Telomere length regulation: coupling DNA end processing to feedback regulation of telomerase

The conventional DNA polymerase machinery is unable to fully replicate the ends of linear chromosomes. To surmount this problem, nearly all eukaryotes use the telomerase enzyme, a specialized reverse transcriptase that utizes its own RNA template to add short TG-rich repeats to chromosome ends, thus reversing their gradual erosion occurring at each round of replication. This unique, non-DNA templated mode of telomere replication requires a regulatory mechanism to ensure that telomerase acts at telomeres whose TG tracts are too short, but not at those with long tracts, thus maintaining the protective TG repeat cap at an appropriate average length. The prevailing notion in the field is that telomere length regulation is brought about through a negative feedback mechanism that counts TG repeat-bound protein complexes to generate a signal that regulates telomerase action. This review summarizes experiments leading up to this model and then focuses on more recent experiments, primarily from yeast, that begin to suggest how this counting mechanism might work. The emerging picture is that of a complex interplay between the conventional DNA replication machinery, DNA damage response factors, and a specialized set of proteins that help to recruit and regulate the telomerase enzyme

Élargir les mandats de responsabilité sociale à la recherche biomédicale dans les facultés canadiennes

Background: Social accountability (SA), as defined by Boelen and Heck, is the obligation of medical schools to address the needs of communities through education, research and service activities. While SA is embedded within health profession education frameworks in medicine, they are rarely taught within graduate-level (MSc/PhD) education. Methods: As these programs train future medical researchers, we invited first-year graduate students enrolled in a mandatory professionalism class at our institution (n = 111) to complete a survey on their perceptions of the importance of SA in their research, training, and future careers. Results: Over 80% (n = 87) of respondents agreed that SA is relevant and felt committed to integrating it into their future research activities, only a limited number of students felt confident and/or supported in their abilities to integrate SA into their research. Conclusions: Specific SA training in graduate education is necessary for students to effectively incorporate elements of SA into their research, and as such support the SA mandates of their training institutions. We posit that awareness of SA principles formalizes the professional standards for biomedical researchers and is thus foundational for developing a professionalism curriculum in graduate education programs in medicine. We propose an expansion of the World Health Organization (WHO) partnership pentagon to include partners within the research ecosystem (funding partners, certification bodies) that collaborate with biomedical researchers to make research socially accountable.Contexte : La responsabilité sociale (RS), telle que définie par Boelen et Heck, est l'obligation pour les facultés de médecine de répondre aux besoins des communautés par l’entremise de l'éducation, de la recherche et des activités de service. Bien que la responsabilité sociale soit intégrée dans les cadres de formation des professionnels de santé en médecine, elle est rarement enseignée au niveau des études supérieures (MSc/PhD). Méthodes : Étant donné que ces programmes forment les futurs chercheurs médicaux, nous avons invité les étudiants de première année inscrits à un cours obligatoire sur le professionnalisme dans notre établissement (n = 111) à participer à une enquête sur leurs perceptions de l'importance de la RS dans leur recherche, leur formation et leur future carrière. Résultats : Plus de 80 % (n = 87) des répondants ont reconnu la pertinence de la RS et se sont engagés à l'intégrer dans leurs futures activités de recherche, mais seul un nombre limité d'étudiants se sont sentis confiants et/ou soutenus dans leurs capacités à intégrer la RS dans leur recherche. Conclusions : Une formation propre à la RS dans le cadre des études supérieures est nécessaire pour que les étudiants puissent intégrer efficacement des éléments de la RS dans leur recherche, et ainsi promouvoir les mandats de RS de leurs établissements de formation. Nous estimons que la sensibilisation aux principes de la RS formalise les normes professionnelles des chercheurs biomédicaux et qu'elle est donc fondamentale pour l'élaboration d'un programme de professionnalisme dans les programmes d'études supérieures en médecine. Nous proposons d'élargir le pentagone du partenariat de l'Organisation mondiale de la santé (OMS) pour y inclure les partenaires de l'écosystème de la recherche (partenaires financiers, organismes de certification) qui collaborent avec les chercheurs biomédicaux pour rendre la recherche socialement responsable

State–Space Forecasting of Schistosoma haematobium Time-Series in Niono, Mali

Adequate forecasting and early warning systems are based upon observations of human behavior, population, disease time-series, climate, environment, and/or a combination thereof, whichever option best compromises among realism, feasibility, robustness, and parsimony. Fully automatic and user-friendly state–space forecasting frameworks, incorporating myriad options (e.g., expert opinion, univariate, multivariate, and spatial-temporal), could considerably enhance disease control and hazard mitigation efforts in regions where vulnerability to neglected tropical diseases is pervasive and statistical expertise is scarce. The operational simplicity, generality, and flexibility of state–space frameworks, encapsulating multiple methods, could conveniently allow for 1) unsupervised model selection without disease-specific methodological tailoring, 2) on-line adaptation to disease time-series fluctuations, and 3) automatic switches between distinct forecasting methods as new time-series perturbations dictate. In this investigation, a univariate state–space framework with the aforementioned properties was successfully applied to the Schistosoma haematobium time-series for the district of Niono, Mali, to automatically generate contemporaneous on-line forecasts and hence, providing a basis for local re-organization and strengthening public health programs in this and potentially other Sahelian districts

Caterpillars and fungal pathogens: two co-occurring parasites of an ant-plant mutualism

In mutualisms, each interacting species obtains resources from its partner that it would obtain less efficiently if alone, and so derives a net fitness benefit. In exchange for shelter (domatia) and food, mutualistic plant-ants protect their host myrmecophytes from herbivores, encroaching vines and fungal pathogens. Although selective filters enable myrmecophytes to host those ant species most favorable to their fitness, some insects can by-pass these filters, exploiting the rewards supplied whilst providing nothing in return. This is the case in French Guiana for Cecropia obtusa (Cecropiaceae) as Pseudocabima guianalis caterpillars (Lepidoptera, Pyralidae) can colonize saplings before the installation of their mutualistic Azteca ants. The caterpillars shelter in the domatia and feed on food bodies (FBs) whose production increases as a result. They delay colonization by ants by weaving a silk shield above the youngest trichilium, where the FBs are produced, blocking access to them. This probable temporal priority effect also allows female moths to lay new eggs on trees that already shelter caterpillars, and so to occupy the niche longer and exploit Cecropia resources before colonization by ants. However, once incipient ant colonies are able to develop, they prevent further colonization by the caterpillars. Although no higher herbivory rates were noted, these caterpillars are ineffective in protecting their host trees from a pathogenic fungus, Fusarium moniliforme (Deuteromycetes), that develops on the trichilium in the absence of mutualistic ants. Therefore, the Cecropia treelets can be parasitized by two often overlooked species: the caterpillars that shelter in the domatia and feed on FBs, delaying colonization by mutualistic ants, and the fungal pathogen that develops on old trichilia. The cost of greater FB production plus the presence of the pathogenic fungus likely affect tree growth

Capacitative calcium influx and proliferation of human osteoblastic-like MG-63 cells

Adult bone tissue is continuously being remodelled and bone mass is maintained by a balance between osteoclastic bone resorption and osteoblastic bone formation. Alteration of osteoblastic cell proliferation may account in part for lack of balance between these two processes in bone loss of osteoporosis. There is calcium (Ca2+) control in numerous cellular functions; however, involvement of capacitative Ca2+ entry (CCE) in proliferation of bone cells is less well investigated. OBJECTIVES: The study described here was aimed to investigate roles of CCE in the proliferation of osteoblast-like MG-63 cells. MATERIALS AND METHODS: Pharmacological characterizations of CCE were undertaken in parallel, with evaluation of the expression of transient receptor potential canonical (TRPC) channels and of cell proliferation. RESULTS: Intracellular Ca2+ store depletion by thapsigargin induced CCE in MG-63 cells; this was characterized by a rapid transient increase of intracellular Ca2+ followed by significant CCE, induced by conditions that stimulated cell proliferation, namely serum and platelet-derived growth factor. Inhibitors of store-operated Ca2+ channels (2-APB and SKF-96365) prevented CCE, while voltage-dependent Ca2+ channel blockers had no effect. Expression of various TRPC channels was shown in the cells, some having been shown to be responsible for CCE. Voltage-dependent Ca2+ channel blockers had no effect on osteoblast proliferation while thapsigargin, 2-APB and SKF-96395, inhibited it. Cell cycle analysis showed that 2-APB and SKF-96395 lengthen the S and G2/M phases, which would account for the reduction in cell proliferation. CONCLUSIONS: Our results indicate that CCE, likely attributed to the activation of TRPCs, might be the main route for Ca2+ influx involved in osteoblast proliferation

Interpretability of spatiotemporal dynamics of the brain processes followed by mindfulness intervention in a brain-inspired spiking neural network architecture

Mindfulness training is associated with improvements in psychological wellbeing and cognition, yet the specific underlying neurophysiological mechanisms underpinning these changes are uncertain. This study uses a novel brain-inspired artificial neural network to investigate the effect of mindfulness training on electroencephalographic function. Participants completed a 4-tone auditory oddball task (that included targets and physically similar distractors) at three assessment time points. In Group A (n = 10), these tasks were given immediately prior to 6-week mindfulness training, immediately after training and at a 3-week follow-up; in Group B (n = 10), these were during an intervention waitlist period (3 weeks prior to training), pre-mindfulness training and post-mindfulness training. Using a spiking neural network (SNN) model, we evaluated concurrent neural patterns generated across space and time from features of electroencephalographic data capturing the neural dynamics associated with the event-related potential (ERP). This technique capitalises on the temporal dynamics of the shifts in polarity throughout the ERP and spatially across electrodes. Findings support anteriorisation of connection weights in response to distractors relative to target stimuli. Right frontal connection weights to distractors were associated with trait mindfulness (positively) and depression (inversely). Moreover, mindfulness training was associated with an increase in connection weights to targets (bilateral frontal, left frontocentral, and temporal regions only) and distractors. SNN models were superior to other machine learning methods in the classification of brain states as a function of mindfulness training. Findings suggest SNN models can provide useful information that differentiates brain states based on distinct task demands and stimuli, as well as changes in brain states as a function of psychological intervention

Novel Bradykinin Analogues Modified in the N-Terminal Part of the Molecule with a Variety of Acyl Substituents

In the current work we present some pharmacological characteristics of ten new analogues of bradykinin (Arg–Pro–Pro–Gly–Phe–Ser–Pro–Phe–Arg) modified in the N-terminal part of the molecule with a variety of acyl substituents. Of the many acylating agents used previously with B2 receptor antagonists, the following residues were chosen: 1-adamantaneacetic acid (Aaa), 1-adamantanecarboxylic acid (Aca), 4-tert-butylbenzoic acid (t-Bba), 4-aminobenzoic acid (Aba), 12-aminododecanoic acid (Adc), succinic acid (Sua), 4-hydroxybenzoic acid, 4-hydroxy-3-methoxybenzoic acid, 3-(4-hydroxyphenyl)propionic acid and 6-hydroxy-2-naphthoic acid. Biological activity of the compounds was assessed in the in vivo rat blood pressure test and the in vitro rat uterus test. Surprisingly, N-terminal substitution of the bradykinin peptide chain itself with aforementioned groups resulted in antagonists of bradykinin in the pressor test and suppressed agonistic potency in the uterotonic test. These interesting findings need further studies as they can be helpful for designing more potent B2 receptor blockers