Elucidating Nature’s Solutions to Heart, Lung, and Blood Diseases and Sleep Disorders

Evolution has provided a number of animal species with extraordinary phenotypes. Several of these phenotypes allow species to survive and thrive in environmental conditions that mimic disease states in humans. The study of evolved mechanisms that responsible for these phenotypes may provide insights into the basis of human disease and guide the design of new therapeutic approaches. Examples include species that tolerate acute or chronic hypoxemia like deep-diving mammals and high-altitude inhabitants, as well as those that hibernate and interrupt their development when exposed to adverse environments. The evolved traits exhibited by these animal species involve modifications of common biological pathways that affect metabolic regulation, organ function, antioxidant defenses, and oxygen transport. In 2006, the National Heart, Lung, and Blood Institute (NHLBI) released a funding opportunity announcement to support studies that were designed to elucidate the natural molecular and cellular mechanisms of adaptation in species that tolerate extreme environmental conditions. The rationale for this funding opportunity is detailed in this Special Article, and the specific evolved mechanisms examined in the supported research are described. Also highlighted are past medical advances achieved through the study of animal species that have evolved extraordinary phenotypes as well as the expectations for new understanding of nature’s solutions to heart, lung, blood, and sleep disorders through future research in this area

Elucidating Nature’s Solutions to Heart, Lung, and Blood Diseases and Sleep Disorders

Evolution has provided a number of animal species with extraordinary phenotypes. Several of these phenotypes allow species to survive and thrive in environmental conditions that mimic disease states in humans. The study of evolved mechanisms that responsible for these phenotypes may provide insights into the basis of human disease and guide the design of new therapeutic approaches. Examples include species that tolerate acute or chronic hypoxemia like deep-diving mammals and high-altitude inhabitants, as well as those that hibernate and interrupt their development when exposed to adverse environments. The evolved traits exhibited by these animal species involve modifications of common biological pathways that affect metabolic regulation, organ function, antioxidant defenses, and oxygen transport. In 2006, the National Heart, Lung, and Blood Institute (NHLBI) released a funding opportunity announcement to support studies that were designed to elucidate the natural molecular and cellular mechanisms of adaptation in species that tolerate extreme environmental conditions. The rationale for this funding opportunity is detailed in this Special Article, and the specific evolved mechanisms examined in the supported research are described. Also highlighted are past medical advances achieved through the study of animal species that have evolved extraordinary phenotypes as well as the expectations for new understanding of nature’s solutions to heart, lung, blood, and sleep disorders through future research in this area

Characterization of the role of ribonucleases in Salmonella small RNA decay

In pathogenic bacteria, a large number of sRNAs coordinate adaptation to stress and expression of virulence genes. To better understand the turnover of regulatory sRNAs in the model pathogen, Salmonella typhimurium, we have constructed mutants for several ribonucleases (RNase E, RNase G, RNase III, PNPase) and Poly(A) Polymerase I. The expression profiles of four sRNAs conserved among many enterobacteria, CsrB, CsrC, MicA and SraL, were analysed and the processing and stability of these sRNAs was studied in the constructed strains. The degradosome was a common feature involved in the turnover of these four sRNAs. PAPI-mediated polyadenylation was the major factor governing SraL degradation. RNase III was revealed to strongly affect MicA decay. PNPase was shown to be important in the decay of these four sRNAs. The stability of CsrB and CsrC seemed to be independent of the RNA chaperone, Hfq, whereas the decay of SraL and MicA was Hfq-dependent. Taken together, the results of this study provide initial insight into the mechanisms of sRNA decay in Salmonella, and indicate specific contributions of the RNA decay machinery components to the turnover of individual sRNAs

Regulation of the small regulatory RNA MicA by ribonuclease III: a target-dependent pathway

MicA is a trans-encoded small non-coding RNA, which downregulates porin-expression in stationary-phase. In this work, we focus on the role of endoribonucleases III and E on Salmonella typhimurium sRNA MicA regulation. RNase III is shown to regulate MicA in a target-coupled way, while RNase E is responsible for the control of free MicA levels in the cell. We purified both Salmonella enzymes and demonstrated that in vitro RNase III is only active over MicA when in complex with its targets (whether ompA or lamB mRNAs). In vivo, MicA is demonstrated to be cleaved by RNase III in a coupled way with ompA mRNA. On the other hand, RNase E is able to cleave unpaired MicA and does not show a marked dependence on its 5′ phosphorylation state. The main conclusion of this work is the existence of two independent pathways for MicA turnover. Each pathway involves a distinct endoribonuclease, having a different role in the context of the fine-tuned regulation of porin levels. Cleavage of MicA by RNase III in a target-dependent fashion, with the concomitant decay of the mRNA target, strongly resembles the eukaryotic RNAi system, where RNase III-like enzymes play a pivotal role

Differences in fetal bovine serum affect the responsiveness of cells to mechanical loads

Nowadays, the end-point of a cell culture in bone tissue engineering\u3cbr/\u3e(BTE) is the acquisition of a well mineralized extracellular\u3cbr/\u3ematrix. The biological performance of BTE relies on evaluation of\u3cbr/\u3ethe cell capacity to proliferate and to produce extracellular matrix by\u3cbr/\u3equantification of gene expression and by histology or calcium\u3cbr/\u3equantification assays. Micro-computed tomography (micro-CT) allows\u3cbr/\u3emonitoring of BTE mineral constructs in a non-destructive\u3cbr/\u3emanner. Although fetal bovine serum (FBS) is commonly used as\u3cbr/\u3esupplement in cell cultures, its high composition variability between\u3cbr/\u3edifferent brands and batches leads to differences in the experimental\u3cbr/\u3eoutcomes. Nevertheless, only few studies have focused on a systematic\u3cbr/\u3einvestigation of the differences. While we have recently\u3cbr/\u3ereported the influence of FBS type on matrix mineralization under\u3cbr/\u3estatic culture conditions, it is still unknown how FBS affects cells in\u3cbr/\u3edynamic cultures. Different FBS types were used to differentiate\u3cbr/\u3ehuman mesenchymal stem cells down the osteogenic lineage under\u3cbr/\u3edynamic spinner-flask bioreactors. Opposite to static culture conditions,\u3cbr/\u3edifferences in FBS affected the responsiveness of cells to\u3cbr/\u3edifferentiate under mechanical loads. Although all FBS types upregulated\u3cbr/\u3ethe expression of bone-specific genes, differences in the\u3cbr/\u3eosteogenic differentiation stage were observed among the different\u3cbr/\u3eFBS. Accordingly, micro-CT analysis only showed mineral deposition\u3cbr/\u3efor cultures in an advanced differentiation stage.\u3cbr/\u3eThus the selection of the FBS type is crucial for the success in the\u3cbr/\u3eacquisition of BTE constructs. The combination of micro-CT with\u3cbr/\u3emolecular biology techniqueswill benefit efforts to optimize scaffolds\u3cbr/\u3edesign and cell culture conditions for scaling-up the BTE constructs

bwHealthApp : a software system to support personalized medicine by individual monitoring of vital parameters of outpatients

Continuous monitoring of individual vital parameters can provide information for the assessment of one’s health and indications of medical problems in the context of personalized medicine. Correlations between parameters and health issues are to be evaluated. As one project in this topic area, a telemedicine platform is implemented to gather data of outpatients via wearables and accumulate them for physicians and researchers to review. This work extracts requirements, draws use case scenarios, and shows the current system architecture consisting of a patient application, a physician application with a web server, and a backend server application. In further work, the prototype will assist to develop a vendor-free and open monitoring solution. A conclusion on functionality and usability will be evaluated in an imminent first study

Paving the way for a wider use of composites in railway industry

Different types of phosphorus containing halogen-free flame retardants (FRs) were added to an epoxy-dicyandiamide resin formulation in order to study to which extent they affect its glass transition temperature (Tg), tensile properties, termal stability and burning behavior of the resin. For this purpose, an additive-type FR (ammonium polyphosphate encapsulated in melamine resin, MAPP) and two reactive-type FRs i) a commercial epoxy resin pre-reacted with 9,10-dihydro-oxa-10- phosphaphenanthrene-10-oxide, (DOPO), and ii) a phosphorus containing hardener (poly(m-phenylene methylphosphonate), (PMP) were used. It was observed that the addition of additive-type FR did not affect in great extent the Tg and provided a V-0 rating in UL94 test at low loadings. The addition of reactive-type FRs (DOPO and/or PMP), however, modified the structure of the chain network resulting in lower crosslink density as a consequence of their higher equivalent mass, but achieving also with low PMP content V-0 rating.This project has received funding from the Shift2Rail Joint Undertaking under the European Union’s Horizon 2020 research and innovation programme under Grant Agreement No 777595

The inhibitory effect of alendronate, a nitrogen-containing bisphosphonate on the PI3K–Akt–NFκB pathway in osteosarcoma cells

1. Bisphosphonates are inhibitors of tumor cell growth as well as of bone resorption by inducing cell apoptosis. However, little is known regarding the mechanisms by which the drug induces cell apoptosis. The aim of the present study was to determine the effect of alendronate, one of the nitrogen-containing bisphosphonates on the phoshoinositide 3-kinase (PI3K)–Akt–NFκB pathway, the major cell survival pathway. 2. The PI3K–Akt–NFκB pathway was activated in the osteosarcoma cell line MG-63 treated with tumor necrosis factor-α or insulin. Saos-2 was also used in some experiments. This was assessed by the production of phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P(3)), increased PI3K activity, phosphorylation of Akt at serine 473 and threonine 308, increase in activity of the inhibitor of nuclear factor κB (IκB) kinase (IKK) and finally phosphorylation of IκB and its subsequent degradation. 3. Pretreatment with alendronate at 100 μM for 24 h prior to the stimulation with tumor necrosis factor-α or insulin partially inhibited the IκB phosphorylation and degradation. These events were more clearly observed in the presence of inhibitors of proteasomes, which are responsible for the degradation of IκB. The drug also partially inhibited the activity of IKK, but almost fully inhibited the phosphorylation of Akt and the production of PtdIns(3,4,5)P(3). 4. The inhibitory effect of alendronate on IκB phosphorylation and degradation was not attenuated by the exogenous addition of geranylgeraniol to replenish the cytosolic isoprenyl lipid substrate. 5. The present findings demonstrate that alendronate inhibited the PI3K–Akt–NFκB cell survival pathway at the point of PI3K activation, thus indicating the presence of new targets of alendronate