and such experiments are often difficult to control. Here we report a method called PRISM that allows pooled screening of mixtures of cancer cell lines by labeling each cell line with 24-nucleotide barcodes. PRISM revealed the expected patterns of cell killing seen in conventional (unpooled) assays. In a screen of 102 cell lines across 8,400 compounds, PRISM led to the identification of BRD-7880 as a potent and highly specific inhibitor of aurora kinases B and C. Cell line pools also efficiently formed tumors as xenografts, and PRISM recapitulated the expected pattern of erlotinib sensitivity in vivo

Incorporation of enzyme concentrations into FBA and identification of optimal metabolic pathways

<p>Abstract</p> <p>Background</p> <p>In the present article, we propose a method for determining optimal metabolic pathways in terms of the level of concentration of the enzymes catalyzing various reactions in the entire metabolic network. The method, first of all, generates data on reaction fluxes in a pathway based on steady state condition. A set of constraints is formulated incorporating weighting coefficients corresponding to concentration of enzymes catalyzing reactions in the pathway. Finally, the rate of yield of the target metabolite, starting with a given substrate, is maximized in order to identify an optimal pathway through these weighting coefficients.</p> <p>Results</p> <p>The effectiveness of the present method is demonstrated on two synthetic systems existing in the literature, two pentose phosphate, two glycolytic pathways, core carbon metabolism and a large network of carotenoid biosynthesis pathway of various organisms belonging to different phylogeny. A comparative study with the existing extreme pathway analysis also forms a part of this investigation. Biological relevance and validation of the results are provided. Finally, the impact of the method on metabolic engineering is explained with a few examples.</p> <p>Conclusions</p> <p>The method may be viewed as determining an optimal set of enzymes that is required to get an optimal metabolic pathway. Although it is a simple one, it has been able to identify a carotenoid biosynthesis pathway and the optimal pathway of core carbon metabolic network that is closer to some earlier investigations than that obtained by the extreme pathway analysis. Moreover, the present method has identified correctly optimal pathways for pentose phosphate and glycolytic pathways. It has been mentioned using some examples how the method can suitably be used in the context of metabolic engineering.</p

Health-seeking behaviour of human brucellosis cases in rural Tanzania

<p>Abstract</p> <p>Background</p> <p>Brucellosis is known to cause debilitating conditions if not promptly treated. In some rural areas of Tanzania however, practitioners give evidence of seeing brucellosis cases with symptoms of long duration. The purpose of this study was to establish health-seeking behaviour of human brucellosis cases in rural Tanzania and explore the most feasible ways to improve it.</p> <p>Methods</p> <p>This was designed as a longitudinal study. Socio-demographic, clinical and laboratory data were collected from patients who reported to selected hospitals in rural northern Tanzania between June 2002 and April 2003. All patients with conditions suspicious of brucellosis on the basis of preliminary clinical examination and history were enrolled into the study as brucellosis suspects. Blood samples were taken and tested for brucellosis using the Rose-Bengal Plate Test (RBPT) and other agglutination tests available at the health facilities and the competitive ELISA (c-ELISA) test at the Veterinary Laboratory Agencies (VLA) in the UK. All suspects who tested positive with the c-ELISA test were regarded as brucellosis cases. A follow-up of 49 cases was made to collect data on health-seeking behaviour of human brucellosis cases.</p> <p>Results</p> <p>The majority of cases 87.7% gave a history of going to hospital as the first point of care, 10.2% purchased drugs from a nearby drug shop before going to hospital and 2% went to a local traditional healer first. Brucellosis cases delayed going to hospital with a median delay time of 90 days, and with 20% of the cases presenting to hospitals more than a year after the onset of symptoms. Distance to the hospital, keeping animals and knowledge of brucellosis were significantly associated with patient delay to present to hospital.</p> <p>Conclusion</p> <p>More efforts need to be put on improving the accessibility of health facilities to the rural poor people who succumb to most of the diseases including zoonoses. Health education on brucellosis in Tanzania should also stress the importance of early presentation to hospitals for prompt treatment.</p

Navigating through digital folders uses the same brain structures as real world navigation

Efficient storage and retrieval of digital data is the focus of much commercial and academic attention. With personal computers, there are two main ways to retrieve files: hierarchical navigation and query-based search. In navigation, users move down their virtual folder hierarchy until they reach the folder in which the target item is stored. When searching, users first generate a query specifying some property of the target file (e.g., a word it contains), and then select the relevant file when the search engine returns a set of results. Despite advances in search technology, users prefer retrieving files using virtual folder navigation, rather than the more flexible query-based search. Using fMRI we provide an explanation for this phenomenon by demonstrating that folder navigation results in activation of the posterior limbic (including the retrosplenial cortex) and parahippocampal regions similar to that previously observed during real-world navigation in both animals and humans. In contrast, search activates the left inferior frontal gyrus, commonly observed in linguistic processing. We suggest that the preference for navigation may be due to the triggering of automatic object finding routines and lower dependence on linguistic processing. We conclude with suggestions for future computer systems design

FACT-MNG: tumor site specific web-based outcome instrument for meningioma patients

To formulate Functional Assessment of Cancer Therapy-Meningioma (FACT-MNG), a web-based tumor site-specific outcome instrument for assessing intracranial meningioma patients following surgical resection or stereotactic radiosurgery. We surveyed the relevant literature available on intracranial meningioma surgery and subsequent outcomes (38 papers), making note of which, if any, QOL/outcome instruments were utilized. None of the surgveyed papers included QOL assessment specific to tumor site. We subsequently developed questions that were relevant to the signs and symptoms that characterize each of 11 intracranial meningioma sites, and incorporated them into a modified combination of the Functional Assessment of Cancer Therapy-Brain (FACT-BR) and SF36 outcome instruments, thereby creating a new tumor site-specific outcome instrument, FACT-MNG. With outcomes analysis of surgical and radiosurgical treatments becoming more important, measures of the adequacy and success of treatment are needed. FACT-MNG represents a first effort to formalize such an instrument for meningioma patients. Questions specific to tumor site will allow surgeons to better assess specific quality of life issues not addressed in the past by more general questionnaires

The Effect of Visual Cues on Auditory Stream Segregation in Musicians and Non-Musicians

Background: The ability to separate two interleaved melodies is an important factor in music appreciation. This ability is greatly reduced in people with hearing impairment, contributing to difficulties in music appreciation. The aim of this study was to assess whether visual cues, musical training or musical context could have an effect on this ability, and potentially improve music appreciation for the hearing impaired. Methods: Musicians (N = 18) and non-musicians (N = 19) were asked to rate the difficulty of segregating a four-note repeating melody from interleaved random distracter notes. Visual cues were provided on half the blocks, and two musical contexts were tested, with the overlap between melody and distracter notes either gradually increasing or decreasing. Conclusions: Visual cues, musical training, and musical context all affected the difficulty of extracting the melody from a background of interleaved random distracter notes. Visual cues were effective in reducing the difficulty of segregating the melody from distracter notes, even in individuals with no musical training. These results are consistent with theories that indicate an important role for central (top-down) processes in auditory streaming mechanisms, and suggest that visual cue

Circulating Microbial Products and Acute Phase Proteins as Markers of Pathogenesis in Lymphatic Filarial Disease

Lymphatic filariasis can be associated with development of serious pathology in the form of lymphedema, hydrocele, and elephantiasis in a subset of infected patients. Dysregulated host inflammatory responses leading to systemic immune activation are thought to play a central role in filarial disease pathogenesis. We measured the plasma levels of microbial translocation markers, acute phase proteins, and inflammatory cytokines in individuals with chronic filarial pathology with (CP Ag+) or without (CP Ag−) active infection; with clinically asymptomatic infections (INF); and in those without infection (endemic normal [EN]). Comparisons between the two actively infected groups (CP Ag+ compared to INF) and those without active infection (CP Ag− compared to EN) were used preliminarily to identify markers of pathogenesis. Thereafter, we tested for group effects among all the four groups using linear models on the log transformed responses of the markers. Our data suggest that circulating levels of microbial translocation products (lipopolysaccharide and LPS-binding protein), acute phase proteins (haptoglobin and serum amyloid protein-A), and inflammatory cytokines (IL-1β, IL-12, and TNF-α) are associated with pathogenesis of disease in lymphatic filarial infection and implicate an important role for circulating microbial products and acute phase proteins