Motion control and synchronisation of multi-axis drive systems

Motion control and synchronisation of multi-axis drive system

Differential Disruption of EWS-FLI1 Binding by DNA-Binding Agents

Fusion of the EWS gene to FLI1 produces a fusion oncoprotein that drives an aberrant gene expression program responsible for the development of Ewing sarcoma. We used a homogenous proximity assay to screen for compounds that disrupt the binding of EWS-FLI1 to its cognate DNA targets. A number of DNA-binding chemotherapeutic agents were found to non-specifically disrupt protein binding to DNA. In contrast, actinomycin D was found to preferentially disrupt EWS-FLI1 binding by comparison to p53 binding to their respective cognate DNA targets in vitro. In cell-based assays, low concentrations of actinomycin D preferentially blocked EWS-FLI1 binding to chromatin, and disrupted EWS-FLI1-mediated gene expression. Higher concentrations of actinomycin D globally repressed transcription. These results demonstrate that actinomycin D preferentially disrupts EWS-FLI1 binding to DNA at selected concentrations. Although the window between this preferential effect and global suppression is too narrow to exploit in a therapeutic manner, these results suggest that base-preferences may be exploited to find DNA-binding compounds that preferentially disrupt subclasses of transcription factors

Improved Multi-User Security Using the Squared-Ratio Method

Proving security bounds in contexts with a large number of users is one of the central problems in symmetric-key cryptography today. This paper introduces a new method for information-theoretic multi-user security proofs, called ``the Squared-Ratio Method\u27\u27. At its core, the method requires the expectation of the square of the ratio of observing the so-called good transcripts (from Patarin\u27s H-coefficient technique) in the real and the ideal world. Central to the method is the observation that for information-theoretic adversaries, the KL-divergence for the multi-user security bound can be written as a summation of the KL-divergence of every single user. We showcase the Squared-Ratio Method on three examples: the Xor of two Permutations by Bellare et al. (EUROCRYPT \u2798) and Hall et al. (CRYPTO \u2798), the Encrypted Davies-Mayer by Cogliati and Seurin (CRYPTO \u2716), and the two permutation variant of the nEHtM MAC algorithm by Dutta et al. (EUROCRYPT \u2719). With this new tool, we provide improved bounds for the multi-user security of these constructions. Our approach is modular in the sense that the multi-user security can be obtained directly from single-user results

The role of receptor dimerization domain residues in growth hormone signaling

While there is a considerable amount of evidence that signal transduction by the growth hormone (GH) receptor requires receptor homodimerization, there has been no systematic study of the role of receptor dimerization domain residues in this process, In conjunction with the distances derived from the crystal structure of the hGH-hGH receptor (extracellular domain) complex, we have used a luciferase based c-fos promoter reporter assay in transiently transfected Chinese hamster ovary (CHO) cells, and stable receptor expressing CHO cell populations to define the dimerization domain residues needed for effective signaling, In addition to alanine substitution, we have used both aspartate and lysine substitutions to allow us to provide evidence for proximity relations through charge complementation. Introduced cysteine substitutions were also used, but unlike the erythropoietin receptor, these were unable to generate constitutively active receptor, We conclude that serine 145, histidine 150, aspartate 152, tyrosine 200, and serine 201, but not leucine 146 or threonine 147 are required for effective signal transduction through the dimerization domain, This information may be valuable in designing small molecule antagonists of GH and other cytokines that block dimerization by binding to the dimerization domain

Central 300 PC of the galaxy probed by the infrared spectra of H3+ and CO: I. Predominance of warm and diffuse gas and high H2 ionization rate

A low-resolution 2.0-2.5 $\mu$m survey of $\sim$500 very red point-like objects in the Central Molecular Zone (CMZ) of our Galaxy, initiated in 2008, has revealed many new bright objects with featureless spectra that are suitable for high resolution absorption spectroscopy of H$_3^+$ and CO.\footnote{Geballe, T. R., Oka, T., Lambridges, E., Yeh, S. C. C., Schlegelmilch, B., Goto, M., Westrick, C. W., WI07 at the 70th ISMS, Urbana, IL, USA,2015} We now have altogether 48 objects mostly close to the Galactic plane located from 142 pc to the west of Sgr A to 120 pc east allowing us to probe dense and diffuse gas by H$_3^+$ and dense gas by CO. Our observations demonstrate that the warm ($\sim$250 K) and diffuse ($\leq$100 cm$^{-3}$) gas with a large column length ($\geq$30 pc) initially observed toward the brightest star in the CMZ, GCS3-2 of the Quintuplet Cluster,\footnote{Oka, T., Geballe, T. R., Goto, M., Usuda, T., McCall, B. J. 2005, ApJ, 632, 882} exists throughout the CMZ with the surface filling factor of $\sim$ 100\% dominating the region. The column densities of CO in the CMZ are found to be much less than those in the three foreground spiral arms except in the directions of Sgr B and Sgr E complexes and indicate that the volume filling factor of dense clouds of 10\% previously estimated is a gross overestimate for the front half of the CMZ. Nevertheless the predominance of the newly found diffuse molecular gas makes the term "Central Molecular Zone" even more appropriate. The ultra-hot X-rays emitting plasma which some thought to dominate the region must be non existent except near the stars and SNRs. Recently the H$_2$ fraction $\mathit{f}$(H$_2$) in diffuse gas of the CMZ has been reported to be $\sim$0.6\footnote{Le Petit, F., Ruaud, M., Bron, E., Godard, B., Roueff, E., Languignon, D., Le Bourlot, J. 2016, A\&A, 585, A105}. If we use this value, the cosmic ray H$_2$ ionization rate $\mathit{\zeta}$ of a few times 10$^{-15}$ s$^{-1}$ reported earlier$^b$ on the assumption of $\mathit{f}$(H$_2$)=1 needs to be increased by a factor of $\sim$3 since the value is approximately inversely proportional to $\mathit{f}$(H$_2$)$^2$

Higher fibrinogen and neutrophil-to-lymphocyte ratio are associated with the early poor response to intravenous thrombolysis in acute ischemic stroke

BackgroundInflammation and platelet activation play pivotal roles in acute ischemic stroke (AIS) pathogenesis. Early response to thrombolysis is a vital indicator for the long-term prognosis of AIS. However, the correlation between fibrinogen or the neutrophil-to-lymphocyte ratio (NLR) and the early response to intravenous thrombolysis in patients with AIS remains unclear.MethodsAIS patients undergoing intravenous thrombolysis were enrolled between January 2018 and May 2023. Blood cell counts were sampled before thrombolysis. A good response was defined as a National Institutes of Health Stroke Scale (NIHSS) score decreased ≥4 or complete recovery 24 h after thrombolysis treatment. A poor response was defined as any increase in the NIHSS score or a decrease in the NIHSS score <4 at the 24 h after thrombolysis treatment compared with that at admission. Logistic regression analysis was performed to explore the relationship of the fibrinogen level and NLR with a poor thrombolysis response. Receiver operating characteristic (ROC) analysis was used to assess the ability of the fibrinogen level and NLR to discriminate poor responders.ResultsAmong 700 recruited patients, 268 (38.29%) were diagnosed with a good response, and 432 (61.71%) were diagnosed with a poor response to intravenous thrombolysis. A binary logistic regression model indicated that an elevated fibrinogen level (odds ratio [OR], 1.693; 95% confidence interval [CI] 1.325–2.122, P < 0.001) and NLR (OR, 1.253; 95% CI, 1.210–2.005, P = 0.001) were independent factors for a poor response. The area under the curve (AUC) values for the fibrinogen level, NLR and fibrinogen level combined with the NLR for a poor response were 0.708, 0.605, and 0.728, respectively.ConclusionsOur research indicates that the levels of fibrinogen and NLR at admission can be used as a prognostic factor to predict early poor response to intravenous thrombolysis

An atypical GdpP enzyme linking cyclic nucleotide metabolism to osmotic tolerance and gene regulation in Mycoplasma bovis

Nucleotide second messengers play an important role in bacterial adaptation to environmental changes. Recent evidence suggests that some of these regulatory molecular pathways were conserved upon the degenerative evolution of the wall-less mycoplasmas. We have recently reported the occurrence of a phosphodiesterase (PDE) in the ruminant pathogen Mycoplasma bovis, which was involved in c-di-AMP metabolism. In the present study, we demonstrate that the genome of this mycoplasma species encodes a PDE of the GdpP family with atypical DHH domains. Characterization of M. bovis GdpP (MbovGdpP) revealed a multifunctional PDE with unusual nanoRNase and single-stranded DNase activities. The alarmone ppGpp was found unable to inhibit c-di-NMP degradation by MbovGdpP but efficiently blocked its nanoRNase activity. Remarkably, MbovGdpP was found critical for the osmotic tolerance of M. bovis under K+ and Na+ conditions. Transcriptomic analyses further revealed the biological importance of MbovGdpP in tRNA biosynthesis, pyruvate metabolism, and several steps in genetic information processing. This study is an important step in understanding the role of PDE and nucleotide second messengers in the biology of a minimal bacterial pathogen

Routine based intervention in the context of group sessions with families

Suvremeni pristupi u ranoj intervenciji naglašavaju važnost podrške roditeljima i njihovu snažnu uključenost u sve oblike intervencija. Naglasak je na poštivanju razvojnih načela, koja su jednaka za svu djecu (s razvojnim poteškoćama ili bez njih). Razvojne miljokaze djeca dostižu interakcijom s odraslima te aktivnostima (rutinama), koje su dio njihove prirodne sredine. S obzirom na specifičnosti djece s razvojnim odstupanjima, roditeljima je puno izazovnije uključiti djecu u svakodnevne rutine, iskoristiti ih i razumjeti kao trenutke učenja i poticanja. S ciljem pružanja podrške roditeljima u organiziranju svakodnevnih rutina, radi poticanja sociokomunikacijskog razvoja, organizirane su radionice na kojima se roditelje poučavalo strategijama – kako iskoristiti svakodnevne aktivnosti, rutine u poticanju djetetova razvoja. Organizirano je 5 grupa roditelja (35 roditelja) djece sa sumnjom ili već utvrđenim poremećajem iz spektra autizma (21 dijete). Svaka grupa imala je 12 strukturiranih susreta, nakon kojih su roditelji ispunili evaluacijski upitnik i ocijenili zadovoljstvo programom. U slobodnom dijelu upitnika roditelji su iznimno visoko ocijenili dobivene materijale, kao i razmjenu iskustava s drugim roditeljima. Rezultati pokazuju da intervencijski pristup koji podržava roditelje da ugrađuju razvojne ciljeve u svakodnevne rutine, iako kod nas neuobičajen i nov, roditelji vrlo pozitivno ocjenjuju te su njime zadovoljni. Zaključujemo da su roditelji time dobili vrlo uspješan i snažan alat, koji im pomaže da potiču dijete u raznim vještinama. Također, poučavanje roditelja novim vještinama u grupi s njihovom djecom, pokazalo se poželjnim oblikom rada i preporučuje se češće primjenjivati taj oblik rada u svakodnevnoj praksi.Contemporary approaches to early intervention emphasize the importance of supporting parents and their strong involvement in all forms of intervention. Emphasis has been put on respecting developmental principles that are the same for all children (with or without development difficulties). Children reach developing milestones through interaction with adults and activities (routines) that are part of their natural environment. Because of the specificities of children with developmental disabilities, it is much more demanding for parents to include them in everyday routines, use them and understand them as moments of learning and encouragement. With the aim of providing support to parents in organizing daily routines for promoting socio-communication development, group sessions were organized in which parents were taught strategies for utilizing everyday activities and routines in encouraging child’s development. Five groups of parents (35 parents) of children with suspected or already diagnosed autism spectrum disorders (21 children) have been formed. Each group had 12 structured meetings, after which parents completed the evaluation questionnaire and evaluated the satisfaction with the program they were involved in together with their children. The evaluation questionnaire was highly appreciated by parents, especially regarding communication with experts, content and applicability of the program. In the open-ended part of the questionnaire, parents highly rated the obtained material, as well as the exchange of experiences with other parents. The findings suggest that an intervention approach that supports parents in incorporating developmental goals into everyday routines is a very successful and powerful tool that helps parents encourage a child in various skills. Also, teaching parents new skills together with their children proved to be a very good form of work and it is highly recommended to apply this form more frequently in everyday practice