TimiRGeN: R/Bioconductor package for time series microRNA-mRNA integration and analysis.

MOTIVATION: The analysis of longitudinal datasets and construction of gene regulatory networks (GRNs) provide a valuable means to disentangle the complexity of microRNA (miRNA)-mRNA interactions. However, there are no computational tools that can integrate, conduct functional analysis and generate detailed networks from longitudinal miRNA-mRNA datasets. RESULTS: We present TimiRGeN, an R package that uses time point-based differential expression results to identify miRNA-mRNA interactions influencing signaling pathways of interest. miRNA-mRNA interactions can be visualized in R or exported to PathVisio or Cytoscape. The output can be used for hypothesis generation and directing in vitro or further in silico work such as GRN construction. AVAILABILITY AND IMPLEMENTATION: TimiRGeN is available for download on Bioconductor (https://bioconductor.org/packages/TimiRGeN) and requires R v4.0.2 or newer and BiocManager v3.12 or newer. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

A dynamic framework for the study of optimal birth intervals reveals the importance of sibling competition and mortality risks.

Human reproductive patterns have been well studied, but the mechanisms by which physiology, ecology and existing kin interact to affect the life history need quantification. Here, we create a model to investigate how age-specific interbirth intervals adapt to environmental and intrinsic mortality, and how birth patterns can be shaped by competition and help between siblings. The model provides a flexible framework for studying the processes underlying human reproductive scheduling. We developed a state-based optimality model to determine age-dependent and family-dependent sets of reproductive strategies, including the state of the mother and her offspring. We parameterized the model with realistic mortality curves derived from five human populations. Overall, optimal birth intervals increase until the age of 30 after which they remain relatively constant until the end of the reproductive lifespan. Offspring helping each other does not have much effect on birth intervals. Increasing infant and senescent mortality in different populations decreases interbirth intervals. We show that sibling competition and infant mortality interact to lengthen interbirth intervals. In lower-mortality populations, intense sibling competition pushes births further apart. Varying the adult risk of mortality alone has no effect on birth intervals between populations; competition between offspring drives the differences in birth intervals only when infant mortality is low. These results are relevant to understanding the demographic transition, because our model predicts that sibling competition becomes an important determinant of optimal interbirth intervals only when mortality is low, as in post-transition societies. We do not predict that these effects alone can select for menopause.

The plastic fly: the effect of sustained fluctuations in adult food supply on life-history traits.

Many adult traits in Drosophila melanogaster show phenotypic plasticity, and the effects of diet on traits such as lifespan and reproduction are well explored. Although plasticity in response to food is still present in older flies, it is unknown how sustained environmental variation affects life-history traits. Here, we explore how such life-long fluctuations of food supply affect weight and survival in groups of flies and affect weight, survival and reproduction in individual flies. In both experiments, we kept adults on constant high or low food and compared these to flies that experienced fluctuations of food either once or twice a week. For these 'yoyo' groups, the initial food level and the duration of the dietary variation differed during adulthood, creating four 'yoyo' fly groups. In groups of flies, survival and weight were affected by adult food. However, for individuals, survival and reproduction, but not weight, were affected by adult food, indicating that single and group housing of female flies affects life-history trajectories. Remarkably, both the manner and extent to which life-history traits varied in relation to food depended on whether flies initially experienced high or low food after eclosion. We therefore conclude that the expression of life-history traits in adult life is affected not only by adult plasticity, but also by early adult life experiences. This is an important but often overlooked factor in studies of life-history evolution and may explain variation in life-history experiments.

Does HIPE data capture the complexity of stroke patients in an acute hospital setting?

The Hospital Inpatient Enquiry (HIPE) system is currently used as a principle source of national data on discharges from acute hospitals. The Casemix Programme is used to calculate funding for patient care (HIPE activity and Specialty Costs Returns). Th coding is usually undertaken by clerical personnel. We were concerned that the medical complexity of our stroke patients was not captured by the process. The aims of this study were to compare activity coded by HIPE coding staff and medical staff in consecutive stroke patients discharged from the hospital. One hundred consecutive discharged patients with stroke as primary diagnosis were coded by clerical staff [usual practice] and by medical staff. We compared the coding and any differences. We calculated the financial comparison of subsequent differences in Diagnostic Related Groups (DRGs) and Relative Values (RVs). Clinician coded DRGs resulted in a higher assigned RV in 45 cases. The total RV value for HIPE using clerical coding was 595,268.94 euros and using medical coding was 725,252.16 euros. We conclude that medical input is useful in detailing the complications arising in stroke patients. We suggest that physicians should assist in the HIPE coding process in order to capture clinical complexity, so that funding can be appropriately assigned to manage these complex patients.

Nine years of DentEd--a global perspective on dental education.

This paper describes the three successive and successful DentEd projects, funded by the European Union, that established a productive thematic network which identified common content within the dental curriculum. It then developed an agreed professional profile, with a defined set of competences and a modular curriculum for all new dental graduates based on the European Credit Transfer System and trends in learning and assessment. The three phases took nine years to complete. Phase one investigated all aspects of dental undergraduate education and included over 30 visits to different dental schools by teams of dental educators. Phase two built on this work and included further visits to dental schools. Phase three refined the competency framework that had been developed in phase two and culminated in a global dental conference which finalised position papers on all aspects of dental education. The work and recommendations of the ICT in dental education group are considered in detail in the paper. The projects provided the stimulus for a number of European and international collaborations, including the web-based International Federation of Dental Education and Associations (IFDEA) Knowledge Centre and the International Virtual Dental School (IVIDENT), both of which aim to make increasingly sophisticated ICT-based educational material available worldwide and to promote international understanding.

The global network on dental education: a new vision for IFDEA.

The advent of globalization has changed our perspectives radically. It presents increased understanding of world affairs, new challenges and exciting opportunities. The inequitable distribution and use of finite energy resources and global warming are just two examples of challenges that can only be addressed by concerted international collaboration. Globalization has become an increasingly important influence on dentistry and dental education. The International Federation for Dental Educators and Associations (IFDEA) welcomes the challenges it now faces as a player in a complex multifaceted global community. This report addresses the new circumstances in which IFDEA must operate, taking account of the recommendations made by other working groups. The report reviews the background and evolution of IFDEA and describes the extensive developments that have taken place in IFDEA over the past year with the introductions of a new Constitution and Bylaws overseen by a newly established Board of Directors. These were the consequence of a new mission, goals and objectives for IFDEA. An expanded organization is planned using http://www.IFDEA.org as the primary instrument to facilitate the exchange of knowledge, programmes and expertise between colleagues and federated associations throughout the world, thereby promoting higher standards in oral health through education in low-, middle- and high-income countries of the world. Such aspirations are modified by the reality and enormity of poverty-related global ill health.

Modelling the checkpoint response to telomere uncapping in budding yeast.

One of the DNA damage-response mechanisms in budding yeast is temporary cell-cycle arrest while DNA repair takes place. The DNA damage response requires the coordinated interaction between DNA repair and checkpoint pathways. Telomeres of budding yeast are capped by the Cdc13 complex. In the temperature-sensitive cdc13-1 strain, telomeres are unprotected over a specific temperature range leading to activation of the DNA damage response and subsequently cell-cycle arrest. Inactivation of cdc13-1 results in the generation of long regions of single-stranded DNA (ssDNA) and is affected by the activity of various checkpoint proteins and nucleases. This paper describes a mathematical model of how uncapped telomeres in budding yeast initiate the checkpoint pathway leading to cell-cycle arrest. The model was encoded in the Systems Biology Markup Language (SBML) and simulated using the stochastic simulation system Biology of Ageing e-Science Integration and Simulation (BASIS). Each simulation follows the time course of one mother cell keeping track of the number of cell divisions, the level of activity of each of the checkpoint proteins, the activity of nucleases and the amount of ssDNA generated. The model can be used to carry out a variety of in silico experiments in which different genes are knocked out and the results of simulation are compared to experimental data. Possible extensions to the model are also discussed.

Differential enhancement of dengue virus immune complex infectivity mediated by signaling-competent and signaling-incompetent human Fcgamma RIA (CD64) or FcgammaRIIA (CD32).

Fcgamma receptor (FcgammaR)-mediated entry of infectious dengue virus immune complexes into monocytes/macrophages is hypothesized to be a key event in the pathogenesis of complicated dengue fever. FcgammaRIA (CD64) and FcgammaRIIA (CD32), which predominate on the surface of such dengue virus-permissive cells, were compared for their influence on the infectivity of dengue 2 virus immune complexes formed with human dengue virus antibodies. A signaling immunoreceptor tyrosine-based activation motif (ITAM) incorporated into the accessory gamma-chain subunit that associates with FcgammaRIA and constitutively in FcgammaRIIA is required for phagocytosis mediated by these receptors. To determine whether FcgammaRIA and FcgammaRIIA activation functions are also required for internalization of infectious dengue virus immune complexes, we generated native and signaling-incompetent versions of each receptor by site-directed mutagenesis of ITAM tyrosine residues. Plasmids designed to express these receptors were transfected into COS-7 cells, and dengue virus replication was measured by plaque assay and flow cytometry. We found that both receptors mediated enhanced dengue virus immune complex infectivity but that FcgammaRIIA appeared to do so far more effectively. Abrogation of FcgammaRIA signaling competency, either by expression without gamma-chain or by coexpression with gamma-chain mutants, was associated with significant impairment of phagocytosis and of dengue virus immune complex infectivity. Abrogation of FcgammaRIIA signaling competency was also associated with equally impaired phagocytosis but had no discernible effect on dengue virus immune complex infectivity. These findings point to fundamental differences between FcgammaRIA and FcgammaRIIA with respect to their immune-enhancing capabilities and suggest that different mechanisms of dengue virus immune complex internalization may operate between these FcgammaRs.

Contents of stomatological curricula in Europe.

The present study focuses on dental education in the Accession Countries to the European Union. Comparisons were made with data from EU dental schools [Eur J Dent Educ 1 (1997) 35]. The findings show a large variation in the hours allocated to individual subjects, medical and dental, both within and between AC and EU dental schools. Stomatology derived from General Medicine and the stomatologist is viewed as a doctor responsible for one part of the body. This was explained by the large proportion of time dedicated to medical subjects, especially in the first 2/3 years of the undergraduate curriculum. The percentage of hours for dental sciences varied inversely to those for bio-medical sciences and increase continuously from the first year to the final year. Curricula in the Stomatological schools tend to have a discipline-structured approach, generally utilising a large number of individual departments, resulting in a multitude of subjects being taught. Curricular extensions from 5 to 6 years were introduced in some schools from 1990 onwards in order to accommodate new dental subjects.

Policies and practices of European dental schools in relation to smoking; a ten-year follow-up.

OBJECTIVE: To investigate the policies and practices of European dental schools in relation to smoking as a ten-year follow-up. DESIGN: A postal survey questionnaire. SETTING: European dental schools in 2003. MATERIALS AND METHODS: Two hundred and one European dental schools were identified from the DentEd database. A postal questionnaire was sent to each with up to three follow-up letters to non-responders. MAIN OUTCOME MEASURES: Results were tabulated and compared with the previous study (1993). RESULTS: The effective response rate (allowing for errors in the database) was 149 of 199 schools (72%). Eighty schools (59%) had written tobacco policies, 132 (92%) banned smoking in clinical areas, 127 (89%) in non-clinical areas and 122 (85%) in public access areas. One hundred and seven (76%) expected students to take tobacco histories from all patients, while 79 (69%) and 100 (70%) respectively taught students anti-smoking advice and expected them to give such advice. The number of schools teaching the role of tobacco in oral cancer aetiology was 133 (93%), in periodontal disease was 135 (94%) and in osseointegrated implant failure was 127 (91%). There was considerable regional variation between northern, southern and eastern Europe. Direct comparison of the responses of the 78 schools that replied in both 1993 and 2003 showed some improvements in most of their policies and practices. However, there was some deterioration in the practices of southern European schools. CONCLUSIONS: While improvements were seen in the practices of most schools, comparison with recent US data suggests that European schools lag behind. However, self-selection of respondents may have introduced bias into the results.

A comparative evaluation of computer literacy amongst dental educators and students.

A task-oriented questionnaire was designed, aiming to quickly assess competence with the use of computers. The questionnaire consisted of distinct computer-related skills, representing various competences in educational computer use. A total score from 0 to 49 was calculated upon completion of the questionnaire, based on the sum of all the positively identified competences. The questionnaire was distributed to an international group of leading dental educators during the DentEd Global Congress in Prague in 2001 and to a cohort of first year dental students (2001) in the Dental Faculty, University of Malmo, Sweden. Certain attitudes towards the role of information and communication technology (ICT) in dental education were also measured through Visual Analogue Scales in the educator's group. A total of 149 questionnaires were collected from the educators' group and 58 from the dental students. There was no significant difference in the average computer competence score between the two groups. The educators' group average score was 20.7 (SD 9.9) and students' average was 18.1 (SD 8.5). A significant positive correlation (r = 0.395277, P < 0.0001) was found between the competence measured by the questionnaire and the year of graduation in the educators' group. The attitudes towards the role of ICT in dental education amongst the educators were very positive, regardless of their competence with computers, year of graduation or academic position. The results from this study indicate that there is wide diversity in computer competence amongst both students and academic staff. In addition, students' actual competence in the use of computers might not be as high as is often perceived through self-assessment and ordinal scales.

Evolution of the human menopause.

Menopause is an evolutionary puzzle since an early end to reproduction seems contrary to maximising Darwinian fitness. Several theories have been proposed to explain why menopause might have evolved, all based on unusual aspects of the human life history. One theory is that menopause follows from the extreme altriciality of human babies, coupled with the difficulty in giving birth due to the large neonatal brain size and the growing risk of child-bearing at older ages. There may be little advantage for an older mother in running the increased risk of a further pregnancy when existing offspring depend critically on her survival. An alternative theory is that within kin groups menopause enhances fitness by producing post-reproductive grandmothers who can assist their adult daughters. Such theories need careful quantitative assessment to see whether the fitness benefits are sufficient to outweigh the costs, particularly in circumstances of relatively high background mortality typical of ancestral environments. We show that individual theories fail this test, but that a combined model incorporating both hypotheses can explain why menopause may have evolved.

Differentiation of Candida dubliniensis from Candida albicans on staib agar and caffeic acid-ferric citrate agar.

The methods currently available for the identification of the pathogenic yeast Candida dubliniensis all have disadvantages in that they are time-consuming, expensive, and/or, in some cases, unreliable. In a recent study (P. Staib and J. Morschhäuser, Mycoses 42:521-524; 1999) of 14 C. dubliniensis and 11 C. albicans isolates, it was suggested that the ability of C. dubliniensis to produce rough colonies and chlamydospores (chlamydoconidia) on Staib agar (SA) provided a simple means of differentiating it from its close relative C. albicans. In the present investigation, we examined the colony morphology and chlamydospore production of 130 C. dubliniensis and 166 C. albicans isolates on SA and on the related defined medium caffeic acid-ferric citrate agar (CAF). All of the C. dubliniensis and C. albicans isolates produced chlamydospores on the control medium, i.e., rice-agar-Tween agar. However, while none of the C. albicans isolates produced chlamydospores on either SA or CAF, 85.4 and 83.8% of the C. dubliniensis isolates produced chlamydospores on SA and CAF, respectively. All of the C. albicans isolates grew as smooth, shiny colonies on SA after 48 to 72 h of incubation at 30 degrees C, while 97.7% of the C. dubliniensis isolates grew as rough colonies, many (65%) with a hyphal fringe. In contrast, 87.4% of the C. albicans and 93.8% of the C. dubliniensis isolates yielded rough colonies on CAF. Although the results of this study confirm that SA is a good medium for distinguishing between C. dubliniensis and C. albicans, we believe that discrimination between these two species is best achieved on the basis of colony morphology rather than chlamydospore production.

Calorie restriction and aging: a life-history analysis.

The disposable soma theory suggests that aging occurs because natural selection favors a strategy in which fewer resources are invested in somatic maintenance than are necessary for indefinite survival. However, laboratory rodents on calorie-restricted diets have extended life spans and retarded aging. One hypothesis is that this is an adaptive response involving a shift of resources during short periods of famine away from reproduction and toward increased somatic maintenance. The potential benefit is that the animal gains an increased chance of survival with a reduced intrinsic rate of senescence, thereby permitting reproductive value to be preserved for when the famine is over. We describe a mathematical life-history model of dynamic resource allocation that tests this idea. Senescence is modeled as a change in state that depends on the resources allocated to maintenance. Individuals are assumed to allocate the available resources to maximize the total number of descendants. The model shows that the evolutionary hypothesis is plausible and identifies two factors, both likely to exist, that favor this conclusion. These factors are that survival of juveniles is reduced during periods of famine and that the organism needs to pay an energetic "overhead" before any litter of offspring can be produced. If neither of these conditions holds, there is no evolutionary advantage to be gained from switching extra resources to maintenance. The model provides a basis to evaluate whether the life-extending effects of calorie-restriction might apply in other species, including humans.

Delusion and desire: erotomania revisited.

OBJECTIVE: This paper examines the phenomonology in a case of erotomania and reviews classical and contemporary treatment options. METHOD: A case of primary erotomania is described. RESULTS: Treatment with hospitalization and risperidone produced rapid clinical improvement. CONCLUSION: Atypical antipsychotic drugs may be useful in the treatment of this interesting syndrome.

Evolution, stress, and longevity.

The disposable soma theory suggests that longevity is determined through the setting of longevity assurance mechanisms so as to provide an optimal compromise between investments in somatic maintenance (including stress resistance) and in reproduction. A corollary is that species with low extrinsic mortality are predicted to invest relatively more effort in maintenance, resulting in slower intrinsic ageing, than species with high extrinsic mortality. We tested this prediction in a comparative study of stress resistance in primary skin fibroblasts and confirmed that cells from long-lived species are indeed more resistant to a variant of stressors. A widely studied example of within-species variation in lifespan is the rodent calorie restriction model. Food-restricted animals show elevations in a range of stress response mechanisms, and it has been suggested that this is an outcome of natural selection for life history plasticity. We have developed a theoretical model for dynamic optimisation of the allocation of effort to maintenance and reproduction in response to fluctuations in food availability. The model supports the suggestion that the response to calorie restriction may be an evolutionary adaptation, raising interesting questions about the hierarchy of genetic control of multiple stress response systems. The model identifies ecological factors likely to support such an adaptation that may be relevant in considering the likely relevance of a similar response to calorie restriction in other species. Comparative and theoretical studies support the role of somatic maintenance and stress response systems in controlling the rate of ageing.