Reshaping the preterm heart: shifting cardiac renin-angiotensin system towards cardioprotection in rats exposed to neonatal high-oxygen stress

Background: Approximately 10% of infants are born preterm. Preterm birth leads to short and long-term changes in cardiac shape and function. By using a rat model of neonatal high-oxygen (80%O2) exposure, mimicking the premature hyperoxic transition to the extrauterine environment, we revealed a major role of the renin-angiotensin system peptide Angio II (angiotensin II) and its receptor AT1 (angiotensin receptor type 1) on neonatal O2-induced cardiomyopathy. Here, we tested whether treatment with either orally active compounds of the peptides Angio-(1–7) or alamandine included in cyclodextrin could prevent postnatal cardiac remodeling and the programming of cardiomyopathy induced by neonatal high-O2 exposure. Methods: Sprague-Dawley pups were exposed to room air or 80% O2 from postnatal day 3 (P3) to P10. Neonatal rats were treated orally from P3 to P10 and assessed at P10 and P28. Left ventricular (LV) shapes were characterized by tridimensional computational atlases of ultrasound images in addition to histomorphometry. Results: At P10, high O2-exposed rats presented a smaller, globular and hypertrophied LV shape versus controls. Treatment with cyclodextrin–Angio-(1–7) significantly improved LV function in the O2-exposed neonatal rats and slightly changed LV shape. Cyclodextrin-alamandine and cyclodextrin–Angio-(1–7) treatments similarly reduced hypertrophy at P10 as well as LV remodeling and dysfunction at P28. Both treatments upregulated cardiac angiotensin-converting enzyme 2 in O2-exposed rats at P10 and P28. Conclusions: Our findings demonstrate LV remodeling changes induced by O2-stress and the potential benefits of treatments targeting the cardioprotective renin-angiotensin system axis, supporting the neonatal period as an important window for interventions aiming at preventing cardiomyopathy in people born preterm

Activated mouse CD4+Foxp3−CD4^+Foxp3^− T cells facilitate melanoma metastasis via Qa-1-dependent suppression of NK-cell cytotoxicity

The regulatory activities of mouse $CD^4+Foxp3^+$ T cells on various immune cells, including NK cells, have been well documented. Under some conditions, conventional $CD4^+Foxp3^−$ T cells in the periphery are able to acquire inhibitory function on other T cells, but their roles in controlling innate immune cells are poorly defined. As a potential cellular therapy for cancer, ex vivo activated $CD4^+Foxp3^−$ effector T cells are often infused back in vivo to suppress tumor growth and metastasis. Whether such activated T cells could affect NK-cell control of tumorigenesis is unclear. In the present study, we found that mitogen-activated $CD4^+Foxp3^−$ T cells exhibited potent suppressor function on NK-cell proliferation and cytotoxicity in vitro, and notably facilitated B16 melanoma metastasis in vivo. Suppression of NK cells by activated $CD4^+Foxp3^−$ T cells is cell-cell contact dependent and is mediated by Qa-1:NKG2A interaction, as administration of antibodies blocking either Qa-1 or NKG2A could completely reverse this suppression, and significantly inhibited otherwise facilitated melanoma metastasis. Moreover, activated $CD4^+Foxp3^−$ cells from Qa-1 knockout mice completely lost the suppressor activity on NK cells, and failed to facilitate melanoma metastasis when transferred in vivo. Taken together, our findings indicate that innate anti-tumor response is counter regulated by the activation of adaptive immunity, a phenomenon we term as “activation-induced inhibition”. Thus, the regulatory role of activated $CD4^+Foxp3^−$ T cells in NK-cell activity must be taken into consideration in the future design of cancer therapies

Plant responses to photoperiod

Photoperiod controls many developmental responses in animals, plants and even fungi. The response to photoperiod has evolved because daylength is a reliable indicator of the time of year, enabling developmental events to be scheduled to coincide with particular environmental conditions. Much progress has been made towards understanding the molecular mechanisms involved in the response to photoperiod in plants. These mechanisms include the detection of the light signal in the leaves, the entrainment of circadian rhythms, and the production of a mobile signal which is transmitted throughout the plant. Flowering, tuberization and bud set are just a few of the many different responses in plants that are under photoperiodic control. Comparison of what is known of the molecular mechanisms controlling these responses shows that, whilst common components exist, significant differences in the regulatory mechanisms have evolved between these responses

A lncRNA fine tunes the dynamics of a cell state transition involving Lin28, let-7 and de novo DNA methylation

Execution of pluripotency requires progression from the naive status represented by mouse embryonic stem cells (ESCs) to a state capacitated for lineage specification. This transition is coordinated at multiple levels. Non-coding RNAs may contribute to this regulatory orchestra. We identified a rodent-specific long non-coding RNA (lncRNA) linc1281, hereafter Ephemeron (Eprn), that modulates the dynamics of exit from naive pluripotency. Eprn deletion delays the extinction of ESC identity, an effect associated with perduring Nanog expression. In the absence of Eprn, Lin28a expression is reduced which results in persistence of let-7 microRNAs, and the up-regulation of de novo methyltransferases Dnmt3a/b is delayed. Dnmt3a/b deletion retards ES cell transition, correlating with delayed Nanog promoter methylation and phenocopying loss of Eprn or Lin28a. The connection from lncRNA to miRNA and DNA methylation facilitates the acute extinction of naive pluripotency, a pre-requisite for rapid progression from preimplantation epiblast to gastrulation in rodents. Eprn illustrates how lncRNAs may introduce species-specific network modulations

Characterization of the Interaction and Cross-Regulation of Three Mycobacterium tuberculosis RelBE Modules

RelBE represents a typical bacterial toxin-antitoxin (TA) system. Mycobacterium tuberculosis H37Rv, the pathogen responsible for human tuberculosis, contains three RelBE-like modules, RelBE, RelFG, and RelJK, which are at least partly expressed in human macrophages during infection. RelBE modules appear to be autoregulated in an atypical manner compared to other TA systems; however, the molecular mechanisms and potential interactions between different RelBE modules remain to be elucidated. In the present study, we characterized the interaction and cross-regulation of these Rel toxin-antitoxin modules from this unique pathogen. The physical interactions between the three pairs of RelBE proteins were confirmed and the DNA-binding domain recognized by three RelBE-like pairs and domain structure characteristics were described. The three RelE-like proteins physically interacted with the same RelB-like protein, and could conditionally regulate its binding with promoter DNA. The RelBE-like modules exerted complex cross-regulation effects on mycobacterial growth. The relB antitoxin gene could replace relF in cross-neutralizing the relG toxin gene. Conversely, relF enhanced the toxicity of the relE toxin gene, while relB increased the toxicity of relK. This is the first report of interactions between different pairs of RelBE modules of M. tuberculosis

The effects of online negative word‐of‐mouth on dissatisfied customers:A frustration–aggression perspective

Conceptualizing how customers construe online negative word‐of‐mouth (nWOM) following failure experiences remains unsettled, leaving providers with inconclusive recovery strategy programmes. This empirical study recognizes online nWOM as a co‐created encounter between the complainant (i.e., the initiator of the online nWOM) and the recipient (i.e., the consumer who engages with the online nWOM), examining their idiosyncrasies to discern their understanding of the experience. It introduces frustration–aggression theory to online WOM literature, recognizing that it can support a higher‐order understanding of phenomena. Through phenomenological hermeneutics, interviews and focus groups, data were collected from millennials in Albania and Kosovo that provided accounts of nuanced and distinctive online nWOM realities. The emerged insights extended extant theory to a three‐fold online nWOM typology (i.e., lenient online nWOM, moderate online nWOM and severe online nWOM) recognizing the negative impact customers have on a provider, which is controlled by frustration–aggression tags. Frustration–aggression variations across online nWOM led to the construct of three types of customers that engage in online nWOM, namely tolerable online nWOM customers, rigorous online nWOM customers and confrontational online nWOM customers. Findings culminated with satisfactory recovery strategies aligned to customer inferences regardless of the nWOM context

Using social cognitive career theory to understand why students choose to study computer science

The aim of this research is to use Social Cognitive Career Theory (SCCT) to identify and understand reasons why students choose to study Computer Science (CS) at university. SCCT focuses on students’ prior experience, social support, self-efficacy and outcome expectation. The research is part motivated by the desire to increase female participation rates in CS, particularly in the UK. Policymakers can use the factors that both females and males identify as influencing their choice of studying CS to enhance the experiences of all students prior to coming to university, but female students in particular. The study uses a semi-structured interview with 17 mixed gender subjects currently studying CS at three Scottish universities. The findings are that social support from family, teachers, friends and mentors is a particularly important factor in choosing to study CS, especially for female subjects. The career paths offered by a CS degree is another major factor, not just the potential jobs, but also the general value of a CS education and the potential to make useful contributions to society. School education appeared to have limited influence, though exposure to problem solving, programming, online self-learning and internships are positive influences. The stereotypical view of CS students as ‘geeks’ is outdated and unhelpful – it is more appropriate to see them as ‘analytical’ or ‘over-achievers’. Subjects make many suggestions for improving the CS education provided at school, especially to make it more attractive to females, including: make it compulsory, teach it earlier, include more programming and problem solving, and increase the visibility of female exemplars and role models

Multivariate GR&R through factor analysis

Several measurement tasks present multivariate nature. In the cases with quality characteristics highly correlated within groups, but with a relatively small correlation between groups, the available multivariate GR&R methods are not suitable to provide a correct interpretation of the results. The present work presents a new multivariate GR&R approach through factor analysis. Factor analysis is a multivariate statistical method which focuses on the explanation of the covariance structure of the data. Through orthogonal rotation of the factors a suitable structure can be achieved with loadings easy to relate the variables to the factors. The proposed multivariate GR&R method through factor analysis is described and applied in the quality evaluation of holes obtained through helical milling process of AISI H13 hardened steel. The method succeeded in achieving a simple structure, with one factor related to the roughness outcomes and other related to the roundness ones, simplifying the gage capability evaluation.publishe

Evolutionary games on graphs

Game theory is one of the key paradigms behind many scientific disciplines from biology to behavioral sciences to economics. In its evolutionary form and especially when the interacting agents are linked in a specific social network the underlying solution concepts and methods are very similar to those applied in non-equilibrium statistical physics. This review gives a tutorial-type overview of the field for physicists. The first three sections introduce the necessary background in classical and evolutionary game theory from the basic definitions to the most important results. The fourth section surveys the topological complications implied by non-mean-field-type social network structures in general. The last three sections discuss in detail the dynamic behavior of three prominent classes of models: the Prisoner's Dilemma, the Rock-Scissors-Paper game, and Competing Associations. The major theme of the review is in what sense and how the graph structure of interactions can modify and enrich the picture of long term behavioral patterns emerging in evolutionary games.Comment: Review, final version, 133 pages, 65 figure