Reshaping Global Change Science for the 21st Century: Young Scientists’ Perspectives

Humanity is facing unprecedented environmental, social, and economic challenges. We ask what the role of the global science community should be in tackling these challenges. Increased awareness of the social context in which science is being produced; acceptance of the importance of controversy; and reflection around normative assumptions underlying research are needed. To help solve humanity’s grand challenges scientists need to move towards a transdisciplinary view of science where knowledge emerges from a collaborative environment and where young scientists are trained to work across disciplinary boundaries and engage with policy communities

Left ventricular torsional mechanics in term fetuses and neonates

Objective Left ventricular (LV) torsion is an important aspect of cardiac mechanics and is fundamental to normal ventricular function. The myocardial mechanics of the fetal heart and the changes that occur during the transition to the neonatal period have not been explored previously. The aim of this study was to evaluate perinatal changes in LV torsion and its relationship with myocardial function. Methods This was a prospective study of 36 women with an uncomplicated term pregnancy. Fetal and neonatal conventional, spectral tissue Doppler and two‐dimensional (2D) speckle tracking echocardiography were performed a few days before and within hours after delivery to measure cardiac indices including LV rotational parameters derived from short‐axis views at the base and apex of the heart. Linear regression analysis was used to examine the relationship between LV rotational parameters and cardiac geometric and functional indices in term fetuses and neonates. Perinatal changes in LV rotational parameters were assessed. Results There were three patterns of LV twist in term fetuses: those with reversed‐apex‐type LV twist had the lowest median values of LV torsion (0.1°/cm), with higher values (1.6°/cm) in those with infant‐type LV twist and the highest values (4.4°/cm) in those with adult‐type LV twist. LV torsion was associated significantly with cardiac geometric and functional indices. Perinatal evaluation revealed a significant increase in LV torsion following delivery in fetuses exhibiting reversed‐apex‐type LV twist (increase of 2.8°/cm, P = 0.009) and a significant decrease in those with adult‐type LV twist (decrease of 3.2°/cm, P = 0.008). Conclusions This study demonstrates the feasibility of 2D speckle tracking imaging for accurate assessment of rotational cardiac parameters in term fetuses. There are unique perinatal patterns of LV twist that demonstrate different values of LV torsion, which was found to correlate with indices of ventricular geometry and myocardial function. Differences in patterns of LV twist may therefore reflect differences in compensatory myocardial adaptation to the physiological environment/loading conditions in late gestation in fetuses and postnatal cardiac adjustment to the acute loading changes that occur at delivery

Re-shaping Sustainability Science for the 21st Century: Young Scientists’ Perspectives

Humanity is facing unprecedented environmental, social and economic challenges. We ask what the role of the sustainability science community should be in tackling these challenges, focusing particularly on young scientists’ perspectives on the issue. On the basis of a questionnaire and a workshop with young scientists, we identify four major challenges facing humanity and develop three guidelines for sustainability science that seeks to address them. Results show that to help address humanity’s grand challenges, sustainability scientists need to move towards a trans-disciplinary system view of science and sustainability science problems. According to this view knowledge emerges from a collaborative and transdisciplinary environment and young scientists are trained to work across disciplinary boundaries and engage with policy communities

Microfludic Device for Creating Ionic Strength Gradients over DNA Microarrays for Efficient DNA Melting Studies and Assay Development

The development of DNA microarray assays is hampered by two important aspects: processing of the microarrays is done under a single stringency condition, and characteristics such as melting temperature are difficult to predict for immobilized probes. A technical solution to these limitations is to use a thermal gradient and information from melting curves, for instance to score genotypes. However, application of temperature gradients normally requires complicated equipment, and the size of the arrays that can be investigated is restricted due to heat dissipation. Here we present a simple microfluidic device that creates a gradient comprising zones of defined ionic strength over a glass slide, in which each zone corresponds to a subarray. Using this device, we demonstrated that ionic strength gradients function in a similar fashion as corresponding thermal gradients in assay development. More specifically, we noted that (i) the two stringency modulators generated melting curves that could be compared, (ii) both led to increased assay robustness, and (iii) both were associated with difficulties in genotyping the same mutation. These findings demonstrate that ionic strength stringency buffers can be used instead of thermal gradients. Given the flexibility of design of ionic gradients, these can be created over all types of arrays, and encompass an attractive alternative to temperature gradients, avoiding curtailment of the size or spacing of subarrays on slides associated with temperature gradients

Ventricular-vascular coupling is predictive of adverse clinical outcome in paediatric pulmonary arterial hypertension

AIMS: Ventricular-vascular coupling, the ratio between the right ventricle's contractile state (Ees) and its afterload (Ea), may be a useful metric in the management of paediatric pulmonary arterial hypertension (PAH). In this study we assess the prognostic capacity of the ventricular-vascular coupling ratio (Ees/Ea) derived using right ventricular (RV) pressure alone in children with PAH. METHODS: One hundred and thirty paediatric patients who were diagnosed with PAH via right heart catheterisation were retrospectively reviewed over a 10-year period. Maximum RV isovolumic pressure and end-systolic pressure were estimated using two single-beat methods from Takeuchi et al (Ees/Ea_(Takeuchi)) and from Kind et al (Ees/Ea_(Kind)) and used with an estimate of end-systolic pressure to compute ventricular-vascular coupling from pressure alone. Patients were identified as either idiopathic/hereditary PAH or associated PAH (IPAH/HPAH and APAH, respectively). Haemodynamic data, clinical functional class and clinical worsening outcomes-separated into soft (mild) and hard (severe) event categories-were assessed. Adverse soft events included functional class worsening, syncopal event, hospitalisation due to a proportional hazard-related event and haemoptysis. Hard events included death, transplantation, initiation of prostanoid therapy and hospitalisation for atrial septostomy and Pott's shunt. Cox proportional hazard modelling was used to assess whether Ees/Ea was predictive of time-to-event. RESULTS: In patients with IPAH/HPAH, Ees/Ea_(Kind) and Ees/Ea_(Takeuchi) were both independently associated with time to hard event (p=0.003 and p=0.001, respectively) and when adjusted for indexed pulmonary vascular resistance (p=0.032 and p=0.013, respectively). Neither Ees/Ea_(Kind) nor Ees/Ea_(Takeuchi) were associated with time to soft event. In patients with APAH, neither Ees/Ea_(Kind) nor Ees/Ea_(Takeuchi) were associated with time to hard event or soft event. CONCLUSIONS: Ees/Ea derived from pressure alone is a strong independent predictor of adverse outcome and could be a potential powerful prognostic tool for paediatric PAH

Modular microfluidic system as a model of cystic fibrosis airways

A modular microfluidic airways model system that can simulate the changes in oxygen tension in different compartments of the cystic fibrosis (CF) airways was designed, developed, and tested. The fully reconfigurable system composed of modules with different functionalities: multichannel peristaltic pumps, bubble traps, gas exchange chip, and cell culture chambers. We have successfully applied this system for studying the antibiotic therapy of Pseudomonas aeruginosa, the bacteria mainly responsible for morbidity and mortality in cystic fibrosis, in different oxygen environments. Furthermore, we have mimicked the bacterial reinoculation of the aerobic compartments (lower respiratory tract) from the anaerobic compartments (cystic fibrosis sinuses) following an antibiotic treatment. This effect is hypothesised as the one on the main reasons for recurrent lung infections in cystic fibrosis patients

Optimal Homogenization of Perfusion Flows in Microfluidic Bio-Reactors: A Numerical Study

In recent years, the interest in small-scale bio-reactors has increased dramatically. To ensure homogeneous conditions within the complete area of perfused microfluidic bio-reactors, we develop a general design of a continually feed bio-reactor with uniform perfusion flow. This is achieved by introducing a specific type of perfusion inlet to the reaction area. The geometry of these inlets are found using the methods of topology optimization and shape optimization. The results are compared with two different analytic models, from which a general parametric description of the design is obtained and tested numerically. Such a parametric description will generally be beneficial for the design of a broad range of microfluidic bioreactors used for, e.g., cell culturing and analysis and in feeding bio-arrays

A compact multifunctional microfluidic platform for exploring cellular dynamics in real-time using electrochemical detection

Downscaling of microfluidic cell culture and detection devices for electrochemical monitoring has mostly focused on miniaturization of the microfluidic chips which are often designed for specific applications and therefore lack functional flexibility. We present a compact microfluidic cell culture and electrochemical analysis platform with in-built fluid handling and detection, enabling complete cell based assays comprising on-line electrode cleaning, sterilization, surface functionalization, cell seeding, cultivation and electrochemical real-time monitoring of cellular dynamics. To demonstrate the versatility and multifunctionality of the platform, we explored amperometric monitoring of intracellular redox activity in yeast (Saccharomyces cerevisiae) and detection of exocytotically released dopamine from rat pheochromocytoma cells (PC12). Electrochemical impedance spectroscopy was used in both applications for monitoring cell sedimentation and adhesion as well as proliferation in the case of PC12 cells. The influence of flow rate on the signal amplitude in the detection of redox metabolism as well as the effect of mechanical stimulation on dopamine release were demonstrated using the programmable fluid handling capability. The here presented platform is aimed at applications utilizing cell based assays, ranging from e.g. monitoring of drug effects in pharmacological studies, characterization of neural stem cell differentiation, and screening of genetically modified microorganisms to environmental monitoring

Human endogenous retroviruses form a reservoir of T cell targets in hematological cancers

Human endogenous retroviruses (HERV) form a substantial part of the human genome, but mostly remain transcriptionally silent under strict epigenetic regulation, yet can potentially be reactivated by malignant transformation or epigenetic therapies. Here, we evaluate the potential for T cell recognition of HERV elements in myeloid malignancies by mapping transcribed HERV genes and generating a library of 1169 potential antigenic HERV-derived peptides predicted for presentation by 4 HLA class I molecules. Using DNA barcode-labeled MHC-I multimers, we find CD8+ T cell populations recognizing 29 HERV-derived peptides representing 18 different HERV loci, of which HERVH-5, HERVW-1, and HERVE-3 have more profound responses; such HERV-specific T cells are present in 17 of the 34 patients, but less frequently in healthy donors. Transcriptomic analyses reveal enhanced transcription of the HERVs in patients; meanwhile DNA-demethylating therapy causes a small and heterogeneous enhancement in HERV transcription without altering T cell recognition. Our study thus uncovers T cell recognition of HERVs in myeloid malignancies, thereby implicating HERVs as potential targets for immunotherapeutic therapies