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Prions are the infectious agents responsible for transmissible spongiform encephalopathies. The principal component of prions is the glycoprotein PrP Sc , which is a conformationally modified isoform of a normal cell-surface protein called PrP C (ref. 1 ). During the time between infection and the appearance of the clinical symptoms, minute amounts of PrP Sc replicate by conversion of host PrP C , generating large amounts of PrP Sc aggregates in the brains of diseased individuals. We aimed to reproduce this event in vitro . Here we report a procedure involving cyclic amplification of protein misfolding that allows a rapid conversion of large excess PrP C into a protease-resistant, PrP Sc -like form in the presence of minute quantities of PrP Sc template. In this procedure, conceptually analogous to polymerase chain reaction cycling, aggregates formed when PrP Sc is incubated with PrP C are disrupted by sonication to generate multiple smaller units for the continued formation of new PrP Sc . After cyclic amplification more than 97% of the protease-resistant PrP present in the sample corresponds to newly converted protein. The method could be applied to diagnose the presence of currently undetectable prion infectious agent in tissues and biological fluids, and may provide a unique opportunity to determine whether PrP Sc replication results in the generation of infectivity in vitro .

Transmissible spongiform encephalopathies are associated with a structural transition in the prion protein that results in the conversion of the physiological PrPc to pathological PrP(Sc). We investigated whether this conformational transition can be inhibited and reversed by peptides homologous to the PrP fragments implicated in the abnormal folding, which contain specific residues acting as beta-sheet blockers (beta-sheet breaker peptides). We studied the effect of a 13-residue beta-sheet breaker peptide (iPrP13) on the reversion of the abnormal structure and properties of PrP(Sc) purified from the brains of mice with experimental scrapie and from human beings affected by sporadic and variant Creutzfeldt-Jakob disease. In a cellular model of familial prion disease, we studied the effect of the peptide in the production of the abnormal form of PrP in intact cells. The influence of the peptide on prion infectivity was studied in vivo by incubation time assays in mice with experimental scrapie. The beta-sheet breaker peptide partly reversed in-vitro PrP(Sc) to a biochemical and structural state similar to that of PrPc. The effect of the peptide was also detected in intact cells. Treatment of prion infectious material with iPrP13 delayed the appearance of clinical symptoms and decreased infectivity by 90-95% in mice with experimental scrapie. Beta-sheet breaker peptides reverse PrP conformational changes implicated in the pathogenesis of spongiform encephalopathies. These peptides or their derivatives provide a useful tool to study the role of PrP conformation and might represent a novel therapeutic approach for prion-related disorders.

We compared phenological patterns of tree species of the family Bombacaceae in three seasonal forests in Mexico and Costa Rica whose dry seasons vary in duration and intensity. The objectives were to (1) determine intraspecific variation in phenology between sites in different geographic locations with different precipitation regimes. (2) compare interspecific phenological patterns within sites during one year, and (3) document seasonal pollinator use of floral resources at one site in relation to the flowering phenology of these species. To determine the sequence of phenological events in trees of the family Bombacaceae across three study sites, phenology of marked individuals was recorded every 2 wk from September 2000 through August 2001 for six species. To estimate the importance of bombacaceous species in the diet of nectarivorous bats, pollen samples were collected from the bodies or feces of bats once every 2 wk during flowering. Our study suggests that phenological patterns of the Bombacaceae family in Neotropical dry forests are mainly constrained by phylogenetic membership and adaptive selective pressures associated with competition for pollinators. Abiotic factors related to precipitation and soil water content appear to be regulating leaf flushing and abscission, but the principal causes of flowering are related to ultimate factors associated with competition for pollinators. This study is the first that evaluates the phenological pattern of species and genera of the same family at different latitudes in a similar life zone.

Background Recurrent acute exacerbations are generally associated with accelerated decline of lung function and characterized by reduced physical activity and worsening of clinical status in patients with chronic obstructive pulmonary disease (COPD). Effective practices and therapies aimed at preventing acute exacerbations are continuously under investigation by healthcare providers. This double-blind, placebo-control, randomized clinical trial sought to evaluate the preventive effect of a bacterial lysate (OM-85) on acute exacerbations in patients with COPD or chronic bronchitis in China. Methods A total of 428 patients were randomly assigned either to OM-85 treatment or to placebo. Patients received study drug or placebo for 10 days per month over 3 consecutive months, with a 10-week follow-up. Three hundred and eighty-four (384) patients completed the study (192 in the OM-85 group and 192 in the placebo group) and were included in the full analysis set (FAS). Thirty (30) patients, 21 in the OM-85 and 9 in the placebo groups, were excluded due to protocol violations and drop-outs, and the remaining 354 patients (171 in the OM-85 and 183 in the placebo groups) were included in the per protocol set (PPS). Results The proportion of patients with recurrent acute exacerbations in the OM-85 group was significantly lower than in the placebo group at the end of the treatment period, both, in the FAS (23.4 % vs. 33.3 %, p  = 0.0311) and in the PPS (17.0 % vs. 31.2 %, p  < 0.05). Throughout the entire 22-week study period, the proportion of patients with recurrent acute exacerbations in the OM-85 group was lower than in the placebo group in the FAS (32.8 % vs. 38.0 %, p  = 0.277), while the difference is statistically significant in the PPS (26.3 % vs. 36.1 %, p  < 0.05). Conclusion OM-85 significantly reduced the proportion of patients with acute exacerbation after 12 weeks of therapy and the benefit appeared to be maintained up to 22 weeks, and showed a favorable tolerability profile.

Background: Multiple sclerosis (MS) is a complex disease with a mul tifaceted etiology and heterogeneous pathology. Demyelinated central nervous system (CNS) lesions are the pathologic hallmark of MS and are accompanied by inflammation, reactive gliosis, oligodendro cyte death and axonal loss. Experimental autoimmune encephalomyelitis (EAE) is widely used as an animal model of MS, serving as a valuable tool to study the pathogenesis and test new therapeutic approaches. Objective: The aim is to characterize the gene expression profile in different tissues of MOG-induced EAE in CS7B/6 mice covering different states of the disease. This genomics paradigm enables an extensive concurrent representation of genes and pathways relevant to the pathological and drug treatment processes. Methods: The gene expression profile, characterizing the progression of EAE was studied by microarray analysis following temporal progression (7, 10, 14, 21 and 28 days) after disease induction. RNA from several tissues, CNS areas (spinal cord and cerebellum) lymph nodes, spleen and blood was studied in four individual mice with homogeneous clinical score per time point. The involvement of specific biological pathways and the over and under-representation of biological functions have been investigated by different analysis approaches including hierarchical clustering and pathway analysis. Results: We performed a stepwise analysis. First, at the gene level we observed that the total number of regulated genes was time and clinical score-dependent. Then, the predominant canonical pathways were identified at each time point to characterize the main physiopathological mechanisms taking place during disease progression. The next step involved identifying modulated pathways in the same model and tissues in animals receiving pharmacological treatment with recognized mode of action. Examples of such modulated pathways are discussed. Conclusions: We have developed a useful and valuable tool for monitoring pathways in disease models, which can be used to characterize the pharmacological modulation of candidate targets and profile compounds.

Zika virus (ZIKV) is amosquito-borne flavivirus that emerged recently as a global health threat, causing a pandemic in the Americas. ZIKV infection mostly causes mild disease, but is linked to devastating congenital birth defects and Guillain-Barré syndrome in adults. The high level of cross-reactivity among flaviviruses and their cocirculation has complicated serological approaches to differentially detect ZIKV and dengue virus (DENV) infections, accentuating the urgent need for a specific and sensitive serological test. We previously generated a ZIKV nonstructural protein 1 (NS1)-specific human monoclonal antibody, which we used to develop an NS1-based competition ELISA. Well-characterized samples from RT-PCR-confirmed patients with Zika and individuals exposed to other flavivirus infections or vaccination were used in a comprehensive analysis to determine the sensitivity and specificity of the NS1 blockade-of-binding (BOB) assay, which was established in laboratories in five countries (Nicaragua, Brazil, Italy, United Kingdom, and Switzerland). Of 158 sera/plasma from RT-PCR-confirmed ZIKV infections, 145 (91.8%) yielded greater than 50% inhibition. Of 171 patients with primary or secondary DENV infections, 152 (88.9%) scored negative. When the control group was extended to patients infected by other flaviviruses, other viruses, or healthy donors (n = 540), the specificity was 95.9%. We also analyzed longitudinal samples from DENV-immune and DENVnaive ZIKV infections and found inhibition was achieved within 10 d postonset of illness and maintained over time. Thus, the Zika NS1 BOB assay is sensitive, specific, robust, simple, low-cost, and accessible, and can detect recent and past ZIKV infections for surveillance, seroprevalence studies, and intervention trials.

Clonally propagated crop species are less adaptable to environmental changes than those propagating sexually. DNA studies have shown that in all countries where taro ( Colocasia esculenta (L.) Schott) has been introduced clonally its genetic base is narrow. As genetic variation is the most important source of adaptive potential, it appears interesting to attempt to increase genetic and phenotypic diversity to strengthen smallholders’ capacity to adapt to climatic changes. A global experiment, involving 14 countries from America, Africa, Asia and the Pacific was conducted to test this approach. Every country received a set of 50 indexed genotypes in vitro assembling significant genetic diversity. After on-station agronomic evaluation trials, the best genotypes were distributed to farmers for participatory on-farm evaluation. Results indicated that hybrids tolerant to taro leaf blight (TLB, Phytophthora colocasiae Raciborski), developed by Hawaii, Papua New Guinea and Samoa breeding programmes outperformed local cultivars in most locations. However, several elite cultivars from SE Asia, also tolerant to TLB, outperformed improved hybrids in four countries and in one country none of the introductions performed better than the local cultivars. Introduced genotypes were successfully crossed (controlled crossing) with local cultivars and new hybrids were produced. For the first time in the history of Aroids research, seeds were exchanged internationally injecting tremendous allelic diversity in different countries. If climatic changes are going to cause the problems envisaged, then breeding crops with wide genetic diversity appears to be an appropriate approach to overcome the disasters that will otherwise ensue.

This paper presents the results, after a long-term evaluation in marine environments, from an Ibero-American project called “Effect of the environment on reinforcement durability” (DURACON). This project correlates the influence of urban and marine meteorochemical parameters on the performance of reinforced concrete structures in nine countries (Bolivia, Chile, Colombia, Costa Rica, Mexico, Spain, Uruguay, Portugal, and Venezuela). The environment was evaluated using ISO Standard 9223 and the concrete was characterized physically by measuring compressive strength, elastic modulus, total and effective porosity, as well as the effective porosity and resistance to water absorption using the Fagerlund method. To that effect, concrete specimens (with and without reinforcement) were prepared for electrochemical and physical/mechanical/chemical tests using the existing materials in each participating country, following strict procedures that enabled the preparation of similar concrete specimens. Two water/cement (w/c) ratios (0.45 and 0.65) were selected, where 0.45 w/c ratio concrete had a minimum cement content of 400 kg/m3 and the one with 0.65 w/c ratio had a minimum 28-d compressive strength of 210 kg/cm2. Type I Portland cement, siliceous sand, and crushed rock as coarse aggregates (13-mm maximum nominal size) were used. The results showed that the atmospheric aggressiveness was higher in tropical countries, especially when temperature rises above 25°C, with La Voz station (marine) in Venezuela being the most aggressive. Also, the chloride concentration threshold for rebar depassivation onset was much lower (≈0.42%) in a marine tropical environment, such as La Voz in Venezuela, compared to a nontropical one, such as Cabo Raso in Portugal (≈0.89%), with this concentration dependent on rebar depth and influenced by environmental factors such as time of wetness and ambient temperature, and not only from physical concrete properties.

Background. Little is known about the clinical presentation and epidemiology of influenza A H1N1pdm in children in developing countries. We assessed the severity of influenza A H1N1pdm in children in Nicaragua by comparing H1N1pdm cases to seasonal influenza cases in an ongoing cohort study. Methods. The Nicaraguan Influenza Cohort Study was established in June 2007 to study the burden and seasonality of pediatric influenza in a tropical developing country. During the period from June 2007 through November 2009, a total of 4391 children aged 2–14 years participated in the cohort. We examined the attack rate of clinical influenza and assessed symptoms at first presentation in febrile patients with H1N1pdm versus those with seasonal influenza A or B. Results. The estimated clinical attack rate of H1N1pdm in the cohort was 20.1%, compared to 11.7% and 15.1% for seasonal influenza A and 11.9% and 24.2% for seasonal influenza A and B in 2007 and 2008, respectively. Symptoms significantly associated with H1N1pdm cases versus seasonal influenza A cases were sore throat (adjusted odds ratio [OR], 1.7; 95% confidence interval [CI], 1.2–2.5), wheezing (OR, 5.1; 95% CI, 1.3–19.0), rhonchi (OR, 4.6; 95% CI, 1.4–15.0), crepitations (OR, 16.2; 95% CI, 2.1–128.7), pneumonia (OR, 8.0; 95% CI, 1.7–37.3), nausea (OR, 2.8; 95% CI, 1.5–5.1), and loss of appetite (OR, 2.1; 95% CI, 1.4–3.1). In addition, 3 concurrent influenza and dengue virus coinfections were identified. Conclusions. Children with influenza A H1N1pdm presented with significantly more symptoms of lower respiratory infection and gastrointestinal symptoms than children with seasonal influenza. The clinical influenza attack rate was high in both pandemic and seasonal years.