Mechatronic design of the Twente humanoid head

This paper describes the mechatronic design of the Twente humanoid head, which has been realized in the purpose of having a research platform for human-machine interaction. The design features a fast, four degree of freedom neck, with long range of motion, and a vision system with three degrees of freedom, mimicking the eyes. To achieve fast target tracking, two degrees of freedom in the neck are combined in a differential drive, resulting in a low moving mass and the possibility to use powerful actuators. The performance of the neck has been optimized by minimizing backlash in the mechanisms, and using gravity compensation. The vision system is based on a saliency algorithm that uses the camera images to determine where the humanoid head should look at, i.e. the focus of attention computed according to biological studies. The motion control algorithm receives, as input, the output of the vision algorithm and controls the humanoid head to focus on and follow the target point. The control architecture exploits the redundancy of the system to show human-like motions while looking at a target. The head has a translucent plastic cover, onto which an internal LED system projects the mouth and the eyebrows, realizing human-like facial expressions

Potential peptidic proteasome inhibitors by incorporation of an electrophilic trap based on amino acid derived α-substituted sulfonyl fluorides

Peptido sulfonyl fluoride derivatives were designed and synthesized containing a substituent on the alpha position (αPSFs) with respect to the sulfonyl fluoride electrophilic trap. The chemical reactivity of these α-substituted amino sulfonyl fluorides was studied and compared with the previously described β-substituted amino sulfonyl fluorides in order to get a deeper insight into the importance of the immediate structural environment of the sulfonyl fluoride moiety. Unfortunately, the poor solubility of the resulting αPSFs precluded a proper evaluation of their biological activity

Proteasome inhibition by new dual warhead containing peptido vinyl sulfonyl fluorides

The success of inhibition of the proteasome by formation of covalent bonds is a major victory over the long held-view that this would lead to binding the wrong targets and undoubtedly lead to toxicity. Great challenges are now found in uncovering ensembles of new moieties capable of forming long lasting ties. We have introduced peptido sulfonyl fluorides for this purpose. Tuning the reactivity of this electrophilic trap may be crucial for modulating the biological action. Here we describe incorporation of a vinyl moiety into a peptido sulfonyl fluoride backbone, which should lead to a combined attack of the proteasome active site threonine on the double bond and the sulfonyl fluoride. Although this led to strong proteasome inhibitors, in vitro studies did not unambiguously demonstrate the formation of the proposed seven-membered ring structure. Possibly, formation of a seven-membered covalent adduct with the proteosomal active site threonine can only be achieved within the context of the enzyme. Nevertheless, this dual warhead concept may provide exclusive possibilities for duration and selectivity of proteasome inhibition

Self-destructive percolation

Consider ordinary site percolation on an infinite graph in which the sites, independent of each other, are occupied with probability $p$ and vacant with probability $1-p$. Now suppose that, by some `catastrophe', all sites which are in an infinite occupied cluster become vacant. Finally, each vacant site gets an extra enhancement to become occupied. More precisely, each site that was already vacant or that was made vacant by the catastrophe, becomes occupied with probability $delta$ (independent of the other sites). When $p$ is larger than but close to the critical value $p_c$ one might believe (for `nice' graphs) that only a small $delta$ is needed to have an infinite occupied cluster in the final configuration. This appears to be indeed the case for the binary tree. However, on the square lattice we strongly conjecture that this is not true. We discuss the background for these problems and also show that the conjecture, if true, has some remarkable consequences

Cellular senescence contributes to radiation-induced hyposalivation by affecting the stem/progenitor cell niche

Radiotherapy for head and neck cancer is associated with impairment of salivary gland function and consequent xerostomia, which has a devastating effect on the quality of life of the patients. The mechanism of radiation-induced salivary gland damage is not completely understood. Cellular senescence is a permanent state of cell cycle arrest accompanied by a secretory phenotype which contributes to inflammation and tissue deterioration. Genotoxic stresses, including radiation-induced DNA damage, are known to induce a senescence response. Here, we show that radiation induces cellular senescence preferentially in the salivary gland stem/progenitor cell niche of mouse models and patients. Similarly, salivary gland-derived organoids show increased expression of senescence markers and pro-inflammatory senescence-associated secretory phenotype (SASP) factors after radiation exposure. Clearance of senescent cells by selective removal of p16Ink4a-positive cells by the drug ganciclovir or the senolytic drug ABT263 lead to increased stem cell self-renewal capacity as measured by organoid formation efficiency. Additionally, pharmacological treatment with ABT263 in mice irradiated to the salivary glands mitigates tissue degeneration, thus preserving salivation. Our data suggest that senescence in the salivary gland stem/progenitor cell niche contributes to radiation-induced hyposalivation. Pharmacological targeting of senescent cells may represent a therapeutic strategy to prevent radiotherapy-induced xerostomia

Generation and Characterization of Fmr1 Knockout Zebrafish

Fragile X syndrome (FXS) is one of the most common known causes of inherited mental retardation. The gene mutated in FXS is named FMR1, and is well conserved from human to Drosophila. In order to generate a genetic tool to study FMR1 function during vertebrate development, we generated two mutant alleles of the fmr1 gene in zebrafish. Both alleles produce no detectable Fmr protein, and produce viable and fertile progeny with lack of obvious phenotypic features. This is in sharp contrast to published results based on morpholino mediated knock-down of fmr1, reporting defects in craniofacial development and neuronal branching in embryos. These phenotypes we specifically addressed in our knock-out animals, revealing no significant deviations from wild-type animals, suggesting that the published morpholino based fmr1 phenotypes are potential experimental artifacts. Therefore, their relation to fmr1 biology is questionable and morpholino induced fmr1 phenotypes should be avoided in screens for potential drugs suitable for the treatment of FXS. Importantly, a true genetic zebrafish model is now available which can be used to study FXS and to derive potential drugs for FXS treatment

Potent and highly selective inhibitors of the proteasome trypsin-like site by incorporation of basic side chain containing amino acid derived sulfonyl fluorides

A unique category of basic side chain containing amino acid derived sulfonyl fluorides (SFs) has been synthesized for incorporation into new proteasome inhibitors targeting the trypsin-like site of the 20S proteasome. Masking the former α-amino functionality of the amino acid starting derivatives as an azido functionality allowed an elegant conversion to the corresponding amino acid derived sulfonyl fluorides. The inclusion of different SFs at the P1 site of a proteasome inhibitor resulted in 14 different peptidosulfonyl fluorides (PSFs) having a high potency and an excellent selectivity for the proteolytic activity of the β2 subunit over that of the β5 subunit. The results of this study strongly indicate that a free N-terminus of PSFs inhibitors is crucial for high selectivity toward the trypsin-like site of the 20S proteasome. Nevertheless, all compounds are slightly more selective for inhibition of the constitutive over the immunoproteasome

Autophagy induction during stem cell activation plays a key role in salivary gland self-renewal

17 p.-6 figRelatively quiescent tissues like salivary glands (SGs) respond to stimuli such as injury to expand,replace and regenerate. Resident stem/progenitor cells are key in this process because, upon activation, they possess the ability to self-renew. Macroautophagy/autophagy contributes to and regulates differentiation in adult tissues, but an important question is whether this pathway promotes stem cell self-renewal in tissues. We took advantage of a 3D organoid system that allows assessing the self-renewal of mouse SGs stem cells (SGSCs). We found that autophagy in dormant SGSCs has slower flux than self-renewing SGSCs. Importantly, autophagy enhancement upon SGSCs activation is a self-renewal feature in 3D organoid cultures and SGs regenerating in vivo. Accordingly,autophagy ablation in SGSCs inhibits self-renewal whereas pharmacological stimulation promotes self-renewal of mouse and human SGSCs. Thus, autophagy is a key pathway for self-renewal activation in low proliferative adult tissues, and its pharmacological manipulation has the potential to promote tissue regeneration.F.R. is supported by Marie Skłodowska-Curie Cofund [713660], Marie Skłodowska-Curie ITN [765912], ALW Open Program [ALWOP.310]and ZonMW VICI [016.130.606] grants. R.C. and C.R. are supported by the Dutch Cancer Society [Grant number 5792 and 12458]. Patricia Boya is supported by the Ministerio de Ciencia, Innovación y Universidades (MCIU), the Agencia Estatal de Investigación (AEI),the Fondo Europeo de Desarrollo Regional (FEDER) [PGC2018-098557-B-I00] and a Marie Skłodowska-Curie ITN grant [765912]. Idil Orhon is a recipient of a FEBS postdoctoral fellowship and Beatriz Villarejo-Zori of a Fundacion Tatiana Perez de Guzman el Bueno predoctoral fellowhip.Peer reviewe

M & L Jaargang 20/6

Marjan Buyle Ervaringspraktijk als basis voor een gefundeerde adviesverlening. De vakafdelingen binnen de Afdeling Monumenten en Landschappen. [Empirical practice as the basis for well-founded advice. The Conservation Team division.]Marjan Buyle Van pigmenten, kalkmortels en houtwormen. De vakafdeling Conserveringsploeg.Rob Buelens Spitstechnologie en vakmanschap ten dienste van een beveiligd kunstbezit. De vakafdeling Beveiliging. [Secured art treasures with high technology and craftsmanship. Specialist Department for Security.]Jo De Schepper Duizend kolommen & kanalen. De vakafdeling Industrieel Erfgoed. [Specialist Department for Industrial Heritage.]Antoon Fauconnier Monumenten met noten op hun zang. Vakafdeling Orgels, Beiaarden, Klokken en Torenuurwerken. [Musical Monuments Specialist Department for Organs, Carillons, Bells and Tower Clocks.]Erik Smaege en Denise De Brouwer De restauratie van het Lion torenuurwerk in de Agathakerk van Sint-Agatha-Rode.Summar

Increased circulating desmosine and age-dependent elastinolysis in idiopathic pulmonary fibrosis

Abstract Although chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) seem to be opposite entities from a clinical perspective, common initial pathogenic steps have been suggested in both lung diseases. Emphysema is caused by an elastase/anti-elastase imbalance leading to accelerated elastin degradation. Elastinolysis is however, also accelerated in the IPF patients’ lungs. The amino acids desmosine and isodesmosine (DES) are unique to elastin. During the degradation process, elastases liberate DES from elastin fibers. Blood DES levels consequently reflect the rate of systemic elastinolysis and are increased in COPD. This is the first report describing elevated DES levels in IPF patients. We also demonstrated that the age-related increment of DES concentrations is enhanced in IPF. Our current study suggests that elastinolysis is a shared pathogenic step in both COPD and IPF. Further investigation is required to establish the relevance of accelerated elastin degradation in IPF and to determine whether decelerating this process leads to slower progression of lung fibrosis and better survival for patients with IPF.https://deepblue.lib.umich.edu/bitstream/2027.42/142803/1/12931_2018_Article_747.pd