No abstract

The yeast telomerase holoenzyme, which adds telomeric repeats at the chromosome ends, is composed of the TLC1 RNA and the associated proteins Est1, Est2 and Est3. To study the biogenesis of telomerase in endogenous conditions, we performed fluorescent in situ hybridization on the native TLC1 RNA. We found that the telomerase RNA colocalizes with telomeres in G1-to S-phase cells. Strains lacking any one of the Est proteins accumulate TLC1 RNA in their cytoplasm, indicating that a critical stage of telomerase biogenesis could take place outside of the nucleus. We were able to demonstrate that endogenous TLC1 RNA shuttles between the nucleus and the cytoplasm, in association with the Crm1p exportin and the nuclear importins Mtr10p-Kap122p. Furthermore, nuclear retention of the TLC1 RNA is impaired in the absence of yKu70p, Tel1p or the MRX complex, which recruit telomerase to telomeres. Altogether, our results reveal that the nucleo-cytoplasmic trafficking of the TLC1 RNA is an important step in telomere homeostasis, and link telomerase biogenesis to its recruitment to telomeres.

In Saccharomyces cerevisiae, over twenty mRNAs localize to the bud tip of daughter cells, playing roles in processes as different as mating type switching and plasma membrane targeting. The localization of these transcripts depends on interactions between a cis-acting localization element(s) or zipcodes and the RNAbinding protein She2p. While previous studies identified four different localization elements in the budlocalized ASH1 mRNA, the main determinants for She2p recognition are still unknown. To investigate the RNA-binding specificity of She2p, we isolated She2p-binding RNAs by in vivo selection from libraries of partially randomized ASH1 localization elements. The RNAs isolated contained a similar loop-stem-loop structure with a highly conserved CGA triplet in one loop and a single conserved cytosine in the other loop. Mutating these conserved nucleotides or the stem separating them resulted in the loss of She2p binding and in the delocalization of a reporter mRNA. Using this information, we identified the same RNA motif in two other known bud-localized transcripts, suggesting that this motif is conserved among bud-localized mRNAs. These results show that mRNAs with zipcodes lacking primary sequence similarity can rely on a few conserved nucleotides properly oriented in their three-dimensional structure in order to be recognized by the same localization machinery.

Alzheimer's disease (AD) is characterized by a progressive deterioration of various cognitive and behavioral abilities, and it also has a health impact on the patients' caregiver. Our aim was to determine the patient (and to a lesser extent the caregiver) characteristics that contribute most to the caregiver burden. We used the baseline data from the ICTUS study, a European longitudinal cohort of patients with mild to moderate AD. Data from 1091 patients and their caregivers was used for analysis. Three principal components analyses were performed on variables from the domains of cognition, neuropsychiatric symptoms, and daily function using the MMSE plus the ADAS-Cog, NPI, and IADL subscores, respectively. These were followed by a stepwise logistic regression to identify patient characteristics which best predict caregiver burden. The regression model (R2 = 0.35, p < 0.001) shows that the best explanatory variables are: 1) neuropsychiatric symptoms (NPI); 2) difficulties in the IADL; 3) time taken by caregiving; 4) demographic variables such as caregiver's age and patient sex; and 5) severity of cognitive impairment. In conclusion, our results demonstrate that although the strongest determinant of the caregiver burden is behavioral disturbance, the impact of the degree of cognitive impairment on burden is also significant.

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Pertussis is an acute respiratory disease caused by Bordetella pertussis . Due to its frequency and severity, prevention of pertussis has been considered an important public health issue for many years. The development of the whole-cell pertussis vaccine (wPV) and its introduction into the pediatric immunization schedule was associated with a marked reduction in pertussis cases in the vaccinated cohort. However, due to the frequency of local and systemic adverse events after immunization with wPV, work on a less reactive vaccine was undertaken based on isolated B. pertussis components that induced protective immune responses with fewer local and systemic reactions. These component vaccines were termed acellular vaccines and contained one or more pertussis antigens, including pertussis toxin (PT), filamentous haemagglutinin (FHA), pertactin (PRN), and fimbrial proteins 2 (FIM2) and 3 (FIM3). Preparations containing up to five components were developed, and several efficacy trials clearly demonstrated that the aPVs were able to confer comparable short-term protection than the most effective wPVs with fewer local and systemic reactions. There has been a resurgence of pertussis observed in recent years. This paper reports the results of a Consensus Conference organized by the World Association for Infectious Disease and Immunological Disorders (WAidid) on June 22, 2018, in Perugia, Italy, with the goal of evaluating the most important reasons for the pertussis resurgence and the role of different aPVs in this resurgence.

Partnerships involving NGOs and academic researchers (NGO-R partnerships) are increasing in global health research. Such collaborations present opportunities for knowledge translation in global health, yet are also associated with challenges for establishing and sustaining effective and respectful partnerships. We conducted a narrative review of the literature to identify benefits and challenges associated with NGO-R partnerships, as well as approaches that promote successful partnerships. We illustrate this analysis with examples from our own experiences. The results suggest that collaborations characterised by trust, transparency, respect, solidarity, and mutuality contribute to the development of successful and sustainable NGO-R partnerships. Les partenariats englobant des ONG et des chercheurs universitaires (partenariats ONG-C) sont de plus en plus nombreux dans le domaine de la recherche mondiale sur la santé. Ces collaborations présentent des occasions de traduction des connaissances en matière de santé globale, mais sont également associées à des difficultés sur le plan de l'établissement et du maintien de partenariats respectueux. Nous avons effectué une revue documentaire narrative afin d'identifier les avantages et les difficultés associées aux partenariats ONG-C, ainsi que les approches qui favorisent des partenariats réussis. Nous illustrons ces analyses au moyen d'exemples tirés de nos propres expériences. Les résultats suggèrent que les collaborations se caractérisant par la confiance, la transparence, le respect, la solidarité et la réciprocité contribuent au développement de partenariats ONG-C efficaces.En el ámbito de las pesquisas efectuadas en torno a la salud a nivel mundial, cada vez existen más alianzas entre ONG e investigadores académicos (alianzas ONG-I). Si bien estas colaboraciones representan oportunidades para difundir mundialmente los conocimientos en salud, también se caracterizan por los retos que implica establecer y sostener alianzas efectivas y respetuosas. A partir de una revisión narrativa de la literatura académica, los autores del presente estudio buscaron identificar los beneficios y los retos asociados a las alianzas ONG-I, así como los enfoques que promueven alianzas exitosas. Para ilustrar este análisis, los autores aportan ejemplos de su propia experiencia. En este sentido, los resultados sugieren que aquellas colaboraciones caracterizadas por la confianza, la transparencia, el respeto, la solidaridad y la mutualidad contribuyen al establecimiento de alianzas ONG-I exitosas y sostenibles.

The incidence of rheumatic fever has declined in industrialized countries since the 1950s and now has an annual incidence of around 0.5 cases per 100,000 children of school age. In developing countries it remains an endemic disease with annual incidences ranging from 100 to 200 per 100,000 school-aged children and is a major cause of cardiovascular mortality. Interest in the pathogenesis of rheumatic fever was rekindled by outbreaks in the USA (1985-1987) and the rare cases still seen in industrialized countries. The current concept is that the disease results from the host's poorly adapted autoimmune response to group A beta-haemolytic streptococci. The risk of developing rheumatic fever following untreated tonsillopharyngitis is 1% in the civilian population. Knowledge of virulence factors has been greatly enriched by progress in molecular biology. One of the key elements is protein M, a surface protein on the bacterial wall which carries specific epitopes. Several serotypes which lead to rheumatic fever have been recognized among more than 80 identified serotypes. However, the reason why specific strains within a given serotype have increased rheumatogenic virulence remains unknown. The causal strain adheres to the oral and pharyngeal cells and then releases its degradation products. These products present antigenic determinants which cross-react with certain human tissues, particularly in cardiac valve tissue and myocardium. Diagnosis is now difficult owing to the low incidence. Late diagnosis can have serious consequences and acute rheumatic fever is a therapeutic emergency requiring immediate antibiotic and anti-inflammatory treatment. In most of Europe there is tacit agreement that all cases of pharyngitis and tonsillitis should be treated with antibiotics without identification of the causal agent despite the fact that only about 20% of the cases are caused by group A beta-haemolytic streptococci, and could lead to rheumatic fever.