Rapid identification of malaria vaccine candidates based on alpha-helical coiled coil protein motif.

To identify malaria antigens for vaccine development, we selected alpha-helical coiled coil domains of proteins predicted to be present in the parasite erythrocytic stage. The corresponding synthetic peptides are expected to mimic structurally "native" epitopes. Indeed the 95 chemically synthesized peptides were all specifically recognized by human immune sera, though at various prevalence. Peptide specific antibodies were obtained both by affinity-purification from malaria immune sera and by immunization of mice. These antibodies did not show significant cross reactions, i.e., they were specific for the original peptide, reacted with native parasite proteins in infected erythrocytes and several were active in inhibiting in vitro parasite growth. Circular dichroism studies indicated that the selected peptides assumed partial or high alpha-helical content. Thus, we demonstrate that the bioinformatics/chemical synthesis approach described here can lead to the rapid identification of molecules which target biologically active antibodies, thus identifying suitable vaccine candidates. This strategy can be, in principle, extended to vaccine discovery in a wide range of other pathogens.

Rate and processes of river network rearrangement during incipient faulting: The case of the Cahabon river, Guatemala

Deeply incised river networks are generally regarded as robust features that are not easily modified by erosion or tectonics. Although the reorganization of deeply incised drainage systems has been documented, the corresponding importance with regard to the overall landscape evolution of mountain ranges and the factors that permit such reorganizations are poorly understood. To address this problem, we have explored the rapid drainage reorganization that affected the Cahabon River in Guatemala during the Quaternary. Sediment-provenance analysis, field mapping, and electrical resistivity tomography (ERT) imaging are used to reconstruct the geometry of the valley before the river was captured. Dating of the abandoned valley sediments by the Be-10-Al-26 burial method and geomagnetic polarity analysis allow us to determine the age of the capture events and then to quantify several processes, such as the rate of tectonic deformation of the paleovalley, the rate of propagation of post-capture drainage reversal, and the rate at which canyons that formed at the capture sites have propagated along the paleovalley. Transtensional faulting started 1 to 3 million years ago, produced ground tilting and ground faulting along the Cahabon River, and thus generated differential uplift rate of 0.3 +/- 0.1 up to 0.7 +/- 0.4 mm . y(-1) along the river's course. The river responded to faulting by incising the areas of relative uplift and depositing a few tens of meters of sediment above the areas of relative subsidence. Then, the river experienced two captures and one avulsion between 700 ky and 100 ky. The captures breached high-standing ridges that separate the Cahabon River from its captors. Captures occurred at specific points where ridges are made permeable by fault damage zones and/or soluble rocks. Groundwater flow from the Cahabon River down to its captors likely increased the erosive power of the captors thus promoting focused erosion of the ridges. Valley-fill formation and capture occurred in close temporal succession, suggesting a genetic link between the two. We suggest that the aquifers accumulated within the valley-fills, increased the head along the subterraneous system connecting the Cahabon River to its captors, and promoted their development. Upon capture, the breached valley experienced widespread drainage reversal toward the capture sites. We attribute the generalized reversal to combined effects of groundwater sapping in the valley-fill, axial drainage obstruction by lateral fans, and tectonic tilting. Drainage reversal increased the size of the captured areas by a factor of 4 to 6. At the capture sites, 500 m deep canyons have been incised into the bedrock and are propagating upstream at a rate of 3 to 11 mm . y(-1) deepening at a rate of 0.7 to 1 5 mm . y(-1). At this rate, 1 to 2 million years will be necessary for headward erosion to completely erase the topographic expression of the paleovalley. It is concluded that the rapid reorganization of this drainage system was made possible by the way the river adjusted to the new tectonic strain field, which involved transient sedimentation along the river's course. If the river had escaped its early reorganization and had been given the time necessary to reach a new dynamic equilibrium, then the transient conditions that promoted capture would have vanished and its vulnerability to capture would have been strongly reduced.

Audit report on the Iowa Communications Network (ICN) for the year ended June 30, 2009

Audit report on the Iowa Communications Network (ICN) for the year ended June 30, 2009

Gp74 a membrane glycoprotein of the cis-Golgi network that cycles through the endoplasmic reticulum and intermediate compartment

A monoclonal antibody CC92 (IgM), raised against a fraction of rat liver enriched in Golgi membranes, recognizes a novel Endo H-resistant 74-kD membrane glycoprotein (gp74). The bulk of gp74 is confined to the cis-Golgi network (CGN). Outside the Golgi gp74 is found in tubulovesicular structures and ER foci. In cells incubated at 37 degrees C the majority of gp74 is segregated from the intermediate compartment (IC) marker p58. However, in cells treated with organelle perturbants such as low temperature, BFA, and [AIF4]- the patterns of the two proteins become indistinguishable. Both proteins are retained in the Golgi complex at 20 degrees C and in the IC at 15 degrees C. Incubation of cells with BFA results in relocation of gp74 to p58 positive IC elements. [AIF4]- induces the redistribution of gp74 from the Golgi to p58-positive vesicles and does not retard the translocation of gp74 to IC elements in cells treated with BFA. Disruption of microtubules by nocodazol results in the rapid disappearance of the Golgi elements stained by gp74 and redistribution of the protein into vesicle-like structures. The responses of gp74 to cell perturbants are in sharp contrast with those of cis/middle and trans-Golgi resident proteins whose location is not affected by low temperatures or [AIF4]-, are translocated to the ER upon addition of BFA, and stay in slow disintegrating Golgi elements in cells treated with nocodazol. The results suggest that gp74 is an itinerant protein that resides most of the time in the CGN and cycles through the ER/IC following the pathway used by p58.

Recovery of biological motion perception and network plasticity after cerebellar tumor removal.

Visual perception of body motion is vital for everyday activities such as social interaction, motor learning or car driving. Tumors to the left lateral cerebellum impair visual perception of body motion. However, compensatory potential after cerebellar damage and underlying neural mechanisms remain unknown. In the present study, visual sensitivity to point-light body motion was psychophysically assessed in patient SL with dysplastic gangliocytoma (Lhermitte-Duclos disease) to the left cerebellum before and after neurosurgery, and in a group of healthy matched controls. Brain activity during processing of body motion was assessed by functional magnetic resonance imaging (MRI). Alterations in underlying cerebro-cerebellar circuitry were studied by psychophysiological interaction (PPI) analysis. Visual sensitivity to body motion in patient SL before neurosurgery was substantially lower than in controls, with significant improvement after neurosurgery. Functional MRI in patient SL revealed a similar pattern of cerebellar activation during biological motion processing as in healthy participants, but located more medially, in the left cerebellar lobules III and IX. As in normalcy, PPI analysis showed cerebellar communication with a region in the superior temporal sulcus, but located more anteriorly. The findings demonstrate a potential for recovery of visual body motion processing after cerebellar damage, likely mediated by topographic shifts within the corresponding cerebro-cerebellar circuitry induced by cerebellar reorganization. The outcome is of importance for further understanding of cerebellar plasticity and neural circuits underpinning visual social cognition.

Iowa Communications Network Fiscal Year 2010 Annual Report

Use of ICN’s Internet and data services have continued to increase exponentially, which reflects the capacity needed for greater access to high-speed Internet (Broadband). Users are incorporating more web-based applications, which uses larger amounts of bandwidth; such as transmitting hospital MRIs, video streaming, and web-based systems.

Iowa Department of Transportation Fiscal Year 2010 Report of Savings by Using Video Conferencing Through Iowa Communications Network to the Iowa General Assembly Pursuant to Iowa Code § II 84 Acts and Joint Resolutions Enacted at the 1994 Regular Session of the 75th General Assembly of the State of Iowa

Introduction and summary Iowa Code § 8D.10 requires certain state agencies to prepare an annual report to the General Assembly certifying the identified savings associated with that state agency’s use of the Iowa Communications Network (ICN). This report covers estimated cost savings related to video conferencing via ICN for the Iowa Department of Transportation (DOT). In FY 2010, the DOT did not conduct any sessions utilizing ICN’s video conferencing system. Therefore, no cost savings were calculated for this report.

Outcome and Prognostic Factors in Adenosquamous Carcinoma of the Head and Neck: A Multicenter Rare Cancer Network Study

Purpose/Objective(s): Adenosquamous carcinoma (AC) of the head and neck is a distinct entity first described in 1968. Its natural history is more aggressive than squamous cell carcinoma but this is based on very small series reported in the literature. The goal of this study was to assess the clinical profile, outcome, patterns of failure and prognostic factors in patients with AC of the head and neck treated by radiation therapy (RT) with or without chemotherapy (CT).Materials/Methods: Data from 18 patients with Stage I (n = 3), II (n = 1), III (n = 4), or IVa (n = 10) AC, treated between 1989 and 2009, were collected in a retrospective multicenter Rare Cancer Network study. Median age was 60 years (range, 48 - 73 years). Fourteen patients were male and 4 female. Risk factors, including perineural invasion, lymphangitis, vascular invasion, positive margins, were present in 83% of the patients. Tumor sites included oral cavity in 4, oropharynx in 4, hypopharynx in2, larynx in 2, salivary glands in 2, nasal vestibule in 2, nasopharynx in 1, and maxillary sinus in 1 patient. Surgery (S) was performed in all but 5 patients. S alone was performed in only 1 patient, and definitive RT alone in 3 patients. Fourteen patients received combined modality treatment (S+RT in 10, RT+CT in 2, and all of the three modalities in 2 patients). Median RT dose to the primary and to the nodes was 66 Gy (range, 50 - 72 Gy) and 53 Gy (range, 44 - 66 Gy), respectively (1.8 - 2.0 Gy/fr., 5 fr./ week). In 4 patients, the planning treatment volume included the primary tumor site only. Seven patients were treated with 2D RT, 7 with 3D conformal RT, and 2 with intensity-modulated RT.Results: After a median follow-up period of 38 months (range, 9 - 62 months), 8 patients developed distant metastases (lung, bone, mediastinum, and liver), 6 presented nodal recurrences, and only 4 had a local relapse at the primary site (all in-field recurrences). At last follow-up, 6 patients were alive without disease, 1 alive with disease, 9 died from progressive disease, and 2 died from intercurrent disease. The 3-year and median overall survival, disease-free survival (DFS) and locoregional control rates were 52% (95% confidence interval [CI]: 28 - 76%) and 39 months, 36% (95% CI: 13 - 49%) and 12 months, and 54% (95% CI: 26 - 82%) and 40 months, respectively. In multivariate analysis (Cox model), DFS was negatively influenced by the presence of extracapsular extension (p = 0.02) and advanced stage (IV versus I-III, p = 0.003).Conclusions: Overall prognosis of locoregionally advanced AC remains poor, and distant metastases and nodal relapse occur in almost half of the cases. However, local control is relatively good, and early stage AC patients had prolonged DFS when treated with combined modality treatment.

The essential role of radiotherapy in the treatment of Merkel cell carcinoma: a study from the Rare Cancer Network.

PURPOSE: To evaluate the role of postoperative radiotherapy (RT) in Merkel cell carcinoma (MCC). METHODS AND MATERIALS: A retrospective multicenter study was performed in 180 patients with MCC treated between February 1988 and September 2009. Patients who had had surgery alone were compared with patients who received surgery and postoperative RT or radical RT. Local relapse-free survival (LRFS), regional relapse-free survival (RRFS), and distant metastasis-free survival (DMFS) rates were assessed together with disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) rates. RESULTS: Seventy-nine patients were male and 101 patients were female, and the median age was 73 years old (range, 38-93 years). The majority of patients had localized disease (n = 146), and the remaining patients had regional lymph node metastasis (n = 34). Forty-nine patients underwent surgery for the primary tumor without postoperative RT to the primary site; the other 131 patients received surgery for the primary tumor, followed by postoperative RT (n = 118) or a biopsy of the primary tumor followed by radical RT (n = 13). Median follow-up was 5 years (range, 0.2-16.5 years). Patients in the RT group had improved LRFS (93% vs. 64%; p < 0.001), RRFS (76% vs. 27%; p < 0.001), DMFS (70% vs. 42%; p = 0.01), DFS (59% vs. 4%; p < 0.001), and CSS (65% vs. 49%; p = 0.03) rates compared to patients who underwent surgery for the primary tumor alone; LRFS, RRFS, DMFS, and DFS rates remained significant with multivariable Cox regression analysis. However OS was not significantly improved by postoperative RT (56% vs. 46%; p = 0.2). CONCLUSIONS: After multivariable analysis, postoperative RT was associated with improved outcome and seems to be an important component in the multimodality treatment of MCC.

Radioimmunotherapy confers long-term survival to lymphoma patients with acceptable toxicity: registry analysis by the international radioimmunotherapy network.

The Radioimmunotherapy Network (RIT-N) is a Web-based, international registry collecting long-term observational data about radioimmunotherapy-treated patients with malignant lymphoma outside randomized clinical studies. The RIT-N collects unbiased data on treatment indications, disease stages, patients' conditions, lymphoma subtypes, and hematologic side effects of radioimmunotherapy treatment. Methods: RIT-N is located at the University of Gottingen, Germany, and collected data from 14 countries. Data were entered by investigators into a Web-based central database managed by an independent clinical research organization. Results: Patients (1,075) were enrolled from December 2006 until November 2009, and 467 patients with an observation time of at least 12 mo were included in the following analysis. Diagnoses were as follows: 58% follicular lymphoma and 42% other B-cell lymphomas. The mean overall survival was 28 mo for follicular lymphoma and 26 mo for other lymphoma subtypes. Hematotoxicity was mild for hemoglobin (World Health Organization grade II), with a median nadir of 10 g/dL, but severe (World Health Organization grade III) for platelets and leukocytes, with a median nadir of 7,000/mu L and 2.2/mu L, respectively. Conclusion: Clinical usage of radioimmunotherapy differs from the labeled indications and can be assessed by this registry, enabling analyses of outcome and toxicity data beyond clinical trials. This analysis proves that radioimmunotherapy in follicular lymphoma and other lymphoma subtypes is a safe and efficient treatment option.

A common ancestor DNA motif for invertebrate and vertebrate hormone response elements.

The ecdysone-responsive DNA sequence of the Drosophila hsp27 gene promoter contains four direct and inverted repeats reminiscent of those that compose the vertebrate palindromic estrogen response element (ERE) and the thyroid hormone/retinoic acid response element (TRE/RRE). Interestingly, a 3 bp substitution in the wild-type Hsp27 ecdysone response element (EcdRE) increases both its similarity with the vertebrate ERE and TRE/RRE and its capacity to confer ecdysone responsiveness to a heterologous promoter. Remarkably, increasing the spacing between the inverted repeats of this strong EcdRE by two nucleotides converts it into an ERE. Inversely, decreasing the spacing between the two inverted repeats of the vertebrate consensus palindromic ERE, from three to one nucleotide, converts it into a functional EcdRE. Thus, the only difference between an invertebrate EcdRE and a vertebrate palindromic ERE or TRE/RRE is in the spacing between the conserved inverted repeated motifs forming these palindromic HREs. The finding that the sequence motif 5'-GGTCA-3' present in the vertebrate ERE and TRE/RRE is also a functionally important characteristic of an invertebrate HRE, suggests that a common ancestor regulatory DNA sequence gave rise to all HREs known so far. We discuss the possibility that this progenitor motif is the GGTCA sequence.

An investment social network beside the Banco de Barcelona, an unusual case?

[cat] L’extensió de les activitats bancàries al segle XIX va ser liderat per alguns grups socials connectats amb el comerç, que van treure profit de la seva experiència i coneixement per estendre la seva influència al voltant del món del crèdit. A la historiografia espanyola, hi ha un conjunt de treballs que s’han centrat en aquesta gent, però en molts pocs casos s’ha fet una classificació que permeti detectar el conjunt de grups econòmics que han liderat el procés de modernització financera de l’Espanya de mitjans del segle XIX. El principal objectiu del treball és l’anàlisi dels grups socials que van formar el Banco de Barcelona entre 1844 i 1854. Aquesta institució va ser important per a la història financera i bancària d’Espanya per ser pionera en la seva activitat creditícia i d’emissió: a més, la seva experiència va servir com a base en la constitució d’un sistema financer modern a Espanya. En una societat com la catalana de mitjans del segle XIX, la confiança era un factor important per explicar la decisió d’invertir. L’aparició de noves companyies i les seves necessitats d’inversió van transformar el comportaments previs. Quin va ser el comportament dels inversors potencials? Va ser el grup que hi havia al voltant del banc el que va ascendir econòmicament en els anys centrals del segle XIX? La resposta és prou clara, els membres del consell d’administració del Banc de Barcelona formaven un grup apart dins dels grups que sorgeixen a l’economia catalana en el seu conjunt.

Report on the Iowa Communications Network (ICN) for the year ended June 30, 2010

Report on the Iowa Communications Network (ICN) for the year ended June 30, 2010

The caveolin-binding motif of the pathogen-related yeast protein Pry1, a member of the CAP protein superfamily, is required for in vivo export of cholesteryl acetate.

Proteins belonging to the CAP superfamily are present in all kingdoms of life and have been implicated in different physiological processes. Their molecular mode of action, however, is poorly understood. Saccharomyces cerevisiae expresses three members of this superfamily, pathogen-related yeast (Pry)1, -2, and -3. We have recently shown that Pry function is required for the secretion of cholesteryl acetate and that Pry proteins bind cholesterol and cholesteryl acetate, suggesting that CAP superfamily members may generally act to bind sterols or related small hydrophobic compounds. Here, we analyzed the mode of sterol binding by Pry1. Computational modeling indicates that ligand binding could occur through displacement of a relatively poorly conserved flexible loop, which in some CAP family members displays homology to the caveolin-binding motif. Point mutations within this motif abrogated export of cholesteryl acetate but did not affect binding of cholesterol. Mutations of residues located outside the caveolin-binding motif, or mutations in highly conserved putative catalytic residues had no effect on export of cholesteryl acetate or on lipid binding. These results indicate that the caveolin-binding motif of Pry1, and possibly of other CAP family members, is crucial for selective lipid binding and that lipid binding may occur through displacement of the loop containing this motif.