Systemic studies of RNA binding proteins in stem cell differentiation and pluripotency

What mechanisms govern and maintain cell states during the process of differentiation is a pivotal question in science. What factors govern the commitment of developmental progenitors from pluripotent stem cells is a representative example of this question. Studies of transcriptional, signaling and chromatin regulation have been highly instrumental for elucidating mechanisms pluripotency maintenance. Nevertheless, current knowledge falls short in explaining the exit from pluripotency and its coupling to lineage commitment. It is unclear how pluripotency and differentiation become stabilized in a mutually exclusive manner. Here, I deepen our knowledge concerning post-transcriptional mechanisms in pluripotency-differentiation transition. For this purpose I first characterize by quantitative mass spectrometry the changes that occur in the mRNA bound proteome (RBPome) and identify extensive dynamic rearrangements of the RBPome during early embryonic development, from naive to primed stem cell state and to purified primitive streak progenitors (Chapter I). In parallel I identified developmental post-transcriptional processing landscape and show that the dynamic mRNA binding of the RNA-binding protein TDP-43 is critical in pluripotent stem cells (PSCs) for the choice between self-renewal and differentiation/ pluripotency breakdown (Chapter II). In detail, I discovered that TDP-43 directly regulates an evolutionary conserved switch in alternative polyadenylation (APA) of hundreds of transcripts during early differentiation of mouse and human PSCs. Functional analysis revealed that TDP-43 integrates into pluripotency circuitry by repressing the production of lengthened transcripts of the pluripotency factor SOX2, which is targeted for degradation by miR-21. Furthermore, in pluripotent stem cells TDP-43 also promotes self-renewal by repressing the formation of paraspeckles, membraneless nuclear compartments found only in differentiated cells, by enhancing production of short isoform of the lncRNA NEAT1. Conversely, reduction of TDP-43 during differentiation triggers a short-to-long isoform switch of NEAT1, which polymerizes paraspeckles that in turn recruit TDP-43 and relocalise it away from its other RNA targets. Consistent with this cross-regulation, TDP-43 inhibits differentiation and improves somatic cell reprogramming, while paraspeckles promote early differentiation. These findings reveal how the exit of pluripotency is regulated by a complex posttranscriptional network, which is functionally independent from lineage choices. Apart from its role in the exit of pluripotency, this cross-regulation between paraspeckles and TDP-43 has implications in cancer and neurodegeneration

Thermodynamic constraints on the amplitude of quantum oscillations

Magneto-quantum oscillation experiments in high temperature superconductors show a strong thermally-induced suppression of the oscillation amplitude approaching critical dopings---in support of a quantum critical origin of their phase diagrams. We suggest that, in addition to a thermodynamic mass enhancement, these experiments may directly indicate the increasing role of quantum fluctuations that suppress the oscillation amplitude through inelastic scattering. We show that the traditional theoretical approaches beyond Lifshitz-Kosevich to calculate the oscillation amplitude in correlated metals result in a contradiction with the third law of thermodynamics and suggest a way to rectify this problem.Comment: PRB Rapid commun. (2017

Chiral spin-order in some purported Kitaev spin-liquid compounds

We examine recent magnetic torque measurements in two compounds, $\gamma$-Li$_2$IrO$_3$ and RuCl$_3$, which have been discussed as possible realizations of the Kitaev model. The analysis of the reported discontinuity in torque, as an external magnetic field is rotated across the $c-$axis in both crystals, suggests that they have a translationally-invariant chiral spin-order of the from $\ne 0$ in the ground state and persisting over a very wide range of magnetic field and temperature. An extra-ordinary $|B|B^2$ dependence of the torque for small fields, beside the usual $B^2$ part, is predicted due to the chiral spin-order, and found to be consistent with experiments upon further analysis of the data. Other experiments such as inelastic scattering and thermal Hall effect and several questions raised by the discovery of chiral spin-order, including its topological consequences are discussed.Comment: Clearer figures of the experimental data provided. Also clearer exposition and comment on related recent wor

Reversible carrier-type transition in gas-sensing oxides and nanostructures

Despite many important applications of a-Fe2O3 and Fe doped SnO2 in semiconductors, catalysis, sensors, clinical diagnosis and treatments, one fundamental issue that is crucial to these applications remains theoretically equivocal- the reversible carrier-type transition between n- and p-type conductivities during gas-sensing operations. Here, we give unambiguous and rigorous theoretical analysis in order to explain why and how the oxygen vacancies affect the n-type semiconductors, a-Fe2O3 and Fe doped SnO2 in which they are both electronically and chemically transformed into a p-type semiconductor. Furthermore, this reversible transition also occurs on the oxide surfaces during gas-sensing operation due to physisorbed gas molecules (without any chemical reaction). We make use of the ionization energy theory and its renormalized ionic displacement polarizability functional to reclassify, generalize and to explain the concept of carrier-type transition in solids, and during gas-sensing operation. The origin of such a transition is associated to the change in ionic polarizability and the valence states of cations in the presence of (a) oxygen vacancies and (b) physisorped gas molecules.Comment: To be published in ChemPhysChe

Regulating the antibiotic drug release from ß-tricalcium phosphate ceramics by atmospheric plasma surface engineering

Calcium phosphate (CaP) ceramics are of interest in bone substitution due to their good biocompatibility and bioresorbability. Currently certain CaPs in the market are loaded with antibiotics in order to prevent infections but further control is needed over antibiotic release patterns. Cold plasmas have emerged as a useful means of modifying the interactions with drugs through surface modification of polymer materials. In this work we explore the possibility of using atmospheric pressure plasmas as a tool for the surface modification of these CaP materials with newly populated bonds and charges, with views on enabling higher loading and controlled drug release. Herein the surface modification of ß-tricalcium phosphate ceramics is investigated using an atmospheric pressure helium plasma jet as a tool for tuning the controlled release of the antibiotic doxycycline hyclate, employed as a drug model. The surface chemistry is tailored mainly by plasma jet surface interaction with an increasing O/C ratio without changes in the topography as well as by build-up of surface charges. With this surface tailoring it is demonstrated that the atmospheric plasma jet is a new promising tool that leads to the design of a control for drug release from bioceramic matrices.Peer ReviewedPostprint (author's final draft

Status pooblaščenega gospodarskega subjekta in varnost podjetja

Status pooblaščenega gospodarskega subjekta je bil uveden v okviru sprememb Carinskega zakonika Evropske unije, ki se nanašajo na izboljšanje varnosti na zunanjih mejah Evropske unije in na hitrejši pretok blaga s poenostavljenimi postopki ter uporabo informacijske tehnologije. Razlog za pisanje prispevka je pomen uvedbe statusa pooblaščenega gospodarskega subjekta, ki je zagotavljanje varnosti celotne dobavne verige in njenih posameznih členov – gospodarskih subjektov. Cilj prispevka je predstavitev procesa pridobivanja statusa pooblaščenega gospodarskega subjekta z vidika zahtev, ki jih mora gospodarski subjekt izpolnjevati, da ustreza merilom za podelitev statusa, s poudarkom na varnostnih in varstvenih zahtevah

Regionalni sustavi inovacija kao društvena polja

The world today is subject to ambiguous, complex and mutually reinforcing global trends. The same could be said for the adaptations of social settings to these global trends. As a consequence, societies attempt to develop various increasingly sophisticated and complex systems of innovations, with all its material, social and cognitive consequences. In this article we consider systems of innovations as special type of social fields influenced by three social forces: institutions, networks and cognitive frames. Through the fuzzy-set analysis, we are examining whether these are necessary and sufficient conditions of successful adaptation to global trends via increasing innovative performance. We need a combination of at least two, but best if three, social forces to structure the social field in order to exhibit positive adaptation to global trends. This implies that the ability of social settings to meet challenges posed by global trends can indeed be a subject of rational action.Današnji svijet postao je predmetom dvoznačnih, kompleksnih i uzajamno podržavajućih globalnih trendova. Isto se može reći i za socijalno okruženje koje se adaptira tim globalnim trendovima. Posljedično, društva nastoje razviti različite sustave inovacija koji postaju sve sofisticiranijima i kompleksnijima, uključujući i njihove materijalne, društvene i kognitivne posljedice. U ovom članku bavimo se sustavima inovacija kao posebnim društvenim područjima koja su pod utjecajem triju društvenih sila: institucija, mreža i kognitivnih okvira. Fuzzy-set analizom ispitujemo jesu li ovo nužni i dostatni uvjeti uspješne adaptacije globalnim trendovima kroz povećanje inovativne performanse. Potrebna nam je kombinacija barem dviju, a najbolje triju društvenih sila koje bi strukturirale društveno područje kako bi pokazali pozitivnu prilagodbu globalnim trendovima. To znači da sposobnost socijalnog okruženja da se suoči s izazovima globalnih trendova može biti predmetom racionalnog djelovanja

European automotive technological innovation systems in the age of disruption : The suppliers' view

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